U.S. patent application number 17/104734 was filed with the patent office on 2021-03-18 for method for preventing or treating osteoporosis, characterized by administering teriparatide or salt thereof at a frequency of twice a week.
This patent application is currently assigned to ASAHI KASEI PHARMA CORPORATION. The applicant listed for this patent is ASAHI KASEI PHARMA CORPORATION. Invention is credited to Ryo KATO, Kazuhiko KITAGAWA, Akihiro KITAMI, Akira KOIKE, Takashi MAKIYAMA, Takeshi MINAMIDA, Atsushi OSE, Ryoko TAKAO, Hikaru YAMAMOTO.
Application Number | 20210077590 17/104734 |
Document ID | / |
Family ID | 1000005273083 |
Filed Date | 2021-03-18 |
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United States Patent
Application |
20210077590 |
Kind Code |
A1 |
MINAMIDA; Takeshi ; et
al. |
March 18, 2021 |
METHOD FOR PREVENTING OR TREATING OSTEOPOROSIS, CHARACTERIZED BY
ADMINISTERING TERIPARATIDE OR SALT THEREOF AT A FREQUENCY OF TWICE
A WEEK
Abstract
[Problems] To provide a method for treating and/or preventing
osteoporosis with teriparatide or a salt thereof, the method having
excellent safety and/or efficacies. [Solving Means] A method for
treating and/or preventing osteoporosis in which teriparatide or a
salt thereof is an active ingredient, including administering
teriparatide or a salt thereof in a unit dose of 28.2 .mu.g at a
frequency of twice a week.
Inventors: |
MINAMIDA; Takeshi; (Tokyo,
JP) ; KATO; Ryo; (Tokyo, JP) ; KOIKE;
Akira; (Tokyo, JP) ; OSE; Atsushi; (Tokyo,
JP) ; KITAMI; Akihiro; (Tokyo, JP) ; MAKIYAMA;
Takashi; (Tokyo, JP) ; YAMAMOTO; Hikaru;
(Tokyo, JP) ; KITAGAWA; Kazuhiko; (Tokyo, JP)
; TAKAO; Ryoko; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ASAHI KASEI PHARMA CORPORATION |
Tokyo |
|
JP |
|
|
Assignee: |
ASAHI KASEI PHARMA
CORPORATION
Tokyo
JP
|
Family ID: |
1000005273083 |
Appl. No.: |
17/104734 |
Filed: |
November 25, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/JP2019/030099 |
Jul 31, 2019 |
|
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|
17104734 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/29 20130101;
A61K 9/0019 20130101 |
International
Class: |
A61K 38/29 20060101
A61K038/29 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 29, 2018 |
JP |
2018-203235 |
Claims
1. An osteoporosis therapeutic and/or prophylactic agent comprising
teriparatide or a salt thereof as an active ingredient,
characterized in that the teriparatide or a salt thereof is
administered m a unit dose of 28.2 .mu.g at a frequency of mice a
week.
2. The osteoporosis therapeutic and/or prophylactic agent according
to claim 1, wherein the intervals (not including the days of
administration) of administration of twice a week are a 2-day
interval and a 3-day interval.
3. The osteoporosis therapeutic and/or prophylactic agent according
to claim 1, wherein when the number of weeks of a period
administered at a frequency of twice a week is defined as n, and
the number of weeks in which the intervals (not including the days
of administration) of administration of twice a week out of the n
weeks are a 2-day interval and a 3-day interval is defined as m,
(m/n).times.100(%) is 70% or more.
4. The osteoporosis therapeutic and/or prophylactic agent according
to claim 1, which is subcutaneously administered.
5. The osteoporosis therapeutic and/or prophylactic agent according
to claim 2, which is subcutaneously administered.
6. The osteoporosis therapeutic and/or prophylactic agent according
to claim 3, which is subcutaneously administered.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method for preventing or
treating osteoporosis, characterized by administering teriparatide
or a salt thereof at a frequency of twice a week.
BACKGROUND ART
[0002] Osteoporosis is defined as "a skeletal disease characterized
by compromised bone strength predisposing a person to an increased
risk of fracture" (Non-Patent Publication 1), and this definition
has been generally used.
[0003] It has been said that main purposes of prevention and
treatment of osteoporosis are to prevent or inhibit bone fractures,
maintain the life functions and the QOL (Quality of Life), and the
like. Pains caused by bone fractures and decrease in physical
support functions, and subsequent life functional disorders caused
by motor functional disorders are serious problems, so that it is
said to particularly have a high clinical significance in the
prevention and treatment of osteoporosis with a high risk of bone
fractures.
[0004] Under the background described above, as a drug having the
efficacies and effects for osteoporosis with a high risk of bone
fractures, a daily administered preparation or a once-weekly
administered preparation, each containing teriparatide or a salt
thereof as an active ingredient, has been developed. After being
approved for sales thereof, the preparation has been actually used
in clinical situations (Non-Patent Publications 4 and 8).
[0005] However, it is said that a daily administered preparation or
a once-weekly administered preparation, each containing
teriparatide or a salt thereof as an active ingredient, is not
necessarily satisfactorily excellent from the viewpoint of
safety.
[0006] PTH has been known to have a relaxation action of vascular
smooth muscles (Non-Patent Publication 21). In clinical tests using
a daily administered preparation, it has been reported that
dizziness is significantly high as compared to that of a placebo
group (Non-Patent Publication 9). In addition, it has also been
known to show shocks, or unconsciousness accompanying a transient
drastic blood pressure drop, convulsion, or fall, from immediately
after to several hours after the administration of a daily
administered preparation or a once-weekly administered preparation
(Non-Patent Publications 4 and 8).
[0007] Alternatively, it has been reported that nausea, vomiting,
headaches, or the like is often observed by the administration of
teriparatide acetate (Non-Patent Publication 9). For example, it
has been reported that in clinical tests using a once-weekly
administered preparation, the nauseation frequency is significantly
high, as compared to that of a placebo group, and the numerical
value also exceeded 20% of the entire group of the once-weekly
administered preparations, and that the administration
discontinuation rate due to adverse events also showed a high
numerical value of about 20% (Non-Patent Publication 5).
[0008] Further, it has been reported that in clinical tests using a
daily administered preparation, the incidence rate of a mid-level
hypercalcemia (exceeding 10.6 mg/dl) was 11% (2% in a placebo
group) (Non-Patent Publication 7).
[0009] Besides, in tests using a once-weekly administered
preparation or a daily administered preparation, fervescence has
been observed as an adverse event (Non-Patent Publications 6 and
21).
[0010] In general, it has been reported that the drug ingestion
situations in drug therapies for osteoporosis are such that 52.1%
of the individuals undesirably drop out from the ingestion within 5
years after the beginning of the treatment, and there are some
disadvantages addressed to the lowering in the inhibition of bone
fractures, the increased needs of use of facilities, and stagnancy
in medical cost reductions, due to unsatisfactory compliance to
drug ingestions (Non-Patent Publication 9). Factors associated with
the failure to the compliance to the drug ingestions are
exemplified by the presence of pains, side effects, drugs ingested
for gastrointestinal disorders, and the like (Non-Patent
Publication 9).
[0011] On the other hand, it has been pointed out that a
preparation containing teriparatide or a salt thereof as an active
ingredient has the lowness of the continuation rate of treatment,
and it has been reported that the continuation rate of treatment
over a period of 12 months is 34.9% (Non-Patent Publication 22). As
to safety, it has been known to have the concern of the lowering in
the drug ingestion adherence due to side reactions. It has been
reported that in tests using a once-weekly administered
preparation, adverse events that lead to the discontinuation of
administration of the investigational products other than the
serious cases are as high as 14.1% in the present preparation group
(Non-Patent Publication 23).
[0012] As described above, a daily administered preparation or a
once-weekly administered preparation, each containing teriparatide
or a salt thereof as an active ingredient, shows many disadvantages
in the aspects of safety, and it is also not necessarily said to
provide sufficient benefits from the aspects of efficacies.
[0013] For example, it has been reported that in clinical tests
having an administration period of 72 weeks in which a once-weekly
administered preparation is used in osteoporosis patients with high
risks of bone fractures, the bone mineral density of lumbar
vertebrae at a time point of 48 weeks after the beginning of
administration is elevated by 4.9 to 6.0% or so (Patent Publication
1 (Table 26), Non-Patent Publication 5 (FIG. 3)). In addition, it
has been reported that in clinical tests having an administration
period of 24 months in which a once-weekly preparation is used to
osteoporosis patients with high risks of bone fractures, the bone
mineral density of lumbar vertebrae at the time point of 48 weeks
after the beginning of administration is elevated by about 6.9%
(Non-Patent Publication 6).
[0014] As to the efficacies regarding both the preparations, not
only the effects of increasing bone mineral density but also the
effects of inhibiting bone fractures have been known. For example,
it has been reported that in clinical tests using a daily
administered preparation, the risks of bone fractures of lumbar
vertebrae are lowered by 65% (Non-Patent Publication 7).
[0015] In addition, it has been reported in recent year animal
experiments and investigational studies that the daily
administration of teriparatide shows strong bone
formation-accelerating action at sites with abundant trebeculae
such as centra, but on the other hand, the administration increases
voids in cortical bones such as quadrupedal bones, that a
possibility of having a different action to the cortical bones
according to the administration frequencies has been considered
even in the intermittent administration of PTH, or the like
(Non-Patent Publication 14). Further, it has been reported that
CTX, which is one of bone resorption markers, is found to have a
tendency of elevating in a dose-dependent manner, as compared to
that at the beginning of administration, at 24 weeks after the
beginning of the daily administration of teriparatide.
[0016] It has been reported from the studies in ovary-excised rats
which have been widely used as osteoporosis models that bone
mineral density and bone strength are increased in accordance with
a weekly dosage of teriparatide (Non-Patent Publication 14).
PRIOR ART REFERENCES
Patent Publications
[0017] Patent Publication 1: WO 2011/030774 [0018] Patent
Publication 2: Japanese Patent Laid-Open No. Hei-8-73376 [0019]
Patent Publication 3: WO 2000/10596
Non-Patent Publications
[0019] [0020] Non-Patent Publication 1: JAMA, (2001), 285(6),
785-795 [0021] Non-Patent Publication 2: Osteoporos Int, (1999), 9,
296-306 Non-Patent Publication 3: J Bone Miner Metab (2004), 22,
569-576 [0022] Non-Patent Publication 4: Package Insert of Teribone
(Registered Trademark) Subcutaneous Injection 56.5 .mu.g (revised
August, 2018) [0023] Non-Patent Publication 5: J Clin Endocrinol
Metab (2012), 97(9), 3097-3106 [0024] Non-Patent Publication 6: Adv
Ther (2017), 34, 1727-1740 [0025] Non-Patent Publication 7: N Engl
J Med (2001), 344(19), 1434-1441 [0026] Non-Patent Publication 8:
Package Insert of Forteo (Registered Trademark) Subcutaneous
Injection Kit 600 .mu.g (revised January, 2018) [0027] Non-Patent
Publication 9: Kotsusoshoshou no Yobo to Chiryo Gaidorain
(Guidelines for Osteoporosis Prevention and Treatment) 2015 Edition
[0028] Non-Patent Publication 10: Genpatsusei Kotsusoshoshou no
Shindan Kijun (Diagnostic Criteria for Primary Osteoporosis)
(Revised edition in the fiscal year of 2012) [0029] Non-Patent
Publication 11: J Bone Miner Res (1993), 8, 1137-1148 [0030]
Non-Patent Publication 12: Osteoporos Int (1995), 5, 354-370 [0031]
Non-Patent Publication 13: J Bone Miner Metab (2004), 22, 104-110
[0032] Non-Patent Publication 14: Journal of Japanese Society for
Bone Morphometry (2018), 28, 31-37 [0033] Non-Patent Publication
15: "Kotsusoshoshou you Yaku no Rinsho Hyokahoho ni Kansuru
Gaidorain no Kaitei nitsuite (Revision on Guidelines on Clinical
Assessment Method for Drugs for Osteoporosis)" (2017),
Yaku-sei-yaku-shin-hatsu (Pharmaceutical Sanitation Bureau Drug
Examination Management Notification) 0707, no. 1 [0034] Non-Patent
Publication 16: Bone 45 (2009), 1053-1058 [0035] Non-Patent
Publication 17: J Bone Miner Metab (2008), 26, 624-634 [0036]
Non-Patent Publication 18: Kagoshima-shi Iho (JOURNAL OF THE
KAGOSHIMA CITY MEDICAL ASSOCIATION) (2006), 45(9) "Yakuzai Netsu
nitsuite (Drug Fever)" [0037] Non-Patent Publication 19: JAPI
(2008), 56, 418-424 [0038] Non-Patent Publication 20: Calcif Tissue
Int (2014), 94, 170-175 [0039] Non-Patent Publication 21: Endocrine
Reviews (1989), 10(4), 420-436 [0040] Non-Patent Publication 22:
Arch Osteoporos. (2018), 13(1):54, s11657-018-0466-0 [0041]
Non-Patent Publication 23: Iyakuhin Intabyu Fohm Nihon Hyojun
Shohin Bunrui Bango (Pharmaceutical Interview Form Japan Standard
Goods Classification Number): 872439 [0042] Non-Patent Publication
24: The Journal of the Japanese Society of Internal Medicine
(2012), 101(4), 1007-1014 [0043] Non-Patent Publication 25: BoneKEy
Rep (2014), 3(512) [0044] Non-Patent Publication 26: Kawasaki
Medical Journal (2010), 36(2), 153-157 [0045] Non-Patent
Publication 27: PLOS ONE 12(4) e0175329 "Acute development of
cortical porosity and endosteal naive bone formation from the daily
but not weekly short-term administration of PTH in rabbit."
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0046] An object of the present invention is to provide a method
for treating and/or preventing osteoporosis with teriparatide or a
salt thereof having excellent safety and/or efficacies; and an
osteoporosis therapeutic and/or prophylactic agent containing
teriparatide or a salt thereof as an active ingredient.
Means to Solve the Problems
[0047] One embodiment of an osteoporosis therapeutic and/or
prophylactic agent and a method for treating and/or method for
preventing osteoporosis of the present invention is characterized
in that teriparatide or a salt thereof is contained as an active
ingredient, and that the teriparatide or a salt thereof is
administered in a unit dose of 28.2 .mu.g at a frequency of twice a
week.
[0048] The osteoporosis therapeutic and/or prophylactic agent and
the method for treating and/or method for preventing osteoporosis
mentioned above exhibit excellent safety and/or efficacies.
[0049] Specifically, the present invention relates to the following
inventions and the like.
[1] An osteoporosis therapeutic and/or prophylactic agent
containing teriparatide or a salt thereof as an active ingredient,
characterized in that the teriparatide or a salt thereof is
administered in a unit dose of 28.2 .mu.g at a frequency of twice a
week. [2] The osteoporosis therapeutic and/or prophylactic agent
according to the above [1], wherein the intervals of administration
of twice a week (not including the days of administration) are a
2-day interval and a 3-day interval. [3] The osteoporosis
therapeutic and/or prophylactic agent according to the above [1],
wherein when the number of weeks of a period administered at a
frequency of twice a week is defined as n, and the number of weeks
out of the n weeks in which the intervals of administration of
twice a week (not including the days of administration) are 2 days
and 3 days is defined as m, (m/n).times.100(%) is 70% or more. [4]
The osteoporosis therapeutic and/or prophylactic agent according to
any one of the above [1] to [3], which is subcutaneously
administered. [5] The osteoporosis therapeutic and/or prophylactic
agent according to any one of the above [1] to [4], which is
administered to an individual having a bone mineral density of
lumbar vertebrae less than 60% of a young adult mean. [6] The
osteoporosis therapeutic and/or prophylactic agent according to any
one of the above [1] to [4], which is administered to an individual
with one prevalent vertebral fracture. [7] The osteoporosis
therapeutic and/or prophylactic agent according to any one of the
above [1] to [4], which is administered to an individual having a
serum osteocalcin concentration of less than 15.2 (ng/mL). [8] The
osteoporosis therapeutic and/or prophylactic agent according to any
one of the above [1] to [4], which is administered to an individual
with an age 80 years or older. [9] The osteoporosis therapeutic
and/or prophylactic agent according to any one of the above [1] to
[4], which is administered to male. [10] The osteoporosis
therapeutic and/or prophylactic agent according to any one of the
above [1] to [4], which is administered to an osteoporosis patient
with a high risk of bone fractures. [11] The osteoporosis
therapeutic and/or prophylactic agent according to any one of the
above [1] to [4], which is administered to an osteoporosis patient
with all the bone fracture risk factors of aging, prevalent bone
fractures, and low bone mineral density. [12] The osteoporosis
therapeutic and/or prophylactic agent according to any one of the
above [1] to [4], which is administered to an osteoporosis patient
satisfying the following conditions (1) to (3): (1) an age 65 years
or older; (2) prevalent vertebral bone fractures of one or more and
five or less; and (3) a bone mineral density of lumbar vertebrae
less than 80% of a young adult mean.
Advantageous Effects of the Invention
[0050] According to the present invention, the osteoporosis
therapeutic and/or prophylactic agent and the method for treating
and/or method for preventing osteoporosis, in which teriparatide or
a salt thereof is contained as an active ingredient, with excellent
safety and/or efficacies are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] FIG. 1 is a diagram showing administration scheme examples
in cases where an osteoporosis therapeutic agent or the like of the
present invention is administered at a frequency of twice a week
over two weeks, in which the intervals of administration are set at
a 1-day interval and a 6-day interval (a 0-day interval and a 5-day
interval, when not including the days of administration), set at a
2-day interval and a 5-day interval (a 1-day interval and a 4-day
interval, when not including the days of administration), or set at
a 3-day interval and a 4-day interval (a 2-day interval and a 3-day
interval, when not including the days of administration).
[0052] FIG. 2 is a diagram showing administration scheme examples
in cases where an osteoporosis therapeutic agent or the like of the
present invention is administered at a frequency of twice a week
over two weeks, in which the intervals of administration are set at
a 3-day interval and a 4-day interval (a 2-day interval and a 3-day
interval, when not including the days of administration).
[0053] FIG. 3 is a chart schematically showing a treatment scheme
in Working Examples of the present invention. In addition, FIGS. 4
to 28 are graphs relating to the test results of Working Examples,
and the details of each drawing are explained as follows.
[0054] FIG. 4 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) when the osteoporosis
therapeutic agent or the like of the present invention is
administered to osteoporosis patients over a period of 48 weeks,
wherein the axis of abscissas is the number of weeks administered,
and the axis of ordinates is a mean value of change rates (%) from
the beginning; "BL" is Baseline; and "Final" means "at final of the
treatment" for showing a change rate (%) in bone mineral densities
of lumbar vertebrae (second to fourth lumbar vertebrae) at final of
the treatment for each patient, including change rates (%) in bone
mineral densities of lumbar vertebrae (second to fourth lumbar
vertebrae) of patients in which the treatment is discontinued
during the course of 48 weeks. The numerical values shown in the
two lower rows mean the number of treated patients in each week;
and "*" denotes for p<0.01.
[0055] FIG. 5 is a graph showing the transition of a median value
of change rates (%) in serum CTX when the osteoporosis therapeutic
agent or the like of the present invention is administered to
osteoporosis patients over a period of 48 weeks, wherein the axis
of abscissas is the number of weeks administered, and the axis of
ordinates is a median value of change rates (%) from the beginning;
and "BL" is Baseline. The numerical values shown in the two lower
rows mean the number of patients who took the tests in each
week.
[0056] FIG. 6 is a graph showing the transition of a median value
of change rates (%) in serum NTX when the osteoporosis therapeutic
agent or the like of the present invention is administered to
osteoporosis patients over a period of 48 weeks, wherein the axis
of abscissas is the number of weeks administered, and the axis of
ordinates is a median value of change rates (%) from the beginning;
and "BL" is Baseline. The numerical values shown in the two lower
rows mean the number of patients who took the tests in each
week.
[0057] FIG. 7 is a graph showing the transition of a median value
of change rates (%) in urine NTX when the osteoporosis therapeutic
agent or the like of the present invention is administered to
osteoporosis patients over a period of 48 weeks, wherein the axis
of abscissas is the number of weeks administered, and the axis of
ordinates is a median value of change rates (%) from the beginning;
and "BL" is Baseline. The numerical values shown in the two lower
rows mean the number of patients who took the tests in each
week.
[0058] FIG. 8 is a graph showing the transition of a median value
of change rates (%) in serum OC (osteocalcin) when the osteoporosis
therapeutic agent or the like of the present invention is
administered to osteoporosis patients over a period of 48 weeks,
wherein the axis of abscissas is the number of weeks administered,
and the axis of ordinates is a median value of change rates (%)
from the beginning; and "BL" is Baseline. The numerical values
shown in the two lower rows mean the number of patients who took
the tests in each week; "*" denotes that a Wilcoxon rank sum test
p<0.05, and "*" denotes that a Wilcoxon rank sum test p<0.01,
respectively.
[0059] FIG. 9 is a graph showing the transition of a median value
of change rates (%) in serum P1NP when the osteoporosis therapeutic
agent or the like of the present invention is administered to
osteoporosis patients over a period of 48 weeks, wherein the axis
of abscissas is the number of weeks administered, and the axis of
ordinates is a median value of change rates (%) from the beginning;
and "BL" is Baseline. The numerical values shown in the two lower
rows mean the number of patients who took the tests in each week;
"*" denotes that a Wilcoxon rank sum test p<0.05, and "*"
denotes that a Wilcoxon rank sum test p<0.01, respectively.
[0060] FIG. 10 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) when the osteoporosis
therapeutic agent or the like of the present invention is
administered to osteoporosis patients over a period of 48 weeks, in
which a proportion in compliance with administration intervals is
classified by 70% or more and less than 70%, wherein the axis of
abscissas is the number of weeks administered, and the axis of
ordinates is a mean value of change rates (%) from the beginning.
The numerical values shown in the two lower rows mean the number of
patients that are subjects to be analyzed in each week.
[0061] FIG. 11 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) when the osteoporosis
therapeutic agent or the like of the present invention is
administered to osteoporosis patients over a period of 48 weeks, in
which a proportion in compliance with administration intervals is
classified by 75% or more and less than 75%, wherein the axis of
abscissas is the number of weeks administered, and the axis of
ordinates is a mean value of change rates (%) from the beginning.
The numerical values shown in the two lower rows mean the number of
patients that are subjects to be analyzed in each week.
[0062] FIG. 12 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) when the osteoporosis
therapeutic agent or the like of the present invention is
administered to osteoporosis patients over a period of 48 weeks, in
which a proportion in compliance with administration intervals is
classified by 80% or more and less than 80%, wherein the axis of
abscissas is the number of weeks administered, and the axis of
ordinates is a mean value of change rates (%) from the beginning.
The numerical values shown in the two lower rows mean the number of
patients that are subjects to be analyzed in each week.
[0063] FIG. 13 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) when the osteoporosis
therapeutic agent or the like of the present invention is
administered to osteoporosis patients over a period of 48 weeks, in
which a proportion in compliance with administration intervals is
classified by 85% or more and less than 85%, wherein the axis of
abscissas is the number of weeks administered, and the axis of
ordinates is a mean value of change rates (%) from the beginning.
The numerical values shown in the two lower rows mean the number of
patients that are subjects to be analyzed in each week.
[0064] FIG. 14 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) when the osteoporosis
therapeutic agent or the like of the present invention is
administered to osteoporosis patients over a period of 48 weeks, in
which a proportion in compliance with administration intervals is
classified by 90% or more and less than 90%, wherein the axis of
abscissas is the number of weeks administered, and the axis of
ordinates is a mean value of change rates (%) from the beginning.
The numerical values shown in the two lower rows mean the number of
patients that are subjects to be analyzed in each week.
[0065] FIG. 15 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of the femoral neck
parts when the osteoporosis therapeutic agent or the like of the
present invention is administered to osteoporosis patients over a
period of 48 weeks, in which a proportion in compliance with
administration intervals is classified by 70% or more and less than
70%, wherein the axis of abscissas is the number of weeks
administered, and the axis of ordinates is a mean value of change
rates (%) from the beginning. The numerical values shown in the two
lower rows mean the number of patients that are subjects to be
analyzed in each week.
[0066] FIG. 16 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of the femoral neck
parts when the osteoporosis therapeutic agent or the like of the
present invention is administered to osteoporosis patients over a
period of 48 weeks, in which a proportion in compliance with
administration intervals is classified by 75% or more and less than
75%, wherein the axis of abscissas is the number of weeks
administered, and the axis of ordinates is a mean value of change
rates (%) from the beginning. The numerical values shown in the two
lower rows mean the number of patients that are subjects to be
analyzed in each week.
[0067] FIG. 17 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of the femoral neck
parts when the osteoporosis therapeutic agent or the like of the
present invention is administered to osteoporosis patients over a
period of 48 weeks, in which a proportion in compliance with
administration intervals is classified by 80% or more and less than
80%, wherein the axis of abscissas is the number of weeks
administered, and the axis of ordinates is a mean value of change
rates (%) from the beginning. The numerical values shown in the two
lower rows mean the number of patients that are subjects to be
analyzed in each week.
[0068] FIG. 18 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of the femoral neck
parts when the osteoporosis therapeutic agent or the like of the
present invention is administered to osteoporosis patients over a
period of 48 weeks, in which a proportion in compliance with
administration intervals is classified by 85% or more and less than
85%, wherein the axis of abscissas is the number of weeks
administered, and the axis of ordinates is a mean value of change
rates (%) from the beginning. The numerical values shown in the two
lower rows mean the number of patients that are subjects to be
analyzed in each week.
[0069] FIG. 19 is a graph showing the transition of a mean value of
change rates (%) in bone mineral densities of the femoral neck
parts when the osteoporosis therapeutic agent or the like of the
present invention is administered to osteoporosis patients over a
period of 48 weeks, in which a proportion in compliance with
administration intervals is classified by 90% or more and less than
90%, wherein the axis of abscissas is the number of weeks
administered, and the axis of ordinates is a mean value of change
rates (%) from the beginning. The numerical values shown in the two
lower rows mean the number of patients that are subjects to be
analyzed in each week.
[0070] FIG. 20 is a graph showing the transition of a mean value of
change rates (%) in a bone mineral density of the femoral proximal
total when the osteoporosis therapeutic agent or the like of the
present invention is administered to osteoporosis patients over a
period of 48 weeks, in which a proportion in compliance with
administration intervals is classified by 70% or more and less than
70%, wherein the axis of abscissas is the number of weeks
administered, and the axis of ordinates is a mean value of change
rates (%) from the beginning. The numerical values shown in the two
lower rows mean the number of patients that are subjects to be
analyzed in each week.
[0071] FIG. 21 is a graph showing the transition of a mean value of
change rates (%) in a bone mineral density of the total proximal
part of the femur when the osteoporosis therapeutic agent or the
like of the present invention is administered to osteoporosis
patients over a period of 48 weeks, in which a proportion in
compliance with administration intervals is classified by 75% or
more and less than 75%, wherein the axis of abscissas is the number
of weeks administered, and the axis of ordinates is a mean value of
change rates (%) from the beginning. The numerical values shown in
the two lower rows mean the number of patients that are subjects to
be analyzed in each week.
[0072] FIG. 22 is a graph showing the transition of a mean value of
change rates (%) in a bone mineral density of the total proximal
part of the femur when the osteoporosis therapeutic agent or the
like of the present invention is administered to osteoporosis
patients over a period of 48 weeks, in which a proportion in
compliance with administration intervals is classified by 80% or
more and less than 80%, wherein the axis of abscissas is the number
of weeks administered, and the axis of ordinates is a mean value of
change rates (%) from the beginning. The numerical values shown in
the two lower rows mean the number of patients that are subjects to
be analyzed in each week.
[0073] FIG. 23 is a graph showing the transition of a mean value of
change rates (%) in a bone mineral density of the total proximal
parts of the femur when the osteoporosis therapeutic agent or the
like of the present invention is administered to osteoporosis
patients over a period of 48 weeks, in which a proportion in
compliance with administration intervals is classified by 85% or
more and less than 85%, wherein the axis of abscissas is the number
of weeks administered, and the axis of ordinates is a mean value of
change rates (%) from the beginning. The numerical values shown in
the two lower rows mean the number of patients that are subjects to
be analyzed in each week.
[0074] FIG. 24 is a graph showing the transition of a mean value of
change rates (%) in a bone mineral density of the total proximal
parts of the femur when the osteoporosis therapeutic agent or the
like of the present invention is administered to osteoporosis
patients over a period of 48 weeks, in which a proportion in
compliance with administration intervals is classified by 90% or
more and less than 90%, wherein the axis of abscissas is the number
of weeks administered, and the axis of ordinates is a mean value of
change rates (%) from the beginning. The numerical values shown in
the two lower rows mean the number of patients that are subjects to
be analyzed in each week.
[0075] FIG. 25 is a graph showing a mean value of change rates (%)
in bone mineral densities of lumbar vertebrae (second to fourth
lumbar vertebrae) observed after 48 weeks of administration when
the osteoporosis therapeutic agent or the like of the present
invention is administered to osteoporosis patients showing some
recordation of compliance in which the proportions in compliance of
administration of each of two- to three-day intervals are each of
specified numerical values (70, 75, 80, 85, or 90%) or more.
[0076] FIG. 26 is a graph showing a fracture incidence rate (%) in
clinical bone fractures when the osteoporosis therapeutic agent or
the like of the present invention is administered to osteoporosis
patients showing some recordation of compliance in which the
proportions in compliance with the administration of each of two-
to three-day intervals are each of specified numerical values (70,
75, 80, 85, or 90%) or more.
[0077] FIG. 27 is a graph showing a median value of change rates
(%) of OC at four weeks after the beginning of administration
observed when the osteoporosis therapeutic agent or the like of the
present invention is administered to osteoporosis patients showing
some recordation of compliance in which the proportions in
compliance with the administration of each of two-to three-day
intervals are each of specified numerical values (70, 75, 80, 85,
or 90%) or more.
[0078] FIG. 28 is a graph showing a proportion (%) expressing
nausea (side effects) when the osteoporosis therapeutic agent or
the like of the present invention is administered to osteoporosis
patients showing some recordation of compliance in which the
proportions in compliance with the administration of each of two-
to three-day intervals are each of specified numerical values (70,
75, 80, 85, or 90%) or more.
[0079] FIG. 29 is a basic administration schedule for the test drug
group and the control drug group.
MODES FOR CARRYING OUT THE INVENTION
[0080] The present invention shall be described in detail
hereinbelow on the basis of specific embodiments. However, the
present invention is not intended to be bound to the following
embodiments, and can be carried out in any embodiments within the
range that would not depart from the spirit of the present
invention.
[0081] (1) Teriparatide or Salt Thereof (Hereinafter Also Referred
to as an Active Ingredient):
[0082] In the present invention, human PTH(1-34) is a peptide
represented by a partial amino acid sequence consisting of amino
acid residues of the position 1 to the position 34 from an
N-terminal side in the amino acid sequence of human PTH(1-84) which
is human parathyroid hormone.
[0083] In the present invention, teriparatide means human PTH(1-34)
in a free form. Teriparatide can also be in a salt form.
[0084] In the present invention, the salt of teriparatide includes
any salts formed by teriparatide and one or more volatile organic
acids. The volatile organic acids are exemplified by
trifluoroacetic acid, formic acid, acetic acid, and the like. When
teriparatide in a free form and the volatile organic acid form a
salt, the ratio thereof is not particularly limited so long as the
salt is formed. In particular, as the volatile organic acid, acetic
acid is preferred. Specifically, the salt of teriparatide in the
present invention is preferably exemplified by teriparatide
acetate.
[0085] Teriparatide or a salt thereof can be produced by methods
that themselves are known (for example, Patent Publications 1 to 3
and the like).
[0086] (2) Dosage:
[0087] The unit dose of the active ingredient, which is contained
in the osteoporosis therapeutic and/or prophylactic agent of the
present invention, or which is used in the method for treating
and/or method for preventing osteoporosis of the present invention
is preferably exemplified by, but not particularly limited to, as
follows.
[0088] Specifically, the unit dose of the active ingredient is more
preferably 20 .mu.g or more, 25 .mu.s or more, 27 .mu.g or more, or
28 .mu.s or more. In addition, the unit dose of the active
ingredient which is contained in the osteoporosis therapeutic
and/or prophylactic agent of the present invention is preferably 40
.mu.s or less, and more preferably 35 .mu.g or less, or 30 .mu.s or
less.
[0089] In particular, it is preferable that the unit dose of the
active ingredient is 28.2 .mu.g or 29.2 in terms of teriparatide.
When teriparatide used is an acetate, examples include the amount
added with the acetate amount. For example, in a case where
teriparatide pentaacetate is used, the unit dose of the active
ingredient is preferably 30.3 .mu.g or 31.3 .mu.g, in terms of
teriparatide acetate. Therefore, in the present invention, the
phrase "teriparatide or a salt thereof . . . in a unit dose of 28.2
.mu.g" means that a unit dose is an amount of 28.2 in terms of
teriparatide, or an amount of 30.3 in terms of teriparatide
acetate.
[0090] (3) Administration Frequency and Intervals of
Administration:
[0091] One of the features of the osteoporosis therapeutic and/or
prophylactic agent of the present invention and the method for
treating and/or method for preventing osteoporosis of the present
invention is in that the administration is carried out at a
frequency of twice a week.
[0092] When the osteoporosis therapeutic agent or the like of the
present invention is administered at a frequency of twice a week,
the intervals of the administration in a week can be set at 1) a
1-day interval and a 6-day interval (a 0-day interval and a 5-day
interval, when not including the days of administration), 2) at a
2-day interval and a 5-day interval (a 1-day interval and a 4-day
interval, when not including the days of administration), or 3) at
a 3-day interval and a 4-day interval (a 2-day interval and a 3-day
interval, when not including the days of administration) (FIG.
1).
[0093] The intervals of administration in a week are not
particularly limited, and an embodiment in which the intervals are
a 3-day interval and a 4-day interval (a 2-day interval and a 3-day
interval, when not including the days of administration) is most
preferred.
[0094] An embodiment in which the intervals of administration in a
week are a 3-day interval and a 4-day interval (a 2-day interval
and a 3-day interval, when not including the days of
administration) will be specifically described by administration
schedule examples over two weeks from the initial administration.
The administration of twice a week can be carried out in the week
of the initial administration (week 1) by administration at Day 4
or Day 5 from the date of initial administration, and subsequently,
the administration of twice a week in week 2 can be carried out by
administration at Day 8, and administration at Day 11 or Day 12
(FIG. 2).
[0095] The time zone for the administration is not particularly
limited, and the time zone may be during the day or may be at
night. When the time zone for the administration is during the day,
the administration may be administration in the morning, or
administration in the afternoon or evening (in the p.m.). However,
when used in combination with another therapeutic drug or basal
drug (Ca, vD preparations or the like), it is more preferred that
the ingestion time does not overlap with each other.
[0096] When the number of weeks of a period in which an
osteoporosis therapeutic agent of the present invention or the like
is administered at a frequency of twice a week is defined as n, and
the number of weeks out of the n weeks in which the intervals of
administration of twice a week are a 3-day interval and a 4-day
interval (a 2-day interval and a 3-day interval, when not including
the days of administration) is defined as m, (m/n).times.100(%) can
be a given level or higher. The lower limit of the proportion is
exemplified by 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95%, and the
lower limit of the proportion is preferably 80% or more, and more
preferably 90% or more.
[0097] For example, in a case where a period in which an
osteoporosis therapeutic agent or the like of the present invention
is administered at a frequency of twice a week is 34 days, and the
number of weeks in which the intervals of administration of twice a
week are a 3-day interval and a 4-day interval (a 2-day interval
and a 3-day interval, when not including the days of
administration) is 2, (m/n).times.100 defined above would be
calculated to be 2/(34/7).times.100, i.e. about 41.2(%).
[0098] (4) Administration Route and Administration Sites:
[0099] The administration route for the osteoporosis therapeutic
and/or prophylactic agent of the present invention and the method
for treating and/or method for preventing osteoporosis of the
present invention is not particularly limited, and the
administration can be carried out intravenously, subcutaneously, or
intramuscularly. In particular, the subcutaneous administration is
preferably exemplified.
[0100] The administration sites for the osteoporosis therapeutic
and/or prophylactic agent of the present invention and the method
for treating and/or method for preventing osteoporosis of the
present invention are not particularly limited, and for example,
the administration can be carried out to upper arm parts, femur
parts, or abdominal parts. However, in the second or subsequent
administrations, it is preferable that the administration is
carried out to a site at least 3 cm or so away from the previous
administration site. In addition, the administration can be
facilitated by pinching the surrounding of the administration site
with a hand, and raising up the administration site and the
surroundings thereof from the skin surface immediately before the
administration.
[0101] (5) Period of Administration:
[0102] The period of administration for the osteoporosis
therapeutic and/or prophylactic agent of the present invention and
the method for treating and/or method for preventing osteoporosis
of the present invention is not particularly limited, and the
period of administration can be properly determined by the
prescription of a physician in charge depending upon the patients
or the like.
[0103] The lower limit of the period of administration is not
particularly limited, and the period of administration is
preferably exemplified by, for example, preferably 4 weeks or more,
8 weeks or more, 12 weeks or more, 24 weeks or more, 48 weeks or
more, or 1 year or more. The upper limit of the period of
administration is also not limited in the same manner, and the
upper limit of the period of administration preferably includes,
for example, within 5 years, within 4 years, within 3 years, or
within 2 years.
[0104] (6) Diseases and Patients:
(6-1) Diseases:
[0105] One of the features of the osteoporosis therapeutic and/or
prophylactic agent of the present invention and the method for
treating and/or method for preventing osteoporosis of the present
invention is in that administration is carried out for the purpose
of treatment and/or prevention of osteoporosis.
[0106] The osteoporosis in the present invention means "a skeletal
disease characterized by compromised bone strength predisposing a
person to an increased risk of fracture" (Non-Patent Publication 1;
the definition in Consensus Conference in NIH in 2000), which
includes both primary osteoporosis and secondary osteoporosis.
[0107] The primary osteoporosis is exemplified by involutional
osteoporosis (postmenopausal osteoporosis and senile osteoporosis),
and idiopathic osteoporosis (post-pregnancy osteoporosis, juvenile
osteoporosis, or the like). The secondary osteoporosis is
osteoporosis triggered by a specified disease, a specified drug,
and other causations. The causations include specified drugs,
rheumatoid arthritis, diabetes, hyperthyroidism, sexual
dysfunctions, immobility, nutrition, congenital diseases, and the
like. The specified drugs include, for example, steroids. The
diagnostic criteria for the primary osteoporosis are well known
(Non-Patent Publication 10).
[0108] The osteoporosis in the present invention includes
preferably osteoporosis with high risks of bone fractures. The
osteoporosis with high risks of bone fractures may be patients with
risk factors such as low bone mineral density, prevalent bone
fractures, aging, and family history with bone fractures at the
femoral neck parts (Non-Patent Publication 9).
[0109] As mentioned above, as drugs with efficacies and effects for
osteoporosis with high risks of bone fractures, a daily
administered preparation or a once-weekly administered preparation,
each containing teriparatide or a salt thereof as an active
ingredient, has been developed. After being approved for sales
thereof, the preparation has been actually used in clinical
situations. In addition, as osteoporosis therapeutic agents with
high risks of bone fractures, the development of human
anti-sclerostin antibodies has been advanced. From these
situations, one of ordinary skill in the art can easily and clearly
recognize osteoporosis with high risks of bone fractures.
[0110] As a tool for assessing the absolute riskiness of bone
fractures of individuals, FRAX (registered trademark) of the WHO
(World Health Organization) has been known, which can calculate the
incidence probability (%) of bone fractures in the future 10 years
of the individuals. In the daily medical services, the tool can be
used as a screening means for discriminating individuals with
latent high risks of bone fractures in aged individuals without
symptoms who are outpatients in the medical institutions.
(6-2) Patients:
[0111] The osteoporosis patients in the present invention can be
osteoporosis patients with at least one or more of the risk factors
for bone fractures mentioned above. The patients described above
can be preferably exemplified by osteoporosis patients with three
risk factors for bone fractures of aging, prevalent bone fractures,
and low bone mineral density.
[0112] In addition, the osteoporosis patients in the present
invention can be osteoporosis patients in which at least one risk
factor out of the above risk factors for bone fractures satisfies
specified conditions (for example, a specified threshold value or
less, a specified threshold value or more, a specified numerical
range, the presence or absence, or the like).
[0113] In particular, it is preferable that the osteoporosis
patients in the present invention are osteoporosis patients with
high risks of bone fractures. The osteoporosis patients with high
risks of bone fractures as described above can be preferably
exemplified by osteoporosis patients satisfying the following 3
conditions.
1) an age 65 years or older; 2) prevalent bone fractures of one or
more; and 3) a bone mineral density of the lumbar vertebrae of less
than 80% of the young adult mean (Young Adult Mean, which may also
be referred to as YAM).
[0114] Here, the prevalent bone fractures include preferably
prevalent vertebral bone fractures, and the number of prevalent
bone fractures can be 1 or more and 5 or less. In addition, the
prevalent vertebral bone fractures can be graded as prevalent
vertebral bone fractures of a low-level deformation (grade 1), a
mid-level deformation (grade 2), or a high-level deformation (grade
3) (Non-Patent Publication 9).
[0115] Specific examples of the grade 1 include low-level bone
fractures in which the decrease is 20 to 25% in the centrum height;
specific examples of the grade 2 include mid-level bone fractures
in which the decrease is 25 to 40% in the centrum height; and
specific examples of the grade 3 include high-level bone fractures
in which the decrease is 40% or more in the centrum height,
respectively.
[0116] The osteoporosis patients in the present invention can be
osteoporosis patients that are not patients satisfying at least any
one out of the following six conditions:
1) patients which are considered to have high risks of the
incidence of osteosarcoma; 2) patients with hypercalcemia; 3)
patients with primary malignant osteocarcinoma or metastatic
osteocarcinoma; 4) patients with metabolic bone diseases other than
osteoporosis; 5) patients with prevalence of hypersensitivity to an
active ingredient of the osteoporosis therapeutic and/or
prophylactic agent of the present invention or other teriparatide
preparation; and 6) female adult who are pregnant or possibly
pregnant.
[0117] The patients which are considered to have high risks of the
incidence of osteosarcoma include, for example, patients with
Paget's disease of the bone, patients showing high alkaline
phosphatase values, patients in which epiphysical line is not
closed in infants or the like and juvenile individuals, and
patients that took radiation therapy which are considered to affect
the bones in the past.
[0118] In addition, the osteoporosis patients in the present
invention can be osteoporosis patients that are not patients
satisfying at least any one of the following five conditions.
1) patients with low blood pressure; 2) patients with renal
disorders; 3) patients with serious cardiac diseases; 4) patients
with serious hepatic dysfunctions; and 5) patients with urinary
calculus and patients with prevalence thereof.
[0119] Alternatively, the osteoporosis patients in the present
invention can be osteoporosis patients having low-level or
mid-level renal disorders. The normal renal function, renal
dysfunctions, and the levels of disorders can be discriminated on
the basis of the creatinine clearance. Specifically, a creatinine
clearance of 80 mL/min or more can be judged as normal renal
function, a creatinine clearance of 50 mL/min or more and less than
80 mL/min can be judged as a low-level renal dysfunction, and a
creatinine clearance of 30 mL/min or more and less than 50 mL/min
can be judged as a mid-level renal dysfunction. The method for
calculating a creatinine clearance includes, for example, the
formulas of Cockcroft-Gault (male: (140-age).times.body
weight/(72.times.serum creatinine value), female:
0.85.times.(140-age).times.body weight/(72.times.serum creatinine
value)) as an example.
[0120] In addition, the osteoporosis patients in the present
invention can be osteoporosis patients that satisfy such that each
of the factors respectively has specified conditions (for example,
a specified threshold value or less, a specified threshold value or
more, a specified numerical range, the kinds, the presence or
absence, or the like), with respect to at least any one of the
factors out of the following 18 factors which the patients
have:
1) gender; 2) age; 3) height; 4) body weight;
5) BMI;
[0121] 6) the number of years after menopause (limited to women,
patients with menopause); 7) history of suffering from nonvertebral
bone fractures at age 50 or older (limited to patients of age 50 or
older); 8) history of suffering from nonvertebral bone fractures
without accompanying external force at age 50 or older (limited to
patients of age 50 or older); 9) prevalence that affects bone
metabolism; 10) smoking; 11) alcohol consumption; 12) parental
history of femoral bone fractures; 13) previous therapeutic drugs
of osteoporosis; 14) 25-hydroxyvitamin D; 15) the number of
prevalent vertebral bone fractures; 16) a bone mineral density of
the lumbar vertebrae (value calculated as YAM) (%); 17) a bone
mineral density at the femoral neck part (value calculated as YAM)
(%); and 18) a bone mineral density of the total proximal parts of
the femur (value calculated as YAM) (%).
[0122] For example, the osteoporosis patients in the present
invention can be male or female patients; patients of age 65 years
or older and younger than 75 years; patients of age 75 years or
older and younger than 80 years; patients of age 80 years or older;
patients with a bone mineral density of lumbar vertebrae (value
calculated as YAM) (%) of less than 60%, those of 60% or more and
less than 70%, or those of 70% or more and less than 80%; patients
with the number of prevalent vertebral bone fractures of zero;
patients with the number of prevalent vertebral bone fracture of
one; patients with the number of prevalent vertebral bone fractures
of two to three; patients with the number of prevalent vertebral
bone fractures of four to five; patients with the number of
prevalent vertebral bone fractures of six or more, or the like.
[0123] The osteoporosis patients in the present invention are
osteoporosis patients in which each of the items of at least any
one of items out of the following 26 investigational study items
respectively satisfies specified conditions (for example, a
specified threshold value or less, a specified threshold value or
more, a specified numerical range, or the like).
1) blood general test items (a total of 6 items) (red blood cell
count, hemoglobin, hematocrit, white blood cell count, white blood
cell fraction, platelet count); 2) blood biochemical test items (a
total of 14 items) (AST (GOT), ALT (GPT), alkaline phosphatase,
total cholesterol, urea nitrogen, uric acid, creatinine, CPK,
calcium, inorganic phosphorus, sodium, potassium, chlorine,
albumin); and 3) urine test items (a total of 6 items) (occult
blood, protein, sugar, urobilinogen, bilirubin, pH).
[0124] AST (GOT) as used herein means aspartate aminotransferase
(glutamic-oxaloacetic transaminase)), and ALT (GPT) as used herein
means alanine aminotransferase (glutamic-pyruvic transaminase)).
Here, CPK as used herein means creatinine phosphokinase.
[0125] In addition, the osteoporosis patients in the present
invention can be osteoporosis patients in which each of the items
of at least any one of items out of the vital sign items (sitting
systolic blood pressure, sitting diastolic blood pressure, pulse
rate, and the like) respectively satisfies specified conditions
(for example, a specified threshold value or less, a specified
threshold value or more, a specified numerical range, or the
like).
[0126] Alternatively, the osteoporosis patients in the present
invention can also be osteoporosis patients which are capable of
producing anti-drug antibodies (for example, antibodies against
teriparatide or a salt thereof, and the like) and neutralizing
antibodies (for example, antibodies capable of lowering or losing
the activity of teriparatide or a salt thereof, and the like), with
the ingestion of the osteoporosis therapeutic and/or prophylactic
agent of the present invention.
[0127] In addition, the osteoporosis patients in the present
invention can be osteoporosis patients in which each of the markers
of at least any one of the markers out of the following 12 markers
respectively satisfies specified conditions (for example, a
specified threshold value or less, a specified threshold value or
more, a specified numerical range, or the like).
1) blood markers (osteocalcin, P1NP, NTX, CTX, calcium, inorganic
phosphorus, albumin, 25-hydroxyvitamin D fraction); and 2) urine
markers (NTX, calcium, inorganic phosphorus, creatinine).
[0128] P1NP as used herein means procollagen type I amino-terminal
propeptide, NTX as used herein means crosslinked N-telopeptide of
type I collagen, and CTX as used herein means type I collagen
crosslinked C-telopeptide, respectively.
[0129] The osteoporosis patients in the present invention include
patients with a blood osteocalcin concentration of less than 15.2
(ng/mL), patients with a blood osteocalcin concentration of 15.2
(ng/mL) or more and less than 21.8 (ng/mL), and patients with a
blood osteocalcin concentration of 21.8 (ng/mL) or more.
[0130] Alternatively, the osteoporosis patients in the present
invention include, for example, a blood osteocalcin concentration
of less than 14.8 (ng/mL), patients with a blood osteocalcin
concentration of 14.8 (ng/mL) or more and less than 21.9 (ng/mL),
and patients with a blood osteocalcin concentration of 21.9 (ng/mL)
or more.
[0131] In addition, the osteoporosis patients in the present
invention include, for example, patients with a blood P1NP
concentration of less than 38.0 (.mu.g/L), patients with a blood
P1NP concentration of 38.0 (m/L) or more and less than 58.5 (m/L),
and patients with those of 58.5 (.mu.g/L) or more.
[0132] Alternatively, the osteoporosis patients in the present
invention include, for example, patients with a blood P1NP
concentration of less than 37.4 (.mu.g/L), patients with a blood
P1NP concentration of 37.4 (.mu.g/L) or more and less than 57.3
(.mu.g/L), and patients with those of 57.3 (.mu.g/L) or more.
[0133] The osteoporosis patients in the present invention can also
be patients having therapeutic history with previous therapeutic
drugs for osteoporosis. The previous therapeutic drugs for
osteoporosis include calcium drugs, female hormone drugs, SERMs
(selective estrogen receptor modulators), active vitamin D.sub.3
drugs, vitamin K.sub.2 drugs, calcitonin drugs, parathyroid hormone
drugs, bisphosphonate drugs, and denosumab.
[0134] Here, the SERMs are preferably exemplified by raloxifene and
bazedoxifene; the active vitamin D.sub.3 drugs are preferably
exemplified by eldecalcitol, alfacalcidol, and calcitriol; and the
vitamin K.sub.2 drugs are preferably exemplified by menatetrenone,
respectively. Further, the bisphosphonate drugs are exemplified by
etidronate, alendronate, risedronate, minodronate, and ibandronate.
The calcitonin drugs are exemplified by calcitonin salmon and
elcatonin. The parathyroid hormone drugs include a daily
administered preparation or a once-weekly administered preparation,
containing teriparatide or a salt thereof mentioned above as an
active ingredient.
[0135] In addition, the osteoporosis patients in the present
invention can be osteoporosis patients suffering from other
diseases, in other words, osteoporosis patients having
complications. Other diseases include diabetes, hypertension,
adipogenetic aberrancy (hyperlipemia or the like), chronic kidney
diseases (CKD), rheumatoid arthritis, gout, hyperuricemia,
dementia, cataract, senile hearing impairments, dysuria,
cerebrovascular diseases, ischemic cardiac diseases, and the
like.
[0136] Alternatively, the osteoporosis patients in the present
invention can also be osteoporosis patients who are in a
care-needed state.
[0137] (7) Combination Use:
[0138] The osteoporosis therapeutic and/or prophylactic agent of
the present invention and the method for treating and/or method for
preventing osteoporosis of the present invention can be used in
combination with other drugs. Other drugs can be administered in
the identical or different routes, simultaneously or successively
(i.e., at separate time) with the osteoporosis therapeutic and/or
prophylactic agent of the present invention.
[0139] Other drugs include at least one of the drugs in the
previous therapeutic drugs for osteoporosis mentioned above.
Alternatively, other drugs also include a therapeutic and/or
prophylactic agent for complications mentioned above. In addition,
other drugs may be a basal drug (Ca, vD preparations, and the
like).
[0140] Preferred basal drugs include vD.sub.3 (vitamin D.sub.3)
preparations, magnesium preparations, and calcium preparations.
These basal drugs can be used together in any combinations, and
they may be in the form of a combination preparation. For example,
calcium preparations formulated with vD.sub.3 and magnesium are
preferably exemplified as a basal drug. The combination preparation
as described above is preferably ingested once a day after an
evening meal, the combination preparation containing vD.sub.3 400
IU, magnesium 30 mg, and calcium 610 mg per dose.
[0141] When the osteoporosis therapeutic and/or prophylactic agent
of the present invention is subjected to a clinical test as a test
drug, the evaluation can also be carried out in the state that the
test individuals are ingested with the above or equivalent basal
drug (Non-Patent Publication 15). Here, the considerations can be
made to the ideas that the decrease in the risks of bone fractures
by a combined use of vD and a calcium preparation is indefinite
(Non-Patent Publication 25), and that when both the test drug group
and the control drug group are given with a basal drug, the
influences of the basal drug in the differences between the two
groups on efficacies and safety are not probably substantially
recognized. In view of these ideas, when the osteoporosis
therapeutic and/or prophylactic agent of the present invention is
used in a clinically practiced site, the use of vD and a calcium
preparation is not necessarily needed.
[0142] (8) Preparation:
[0143] The osteoporosis therapeutic and/or prophylactic agent of
the present invention can take various preparation forms. In
general, it is preferable that the present preparation is in the
form of an injection containing pharmaceutically acceptable
excipients and additives, from the viewpoint of safety or the
like.
[0144] The excipients and the additives are not particularly
limited, including, for example, a sugar alcohol (mannitol or the
like), an inorganic salt (sodium chloride or the like), a
saccharide (sucrose or the like), or an amino acid (methionine or
the like). The present preparation may contain a buffer, or may not
contain a buffer. The pH of the present preparation can be
appropriately adjusted, and the pH can be adjusted to, for example,
from 3.5 to 5.5.
[0145] The concentration of the active ingredient in the present
preparation is also not particularly limited, and the concentration
can be, for example, 50 .mu.g/mL or more, and can also be from 100
to 200 .mu.g/mL.
[0146] When the present preparation is in the form of an injection,
the present preparation can be produced by dissolving an active
ingredient, excipients and additives in a proper solvent (sterile
water, a buffer, physiological saline or the like), subjecting the
solution to filtration with a filter or the like and/or sterile
treatment, and subsequently dispensing and sealing the filtrate in
a container previously cleaned and subjected to sterile
treatment.
[0147] Here, examples of the dispensing container include, for
example, ampules, vials, pre-filled syringes, bags, and the like.
The materials for the container include, but not particularly
limited to, glass and plastics. The materials for the container are
preferably exemplified by plastics, from the viewpoint of strength,
easiness in handling, safety, and the like.
[0148] For example, the preparation may be an automatically
administered preparation in which a pre-filled syringe with a
needle which is previously dispensed with a drug solution is
incorporated into an auto-injector. Since the osteoporosis
therapeutic agent or the like according to the present invention
shows sufficient safety, the preparation can serve as an
automatically administered preparation for domiciliary care.
[0149] (9) Efficacies:
[0150] The main purpose of the therapeutic and/or prophylactic
agent for osteoporosis according to the present invention and the
method for treating and/or method for preventing osteoporosis of
the present invention is to prevent or inhibit bone fractures.
(9-1) Prevention or Inhibition of Bone Fractures:
[0151] The bone fractures in the present invention include
pathological bone fractures caused by osteoporosis, osteogenesis
imperfecta, bone tumor, or the like, and traumatic bone fractures
caused by traffic accidents, bruises, or the like. The bone
fractures preferably include bone fractures caused by
osteoporosis.
[0152] The bone fractures in the present invention include both
vertebral bone fractures and non-vertebral bone fractures. The
non-vertebral bone fractures include, but also not particularly
limited to, for example, bone fractures in the proximal part of the
femur, the distal end of the radius, the proximal part of the
humerus, the tibiae, pelvis, costa, and the like. The bone
fractures in the present invention preferably include vertebral
bone fractures (new vertebral bone fractures, worsening vertebral
bone fractures, and the like).
[0153] In general, the femoral proximal fractures mean hip
fractures of elderly individuals, which are understood to be bone
fractures that are different from the fractures of the proximal
part of the femur (Non-Patent Publication 9). The bone fractures
that are included in the femoral proximal fractures include, for
example, subchondral insufficiency fracture of the femoral head,
femoral neck fracture, basal neck fracture of the femur,
trochanteric fracture of the femur, and subtrochanteric fracture of
the femur (Non-Patent Publication 9).
[0154] Here, since the subchondral insufficiency fracture of the
femoral head is very rare and the diagnosis of the basal neck
fracture of the femur is difficult, they can also be classified
into either one of femoral neck fracture and trochanteric fracture
of the femur. Since the distinctions between the trochanteric
fracture of the femur and the subtrochanteric fracture of the femur
are not clear, it is also possible to employ a method of roughly
classifying the femoral proximal fractures into two groups of the
femoral neck fracture and the trochanteric fracture of the femur
(Non-Patent Publication 9). The femoral proximal part may be also
referred to a femoral proximal total, from the implications of
emphasizing its totality.
[0155] The vertebral bone fractures have a very high clinical
significance in the prevention or inhibition thereof because the
vertebral bone fractures are osteoporosis bone fractures with the
highest frequency and the vertebral bone fractures are important as
an index for diagnosis and treatment of osteoporosis (Non-Patent
Publication 9). In addition, since the femoral proximal fractures
cause the worsening of life functions or the QOL and the femoral
proximal fractures are considered to also be relevant to life
prognosis (Non-Patent Publication 9), it is preferable that
measures for sufficient prevention or inhibition are taken against
the femoral proximal fractures.
[0156] The vertebral bone fractures can be judged as morphometric
bone fractures according to the level of degree of deformation of
vertebrae irrelevant to the presence or absence of clinical
symptoms (Non-Patent Publication 9). The morphometric bone
fractures can be classified into prevalent bone fractures and new
bone fractures.
[0157] The new bone fractures can be defined as bone fractures
which are judged as new incidence by comparing X-ray images or the
like at two time points, and the prevalent bone fractures can be
bone fractures which are judged by the extent of deformation of the
centrum at one time point before the beginning of the treatment. Of
the new bone fractures, those in which the centrum that has not
undergone deformation before the beginning of the treatment is
deformed after the beginning of the treatment are defined as new
vertebral bone fractures, which can also be distinguished from
worsening bone fractures that are those in which the extent of
deformation of the centrum is increased after the beginning of the
treatment. The new vertebral bone fractures and the worsening
vertebral bone fractures as used herein are expressed in the
distinctions as mentioned above.
[0158] The vertebral bone fractures in the present invention
include both new vertebral bone fractures and worsening vertebral
bone fractures. For example, the extent of the deformation of the
centrum can be classified according to Grades in view of the forms
of the total centrum, which is generally classified as Grade 0
(normal), Grade 1 (decrease of about 20 to about 25% in the centrum
height, and decrease of 10 to 20% in the centrum area), Grade 2
(decrease of about 25 to about 40% in the centrum height, and
decrease of 20 to 40% in the centrum area), and Grade 3 (decrease
of about 40% or more in the centrum height, and decrease of 40% or
more in the centrum area). The distinctions of new and worsening
can be carried out in line with the increase patterns of Grade in
accordance with the judgment criteria of Genant. Specifically, in
cases where a change is found from Grade 0 to Grade 1, 2, or 3, it
is diagnosed as a new vertebral bone fracture, and in a case where
a change is found from Grade 1 to Grade 2 or 3, or from Grade 2 to
Grade 3, it can be considered as a worsening bone fracture.
[0159] Of the bone fractures in the present invention, bone
fractures which are diagnosed with clinical symptoms such as pains
can be referred to as clinical bone fractures, and the clinical
bone fractures can be classified into clinical vertebral bone
fractures and clinical non-vertebral bone fractures. The clinical
non-vertebral bone fractures as used herein are simply referred to
as non-vertebral bone fractures. The clinical symptoms are, for
example, acute pains of dorsolumbar parts, and the like, which can
be confirmed by appeals made by the test individuals.
[0160] The bone fracture assessment method using an X-ray image or
MRI is a method that itself is known, and, for example, a
quantitative assessment method (QM method) or a semi-quantitative
assessment method (SQ method) has been known. The SQ method is a
method proposed by Genant et al. in 1993, which has been so far
used in many clinical tests in Japan or elsewhere, and the
evidences thereof have been constructed, so that the method can be
more preferably used (Non-Patent Publication 11). Besides them, a
method by Wu et al. or a method by Fukunaga et al. can also be used
(Non-Patent Publications 11 to 13).
[0161] When the osteoporosis therapeutic and/or prophylactic agent
is tested, it is preferable that the bone fracture inhibitory
action thereof is assessed. When the bone fracture inhibitory
action of a test drug is assessed, the bone fracture inhibitory
action (bone fracture risk reducing property or the like) of the
test drug can be also assessed in the same test without using a
placebo control drug in the same test by subjecting a control drug
which is found to have bone fracture inhibitory property by past
clinical data or the like to a test and carrying out the same test
to obtain a bone fracture incidence rate of the control drug, and
comparing a bone fracture incidence rate of a test drug with a bone
fracture incidence rate of a control drug, or by comparing a bone
fracture incidence rate of a test drug with a bone fracture
incidence rate without treatment for test individuals of the same
test which can be assumed on the basis of the past clinical data or
the like.
(9-2) Increase in Bone Mineral Densities:
[0162] The bone strength is made up of two factors, bone mineral
density and bone quality, and in general, the "bone mineral
density" can account for about 70% of the bone strength, and the
"bone quality" can account for the remaining 30% or so (Non-Patent
Publication 9). Even in a daily administered preparation or a
once-weekly administered preparation, the preparation containing
teriparatide or a salt thereof as an active ingredient, not only
the bone fracture inhibitory effects but also bone mineral density
increasing effects have been known (Non-Patent Publications 4, 5,
8, and 9).
[0163] Here, the bone mineral density refers typically to a bone
mineral content of the lumbar vertebrae. The lumbar vertebrae are
rich in trabecular bones having a fast bone turnover, so that the
sensitivity of a detection change of the change in bone mineral
densities by a drug therapy is also high. In addition, in a case
where the assessment of the bone mineral content of the lumbar
vertebrae is difficult or the like, the bone mineral density can be
expressed by the bone mineral content values of the radius, the
second metacarpal bone, the femoral neck part, or the calcaneus. In
addition, the young adult mean infers to a mean value of bone
mineral densities of ages 20 to 44 years.
[0164] The bone mineral density can be measured by methods that are
themselves known, for example, dual-energy X-ray absorptiometry,
photodensitometry, photon absorptiometry, quantitative CT scan,
quantitative ultrasonography, and the like.
[0165] The change rate in bone mineral densities can be calculated
by, for example, the following formula:
Change rate in bone mineral densities ( % ) at a certain time point
a = ( Bone mineral density at the time point ) - ( Bone mineral
density at the beginning of administration ) ( Bone mineral density
at the beginning of administration ) .times. 100 ##EQU00001##
[0166] In addition, the degree of bone atrophy in the present
invention means a degree of loss in bone mass on an X-ray. The
degree of bone atrophy is classified into no bone atrophy, bone
atrophy grade I, bone atrophy grade II, and bone atrophy grade III.
No bone atrophy in the degree of bone atrophy refers to a normal
condition, which specifically means a condition in which the
trabecular structure cannot be recognized because latitudinal and
longitudinal trabeculae are dense. Bone atrophy grade I means that
longitudinal trabeculae are prominent. Typically, it means a
condition in which the longitudinal trabeculae are thin and visible
but still arranged densely, and the end plates of the centrum are
prominent. Bone atrophy grade II in the degree of bone atrophy
means a state in which the longitudinal trabeculae have become
rough, appear thick, and are roughly arranged, and the end plates
of the centrum also have lighter color. Bone atrophy grade III in
the degree of bone atrophy means a condition in which the
longitudinal trabeculae become indistinct, the centrum shadows
appear blurry as a whole, and the difference from the shadows of
the intervertebral disks is reduced. The degree of bone atrophy can
be judged, for example, from a lateral X-ray image of the lumbar
vertebrae.
(9-3) Fluctuations in Bone Metabolism Markers:
[0167] The fluctuations in the bone metabolism markers are
associated with the prevention or inhibition of bone fractures and
increase in bone mineral densities. Therefore, when the
osteoporosis therapeutic agent is assessed or the like from the
aspect of efficacies, it is considered to be useful to measure bone
metabolism marker values in biological samples (blood samples,
urine samples, and the like) derived from test individuals, and
confirm the fluctuations thereof (for example, differences between
values before the administration and values after the
administration) (Non-Patent Publication 9).
[0168] For the purpose of assessing the osteoporosis therapeutic
and/or prophylactic agent of the present invention in the aspect of
efficacies, the fluctuations of bone metabolism markers, the
increase in bone mineral densities, or the inhibition of bone
fractures can be observed. In an administration embodiment where a
method of administration is twice a week in the present invention
in which the intervals of the administration in a week are a 2-day
interval and a 3-day interval (not including the days of
administration), it is preferable that the efficacies are assessed
by directly observing the increase in bone mineral densities or the
inhibition of bone fractures.
[0169] The bone metabolism markers are roughly classified into bone
formation markers and bone resorption markers. The bone formation
markers can be substances that are directly or indirectly produced
from osteoblasts at each stage of differentiation of the
osteoblasts, and osteocalcin, P1NP or the like has been known. The
bone resorption markers can be substances that are related to
activation or bone resorption of osteoclasts, and NTX, CTX or the
like has been known.
[0170] Conventionally, regarding a daily osteoporosis therapy using
teriparatide, particularly at an early stage, the dissociation of
the bone formation markers which are found to have a rapid increase
from the beginning of administration and the bone resorption
markers is called "anabolic window," which has been considered to
the mechanism of increase in bone mineral densities from an early
stage of administration (Non-Patent Publication 24). Also in the
osteoporosis therapeutic and/or prophylactic agent of the present
invention, the fluctuations of the bone metabolism markers, for
example, "Anabolic window" can serve as an index for therapeutic
monitoring particularly at an early stage of the beginning of
administration (for example, within several months from the
beginning of administration).
[0171] However, the administration embodiment where a method of
administration of twice a week in the present invention in which
the intervals of the administration in a week are a 2-day interval
and a 3-day interval (not including the days of administration) can
be clearly distinguished from the conventional teriparatide
therapeutic method with regard to the relationship between the bone
metabolism markers and the efficacies. Therefore, when the
efficacies are assessed in the same administration embodiment, it
is more preferable that the increase in bone mineral densities or
the inhibition of bone fractures is directly observed, not the
fluctuations of the bone metabolism markers.
[0172] Further, according to the studies on rats subjected to
ovariectomy which are widely used as osteoporosis models
(Non-Patent Publications 14 and 15), it has been reported that the
voids in the cortical bone are increased according to the dosage
when the dosage frequency of teriparatide is high (Non-Patent
Publication 14).
[0173] In addition, it has been reported that teriparatide has been
used as a therapeutic agent for osteoporosis with a high risk of
bone fractures, and the voids in the cortical bone are increased in
the subject patients by aging or pathologies, and it has been
reported that the therapeutic strategies in considerations of
pathologies of the patients and the features of the pharmacological
actions of teriparatide are needed in order to maximize the
therapeutic effects with teriparatide (Non-Patent Publication
14).
[0174] Therefore, in the treatment or prevention in the present
invention, an embodiment such that a blood concentration or a urine
concentration of the bone resorption markers which are deeply
related with the void formation or porosity in the cortical bone is
reduced with the time course or the increase is inhibited with the
time course, while increasing the bone formation markers associated
with an increase in bone mineral densities and a bone fracture
inhibitory rate is preferred. The bone resorption markers which are
deeply related with the void formation or porosity in the cortical
bone can be exemplified by NTX and CTX. Moreover, an embodiment of
the present invention as described above can be an embodiment in
which the intervals between administrations are appropriately taken
so as not to continuously increase bone resorption when repeatedly
administered. More specifically, for example, the treatment or
prevention in which a dosage is 28.2 .mu.g, in terms of
teriparatide, is exemplified, among which a method of
administration twice a week in the present invention (provided that
a unit dose is 28.2 .mu.g in terms of teriparatide), in which the
intervals of administration in a week are a 2-day interval and a
3-day interval (not including the days of administration), is
preferably exemplified.
[0175] (10) Safety:
(10-1) Adverse Events and Side Effects:
[0176] All the unwanted or unintended diseases or symptoms thereof
caused in individuals administered with a drug can be referred to
as adverse events (AE).
[0177] Among the adverse events, those in which cause-and-effect
relationship with a drug cannot be denied can be referred to as
side effects. The matter that the cause-and-effect relationship
cannot be denied includes the matter that a reasonable possibility
of the cause-and-effect relationship is found, and the matter that
no reasonable possibilities of the cause-and-effect relationship
cannot be assessed.
[0178] The adverse events can be roughly classified into serious
adverse events and non-serious adverse events, and the following
six adverse events can be defined as serious adverse events, and
the adverse events other than the serious adverse events can be
defined as non-serious adverse events.
1) those leading to death (death); 2) those threatening life (risks
of death); 3) those in need of hospitalization for the treatment or
extension of the hospitalization period (hospitalization or
extension of the hospitalization period); 4) those suffering from
persistent or marked disorders or dysfunctions (disorders); 5)
those having congenital aberrancy (congenital aberrancy); and 6)
other medically important conditions (risks of disorders,
seriousness in accordance with the above 1) to 4)).
[0179] In addition, in addition to the seriousness and the
cause-and-effect relationships, the adverse events can be roughly
classified by the levels of the adverse events. For example, the
following three levels can be considered.
1) low-level: a level that is transient and easily durable; 2)
mid-level: a level that has some hindrances in an ordinary
activity; and 3) high-level: a level that makes it impossible to
perform an ordinary activity.
[0180] Alternatively, the adverse events can also be classified in
terms of the outcomes of treatment as, for example, being
recovered/resolved, recovering/resolving, being not recovered/not
resolved, being recovered/resolved with sequelae, being dead, and
unknown, from the viewpoint of changes in the time course.
[0181] The method when a certain drug is compared with a different
drug in safety is not particularly limited. For example, a certain
adverse event is remarked, and the comparisons can be made with
respect to expression frequency, seriousness, cause-and-effect
relationship, the outcomes of treatment, and/or levels.
Alternatively, both the drugs can be compared from the viewpoint of
administration discontinuation caused by the entire or a part of
the adverse events or the entire or part of the side effects.
[0182] The adverse events can include abnormality in clinical test
values and vital signs.
[0183] The adverse events are not particularly limited, and can be
classified according to the System Organ Class (SOC). The System
Organ Class in connection with the adverse events is exemplified by
the following.
1) infections and infestations; 2) gastrointestinal disorders; 3)
musculoskeletal and connective tissue disorders; 4) injury,
poisoning and procedural complications; 5) general disorders and
administration site conditions (general and systemic disorders and
administration site conditions); 6) skin and subcutaneous tissue
disorders; 7) nervous system disorders; 8) respiratory, thoracic
and mediastinal disorders; 9) eye disorders; 10) metabolism and
nutrition disorders; 11) investigations (investigational studies);
12) neoplasms benign, malignant and unspecified (incl cysts and
polyps); 13) ear and labyrinth disorders; 14) cardiac disorders;
and 15) vascular disorders.
[0184] The adverse events classified as the "infections and
infestations" can be exemplified by epipharingitis and influenza.
The adverse events classified as the "nervous system disorders" can
be exemplified by headaches and free-floating dizziness. The
adverse events classified as the "respiratory, thoracic and
mediastinal disorders" can be exemplified by inflammations in the
upper airway. The adverse events classified as the
"gastrointestinal disorders" can be exemplified by nausea,
vomiting, constipation, or the like. The adverse events classified
as the "skin and subcutaneous tissue disorders" can be exemplified
by eczema. The adverse events classified as the "musculoskeletal
and connective tissue disorders" can be exemplified by
osteoarthritis. The adverse events classified as the "general and
systemic disorders and administration site conditions" can be
exemplified by malaise, bleeding at injected sites, and
fervescence. The adverse events classified as the "injury,
poisoning and procedural complications" can be exemplified by
contusion.
[0185] As mentioned above, it has been also reported that nausea,
vomiting, headaches, or the like is often observed by the
administration of teriparatide acetate (Non-Patent Publication 9).
In addition, in clinical tests using a daily administered
preparation containing teriparatide or a salt as an active
ingredient, it has been reported that dizziness is significantly
high as compared to that of the placebo group (Non-Patent
Publication 9). Further, it has also known to show shocks, or
unconsciousness or the like accompanying a transient drastic blood
pressure drop, from immediately after the administration to several
hours of a daily administered preparation or a once-weekly
administered preparation, each containing teriparatide or a salt
thereof as an active ingredient (Non-Patent Publications 4 and
8).
[0186] Therefore, in the treatment or prevention in the present
invention, an embodiment in which the expression frequency, the
seriousness, and/or the levels of at least any one of the adverse
effects or side effects out of adverse events or side effects such
as nausea, vomiting, headaches, or the like, (free-floating)
dizziness, shocks, a pressure drop, or unconsciousness is inhibited
as much as possible is preferred.
(10-2) Therapeutic Continuality:
[0187] As mentioned above, in general, it has been reported that
the drug ingestion situations in drug therapies for osteoporosis
are such that 52.1% of the individuals undesirably drop out from
the ingestion within 5 years after the beginning of the treatment,
and there are some disadvantages addressed to the lowering in the
inhibition of bone fractures, the increase in needs of use of
facilities, and stagnancy in medical cost reductions due to lack of
compliance to drug ingestions (Non-Patent Publication 9). Factors
associated with the failure to the compliance to the drug
ingestions are exemplified by the presence of pains, side effects,
drugs ingested for gastrointestinal disorders, and the like
(Non-Patent Publication 9). On the other hand, the preparation
containing teriparatide or a salt thereof as an active ingredient
has been addressed in the lowness in the therapeutic continuality,
and it has been reported that the therapeutic continuality rate
over a period of 12 months is 34.9% (Non-Patent Publication
22).
[0188] Therefore, providing a drug therapy with teriparatide or a
salt thereof, the therapy exhibiting an even higher therapeutic
continuality rate is considered to have a publicly high
significance in social welfare and medicinal economy beyond the
living improvements in the individual patients.
[0189] In view of the above, in the treatment or prevention in the
present invention, an embodiment showing a high therapeutic
continuality rate is preferred.
EXAMPLES
[0190] The present invention will be described more specifically
hereinbelow by means of Working Examples, without intending to bind
the present invention to those following Working Examples, and can
be carried out in any embodiments within the range which does not
depart from the spirit of the present invention.
Working Example 1
[0191] 1. Test Method:
[0192] Test individuals were randomly assigned to either one of
Test Drug Group and Control Drug Group. As shown in FIG. 3, each
test individual of Test Drug Group was subcutaneously administered
with a test drug and a control drug placebo, and each test
individual of Control Drug Group was subcutaneously administered
with a control drug and a test drug placebo, over 48 weeks in
accordance with a double blind method (a double dummy method). In
addition, the test individuals of both the groups ingested two
tablets of a standard concomitant drug at a frequency of once a day
after an evening meal.
[0193] In a case where each test individual uses an osteoporosis
therapeutic agent within 8 weeks before the obtainment of the
consent for the investigational studies, those test individuals
were subjected to a washout. Upon washout, the following day of a
final ingestion or the day of injection of the previous therapeutic
agent for the treatment of osteoporosis is defined as Day 1 of
washout, and it is considered to be acceptable if the beginning day
of the investigational studies with the investigational product is
on or after 8 weeks (56 days) of the washout. However, as a general
rule, the beginning of the treatment with an investigational
product did not exceed 12 weeks (84 days) from the obtainment of
the consent.
[0194] When a physician in charge of the investigational studies or
a contributory physician of the investigational studies
discontinued the investigational studies for the test individuals
when it was acknowledged that test individuals met given criteria
after the beginning of the treatment with an investigational
product. The given criteria were adverse events, lack of effects,
impossibility of tracking studies, judgments by the physician in
charge of the investigational studies or the contributory physician
of the investigational studies, serious departure from the protocol
of the investigational studies, compliance failures to the
administration of an investigational product, proffers by test
individuals, or judgments of the individuals that requested for the
investigational studies.
[0195] 1.1. Test Drug:
[0196] A test drug was an auto-injector preparation containing 0.2
g of a drug solution in one shot, and when an entire amount of a
single shot of the preparation was administered, 28.2 .mu.g in
terms of teriparatide (30.3 .mu.g in terms of teriparatide acetate)
was administered. The drug solution is previously filled in a
prefilled syringe with a needle incorporated in the auto-injector,
the auto-injector being a tool used in subcutaneous injection of a
drug solution to human bodies.
[0197] 1.2. Test Drug Placebo:
[0198] A test drug placebo is an auto-injector preparation which is
not distinguishable in external comparison from a test drug, the
preparation not substantially containing teriparatide.
[0199] 1.3. Control Drug:
[0200] A control drug is a vial preparation, which is a
freeze-dried preparation for injection containing 63.3 .mu.g in
terms of teriparatide (67.9 .mu.g in terms of teriparatide acetate)
in one vial. Here, a control drug is a preparation with which 56.5
.mu.g in terms of teriparatide is administered, when a drug
solution obtained by adding 1 mL of Japanese Pharmacopoeia
physiological saline to the drug to dissolve is administered with a
syringe.
[0201] 1.4. Control Drug Placebo:
[0202] A control drug placebo is a freeze dried preparation for
injection which is not distinguishable in external comparison from
a test drug, the preparation not substantially containing
teriparatide.
[0203] 1.5. Standard Concomitant Drug:
[0204] A standard concomitant drug is a calcium preparation
formulated with vitamin D.sub.3 and magnesium (New CALCICHEW
(registered trademark) D.sub.3; manufactured and sold by Nitto
Pharmaceutical Industries, Ltd., and sold by Takeda Pharmaceuticals
Company, Limited). Two tablets of the standard concomitant drug
contain precipitated calcium carbonate 1,525 mg (610 mg, in terms
of calcium), magnesium carbonate 118.4 mg (30 mg, in terms of
magnesium), cholecalciferol 400 IU (vitamin D.sub.3), and various
additives.
[0205] 1.6. Frequency of Twice a Week:
[0206] The intervals of administration at a frequency of twice a
week are, in principle, three-day to four-day-intervals (two day-
or three day-intervals between administrations). The intervals of
administration (three day- or four day-interval) in principle as
used herein mean that when the day of administration of either one
of administration out of the two consecutive administrations was
defined as Day 1, the day of the other administration was Day 4 or
Day 5. For example, when administered on Monday of a certain week,
the next day of administration would be, in principle, on Thursday
or Friday, as shown below.
(One Example of Administration Intervals in General Rule)
[0207] Monday, Day 1, administered
Tuesday, Day 2
Wednesday, Day 3
[0208] Thursday, Day 4 or Friday, Day 5, administered
[0209] 1.7. Test Individuals:
[0210] Test individuals were osteoporosis patients with all of the
three bone fracture risk factors of "aging," "prevalent bone
fractures," and "low bone mineral density." More specifically, test
individuals were patients with primary osteoporosis that satisfied
all the following conditions (1) to (6) (satisfying the selected
criteria), but did not satisfy any one of the following conditions
(7) to (25) (satisfying the exclusion criteria). Since the test
individuals are osteoporosis patients with all of the three bone
fracture risk factors of "aging," "prevalent bone fractures," and
"low bone mineral density" (satisfying the following conditions (2)
to (4)), the test individuals are osteoporosis patients with high
risks of bone fractures.
[0211] [1] Selected Criteria:
(1) patients diagnosed as primary osteoporosis on the basis of
Genpatsusei Kotsusoshoshou no Shindan Kijun (Diagnostic Criteria
for Primary Osteoporosis) (Revised edition of the fiscal year of
2012); (2) men and women of ages 65 years or older at the time of
the obtainment of the consent; (3) patients with prevalent bone
fractures of one or more and within five at Th4 to L4 vertebrae
(fourth thoracic vertebra to fourth lumbar vertebra) of the
centrum; (4) patients with a bone mineral density at lumbar
vertebrae (L2 to L4) less than 80% of a young adult mean at the
time of provisional registration; (5) self-ambulatory outpatients;
and (6) patients that have learned self-injection techniques before
the initial administration of a test drug or the like, so that a
physician in charge of the investigational studies or a
contributory physician of the investigational studies judged that
the patients are competent of managing and administering a test
drug or the like.
[0212] [2] Exclusion Criteria:
(7) patients diagnosed as secondary osteoporosis; (8) patients with
diseases showing the loss in bone mass other than osteoporosis; (9)
patients having the following X-ray findings which are considered
to influence in the assessment of bone mineral density of lumbar
vertebrae: [0213] found to have a high level of bone fractures of
lumbar vertebrae in any one of lumbar vertebrae L2 to L4; [0214]
found to have a high level of osteosclerosis in any one of lumbar
vertebrae L2 to L4; [0215] found to have a high level of scoliosis,
lordosis, or kyphosis; [0216] found to have a high level of changes
in spondylitis deformans; and [0217] others that the bone
assessment committee members judged as inappropriate such as
admixture of foreign matters.
[0218] Here, the "bone assessment committee members" refer to
committee members which constitute "the bone assessment committee"
which has been founded for the purpose of equally assessing the
assessment of bone mass and the assessment of bone fractures of all
the patients. Each of the assessment committee members is
constituted by experts of imaging diagnosis for osteoporosis.
(10) patients to which a surgery of the centrum is previously
operated; (11) patients that are appealing for acute pains so as to
be in suspect of vertebral bone fractures {patients with expressing
or intensifying acute lumbago or backache from a period of 12 weeks
(84 days) before the obtainment of the consent to the beginning day
of treatment that need resting and additional therapy such as an
antiphlogistic painkiller}; (12) patients that were judged to have
low reliability of diagnosis by physician's inquiries on conditions
of patients (at least patients with cognitive impairment being
excluded); (13) patients with serious renal diseases, hepatic
diseases, or cardiac diseases (provided that the term "serious
renal diseases" as used herein means those showing a serum
creatinine value by a test defined before provisional registration
of 2 mg/dL or more, the term "serious hepatic diseases" means those
showing AST(GOT) or ALT(GPT) value by a test defined before
provisional registration of 2.5 times or more the upper limit of
the standard value or 100 IU/L or more, and the term "serious
cardiac diseases" means those that are judged in reference to grade
2 shown in "Iyakuhin no Fukusayo no Jutokudo Bunrui Kijun nitsuite
(Classification Criteria for Degree of Seriousness of Side Effects
of Pharmaceuticals) (Yaku-an hatsu (PSEHB/PSD Notification) No. 80
dated Jun. 29, 1992)." (14) patients with physical constitutions
that are likely to cause hypersensitivity symptoms such as
bronchial asthma and rashes (erythema, wheal, and the like); (15)
patients with a serum calcium value of 11.0 mg/dL or more according
to a test defined before provisional registration; (16) patients
with an alkaline phosphatase value of double or more of the upper
limit of the standard values according to a test defined before
provisional registration; (17) patients with Paget's disease of the
bone; (18) patients with complications or prevalence of primary
malignant osteocarcinoma or metastatic osteocarcinoma; (19)
patients with complications of malignant osteocarcinoma or with
prevalence within the past 5 years; (20) patients who were
subjected to radiotherapy which is considered to influence the
bones in the past; (21) patients subjected to administration of a
teriparatide preparation or an anti-RANKL antibody preparation in
the past; (22) patients subjected to administration of a
bisphosphonate preparation within 52 weeks (364 days) before the
obtainment of the consent (however, in a drug which is set to have
a certain period of intervals in the usage of the drug, the number
of days are the 52 weeks (364 days) before the obtainment of the
consent added with the period); (23) patients administered with
other investigational products within 26 weeks (182 days) before
the obtainment of the consent; (24) patients subjected to
administration of the following (A) to (G) osteoporosis therapeutic
agents on the day of obtainment of the consent (however, patients
are considered as selectable as subjects if it is possible to
perform washout of 8 weeks (56 days) or more before the beginning
of the treatment (meaning a resting drug for the purpose of
eliminating the influences of the previous therapeutic agent):
[0219] (A) a calcitonin preparation;
[0220] (B) an active vitamin D.sub.3 preparation;
[0221] (C) a vitamin K preparation;
[0222] (D) an ipriflavone preparation;
[0223] (E) an estrogen preparation;
[0224] (F) an SERM preparation; and
[0225] (G) an anabolic hormone preparation; and
(25) Other patients that a physician in charge of the
investigational studies or a contributory physician of the
investigational studies judged to be inappropriate in carrying out
the present investigational studies.
[0226] 1.8. Administration to Test Drug Group and Control Drug
Group:
[0227] Test individuals were randomly assigned to either one of
Test Drug Group and Control Drug Group. As shown in FIG. 3, each
test individual of Test Drug Group was subcutaneously administered
with a test drug and a control drug placebo, and each test
individual of Control Drug Group was subcutaneously administered
with a control drug and a test drug placebo, over 48 weeks in
accordance with a double blind method (a double dummy method). In
addition, the test individuals of both the groups ingested two
tablets of a standard concomitant drug at a frequency of once a day
after an evening meal.
[0228] Each patient assigned to Test Drug Group was subcutaneously
injected with a single shot of a test drug twice a week
(self-injected at any one of sites of upper arm parts, femur parts,
and abdominal parts). The intervals of administration in a general
rule were three to four days (two day- or three day-intervals
between administrations). Further, the same patients were
subcutaneously injected once a week (injected upon visits to
medical institutions) with a solution obtained by dissolving one
vial of a control drug placebo in 1 mL of Japanese Pharmacopoeia
physiological saline upon use.
[0229] Each patient assigned to Control Drug Group was
subcutaneously injected with a single shot of a test drug placebo
twice a week (self-injected at any one of sites of upper arm parts,
femur parts, and abdominal parts). Further, the same patients were
subcutaneously injected once a week (injected upon visits to
medical institutions) with a solution obtained by dissolving one
vial of a control drug in 1 mL of Japanese Pharmacopoeia
physiological saline upon use.
[0230] The main assessment item for the efficacies of the test was
a change rate in bone mineral densities of lumbar vertebrae (second
to fourth lumbar vertebrae).
[0231] The subsidiary assessment items for the efficacies of the
test were a change rate in femoral bone mineral densities, a change
rate in bone mineral densities of lumbar vertebrae (first to fourth
lumbar vertebrae), an incidence rate of new vertebral bone
fractures, an incidence rate of worsening vertebral bone fractures,
incidence rates of (new and worsening) vertebral bone fractures,
incidence rates of clinical bone fractures (clinical vertebral bone
fractures and non-vertebral bone fractures), an incidence rate of
vulnerable clinical bone fractures, an incidence rate of vulnerable
non-vertebral bone fractures, and bone metabolism markers.
[0232] The safety assessment items for the test were adverse
events, vital signs, clinical tests, and immunogenicity.
[0233] 1.9. Measurement of Change Rate in Bone Mineral
Densities:
[0234] The methods for measuring each of change rates in bone
mineral densities of the bone mineral densities of lumbar vertebrae
and the femoral bone mineral densities are shown in the following
Table 1-1.
TABLE-US-00001 TABLE 1-1 Bone mineral density Femoral bone mineral
of lumbar vertebrae density Person taking A physician in charge of
the investigational studies or a contributory measurement physician
of the investigational studies Timing of The beginning day of
treatment, after 24 weeks, after 48 weeks, and measurement at
discontinuation Measurement First to fourth lumbar vertebrae
Femoral proximal part is sites subjected to incycloduction at 20
degrees, and the measurement is only taken on a left side (the
measurement is taken on a right side if the left side is
immeasurable in connection with any prevalence or the like). The
measurement site is taken from the same side throughout the
investigational study period. Measurement Bone mineral content
(BMC; g), Bone mineral content (BMC; g), indices bone area
(cm.sup.2), bone mineral bone area (cm.sup.2), bone mineral density
(BMD; g/cm.sup.2) at each of density (BMD; g/cm.sup.2) of femoral
the first to fourth lumbar proximal total and femoral neck
vertebrae part Measurement In the same test individuals, the
identical sites are measured by the machine type same machine type
and the same scan mode throughout the investigational study
period.
[0235] 1.10. Assessment of Vertebral Bone Fractures:
[0236] The methods for assessing vertebral bone fractures are shown
in the following Table 1-2.
TABLE-US-00002 TABLE 1-2 X-ray A physician in charge of the
investigational studies or photographer a contributory physician of
the investigational studies Subjects to be Thoracic vertebrae and
lumbar vertebrae X-ray photographed Timing of X-ray The beginning
day of treatment, after 24 weeks, after photographing 48 weeks, and
at discontinuation Assessment of An X-ray photograph at the
beginning of treatment vertebral bone from fourth thoracic vertebra
to fourth lumbar vertebra fractures is compared with an X-ray
photograph after the time course of a period. When normal centrum
at the time point of the beginning of treatment is caused to be
deformed after time course of a period and found to have a
morphological fracture, it is defined as a new vertebral fracture.
In addition, an X-ray photograph at the beginning of treatment from
fourth thoracic vertebra to fourth lumbar vertebra is compared with
an X-ray photograph after time course of a period. When deformed
centrum already found at the time point of the beginning of
treatment is again caused to be deformed after the time course of a
period and found to have a morphological fracture, it is defined as
a worsening vertebral fracture. The above judgment is carried out
by the bone assessment committee in accordance with separately
ordained judgment criteria in reference to a method of Genant et
al, a method of Wu et al., and a method of Fukunaga et al.
(Non-Patent Publications 11 to 13).
[0237] 1.11. Assessment of Clinical Bone Fractures (Clinical
Vertebral Bone Fractures and Non-Vertebral Bone Fractures):
[0238] In a case where the test individuals appealed (for clinical
symptoms) up to 48 weeks (at discontinuation) after the beginning
of treatment and a physician in charge of the investigational
studies or a contributory physician of the investigational studies
confirmed the bone fractures by an X-ray photograph, MRI or the
like, the test individuals were diagnosed as clinical bone
fractures. In particular, in a case where test individuals appealed
for acute pains at the lower back parts or back parts, an X-ray
photograph was taken to confirm the presence or absence of the bone
fractures.
[0239] The contents of assessment were the incidence date of bone
fractures (the day a test individual developed the clinical
symptoms), bone fracture sites (the centrum, femoral proximal
parts, radius, upper arm bone, and others), the presence or absence
of a large external force, the bases of judgment for the bone
fractures (X-ray photographing, MRI, the information from other
service departments or other medical institutions, and others), and
the date of photographing X-ray or MRI.
[0240] 1.12. Test of Bone Metabolism Markers:
[0241] The methods for testing bone metabolism markers are shown in
the following Table 1-3.
TABLE-US-00003 TABLE 1-3 Timing of Test The beginning day of
treatment, after 4 weeks, after 12 weeks, after 24 weeks, after 48
weeks, and at discontinuation (treatment period) Test items Blood
Bone formation Osteocalcin, P1NP marker Bone resorption NTX, CTX
tests Others Calcium, inorganic phosphorus, albumin,
25-hydroxyvitamin D fractions Urine Bone formation NTX marker
Others Calcium, inorganic tests phosphorus, creatinine
[0242] 1.13. Studies on Adverse Events:
[0243] A physician in charge of the investigational studies or a
contributory physician of the investigational studies studied on
adverse events by voluntary reports from the test individuals,
diagnosis by physician's inquiries on conditions of patients, and
various tests, over a period from the day of the obtainment of the
consent from each test individual to one week after the final day
of administration.
[0244] The study items were the name of adverse events, the
incidence date, the situations of administration of an
investigational product, the day of disappearance, the outcomes of
treatment, the classifications of degrees of seriousness, the
reasons of seriousness, the levels, the cause-and-effect
relationships between the investigational product and a standard
concomitant drug, and when the adverse events were caused in the
injected sites, the sites thereof, and the presence or absence of
the discontinuation of the investigational studies.
[0245] 1.14. Measurements of Vital Signs:
[0246] The methods for measuring vital signs are shown in the
following Table 1-4.
TABLE-US-00004 TABLE 1-4 Person taking A physician in charge of the
investigational studies or a measurement contributory physician of
the investigational studies Measurement Sitting systolic blood
pressure, sitting diastolic blood items pressure, pulse rate Timing
of The beginning day of treatment, after 4 weeks, after 12
measurement weeks, after 24 weeks, and after 48 weeks Time of
Before administration of an investigational product, 10 measurement
minutes after the administration (allowable range .+-. 5 minutes),
before coming home (to be in the course of one or more hours after
the administration of an investigational product if at all
possible)
[0247] 1.15. Clinical Test:
[0248] The method for a clinical test is shown in the following
Table 1-5.
TABLE-US-00005 TABLE 1-5 Collection of Collection of analytes
(blood and urine) before analytes administration of an
investigational product on each test day Timing of test The
beginning day of treatment, after 4 weeks, after 12 weeks, after 24
weeks, after 48 weeks, and at discontinuation (treatment period)
Test items Blood general Red blood cell count test Hemoglobin
Hematocrit White blood cell count White blood cell count fraction
Platelet count Blood AST (GOT) biochemical ALT(GPT) test Alkaline
phosphatase Total cholesterol Urea nitrogen Uric acid Creatinine
CPK Calcium Inorganic phosphorus Sodium Potassium Chlorine Albumin
Urine test Occult blood (qualitative) Protein (qualitative) Sugar
(qualitative) Urobilinogen (qualitative) Bilirubin (qualitative)
pH
[0249] 1.16. Assessment of Immunogenicity:
[0250] A physician in charge of the investigational studies or a
contributory physician of the investigational studies collected
analytes (blood) before the administration of an investigational
product on the day of each test, and stored. An anti-drug antibody
against the investigational product was measured after the
collection of analytes. Only those analytes in which the anti-drug
antibody was positive were measured for a neutralizing
antibody.
[0251] 2. Test Results:
2.1. Subjects to be Analyzed for Efficacies:
[0252] Test individuals that expressed the consent of the treatment
were 859 people, out of which 553 people registered for the
investigational studies and received the treatment, in which 76
people discontinued the treatment and 477 people completed the
treatment. Of those 553 people that received the treatment, the
backgrounds (outline) of 551 people which were subjects to be
analyzed for the efficacies are shown in the following Table 2-1.
Table 2-1 shows that there are no large imbalances in backgrounds
between Test Drug Group and Control Drug Group, so that the risks
of bone fractures would be probably nearly of the same level.
TABLE-US-00006 TABLE 2-1 Backgrounds (outline) of the subjects to
be analyzed for efficacie Number of Number of Test Drug Control
Drug Group (%) Group (%) Number of patients 275 276 Gender Male 23
(8.4) 25 (9.1) Female 252 (91.6) 251 (90.9) Age 65 .ltoreq. Age
< 70 69 (25.1) 72 (26.1) 70 .ltoreq. Age < 80 158 (57.5) 144
(52.2) 80 .ltoreq. Age 48 (17.5) 60 (21.7) Mean 74.1 74.5 Height
(cm) Height < 140 10 (3.6) 12 (4.3) 140 .ltoreq. Height < 150
112 (40.7) 117 (42.4) 150 .ltoreq. Height < 160 133 (48.4) 125
(45.3) 160 .ltoreq. Height 20 (7.3) 22 (8.0) Mean 151.12 150.78
Body weight (kg) Body weight < 40 19 (6.9) 15 (5.4) 40 .ltoreq.
Body weight < 50 125 (45.5) 106 (38.4) 50 .ltoreq. Body weight
< 60 113 (41.1) 120 (43.5) 60 .ltoreq. Body weight 18 (6.5) 35
(12.7) Mean 50.18 51.23 Body mass index BMI < 18.5 30 (10.9) 25
(9.1) (BMI) (kg/m.sup.2) 18.5 .ltoreq. BMI < 25.0 208 (75.6) 196
(71.0) 25.0 .ltoreq. BMI 37 (13.5) 55 (19.9) Mean 21.97 22.54
Number of years Number of years < 10 1 (0.4) 0 (0.0) passed
after 10 .ltoreq. Number of years < 20 66 (24.0) 65 (23.6)
menopause 20 .ltoreq. Number of years 185 (67.3) 186 (67.4) Mean
24.1 25.0 History of treatment Presence 119 (43.3) 127 (46.0) of
osteoporosis Absence 156 (56.7) 149 (54.0) Number of prevalent 1
156 (56.7) 147 (53.3) vertebral bone 2 to 3 100 (36.4) 115 (41.7)
fractures at 4 to 5 19 (6.9) 14 (5.1) registration Bone mineral
Mean 65.3 65.7 densities of lumbar vertebrae (L2-L4) on the basis
of YAM (%)
2.2. Mean of Number of Administrations and Mean of Administration
Period:
[0253] The mean of the number of administrations and the mean of
the administration period in 553 individuals who received treatment
are shown in Tables 2-2 and 2-3. Here, as to the mean of the number
of administrations, a tested individuals that were previously
administered with a test drug as an actual drug (MN-10-T AI) were
administered with a control drug placebo (MN-10-T Placebo), and
test individuals that were previously administered with a control
drug as an actual drug (MN-10-T) were administered with a test drug
placebo (MN-10-T AI Placebo) (FIG. 29). Therefore, the mean of the
number of administrations of the four agents, a test drug actual
drug, a control drug placebo, a test drug placebo, and a control
drug actual drug, is calculated.
TABLE-US-00007 TABLE 2-2 Mean of number of administrations (times)
Mean of number of administrations Test Drug Group Test drug actual
drug 81.9 Control drug placebo 41.1 Control Drug Group Test drug
placebo 80.1 Control drug actual drug 40.1
TABLE-US-00008 TABLE 2-3 Mean of administration period (weeks) Mean
of administration period Test Drug Group 43.9 Control Drug Group
42.8
[0254] It was considered that there were no significant differences
in the mean of the number of administrations when the test drug
actual drug of Test Drug Group was compared with the test drug
placebo of Control Drug Group, and the control drug placebo of Test
Drug Group was compared with the control drug actual drug of
Control Drug Group.
[0255] It was considered that there were no differences in the mean
of the administration period between Test Drug Group and Control
Drug Group. Here, the reasons why some did not reach 48 weeks are
in that examples that were discontinued in the course were
included.
2.3. Time Transition of Mean Value of Change Rate in Bone Mineral
Densities of Each of Lumbar Vertebrae, Femoral Neck Part, and
Femoral Proximal Total:
[0256] The time transitions of the mean value of a change rate in
bone mineral densities of each of lumbar vertebrae (second to
fourth lumbar vertebrae), lumbar vertebrae (first to fourth lumbar
vertebrae), a femoral neck part, and a femoral proximal total in
the subjects to be analyzed for the efficacies are shown in the
following Tables 2-4 to 2-7. The numerical values in the tables
show a mean value of a change rate (%) from the beginning.
[0257] In addition, the time transitions of the mean value of a
change rate in bone mineral densities of lumbar vertebrae (second
to fourth lumbar vertebrae) in the subjects to be analyzed for the
efficacies are shown in FIG. 4.
TABLE-US-00009 TABLE 2-4 Time transitions of the mean value of
change rate (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) After 24 weeks After 48 weeks
at Final Test Drug Group 5.0** 7.5** 7.3** Control Drug Group 3.8
6.0 5.9 **: p < 0.01 (Statistical analysis results in accordance
with a t-test student)
TABLE-US-00010 TABLE 2-5 Time transitions of the mean value of
change rate (%) in bone mineral densities of lumbar vertebrae
(first to fourth lumbar vertebrae) After 24 weeks After 48 weeks at
Final Test Drug Group 4.8** 7.2** 7.1** Control Drug Group 3.5 5.5
5.4 **: p < 0.01
TABLE-US-00011 TABLE 2-6 Time transitions of the mean value of
change rate (%) in bone mineral densities of femoral neck part
After 24 weeks After 48 weeks at Final Test Drug Group 1.6 2.1 2.0
Control Drug Group 1.0 1.4 1.4
TABLE-US-00012 TABLE 2-7 Time transitions of the mean value of
change rate (%) in bone mineral densities of femoral proximal total
After 24 weeks After 48 weeks at Final Test Drug Group 1.3 1.8 1.8
Control Drug Group 1.0 1.3 1.3
[0258] The treatment with a test drug showed high increase rates in
all of the bone mineral density of lumbar vertebrae, the bone
mineral density of the femoral neck part, and the bone mineral
density of femoral proximal total, as compared to those treatment
with a control drug. Especially, it was significantly high in the
bone mineral densities of lumbar vertebrae.
[0259] When the treatment with a test drug was compared with the
treatment with a control drug, it is considered that the dosage of
teriparatide per week is substantially of the same level. On the
other hand, it has been reported that the bone mineral density and
the bone strength increase in accordance with the dosage of
teriparatide per week (Non-Patent Publication 14). Therefore, it
was considered that the results which can be thought to be
significant in the comparisons between the treatment with a test
drug and the treatment with a control drug can be clearly
distinguished from the conventional medical techniques.
[0260] The subjects to be analyzed for the efficacies were divided
into subgroups in which the bone mineral densities of lumbar
vertebrae (second to fourth lumbar vertebrae) at the beginning or
the number of prevalent vertebral bone fractures was used as an
index. The results of analyzing the mean value of a change rate in
the bone mineral densities of lumbar vertebrae (second to fourth
lumbar vertebrae) at final are shown in the following Tables 2-8
and 2-9. The numerical values in the tables show a mean value of a
change rate (%) from the beginning.
TABLE-US-00013 TABLE 2-8 Mean value of change rate in bone mineral
densities of lumbar vertebrae (second to fourth lumbar vertebrae)
at final classified by bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) from the beginning Bone mineral
densities of lumbar vertebrae Test Drug Group Control Drug Group
(second to fourth Mean value Mean value lumbar vertebrae) No. of of
change No. of of change (%, YAM ratio) cases rate (%) cases rate
(%) Less than 60 74 9.4 61 8.2 60 Or more and less than 93 7.0 89
5.4 70 70 Or more and less than 79 5.9 87 5.0 80
TABLE-US-00014 TABLE 2-9 Mean value of change rate in bone mineral
densities of lumbar vertebrae (second to fourth lumbar vertebrae)
at final classified by the number of prevalent vertebral bone
fractures Test Drug Group Control Drug Group No. of Mean value of
Mean value of prevalent No. of change rate No. of change rate
fractures cases (%) cases (%) 1 138 7.8 128 5.9 2 to 3 95 6.9 101
6.2 4 to 5 18 5.4 10 4.6
[0261] It has been reported that the risks of the vertebral bone
fractures would be 2.3 times by a decrease in the bone mineral
densities of lumbar vertebrae by 1 SD (Non-Patent Publication
9).
[0262] The increase in the bone mineral densities of lumbar
vertebrae by the administration was analyzed using the bone mineral
densities of lumbar vertebrae at the beginning or the number of
prevalent vertebral bone fractures as an index. As a result, the
increase in the bone mineral densities of lumbar vertebrae by the
administration showed the tendency of being high along with the
decrease in the bone mineral densities of lumbar vertebrae at the
beginning, and conversely the increase in the bone mineral
densities of lumbar vertebrae by the administration showed the
tendency of being low along with the increase in the number of
prevalent vertebral bone fractures.
[0263] The subjects to be analyzed for the efficacies were divided
into subgroups in which the value of serum osteocalcin at the
beginning was used as an index. The results of analyzing the time
transitions of the mean value of a change rate in the bone mineral
densities of lumbar vertebrae (second to fourth lumbar vertebrae)
and in the femoral neck part are shown in the following Tables 2-10
and 2-11. The numerical values in the tables show a mean value of a
change rate (%) from the beginning.
TABLE-US-00015 TABLE 2-10 Time transitions of the mean value of
change rate (%) in bone mineral densities of lumbar vertebrae
(second to fourth lumbar vertebrae) After After Serum osteocalcin
(OC) 24 weeks 48 weeks at Final concentration (ng/mL) (no. of (no.
of (no. of at beginning cases) cases) cases) Test OC conc. <
15.2 3.9 5.1 5.3 Drug (84) (82) (85) Group 15.2 .ltoreq. OC conc.
< 21.8 4.5 6.9 6.7 (79) (74) (82) 21.8 .ltoreq. OC conc. 6.5
10.6 9.9 (82) (75) (84) Control OC conc. < 14.8 1.7 3.1 3.1 Drug
(76) (74) (78) Group 14.8 .ltoreq. OC conc. < 21.9 3.6 6.1 6.0
(78) (75) (82) 21.9 .ltoreq. OC conc. 5.9 8.8 8.7 (79) (75)
(79)
TABLE-US-00016 TABLE 2-11 Time transitions of the mean value of
change rate (%) in bone mineral densities of femoral neck part
After After Serum osteocalcin (OC) 24 weeks 48 weeks at Final
concentration (ng/mL) (no. of (no. of (no. of at beginning cases)
cases) cases) Test OC conc. < 15.2 1.0 1.4 1.4 Drug (85) (83)
(86) Group 15.2 .ltoreq. OC conc. < 21.8 1.5 1.9 1.8 (84) (80)
(87) 21.8 .ltoreq. OC conc. 2.3 3.1 2.9 (84) (77) (85) Control OC
conc. < 14.8 0.3 0.2 0.1 Drug (79) (76) (81) Group 14.8 .ltoreq.
OC conc. < 21.9 0.9 1.2 1.2 (79) (77) (84) 21.9 .ltoreq. OC
conc. 2.0 2.9 2.8 (84) (78) (84)
[0264] The subjects to be analyzed for the efficacies were divided
into subgroups in which the value of blood P1NP at the beginning
was used as an index. The results of analyzing the time transitions
of the mean value of a change rate in the bone mineral densities of
lumbar vertebrae (second to fourth lumbar vertebrae) and the
femoral neck part are shown in the following Tables 2-12 and 2-13.
The numerical values in the tables show a mean value of a change
rate (%) from the beginning.
TABLE-US-00017 TABLE 2-12 Time transitions of mean value of change
rate (%) in bone mineral densities of lumbar vertebrae (second to
fourth lumbar vertebrae) Serum P1NP After After concentration 24
weeks 48 weeks at Final (.mu.g/L) (no. of (no. of (no. of at
beginning cases) cases) cases) Test P1NP conc. < 38.0 3.4 4.9
4.9 Drug (79) (76) (82) Group 38.0 .ltoreq. P1NP conc. < 58.5
4.8 7.4 7.2 (86) (83) (87) 58.5 .ltoreq. P1NP conc. 6.7 10.2 9.8
(80) (72) (82) Control P1NP conc. < 37.4 2.1 3.4 3.4 Drug (78)
(75) (80) Group 37.4 .ltoreq. P1NP conc. < 57.3 3.2 5.4 5.5 (78)
(76) (80) 57.3 .ltoreq. P1NP conc. 6.0 9.3 9.0 (77) (73) (79)
TABLE-US-00018 TABLE 2-13 Time transitions of mean value of change
rate (%) in bone mineral densities of femoral neck part Serum P1NP
After After concentration 24 weeks 48 weeks at Final (.mu.g/L) (no.
of (no. of (no. of at beginning cases) cases) cases) Test P1NP
conc. < 38.0 0.5 1.4 1.4 Drug (81) (78) (84) Group 38.0 .ltoreq.
P1NP conc. < 58.5 1.7 1.6 1.6 (86) (84) (87) 58.5 .ltoreq. P1NP
conc. 2.5 3.4 3.1 (86) (78) (87) Control P1NP conc. < 37.4 0.9
0.9 0.8 Drug (76) (73) (78) Group 37.4 .ltoreq. P1NP conc. <
57.3 0.2 1.1 1.0 (82) (79) (84) 57.3 .ltoreq. P1NP conc. 2.0 2.4
2.3 (84) (79) (87)
[0265] On the bases of the data of the above four tables, the
calculated results that the mean value of a change rate in bone
mineral densities at final (Test Drug Group) of the subgroup in
which the OC or P1NP concentration at the beginning was the lowest
was divided by the mean value of a change rate in bone mineral
densities at final (Control Drug Group) of the subgroup in which
the OC or P1NP concentration at the beginning was the lowest are
shown the following Table 2-14.
TABLE-US-00019 TABLE 2-14 Subgroup in which bone Subgroup in which
bone Value calculated by dividing the mean value formation marker
at formation marker at of change rate (%) in bone mineral densities
Bone beginning was lowest beginning was lowest shown at final of A
Group by the mean formation (Test Drug Group) (Control Drug Group)
value of change rate (%) in bone mineral densities marker (A Group)
(B Group) Sites of Bone shown at final of B Group OC OC Conc. <
15.2 OC Conc. < 14.8 Bone mineral densities of 1.71 (ng/mL)
(ng/mL) lumbar vertebrae (second to fourth lumbar vertebrae)
Femoral neck part 14.0 P1NP P1NP Conc. < 38.0 P1NP Conc. <
37.4 Bone mineral densities of 1.44 (.mu.g/L) (.mu.g/L) lumbar
vertebrae (second to fourth lumbar vertebrae) Femoral neck part
1.75
[0266] The treatment with a test drug was considered to be
particularly excellent from the viewpoint of the effects of
increasing the bone mineral density of femoral neck part when the
patients having relatively low blood OC concentrations (for
example, less than 15.2 (ng/mL)) were used as subjects.
2.4. Incidence Rate of Vertebral Bone Fractures:
[0267] The time transitions or the like of the incidence rate of
new vertebral bone fractures and the incidence rate of worsening
vertebral bone fractures in accordance with a Kaplan-Meier method
in the subjects to be analyzed for the efficacies are shown in
Tables 2-15 and 2-16.
TABLE-US-00020 TABLE 2-15 Time transitions or the like of incidence
rate of new vertebral bone fractures Numbers No. of cases
Accumulated incidence No. of discontinued of bone rate of bone
fractures assessed during the fracture Week 24 Week 48 cases course
incidence (%) (%) Test 259 17 3 1.2 1.2 Drug Group Control 247 16 4
1.2 1.7 Drug Group
TABLE-US-00021 TABLE 2-16 Time transitions or the like of incidence
rate of worsening vertebral bone fractures Numbers No. of cases
Accumulated incidence No. of discontinued of bone rate of bone
fractures assessed during the fracture Week 24 Week 48 cases course
incidence (%) (%) Test 259 18 1 0.0 0.4 Drug Group Control 247 16 1
0.4 0.4 Drug Group
2.5. Incidence Rate of Clinical Vertebral Bone Fractures:
[0268] The time transitions or the like of the incidence rate of
clinical vertebral bone fractures in accordance with a Kaplan-Meier
method in the subjects to be analyzed for the efficacies are shown
in the following Table 2-17.
TABLE-US-00022 TABLE 2-17 Time transitions or the like of incidence
rate of clinical vertebral bone fractures Numbers No. of cases
Accumulated incidence No. of discontinued of bone rate of bone
fractures assessed during the fractures Week 24 Week 48 cases
course incidence (%) (%) Test 275 42 3 0.7 1.2 Drug Group Control
276 52 4 1.1 1.6 Drug Group
[0269] According to the above data for the incidence rate of
vertebral bone fractures, it can be considered that the treatment
with a test drug is excellent also from the viewpoint of inhibiting
the vertebral bone fractures in general, as compared to the
treatment with a control drug.
2.6. Bone Resorption Marker:
[0270] The time transitions of the bone resorption markers in the
subjects to be analyzed for the efficacies are shown in the
following Tables 2-18 to 2-20.
TABLE-US-00023 TABLE 2-18 Time transitions of serum CTX No. of
Median value of assessed change rate (%) cases from the baseline
Test After 4 weeks 266 -22.2 Drug After 12 weeks 265 -17.1 Group
After 24 weeks 256 -21.4 After 48 weeks 243 -29.4 Control After 4
weeks 266 -15.3 Drug After 12 weeks 259 -13.0 Group After 24 weeks
248 -23.7 After 48 weeks 237 -19.4
TABLE-US-00024 TABLE 2-19 Time transitions of serum NTX No. of
Median value of assessed change rate (%) cases from the baseline
Test After 4 weeks 266 -5.9 Drug After 12 weeks 265 -5.5 Group
After 24 weeks 256 -8.8 After 48 weeks 243 -7.1 Control After 4
weeks 266 -4.1 Drug After 12 weeks 259 -3.8 Group After 24 weeks
248 -9.0 After 48 weeks 237 -8.4
TABLE-US-00025 TABLE 2-20 Time transitions of urine NTX No. of
Median value of assessed change rate (%) cases from the baseline
Test After 4 weeks 266 -16.0 Drug After 12 weeks 265 -17.9 Group
After 24 weeks 256 -30.8 After 48 weeks 243 -18.6 Control After 4
weeks 266 -12.0 Drug After 12 weeks 259 -11.4 Group After 24 weeks
248 -23.2 After 48 weeks 237 -9.1
[0271] The time transitions of the bone resorption markers
accompanying the treatment with a test drug were of the same level
or slightly inhibited, as compared to the time transitions of the
bone resorption markers accompanying the treatment with a control
drug (FIGS. 5 to 7).
[0272] Non-Patent Publication 17 has reported that the daily
administration of a test drug enhances the bone resorption markers
or the like. Further, in Non-Patent Publication 27 corroded
surfaces indicating bone resorption are found in void surfaces in
cortical bones caused by the daily administration of a test drug
(see, FIG. 7 c etc.), whereby suggesting that there is a deep
relationship between the porosity of the cortical bones and the
increase in bone resorption. In light of the contents or the like
of these publications, it is assumed that the time transitions of
the bone resorption markers in the treatment of twice a week in
this case suggests that the treatment of administration of twice a
week is a treatment that does not show an increase in bone turnover
so as to increase a void ratio of cortical bone as compared to that
of the treatment of administration of once a week.
2.7. Bone Formation Markers:
[0273] The time transitions of the bone formation markers in the
subjects to be analyzed for the efficacies are shown in the
following Tables 2-21 and 2-22.
TABLE-US-00026 TABLE 2-21 Time transitions of serum OC No. of
Median value of assessed change rate (%) cases from the baseline
Test After 4 weeks 266 45.7** Drug After 12 weeks 265 39.9** Group
After 24 weeks 256 21.8* After 48 weeks 243 6.8 Control After 4
weeks 266 29.5 Drug After 12 weeks 259 23.0 Group After 24 weeks
248 10.7 After 48 weeks 237 4.2 *Wilcoxon rank sum test p < 0.05
**Wilcoxon rank sum test p < 0.01
TABLE-US-00027 TABLE 2-22 Time transitions of serum P1NP No. of
Median value of assessed change rate (%) cases from the baseline
Test After 4 weeks 266 28.3** Drug After 12 weeks 265 12.6* Group
After 24 weeks 256 1.3 After 48 weeks 243 -1.4 Control After 4
weeks 266 17.2 Drug After 12 weeks 259 5.2 Group After 24 weeks 248
0.2 After 48 weeks 237 1.0 *Wilcoxon rank sum test p < 0.05
**Wilcoxon rank sum test p < 0.01
[0274] The time transitions of the bone formation markers
accompanying the treatment with a test drug were at high levels, as
compared to the time transitions of the bone formation markers
accompanying the treatment with a control drug (FIGS. 8 and 9). In
particular, at an early stage after the beginning of administration
(meaning herein until 12 weeks or so after the beginning of
administration), the treatment of administration of twice a week
had a significantly high change rate in the bone formation markers,
as compared to the treatment of administration of once a week. In
other words, it can be considered that an increase in bone
formation is excellent, whereby it can be thought that the
treatment of administration of twice a week possibly shows an even
larger increase rate of bone mineral density, as compared to that
of the treatment of administration of once a week.
2.8. Safety:
[0275] The following aggregate analysis was performed by defining
as test individuals subjects to be analyzed for safety who were
administered with a test drug or a control drug in the treatment
phase at least one or more times. The treatment-emergent adverse
event (TEAE) means adverse events that emerged in the treatment
phase.
2.8.1. Expression Ratios of Adverse Events and Side Effects
(Outline):
TABLE-US-00028 [0276] TABLE 2-23 Expression ratios of adverse
events and side effects No. of No. of 95% Confidence assessed
expressed Expression interval of cases cases ratio (%) Difference
difference Adverse Test 277 245 88.4 -0.7 -5.9 to 4.6 events Drug
Group Control 276 246 89.1 Drug Group Side Test 277 110 39.7 -16.4
-24.7 to -8.2 effects Drug Group Control 276 155 56.2 Drug
Group
[0277] The expression ratio for side effects by the administration
of a test drug was markedly decreased, as compared to the
expression ratio for side effects by the administration of a
control drug.
TABLE-US-00029 TABLE 2-24 Expression ratios for adverse events and
side effects relating to TEAE No. of cases No. of cases of Test
Drug of Control Drug Group (%) Group (%) TEAE Adverse events 245
(88.4) 246 (89.1) Side effects 110 (39.7)* 155 (56.2) Serious
adverse Adverse events 20 (7.2) 24 (8.7) events Side effects 1
(0.4) 4 (1.4) Other important Adverse events 16 (5.8) 27 (9.8)
adverse events Side effects 11 (4.0) 24 (8.7) *p < 0.01
[0278] The expression ratios for side effects were classified into
three, the expression ratio for side effects of TEAE, the
expression ratio for side effects of serious adverse events, and
the expression ratio for side effects of other important adverse
events to analyze. As a result, the expression ratio for side
effects by the administration of a test drug was markedly decreased
as compared to the expression ratio for side effects by the
administration of a control drug in all of the expression ratios
for side effects. The important adverse events as used herein were
defined as adverse events that resulted in being serious or in
discontinuation. In addition, the adverse events excluding "the
serious adverse events" from "the important adverse events" were
defined as "other important adverse events."
2.8.2. Expression Ratios for Adverse Events and Side Effects Having
Relatively High Expression Ratios (Nausea, Vomiting or the
Like):
TABLE-US-00030 [0279] TABLE 2-25 Expression ratios for adverse
events and side effects relating to nausea, vomiting or the like
having relatively high expression ratios Test Drug Group Control
Drug Group Rough no. of cases (%) no. of cases (%) classification
Adverse Side Adverse Side by organs events effects events effects
Nervous Headache 18 16 36 29 system (6.5)* (5.8)* (13.0) (10.5)
disorders Gastro- Nausea 60 56 92 88 intestinal (21.7)** (20.2)**
(33.3) (31.9) disorders Vomiting 33 25 38 36 (11.9) (9.0) (13.8)
(13.0) General and Malaise 28 26 35 33 systemic (10.1) (9.4) (12.7)
(12.0) disorders Fervescence 4 3 19 18 and admin- (1.4)** (1.1)**
(6.9) (6.5) istration site conditions *p < 0.05, **p <
0.01
[0280] The expression ratios for adverse events and side effects
relating to nausea, vomiting or the like having relatively high
expression rations that are common in both the groups showed a low
tendency in Test Drug Group, as compared to those of Control Drug
Group. In addition, the expression ratios for adverse events and
side effects of "headache" or "fervescence" showed a low tendency
in Test Drug Group, as compared to those of Control Drug Group.
2.8.3. Expression Ratios for Adverse Events and Side Effects for
Each Organ (Nervous System Disorders or the Like):
TABLE-US-00031 [0281] TABLE 2-26 Expression ratios for adverse
events and side effects relating to nervous system disorders or the
like for each organ Test Drug Group Control Drug Group no. of cases
(%) no. of cases (%) Rough classification Adverse Side Adverse Side
by organs events effects events effects Nervous system disorders 49
24 70 41 (17.7) (8.7) (25.4) (14.9) Gastrointestinal disorders 116
74 130 96 (41.9) (26.7) (47.1) (34.8) General and systemic 67 48 94
84 disorders and administration (24.2) (17.3) (34.1) (30.4) site
conditions Cardiac disorders 7 3 19 13 (2.5) (1.1) (6.9) (4.7)
Vascular disorders 7 2 11 5 (2.5) (0.7) (4.0) (1.8)
[0282] As a result of the aggregate analysis of the adverse events
and the side effects for each organ, the expression ratios for
adverse events and side effects showed a low tendency in Test Drug
Group, as compared to those of Control Drug Group in all the
disorders or conditions of the nervous system disorders, the
gastrointestinal disorders, the general and systemic disorders and
administration site conditions, the cardiac disorders, and the
vascular disorders.
2.8.4. Expression Ratios for Adverse Events and Side Effects
(Shocks, Blood Pressure Drop, Unconsciousness) and Change in Blood
Pressure in Time Course:
TABLE-US-00032 [0283] TABLE 2-27 Expression ratios for adverse
events and side effects relating to shocks or the like Test Drug
Group Control Drug Group no. of cases (%) no. of cases (%) Adverse
Side Adverse Side events effects events effects Events associated
with shocks 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Events associated with
blood 3 (1.1) 3 (1.1) 8 (2.9) 7 (2.5) pressure drop Events
associated with 0 (0.0) 0 (0.0) 1 (0.4) 0 (0.0) unconsciousness
[0284] As mentioned above, it has been known that shocks, or
unconsciousness accompanying a transient drastic blood pressure
drop, convulsion, or fall is found from immediately after the
administration over several hours of a daily administered
preparation or a once-weekly administered preparation of PTH
(Non-Patent Publications 4 and 8).
[0285] Here, as to the events associated with blood pressure drop,
the expression ratios for adverse events and side effects showed a
low tendency in Test Drug Group as compared to those of Control
Drug Group. Further, as to the events associated with shocks or
unconsciousness, Test Drug Group showed excellent safety such that
the expression of adverse events and side effects was not found at
all.
TABLE-US-00033 TABLE 2-28 Time transitions of change in systolic
blood pressure after administration to that administration before
administration Test Drug Group Control Drug Group Test Timing after
No. of Mean No. of Mean timing administration cases (mmHg) cases
(mmHg) After 10 min. after 274 -6.3 275 -8.9 0 weeks administration
Before returning 276 -7.5 275 -12.2 home After 10 min. after 266
-8.0 266 -9.6 4 weeks administration Before returning 266 -7.8 266
-10.9 home After 10 min. after 263 -7.0 253 -8.8 12 weeks
administration Before returning 263 -7.0 253 -10.8 home After 10
min. after 251 -7.9 244 -8.2 24 weeks administration Before
returning 251 -9.4 244 -11.6 home After 10 min. after 241 -6.7 233
-7.4 48 weeks administration Before returning 241 -6.5 233 -7.5
home
[0286] In Test Drug Group, the dropping tendencies of the mean
value of the change rates in systolic blood pressure (value after
administration--value before administration) were the same for all
of the test timings (after 0, 4, 12, 24 and 48 weeks). On the other
hand, in Control Drug Group, the same mean value particularly had a
large dropping range after 0, 4, and 12 weeks, as compared to that
of Test Drug Group. The extent of blood pressure drop was from -6.3
to -9.4 mmHg in Test Drug Group, and from -7.4 to -12.2 mmHg in
Control Drug Group, so that the blood pressure drop in Test Drug
Group were mild as compared to the blood pressure drop in Control
Drug Group.
TABLE-US-00034 TABLE 2-29 Time transitions of change in diastolic
blood pressure after administration to that before administration
Test Drug Group Control Drug Group Test Timing after No. of Mean
No. of Mean Timing administration cases (mmHg) cases (mmHg) After
10 min. after 274 -4.4 275 -6.6 0 weeks administration Before
returning 276 -4.9 275 -8.0 home After 10 min. after 266 -4.4 266
-5.7 4 weeks administration Before returning 266 -4.8 266 -7.4 home
After 10 min. after 263 -4.7 253 -5.7 12 weeks administration
Before returning 263 -5.0 253 -7.3 home After 10 min. after 251
-4.6 244 -4.8 24 weeks administration Before returning 251 -6.3 244
-7.0 home After 10 min. after 241 -5.0 233 -4.3 48 weeks
administration Before returning 241 -4.2 233 -4.8 home
[0287] In Test Drug Group, the dropping tendencies of the mean
value of the change rate in diastolic blood pressure (value after
the administration--value before the administration) were the same
for all of the test timings (after 0, 4, 12, 24 and 48 weeks). On
the other hand, in Control Drug Group, the same mean value
particularly had a large dropping range after 0, 4, and 12 weeks.
The extent of blood pressure drop was from -4.2 to -6.3 mmHg in
Test Drug Group, and from -4.3 to -8.0 mmHg in Control Drug Group,
so that the blood pressure drop in Test Drug Group were mild as
compared to the blood pressure drop in Control Drug Group.
2.8.5. Expression Ratios for Adverse Events and Side Effects by Age
Groups:
TABLE-US-00035 [0288] TABLE 2-30 Expression ratios for adverse
events and side effects by age groups: No. of cases of Test Drug
Group (%) No. of cases of Control Drug Group (%) Ages Age 65 or
older and Age 75 or older and Age 65 or older and Age 75 or older
and age younger than 75 age younger than 80 Age 80 or older age
younger than 75 age younger than 80 Age 80 or older TEAE 131 72 42
132 63 51 (adverse (88.5) (91.1) (84.0) (89.8) (91.3) (85.0)
events) TEAE 72 28 10 89 38 28 (side (48.6) (35.4) (20.0) (60.5)
(55.1) (46.7) effects)
[0289] The tendencies of decreasing the expression ratios in the
frequency of side effects by aging were even more strongly observed
in Test Drug Group, and in particular, the expression ratios of the
frequency of side effects were markedly lowered in the patients of
Test Drug Group of age 80 or older.
2.8.6. Expression Ratios for Adverse Events and Side Effects by
Gender Groups:
TABLE-US-00036 [0290] TABLE 2-31 Expression ratios for adverse
events and side effects by gender groups No. of cases of No. of
cases of Test Drug Group (%) Control Drug Group (%) Female Male
Female Male TEAE Adverse 223 22 225 21 event (88.5) (88.0) (89.6)
(84.0) Side 107 3 143 12 effects (42.5) (12.0) (57.0) (48.0)
Serious Adverse 19 1 20 4 adverse event (7.5) (4.0) (8.0) (16.0)
events Side 1 0 4 0 effects (0.4) (0.0) (1.6) (0.0) Other Adverse
16 0 26 1 important event (6.3) (0.0) (10.4) (4.0) adverse Side 11
0 23 1 events effects (4.4) (0.0) (9.2) (4.0)
[0291] Test Drug Group showed excellent safety regardless of the
genders, as compared to those of Control Drug Group, and in
particular male individuals had remarkably decreased expression
ratios for side effects.
2.8.7. Treatment Continuality:
TABLE-US-00037 [0292] TABLE 2-32 Treatment continuality No. of
cases of No. of cases of Test Drug Group (%) Control Drug Group (%)
Test individuals who 277 (100.0) 276 (100.0) began the treatment
Test individuals who 35 (12.6) 41 (14.9) discontinued the treatment
Test individuals who 242 (87.4) 235 (85.1) completed the
treatment
[0293] The treatment continuality showed high tendencies in Test
Drug Group as compared to those of Control Drug Group.
TABLE-US-00038 TABLE 2-33 Reasons why the treatment was
discontinued No. of No. of No. of cases at cases at cases at Total
no. Reason for 0 to 24 24 to 48 48 weeks of cases discontinuation
weeks weeks or more (%) Test Adverse events 11 9 2 22 Drug (62.9)
Group Judgment of 1 0 0 1 physician (2.9) Departure from 1 0 0 1
protocol of (2.9) investigational studies Ineligibility of 1 0 0 1
compliance (2.9) Judgment of 6 4 0 10 patients (28.6) Total 20 13 2
35 (100.0) Control Adverse events 25 5 0 30 Drug (73.2) Group
Judgment of 2 1 0 3 physician (7.3) Judgment of 5 3 0 8 patients
(19.5) Total 32 9 0 41 (100.0)
[0294] The proportion of discontinuation of the treatment due to
adverse events was low in Test Drug Group as compared to that of
Control Drug Group. In addition, the discontinuation due to adverse
events at less than 24 weeks was 11 individuals in Test Drug Group,
in contrast to 25 individuals in Control Drug Group, so that in
Test Drug Group, the discontinuation cases due to adverse events at
an early stage of the treatment was particularly fewer.
TABLE-US-00039 TABLE 2-34 Breakdown of adverse events resulted in
discontinuation of treatment No. of cases of No. of cases of Test
Drug Group (%) Control Drug Group (%) Adverse Side Adverse Side
Events events effects events effects Headache 3 (1.1) 3 (1.1) 3
(1.1) 3 (1.1) Nausea 6 (2.2) 6 (2.2) 12 (4.3) 11 (4.0) Vomiting 2
(0.7) 2 (0.7) 5 (1.8) 5 (1.8) Dysesthesia 2 (0.7) 1 (0.4) 3 (1.1) 2
(0.7) Fervescence 1 (0.4) 1 (0.4) 4 (1.4) 4 (1.4) (Provided that
only events that were expressed in 3 or more cases)
[0295] The treatment with Test Drug Group was found to have
improvements in the treatment continuality by decreasing the
expression ratios of adverse events or side effects such as nausea
and vomiting, as compared to the treatment with Control Drug
Group.
2.9. Analysis of Influences by Administration Intervals on
Therapeutic Effects:
2.9.1. Method of Analysis:
[0296] Using 242 test individuals who completed the treatment over
48 weeks out of Test Drug Group (hereinafter referred to as Test
Drug Group with Treatment Completed) as subjects, the proportion
occupying the weeks in which the intervals of administration in a
week (not including the days of administration) out of 48 weeks,
the number of weeks of the entire period of administration, were
2-day and 3-day intervals (%) (hereinafter referred to as the
proportion in compliance with administration of 2-day to 3-day
intervals) was calculated for each test individual. At this time,
it was considered that the weeks that satisfy the following
conditions (1) or (2) did not fall under the weeks in which the
intervals of administration in a week (not including the days of
administration) were 2-day and 3-day intervals.
(1) Weeks in a case where the period of the course from the day on
which a control drug placebo was administered to the day on which a
next control drug placebo was administered was within 6 days.
TABLE-US-00040 TABLE 2-35 Case where the period of the course from
the day on which a control drug placebo was administered to the day
on which a next control drug placebo was administered was 5 days
(Days 1 to 7 in the following table fall under the above weeks) Day
1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Test
.circle-solid. .circle-solid. .circle-solid. drug Control
.largecircle. .largecircle. drug placebo
(2) Weeks in a case where a test drug was administered without
intervals of administration, or administered with a 1-day
administration interval, a 4-day administration interval, and a
5-day administration interval, when the period of the course from
the day on which a control drug placebo was administered to the day
on which a next control drug placebo was administered was 7 or more
days.
TABLE-US-00041 TABLE 2-36 Cases of weeks where a test drug was
administered without intervals of administration, when the period
of the course from the day on which a control drug placebo was
administered to the day on which a next control drug placebo was
administered was 7 or more days (Days 1 to 7 in the following table
fall under the above weeks) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day
7 Day 8 Day 9 Test .circle-solid. .circle-solid. .circle-solid.
drug Control .largecircle. .largecircle. drug placebo
TABLE-US-00042 TABLE 2-37 Cases of weeks where a test drug was
administered with a 1-day administration interval, when the period
of the course from the day on which a control drug placebo was
administered to the day on which a next control drug placebo was
administered was 7 or more days (Days 1 to 7 in the following table
fall under the above weeks) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day
7 Day 8 Day 9 Test .circle-solid. .circle-solid. .circle-solid.
drug Control .largecircle. .largecircle. drug placebo
TABLE-US-00043 TABLE 2-38 Cases of weeks where a test drug was
administered with a 4-day administration interval, when the period
of the course from the day on which a control drug placebo was
administered to the day on which a next control drug placebo was
administered was 7 or more days (Days 1 to 7 in the following table
fall under the above weeks) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day
7 Day 8 Day 9 Test .circle-solid. .circle-solid. .circle-solid.
drug Control .largecircle. .largecircle. drug placebo
TABLE-US-00044 TABLE 2-39 Cases of weeks where a test drug was
administered with a 5-day administration interval, when the period
of the course from the day on which a control drug placebo was
administered to the day on which a next control drug placebo was
administered was 7 or more days (Days 1 to 7 in the following table
fall under the above weeks) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day
7 Day 8 Day 9 Test .circle-solid. .circle-solid. .circle-solid.
drug Control .largecircle. .largecircle. drug placebo
[0297] Having defined the proportion in compliance with
administration of 2-day to 3-day intervals as described above, the
following five aggregate analyses were carried out.
(1) The comparative analysis on efficacies and safety of Test Drug
Group with Treatment Completed with a proportion in compliance with
administration of 2-day to 3-day intervals of 70% or more and Test
Drug Group with Treatment Completed with a proportion in compliance
with administration of 2-day to 3-day intervals is less than 70%.
(2) The comparative analysis on efficacies and safety of Test Drug
Group with Treatment Completed with a proportion in compliance with
administration of 2-day to 3-day intervals of 75% or more and Test
Drug Group with Treatment Completed with a proportion in compliance
with administration of 2-day to 3-day intervals is less than 75%.
(3) The comparative analysis on efficacies and safety of Test Drug
Group with Treatment Completed with a proportion in compliance with
administration of 2-day to 3-day intervals of 80% or more and Test
Drug Group with Treatment Completed with a proportion in compliance
with administration of 2-day to 3-day intervals is less than 80%.
(4) The comparative analysis on efficacies and safety of Test Drug
Group with Treatment Completed with a proportion in compliance with
administration of 2-day to 3-day intervals of 85% or more and Test
Drug Group with Treatment Completed with a proportion in compliance
with administration of 2-day to 3-day intervals is less than 85%.
(5) The comparative analysis on efficacies and safety of Test Drug
Group with Treatment Completed with a proportion in compliance with
administration of 2-day to 3-day intervals of 90% or more and Test
Drug Group with Treatment Completed with a proportion in compliance
with administration of 2-day to 3-day intervals is less than
90%.
[0298] Here, the assessment items for the efficacies were change
rates in bone mineral densities of lumbar vertebrae (second to
fourth lumbar vertebrae), change rates in bone mineral densities of
femoral neck part, change rates in bone mineral densities of
femoral proximal total, clinical fracture incidence rates, and
non-vertebral fracture incidence rates. In addition, the assessment
items for the safety were the expression ratios of all the side
effects and the expression ratios of nausea (side effects).
[0299] Further, the mean of the number of administrations and the
mean of the number of the administration period in each group to be
compared were calculated.
2.9.2. Analysis Results:
2.9.2.1. Mean of Number of Administrations and Mean of
Administration Period:
[0300] Using 242 individuals of Test Drug Group with Treatment
Completed as subjects, the mean of the number of administrations
and the mean of the administration period were calculated for each
of the proportions in compliance with administration intervals. The
results are shown in the following Table 2-40.
TABLE-US-00045 TABLE 2-40 Mean of number of administrations and
mean of administration period (days) when distinguished by a
specified value or more/less than a specified value of each of the
proportions in compliance with administration of 2-day to 3-day
intervals Proportion in compliance Mean of with administration of
No. of Mean of Number Administration 2-day to 3-day intervals Cases
of Administration Period (Days) 70% or more 186 90.2 332.3 less
than 56 87.1 332.1 75% or more 165 90.3 332.1 less than 77 87.7
332.5 80% or more 122 90.6 332.4 less than 120 88.3 332.1 85% or
more 83 91.8 332.8 less than 159 88.2 332.0 90% or more 43 93.0
333.1 less than 199 88.7 332.1
[0301] In the comparisons of both cases when distinguished by 70%
or more and that of less than 70% of the proportion in compliance
with administration of 2-day to 3-day intervals, there were no
significance differences in the mean of the number of
administrations and the mean of the administration period, and were
of the same levels. In the cases of comparing a specified value or
more and less than a specified value for each of the values for the
proportion in compliance with administration of 2-day to 3-day
intervals of 75%, 80%, 85% and 90%, similar results were also
obtained as the case where a proportion in compliance with
administration of 2-day to 3-day intervals of 70% or more.
Therefore, it was considered that there were no differences in the
mean of the number of administrations and the mean of the
administration period even in different proportions in compliance
with administration of 2-day to 3-day intervals, so that there are
no differences in the exposed amount of the investigational
product.
2.9.2.2. Mean Value of Change Rates in Bone Mineral Densities for
Each of Lumbar Vertebrae, Femoral Neck Part, and Femoral Proximal
Total when Distinguished by Specified Value or More/Less than
Specified Value of Each of Proportions in Compliance with
Administration of 2-Day to 3-Day Intervals (%):
[0302] The mean value of change rates (%) when distinguished by a
specified value or more/less than a specified value in bone mineral
densities for the lumbar vertebrae, the femoral neck part, and the
femoral proximal total was calculated of the proportions in
compliance with administration of 2-day to 3-day intervals. The
results are shown in the following Tables 2-41 to 2-43.
TABLE-US-00046 TABLE 2-41 Mean value of change rates (%)
distinguished by a specified value or more/less than a specified
value in bone mineral densities of lumbar vertebrae (second to
fourth lumbar vertebrae) of each of the proportions in compliance
with the administration of 2-day to 3-day intervals Proportion in
compliance with administration of 2-day to 3-day intervals After 24
weeks After 48 weeks 70% or more 5.0 7.5 less than 4.9 7.4 75% or
more 5.1 7.6 less than 4.8 7.2 80% or more 5.3 8.0 less than 4.7
7.0 85% or more 5.5 8.0 less than 4.8 7.2 90% or more 5.8 8.6 less
than 4.9 7.3
TABLE-US-00047 TABLE 2-42 Mean value of change rates (%) when
distinguished by a specified value or more/less than a specified
value in bone mineral densities of the femoral neck part of each of
the proportions in compliance with the administration of 2-day to
3-day intervals Proportion in compliance with administration of
2-day to 3-day intervals After 24 weeks After 48 weeks 70% or more
1.5 2.1 less than 2.3 2.4 75% or more 1.6 2.2 less than 1.9 2.1 80%
or more 1.8 2.5 less than 1.6 1.8 85% or more 2.1 2.8 less than 1.5
1.8 90% or more 2.2 3.3 less than 1.6 1.9
TABLE-US-00048 TABLE 2-43 Mean value of change rates (%) when
distinguished by a specified value or more/less than a specified
value in bone mineral densities of the femoral proximal total of
each of the proportions in compliance with the administration of
2-day to 3-day intervals Proportion in compliance with
administration of 2-day to 3-day intervals After 24 weeks After 48
weeks 70% or more 1.2 1.9 less than 1.2 1.7 75% or more 1.4 1.9
less than 0.9 1.7 80% or more 1.4 2.0 less than 1.0 1.6 85% or more
1.4 2.0 less than 1.1 1.7 90% or more 1.9 2.6 less than 1.1 1.7
[0303] In addition, graphs showing the transitions of the mean
value of change rates (%) in each of the bone mineral densities of
lumbar vertebrae (second to fourth lumbar vertebrae), the bone
mineral densities of the femoral neck part, and the bone mineral
densities of the femoral proximal total by comparing the values of
a specified value or more/less than a specified value for each of
the proportions in compliance with the administration of 2-day to
3-day intervals are shown in FIGS. 10 to 24.
[0304] As mentioned above, the bone mineral densities of lumbar
vertebrae (second to fourth lumbar vertebrae) are a main assessment
item for the efficacies of the present test. In view of the above,
the analysis results on the influences given by fluctuations of a
specified value to the mean value of change rates (%) in bone
mineral densities of lumbar vertebrae (second to fourth lumbar
vertebrae) indicated by patients having a proportion in compliance
with the administration of 2-day to 3-day intervals of a specified
value (%) or more at the time point of 48 weeks after the beginning
of administration are shown in FIG. 25.
[0305] In the layer where the proportion in compliance with the
administration of 2-day to 3-day intervals is a specified value or
more, the larger the proportion in compliance with the
administration of 2-day to 3-day intervals, the mean value of
change rates (%) in bone mineral densities tended to be higher.
Therefore, it was considered that the higher the proportion
occupied by the weeks in which the intervals of administration in a
week (not including the days of administration) was 2-day and 3-day
intervals, the higher the therapeutic effects obtained. More
specifically, excellent therapeutic effects are exhibited in an
embodiment where the same proportion is 70% or more, and even more
remarkable therapeutic effects can be acquired in an embodiment
where the same proportion is 90% or more. Moreover, in taking
strong positive correlative tendencies of the same proportion and
the therapeutic effects into account, it was considered that the
therapeutic effects would be generally maximized when the same
proportion is 100%.
[0306] On the other hand, there were two cases where the compliance
rate of the administration of 2-day to 3-day intervals (3-day to
4-day intervals including the days of administration) was 0%, and
the administration was carried out at the frequency of twice a week
by generally 1-day and 4-day intervals (2-day and 5-day intervals
including the days of administration). The mean of change rates (%)
in the bone mineral densities of lumbar vertebrae (second to fourth
lumbar vertebrae) for these two cases were analyzed. As a result,
at 48 weeks after the beginning of the administration, the mean
value for one case was 5.8%, and that for the other case was 5.9%.
The inventor considers that the results also suggest that it is
useful to comply with the administration of 2-day to 3-day
intervals (3-day to 4-day intervals including the days of
administration) when the administration was carried out twice a
week.
2.9.2.3. Mean Value of Change Rates (%) in Bone Mineral Densities
in Each Group when Proportions in Compliance with Administration of
2-Day to 3-Day Intervals were Grouped into Those of from 75 to 85%,
and Those of from 85 to 100%:
TABLE-US-00049 TABLE 2-44 Mean value of change rates (%) in bone
mineral densities in each group when the proportions in compliance
with the administration of 2-day to 3-day intervals were grouped
into those of from 75 to 85%, and those of from 85 to 100% Time
Course from Beginning of 75 to 85% 85 to 100% Administration (N =
82) (N = 83) Mean value of change Week 24 4.8% 5.5% rates (%) in
bone mineral densities Week 48 7.2% 8.0% of lumbar vertebrae
(second to fourth lumbar vertebrae) Mean value of change Week 24
1.3% 1.4% rates (%) in bone mineral densities Week 48 1.8% 2.0% of
femoral proximal total Bone fracture incidence 12.2% 7.2% rate (%)
of clinical bone fractures
2.9.2.4. Incidence Rates of Clinical Bone Fractures and
Non-Vertebral Bone Fractures when Distinguished by Specified Value
or More/Less than Specified Value of Each of Proportions in
Compliance with Administration of 2-Day to 3-Day Intervals:
[0307] The incidence rates of clinical bone fractures and
non-vertebral bone fractures when distinguished by a specified
value or more and less than a specified value of each of the
proportions in compliance with the administration of 2-day to 3-day
administration were calculated. The results are shown in the
following Tables 2-45 to 2-46.
TABLE-US-00050 TABLE 2-45 The number of cases of bone fracture
incidence and the bone fracture incidence rate (%) of the clinical
bone fractures when distinguished by a specified value or more/less
than a specified value of each of the proportions in compliance
with the administration of 2-day to 3-day intervals No. of cases
No. of cases Proportion in compliance of bone of bone Incidence
with administration of fracture fracture rate of bone 2-day to
3-day intervals assessed incidence fractures (%) 70% or more 186 17
9.1 less than 56 6 10.7 75% or more 165 16 9.7 less than 77 7 9.1
80% or more 122 10 8.2 less than 120 13 10.8 85% or more 83 6 7.2
less than 159 17 10.7 90% or more 43 1 2.3 less than 199 22
11.1
TABLE-US-00051 TABLE 2-46 The number of cases of bone fracture
incidence and the bone fracture incidence rate (%) of the
non-vertebral bone fractures when distinguished by a specified
value or more/less than a specified value of each of the
proportions in compliance with the administration of 2-day to 3-day
administration intervals No. of cases No. of cases Proportion in
compliance of bone of bone Incidence with administration of
fracture fracture rate of bone 2-day to 3-day intervals assessed
incidence fractures (%) 70% or more 186 16 8.6 less than 56 6 10.7
75% or more 165 15 9.1 less than 77 7 9.1 80% or more 122 9 7.4
less than 120 13 10.8 85% or more 83 6 7.2 less than 159 16 10.1
90% or more 43 1 2.3 less than 199 21 10.6
[0308] As mentioned above, the clinical bone fractures are bone
fractures that embrace vertebral and non-vertebral bone fractures.
In view of the above, the analysis results on the influences given
by fluctuations of a specified value to the bone fracture incidence
rate (%) for the clinical bone fractures indicated by patients
having a proportion in compliance with the administration of 2-day
to 3-day intervals of a specified value (%) or more are shown in
FIG. 26.
[0309] In the layer where the proportion is a specified value or
more, the larger the proportion in compliance with the
administration of 2-day to 3-day intervals, the bone fracture
incidence rate (%) tended to be generally decreasing. Therefore, it
was considered that the higher the proportion occupied by the weeks
in which the intervals of administration in a week (not including
the days of administration) is 2-day and 3-day intervals, the
higher the therapeutic effects obtained. More specifically,
excellent therapeutic effects are exhibited in an embodiment where
the same proportion is 70% or more, and even more remarkable
therapeutic effects can be acquired in an embodiment where the same
proportion is 90% or more. Moreover, in taking strong positive
correlative tendencies of the same proportion and the therapeutic
effects into account, it was considered that the therapeutic
effects would be generally maximized when the same proportion is
100%.
2.9.2.5. Time Transitions of Bone Metabolism Markers (Urine NTX
(u-NTX), Serum NTX (s-NTX), CTX, OC, and P1NP) when Distinguishing
by Specified Value or More/Less than Specified Value of Each of
Proportions in Compliance with Administration Intervals:
[0310] The time transitions of the bone metabolism markers (urine
NTX (u-NTX), serum NTX (s-NTX), CTX, OC, and P1NP) when
distinguished by a specified value or more/less than a specified
value of each of the proportions in compliance with administration
intervals were calculated. The results are shown in the following
Tables 2-47 to 2-51.
TABLE-US-00052 TABLE 2-47 Median value of change rates (%) in urine
NTX (u-NTX) at each time point when distinguished by a specified
value or more/less than a specified value of each of the
proportions in compliance with the administration of 2-day to 3-day
intervals Proportion in compliance with administration of 2-day to
3-day intervals Week 4 Week 12 Week 24 Week 48 70% or more -20.8
-20.4 -32.2 -25.5 less than -5.4 -1.7 -15.4 -5.9 75% or more -20.9
-21.2 -34.5 -27.1 less than -7.8 -7.1 -16.0 -12.4 80% or more -23.6
-22.3 -35.1 -28.3 less than -8.8 -12.4 -20.0 -13.0 85% or more
-26.1 -22.3 -35.5 -28.7 less than -15.8 -15.8 -25.6 -13.2 90% or
more -22.1 -11.6 -33.4 -24.6 less than -16.2 -18.6 -30.4 -18.3
TABLE-US-00053 TABLE 2-48 Median value of change rates (%) in serum
NTX (s-NTX) at each time point when distinguished by a specified
value or more/less than a specified value of each of the
proportions in compliance with the administration of 2-day to 3-day
intervals Proportion in compliance with administration of 2-day to
3-day intervals Week 4 Week 12 Week 24 Week 48 70% or more -6.3
-6.0 -11.7 -8.8 less than -0.3 -0.9 -2.4 0.0 75% or more -6.6 -6.2
-12.2 -8.8 less than -3.1 -3.7 -3.1 -1.7 80% or more -7.1 -5.7
-12.2 -8.9 less than -3.2 -5.3 -6.5 -5.5 85% or more -6.3 -5.6
-12.2 -10.8 less than -3.7 -5.5 -7.2 -5.5 90% or more -5.1 -2.9
-11.2 -10.8 less than -5.2 -5.7 -7.9 -5.7
TABLE-US-00054 TABLE 2-49 Median value of change rates (%) in CTX
at each time point when distinguished by a specified value or
more/less than a specified value of each of the proportions in
compliance with the administration of 2-day to 3-day intervals
Proportion in compliance with administration of 2-day to 3-day
intervals Week 4 Week 12 Week 24 Week 48 70% or more -22.0 -16.9
-24.3 -31.2 less than -13.8 -11.5 -9.8 -20.0 75% or more -22.2
-16.4 -25.0 -30.6 less than -15.6 -15.9 -13.8 -27.0 80% or more
-23.8 -18.0 -27.0 -30.4 less than -14.5 -14.1 -14.7 -29.3 85% or
more -23.1 -18.8 -27.3 -30.6 less than -17.3 -15.9 -16.6 -28.6 90%
or more -23.5 -15.6 -28.3 -33.3 less than -19.1 -16.3 -18.5
-29.2
TABLE-US-00055 TABLE 2-50 Median value of change rates (%) in OC at
each time point when distinguished by a specified value or
more/less than a specified value of each of the proportions in
compliance with the administration of 2-day to 3-day intervals
Proportion in Compliance with Administration of 2-day to 3-Day
Intervals Week 4 Week 12 Week 24 Week 48 70% or more 46.7 41.2 23.9
6.5 less than 40.3 43.2 19.8 8.2 75% or more 47.5 41.3 24.4 6.7
less than 41.2 42.8 18.5 7.7 80% or more 47.6 39.7 22.8 3.3 less
than 41.9 44.0 25.0 9.1 85% or more 47.0 39.9 23.3 4.1 less than
44.2 43.2 24.6 8.1 90% or more 44.7 39.9 22.3 4.5 less than 46.3
43.2 23.9 7.4
TABLE-US-00056 TABLE 2-51 Median value of change rates (%) in P1NP
at each time point when distinguished by a specified value or
more/less than a specified value of each of the proportions in
compliance with the administration intervals Proportion in
compliance with administration of 2-day to 3-day intervals Week 4
Week 12 Week 24 Week 48 70% or more 27.3 12.9 1.3 -4.4 less than
31.0 15.2 10.3 11.1 75% or more 25.9 13.3 1.4 -5.5 less than 30.5
14.8 7.5 6.1 80% or more 27.6 13.7 0.6 -3.6 less than 28.7 14.1 3.6
1.2 85% or more 29.2 15.3 -1.6 -3.1 less than 28.5 13.6 3.1 0.0 90%
or more 37.5 18.8 3.6 -2.7 less than 28.3 13.6 2.1 -1.4
[0311] As a bone metabolism marker for observing bone formation
action of a daily administered preparation or a once-weekly
administered preparation, each containing teriparatide or a salt
thereof as an active ingredient, serum osteocalcin (OC) has been
widely used (Non-Patent Publication 5 or the like). In addition, in
the administration with a test drug in the present invention, the
peak of OC elevation is found roughly four weeks after the
beginning of administration (FIG. 8). In view of the above, the
analysis results on the influences given by fluctuations of a
specified value to OC indicated by patients having a proportion in
compliance with the administration of 2-day to 3-day intervals of a
specified value (%) or more at four weeks after the beginning of
administration are shown in FIG. 27.
[0312] As to a bone formation marker OC, contrary to the
therapeutic effects mentioned above, a distinct correlation with
the proportion in compliance with the administration of 2-day to
3-day intervals was not found in the layer in which the proportion
was at a level of a specified value or more.
[0313] It has been known that a parathyroid hormone drug is a bone
formation accelerator (Non-Patent Publication 9), and the
dissociation of a bone formation marker and a bone resorption
marker is recognized as an efficacy index in the daily osteoporosis
treatment using teriparatide (Non-Patent Publication 24).
Therefore, with regard to the correlation with the proportion in
compliance with the administration of 2-day or 3-day intervals, the
present analysis results in which different tendencies were shown
between the therapeutic effects and the bone formation marker OC
were considered to be highly epoch-making in light of the findings
of the conventional teriparatide therapies.
2.9.2.6. Number of Cases of Expression and Expression Ratios (%) of
all Side Effects and Nausea (Side Effects) when Distinguished by
Specified Value or More/Less than Specified Value of Each of
Proportions in Compliance of Administration Intervals:
TABLE-US-00057 TABLE 2-52 Number of cases of incidence and
expression ratios (%) of all side effects when distinguished by a
specified value or more/less than a specified value of each of the
proportions in compliance with the administration of 2-day to 3-day
intervals Proportion in compliance with administration No. of
subject No. of cases of Expression intervals cases expression ratio
(%) 70% or more 186 69 37.1 less than 56 24 42.9 75% or more 165 58
35.2 less than 77 35 45.5 80% or more 122 39 32.0 less than 120 54
45.0 85% or more 83 25 30.1 less than 159 68 42.8 90% or more 43 13
30.2 less than 199 80 40.2
TABLE-US-00058 TABLE 2-53 Number of cases of incidence and
expression ratios (%) of nausea (side effects) when distinguished
by a specified value or more and less than a specified value of
each of the proportions in compliance with the administration of
2-day to 3-day intervals Proportion in compliance with
administration No. of subject No. of cases of Expression intervals
cases expression ratio (%) 70% or more 186 32 17.2 less than 56 12
21.4 75% or more 165 26 15.8 less than 77 18 23.4 80% or more 122
16 13.1 less than 120 28 23.3 85% or more 83 11 13.3 less than 159
33 20.8 90% or more 43 5 11.6 less than 199 39 19.6
[0314] As mentioned in the above 2.8.2, the nausea was a side
effect having the highest expression ratio. In view of the above,
the analysis results on the influences given by fluctuations of a
specified value (%) to the expression ratio (%) of nausea indicated
by patients having a proportion in compliance with the
administration of 2-day to 3-day intervals of a specified value (%)
or more are shown in FIG. 28.
[0315] In the group in which the proportion in compliance with the
administration intervals is a specified value or more, the larger
the proportion in compliance with the administration intervals, the
expression ratio of nausea (side effects) tended to be low.
Therefore, it was considered that the higher the proportion
occupied by the weeks in which the administration intervals in a
week (not including the days of administration) are 2-day and 3-day
intervals, the therapy has higher safety. More specifically,
excellent safety was shown in an embodiment in which the same
proportion was 70% or more, and taking the strong positive
correlative tendencies between the same proportion and safety into
account, it was considered that the safety is generally probably
maximized when the same proportion is 100%.
Working Example 2
[0316] 1. Test Method
[0317] To evaluate the influences of the administration frequencies
of teriparatide on the bone metabolism and the bone tissue
morphology, six-month old female rabbits were subcutaneously
administered with an agent in a manner that a weekly dosage of
teriparatide was adjusted to 140 .mu.g/kg at a frequency of once a
week, twice a week or seven times a week over 4 weeks, or with a
control drug without containing teriparatide at a frequency of
seven times a week over 4 weeks (Table 2-54). Also, the bone
mineral density and the bone strength of the tibiae were measured.
The teriparatide solution which was administered was appropriately
prepared by dissolving teriparatide acetate in a water for
injection, filtering the solution, filling the filtrate in a vial,
freeze-drying to give a preparation, and dissolving the preparation
in a physiological saline upon use.
TABLE-US-00059 TABLE 2-54 Contents of each test group Unit dose
(.mu.g/kg) No. of Admin- (concentration admin- Total dose istered
administered istration per week Group drug (.mu.g/mL/kg)) per week
(.mu.g/kg) Control Teriparatide 0 7 0 group acetate (0) Group
Teriparatide 140 1 140 administered acetate (1400) once a week
Group Teriparatide 70 2 140 administered acetate (700) twice a week
Group Teriparatide 20 7 140 administered acetate (200) seven times
a week
[0318] 2. Test Results
(1) Bone Mineral Densities of Tibiae
[0319] The bone mineral densities of the tibiae were analyzed in
divided regions. As a result, the administration of teriparatide
remarkably increased the bone mineral densities in the proximal
part (1/5 site) rich in trabecular bones, as compared to those of
the control group, and the bone mineral densities of the group
administered twice a week had a higher value than that of the group
administered once a week in this site. The present test results
agree with the test results for Working Example 1 (Table 2-4)
showing that the bone mineral densities of the group administered
twice a week had a higher value than that of the group administered
once a week in the lumbar vertebrae (second to fourth lumbar
vertebrae) rich in trabecular bones in the same manner as the
proximal part of the tibiae (the lumbar vertebrae being composed of
60% trabecular bones, and the centrum being composed of 80%
trabecular bones; Non-Patent Publication 26).
TABLE-US-00060 TABLE 2-55 Influences of administration frequency of
teriparatide on bone mineral densities in proximal part (1/5 site)
of the tibiae of rabbits Group Group administered administered
Control group once a week twice a week Bone mineral 254.2 .+-. 10.9
272.5 .+-. 13.6 278.8 .+-.9.8 densities (mg/cm.sup.2)
(2) Bone Strength of Tibiae
[0320] Three-point bending strength of the tibiae collected after
the end of the administration period was measured. As a result, the
maximum load showed higher values in the group administered with
the present drug twice a week and the group administered seven
times a week, than the control group.
TABLE-US-00061 TABLE 2-56 Influences of administration frequency of
teriparatide on bone strength of tibiae of rabbits Group Group
Group administered Control administered administered seven times
group once a week twice a week a week Maximum 578.93 .+-. 583.81
.+-. 624.41 .+-. 656.09 .+-. load (N) 51.42 44.23 45.32 59.86
(3) Bone Tissue Morphology of Diaphysis of Tibiae
[0321] In the group administered seven times a week, the formation
of trabecular bones on the endocortical surfaces, a large number of
intracortical voids (increase of cortical porosity), and
disorderedness in a lamellar structure were observed, but none of
these findings were observed in the group administered once a week
and the group administered twice a week.
[0322] Non-Patent Publication 14 has reported that the
administration of teriparatide at high frequencies enhances the
bone turnover, suggesting that the increase in void ratios of the
cortical bone with teriparatide is strongly influenced by the
administration frequencies. In the present working example, the
enhancement in the bone turnover that would increase the void ratio
of the cortical bones was not found, in the therapy of
administration of twice a week, despite the doubling in the
administration frequencies of the therapy of administration of once
a week. This matter, in light of Non-Patent Publication 14, was
considered to be unexpected and epoch-making results.
[0323] In addition, Non-Patent Publication 17 has reported that the
daily administration of teriparatide increases a bone resorption
marker. Further, it is suggested that in Non-Patent Publication 27,
an eroded surface showing bone resorption in a void surface of the
cortical bone caused by daily administration of teriparatide has
been found (see, FIG. 7 c or the like), so that the porosity of the
cortical bone has a deep relationship with the enhancement of bone
resorption.
[0324] In Working Example 1, the time transitions of the bone
resorption marker with the treatment of administration of twice a
week were of the same level or slightly inhibited, as compared to
the time transitions of the bone resorption marker with the
treatment of administration of once a week (FIGS. 5 to 7). However,
through the mechanisms mentioned above, it can be assumed that the
treatment of administration of twice a week is a therapy that does
not show the acceleration of the bone turnover that would increase
the void ratios of the cortical bones regardless of the doubling of
the administration frequency of that of the therapy of once a week.
Therefore, the effects of Working Example 1 were supported by the
results of the test with rabbits of Working Example 2.
* * * * *