U.S. patent application number 17/394039 was filed with the patent office on 2021-11-25 for methods of administering deflazacort therapy.
The applicant listed for this patent is PTC THERAPEUTICS INC.. Invention is credited to Scott Joseph Brantley, Linda L. Grasfeder, Virginia D. Schmith, Stephen P. Wanaski.
Application Number | 20210361676 17/394039 |
Document ID | / |
Family ID | 1000005756876 |
Filed Date | 2021-11-25 |
United States Patent
Application |
20210361676 |
Kind Code |
A1 |
Wanaski; Stephen P. ; et
al. |
November 25, 2021 |
METHODS OF ADMINISTERING DEFLAZACORT THERAPY
Abstract
The disclosure provides a deflazacort therapy comprising,
administering to a subject suffering from Duchenne muscular
dystrophy (DMD) a fixed dose of deflazacort. Also provided is a
deflazacort therapy comprising, increasing the deflazacort dosage
when the subject loses ambulation; or, increasing the dosage of
deflazacort administered during concomitant administration of a
CYP3A4 inducer; or, decreasing the dosage of deflazacort
administered during concomitant administration of a CYP3A
inhibitor.
Inventors: |
Wanaski; Stephen P.;
(Chicago, IL) ; Schmith; Virginia D.; (Durham,
NC) ; Grasfeder; Linda L.; (Durham, NC) ;
Brantley; Scott Joseph; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PTC THERAPEUTICS INC. |
South Plainfield |
NJ |
US |
|
|
Family ID: |
1000005756876 |
Appl. No.: |
17/394039 |
Filed: |
August 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15607130 |
May 26, 2017 |
11083737 |
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17394039 |
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62408482 |
Oct 14, 2016 |
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62342628 |
May 27, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/08 20130101; G06F
19/3456 20130101; A61K 45/06 20130101; A61K 9/20 20130101; A61J
1/05 20130101; A61B 5/4848 20130101; A61K 9/0053 20130101; A61B
5/224 20130101; A61K 31/58 20130101; A61K 9/10 20130101 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61K 45/06 20060101 A61K045/06; A61K 9/00 20060101
A61K009/00; A61K 9/10 20060101 A61K009/10; A61K 9/20 20060101
A61K009/20; A61J 1/05 20060101 A61J001/05; A61B 5/00 20060101
A61B005/00; A61B 5/22 20060101 A61B005/22; A61B 5/08 20060101
A61B005/08 |
Claims
1. A deflazacort therapy for administration to a subject that is
suffering from Duchenne muscular dystrophy (DMD) comprising,
determining a fixed target dose range of deflazacort to be
administered to the subject using one or more factors selected from
the subject's age, weight and ambulatory status; wherein the
subject's age is selected from an age less than or equal to 11
years of age, an age greater than 11 years to less than or equal to
18 years of age or an age greater than 18 years of age, wherein the
subject's weight is selected from a weight less than or equal to 30
kg, a weight greater than 30 kg to less than or equal to 50 kg or a
weight greater than 50 kg, wherein the subject's ambulatory status
is selected from ambulatory or non-ambulatory, and wherein the
selection of factors determine the fixed target dose range to
administer; administering a target dose from the fixed target dose
range; and measuring a treatment, amelioration or prevention of DMD
symptoms selected from improved muscle strength, response time to a
timed function test and improvement in pulmonary function in the
subject.
2. The method of claim 1, wherein the subject age range is less
than or equal to 11 years of age and the fixed target dose range of
deflazacort is 6-36 mg per day, having a target dose of 18 or 24 mg
per day; or, the age range is greater than 11 years of age and less
than or equal to 18 years of age and the fixed target dose range of
deflazacort is 30-72 mg per day, having a target dose of 36, 42 or
48 mg per day; or, an age range of greater than 18 years of age and
the fixed target dose range of deflazacort is 36-72 mg per day,
having a target dose of 36, 42, 48, 54, 60 or 66 mg per day.
3. The method of claim 2, wherein the fixed target dose range of
deflazacort for a subject less than or equal to 11 years of age is
selected from 6-18 mg per day, having a target dose of 18 mg per
day for an ambulatory subject or, 12-30 mg per day, having a target
dose of 18 or 24 mg per day for a non-ambulatory subject; or,
wherein the fixed target dose range of deflazacort for a subject
greater than 11 years of age and less than or equal to 18 years of
age is selected from 30-60 mg per day, having a target dose of 36
mg per day for an ambulatory subject or, 36-72 mg per day, having a
target dose of 36 or 42 mg per day for a non-ambulatory subject;
or, wherein the fixed target dose range of deflazacort for a
subject greater than 18 years of age is selected from 36-72 mg per
day, having a target dose of 42 mg per day for an ambulatory
subject or, 48-96 mg per day, having a target dose of 54 or 66 mg
per day for a non-ambulatory subject.
4. The method of claim 1, wherein the subject weight range is less
than or equal to 30 kg and the fixed target dose range of
deflazacort is 6-36 mg per day, having a target dose of 18 or 24 mg
per day; or, the subject weight range is greater than 30 kg and
less than or equal to 50 kg and the fixed target dose range of
deflazacort is 24-66 mg per day, having a target dose of 36 mg per
day; or, the subject weight range is greater than 50 kg and the
fixed target dose range of deflazacort is 42-96 mg per day, having
a target dose of 48, 54 or 60 mg per day.
5. The method of claim 4, wherein the fixed target dose range of
deflazacort for a subject weight range less than or equal to 30 kg
is selected from 12-36 mg per day, having a target dose of 18 mg
per day for an ambulatory subject or, 18-54 mg per day, having a
target dose of 24 mg per day for a non-ambulatory subject; or,
wherein the fixed target dose range of deflazacort for a subject
weight range greater than 30 kg and less than or equal to 50 kg is
selected from 24-60 mg per day, having a target dose of 36 mg per
day for an ambulatory subject or 30-72 mg per day, having a target
dose of 42 mg per day for a non-ambulatory subject; or, wherein the
fixed target dose range of deflazacort for a subject weight range
greater than 50 kg is selected from 48-72 mg per day, having a
target dose of 48 mg per day for an ambulatory subject or, 54-96 mg
per day, having a target dose of 54 mg per day for a non-ambulatory
subject.
6. The method of claim 1, wherein the target dose selected from a
fixed target dose range of deflazacort for a subject less than or
equal to 11 years of age and having a subject weight range less
than or equal to 30 kg is selected from 18 mg per day for an
ambulatory subject or, 24 mg per day for a non-ambulatory subject;
or, wherein the target dose selected from a fixed target dose range
of deflazacort for a subject greater than 11 years of age and less
than or equal to 18 years of age and having a subject weight range
greater than 30 kg and less than or equal to 50 kg is selected from
36 mg per day for an ambulatory subject or, 42 mg per day for a
non-ambulatory subject; or, wherein the target dose selected from a
fixed target dose range of deflazacort for a subject greater than
18 years of age and having a subject weight range greater than 50
kg is selected from 48 mg per day for an ambulatory subject or, 54
mg per day for a non-ambulatory subject.
7. The method of claim 1, wherein the dosing schedule comprises, a
scheduled period selected from administering the fixed dose daily;
or, administering twice the daily fixed dose on alternate days; or,
administering thrice the daily fixed dose on each of 10 days
followed by 10 days with no fixed dose administration; or,
administering thrice to five times the daily fixed dose on each of
2 days followed by 5 days with no fixed dose administration.
8. The method of claim 1, wherein the dosing schedule comprises,
administering the fixed dose for a plurality of scheduled periods,
wherein the fixed dose is been reduced by 6 mg for each period
until deflazacort is no longer administered.
9. The method of claim 1, wherein the factors further comprise
concomitant administration of a CYP 3A4 inducer, concomitant
administration of a CYP 3A4 inhibitor or concomitant administration
of a P-glycoprotein (Pgp) inhibitor.
10. The method of claim 9, wherein the CYP3A4 inducer is a moderate
or strong CYP3A4 inducer.
11. The method of claim 10, wherein the CYP3A4 inducer is a
moderate CYP3A4 inducer and the dosage of deflazacort is increased
about Two-Fold to about Three-Fold.
12. The method of claim 10, wherein the CYP3A4 inducer is a strong
CYP3A4 inducer and the dosage of deflazacort is increased about
Four-Fold to about Six-Fold.
13. The method of claim 9, wherein the CYP3A4 inhibitor is a
moderate or strong CYP3A4 inhibitor.
14. The method of claim 13, wherein the CYP3A4 inhibitor is a
moderate CYP3A4 inhibitor and the dosage of deflazacort is reduced
about Two-Fold to about Three-Fold.
15. The method of claim 13, wherein the CYP3A4 inhibitor is a
strong CYP3A4 inhibitor and the dosage of deflazacort is reduced
about Three-Fold to about Four-Fold.
16. The method of claim 9, wherein the fixed dose of deflazacort is
reduced about Three-Fold to about Four-Fold during concomitant
administration of a Pgp inhibitor.
17. A pharmaceutical composition for use in providing a fixed dose
deflazacort therapy to a subject that is suffering from Duchenne
muscular dystrophy (DMD) comprising, oral administration of the
composition formulated as an oral dosage form selected from a
tablet or an oral suspension.
18. The pharmaceutical composition of claim 17, wherein the tablet
contains an amount of deflazacort selected from 6 mg, 18 mg, 30 mg
or 36 mg in admixture with excipients selected from colloidal
silicon dioxide, lactose monohydrate, magnesium stearate, and
pre-gelatinized corn starch.
19. The pharmaceutical composition of claim 17, wherein the oral
suspension contains 22.75 mg/mL of deflazacort in a suspension with
acetic acid, aluminum magnesium silicate, benzyl alcohol,
carboxymethylcellulose sodium, polysorbate 80, purified water, and
sorbitol.
20. The pharmaceutical composition of claim 17, wherein the
deflazacort oral suspension contains 13 mL of the suspension in a
20 mL bottle.
Description
TECHNICAL FIELD
[0001] The application relates generally to an improved deflazacort
therapy and methods for administering novel therapeutic doses of
deflazacort.
BACKGROUND
[0002] Duchenne muscular dystrophy (DMD) is a recessive, X-linked
disorder affecting one in 5000 live male births, making the
disorder the most common and most severe form of muscular dystrophy
(Mendell et al., 2012). The absence of the protein dystrophin leads
to onset of symptoms typically between the ages of 2 to 5 years,
with abnormal gait and frequent falls being hallmark signs of the
disorder (Koenig et al., 1987; Ciafaloni et al., 2009). Progressive
proximal muscle weakness of the legs and pelvis associated with a
loss of muscle mass is observed first, with weakness eventually
spreading to the arms, neck, and other areas. Other signs may
include delays in motor milestones such as sitting, standing
independently, climbing and walking, as well as delays in cognitive
development. As the condition progresses, wasting occurs in muscle,
which is eventually replaced by fat and fibrotic tissue (fibrosis).
Untreated patients with DMD will lose ambulation and become
wheelchair dependent at a mean age of 9.5 years (Humberclaude et
al., 2012). This loss of ambulation due to progressive muscle
weakness also leads to a secondary development of musculoskeletal
deformity; up to 90% of untreated boys with DMD will develop
progressive scoliosis (Bushby et al., 2010). In the second decade
of life, complications of respiratory, cardiac, and orthopedic
origin are common, with death typically occurring in the second or
third decade due to respiratory failure and cardiomyopathy (Eagle
et al., 2002). Currently, deflazacort therapy is the only Food and
Drug Administration (FDA)-approved treatment available to the
entire DMD population. The approved deflazacort therapy is being
administered using the standard of care (SOC) weight-based dosing
regimen of 0.9 mg/kg/day in patients five years of age and older.
The dosing regimen for DMD patients less than five years of age
remains to be explored. With earlier diagnoses of DMD being
provided for children less than 11 years of age, there remains an
opportunity for ensuring such younger patients are administered an
effective deflazacort therapy.
SUMMARY
[0003] The present disclosure provides an improved deflazacort
therapy and methods for administration to all DMD patients,
particularly with respect to subjects who are children suffering
from DMD. In various aspects, the disclosure provides a deflazacort
therapy comprising, administering to a subject suffering from DMD a
fixed dose of deflazacort. The effective fixed target dose
administered is determined using a combination of one or more
factors selected from subject age, weight, ambulatory status or the
presence or absence of an inducer or inhibitor of cytochrome P450
3A (CYP3A), in particular, CYP3A4.
[0004] In one aspect, the disclosure provides a deflazacort therapy
wherein the effective fixed dose to be administered is based on the
age of the subject as a factor. In such an aspect, the subject in
need thereof is a child or adolescent 18 years of age or younger.
In another aspect, the subject is a child (i.e., less than or equal
to 11 years of age) and the fixed dose of deflazacort is 6-36 mg
per day (e.g., including alternative ranges of 6-12 mg, 6-30 mg,
12-24 mg, 18-24 mg, 20-36 mg or 24-36 mg per day, or having a
target dose such as 18 mg or 24 mg per day). In another aspect, the
subject is an adolescent (i.e., between 12-18 years of age) and the
fixed dose of deflazacort is 30-72 mg per day (e.g., including an
alternative range of 30-36 mg, 30-48 mg, 30-54 mg, 36-54 mg, 36-60
mg, 36-72 mg, 42-60 mg, 42-66 mg, 42-72 mg, 48-54 mg, 48-72 mg or
54-72 mg per day, having a target dose such as 36 mg or 42 mg or 48
mg per day). In another aspect, the subject is an adult (i.e.,
greater than 18 years of age), and the fixed dose of deflazacort is
36-72 mg of deflazacort per day (e.g., including an alternative
range of 36-54 mg, 36-60 mg, 42-60 mg, 42-66 mg, 42-72 mg, 48-54
mg, 48-72 mg, 54-60 mg, 54-66 mg, 54-72 mg, 60-66 mg, 60-72 mg or
66-72 mg per day, having a target dose 36 mg, 42 mg, 48 mg, 54 mg,
60 mg, or 66 mg).
[0005] In another aspect, the disclosure further provides a
deflazacort therapy wherein the effective fixed dose to be
administered is based on the weight of the subject as a factor. In
such an aspect, the subject in need thereof has a weight that is 30
kg or less and may be administered a fixed dose of deflazacort of
6-36 mg per day (e.g., including an alternative range of 6-12 mg,
6-18 mg, 6-30 mg, 12-18 mg, 12-24 mg, 18-24 mg, 18-30 mg, 18-36 mg,
24-30 mg or 24-36 mg per day, having a target dose such as 18 mg or
24 mg per day). In another aspect, the subject has a weight that is
less than or equal to 16 kg, and may be administered a fixed dose
of 6-18 mg (e.g., including an alternative range of 6-12 mg or
12-18 mg per day, having a target dose such as 12 mg) of
deflazacort per day. In another aspect, the subject has a weight
that is greater than 16 kg and less than or equal to 30 kg, and may
be administered a fixed dose of 18-36 mg (e.g., including an
alternative range of 18-24 mg, 24-30 mg or 24-36 mg per day, having
a target dose such as 18, 24 or 30 mg) of deflazacort per day.
[0006] In another aspect disclosed herein, the subject has a weight
that is greater than 30 kg, and may be administered a fixed dose of
deflazacort of 24-96 mg per day (e.g., including alternative ranges
of 36-54 mg per day, 36-60 mg per day, 36-96 mg per day, 24-72 mg
per day, 36-72 mg per day, 24-48 mg per day, 36-48 mg per day,
42-60 mg per day, 42-66 mg per day, 42-72 mg per day, 42-96 mg per
day, 48-54 mg per day, 48-72 mg per day, 48-96 mg per day, 54-72 mg
per day or 54-96 mg per day or having a target dose such as 36 mg
or 42 mg or 48 mg). In another aspect, the subject has a weight
that is greater than 30 kg and less than or equal to 50 kg, and may
be administered a fixed dose of 24-66 mg of deflazacort per day
(e.g., including alternative ranges of 24-48 mg per day, 24-54 mg
per day, 30-42 mg per day, 36-48 mg per day, 36-54 mg per day,
36-60 mg per day, 36-66 mg per day, 42-54 mg per day, 42-60 mg per
day, 42-66 mg per day, 42-72 mg per day, 48-54 mg per day, 48-66 mg
per day, 48-72 mg per day, 48-96 mg per day, 54-60 mg per day,
54-66 mg per day, 54-72 mg per day or 54-96 mg per day, or having a
target dose such as 36 mg per day). In another aspect, the subject
has a weight that is greater than 50 kg, and may be administered a
fixed dose of 42-96 mg of deflazacort per day (e.g., including
alternative ranges of 42-60 mg, 42-66 mg, 48-54 mg, 48-66 mg, 48-96
mg, 48-72 mg, 42-72 mg, 54-66 mg, 54-72 mg or 54-96 mg, or having a
target dose such as 48 mg, 54 mg, or 60 mg).
[0007] In another aspect, the subject has a weight that is less
than or equal to 16 kg, and is ambulatory and may be administered a
fixed dose of 6-18 mg (e.g., including an alternative range of 6-12
mg or 12-18 mg per day; or, having a target dose such as 12 mg) of
deflazacort per day. In another aspect, the subject has a weight
that is less than or equal to 16 kg, and is non-ambulatory and may
be administered a fixed dose of 12-24 mg (e.g., including an
alternative range of 12-18 mg per day or 18-24 mg per day; or,
having a target dose such as 18 mg) of deflazacort per day. In
another aspect, the subject has a weight that is greater than 16 kg
and less than or equal to 30 kg, and is ambulatory and may be
administered a fixed dose of 18-30 mg (e.g., including an
alternative range of 18-24 mg or 24-30 mg per day, having a target
dose such as 24 mg) of deflazacort per day. In another aspect, the
subject has a weight that is greater than 16 kg and less than or
equal to 30 kg, and is non-ambulatory and may be administered a
fixed dose of 24-36 mg (e.g., including an alternative range of
24-30 mg or 30-36 mg per day, having a target dose such as 30 mg)
of deflazacort per day. In another aspect, the subject has a weight
that is 30 kg or less and is ambulatory, and may be administered a
fixed dose of 12-36 mg per day (e.g., including alternative ranges
of 24-36 mg per day, 18-36 mg per day, 18-30 mg per day, 18-24 mg
per day, 12-30 mg per day or 12-24 mg per day, or having a target
dose such as 18 mg per day). Alternatively, the subject has a
weight that is 30 kg or less is non-ambulatory, and may be
administered a fixed dose of 18-54 mg per day (e.g., including
alternative ranges of 18-36 mg per day, 18-30 mg per day, 18-24 mg
per day, 24-36 mg per day, 24-48 mg per day or 24-54 mg per day, or
having a target dose such as 24 mg per day).
[0008] In another aspect, the subject has a weight that is greater
than 30 kg and is ambulatory, and may be administered a fixed dose
of deflazacort of 24-60 mg per day (e.g., including alternative
ranges of 24-48 mg per day, 24-54 mg per day, 30-42 mg per day,
36-48 mg per day, 36-54 mg per day, 36-60 mg per day, 36-66 mg per
day, 42-54 mg per day, 42-60 mg per day, 48-54 mg per day, 48-60 mg
per day or 54-60 mg per day or having a target dose such as 36 mg
per day). In another aspect, the subject has a weight that is
greater than 30 kg and is non-ambulatory, and may be administered a
fixed dose of deflazacort of 30-72 mg per day (e.g., including an
alternative range of 30-36 mg per day, 30-42 mg per day, 30-48 mg
per day, 30-54 mg per day, 36-48 mg per day, 36-54 mg per day,
36-72 mg per day, 42-54 mg per day, 42-60 mg per day, 42-66 mg per
day, 48-54 mg per day or 54-72 mg per day, or having a target dose
such as 42 mg per day). In another aspect, the subject has a weight
greater than 30 kg and less than or equal to 50 kg and is
ambulatory, the fixed dose of deflazacort administered may be 24-54
mg per day (e.g., including an alternative range of 24-48 mg per
day, 30-42 mg per day, 36-48 mg per day, 36-54 mg per day, 36-66 mg
per day, 42-54 mg per day, 42-60 mg per day or 48-54 mg per day, or
having a target dose such as 36 mg per day); if the subject having
a weight greater than 30 kg and less than or equal to 50 kg is
non-ambulatory, the fixed dose of deflazacort is 30-66 mg per day
(e.g., including an alternative range of 30-36 mg per day, 30-60 mg
per day, 36-54 mg per day, 36-60 mg per day, 42-54 mg per day,
42-60 mg per day, 42-66 mg per day, 48-54 mg per day, 48-66 mg per
day or 54-66 mg per day, or having a target dose such as 42 mg per
day). In another aspect, the subject has a weight that is greater
than 50 kg, the fixed dose of deflazacort administered may be 48-72
mg per day (e.g., including an alternative range of 48-54 mg per
day, 48-60 mg per day, 48-66 mg per day, 54-60 mg per day, 54-66 mg
per day or 54-72 mg per day, or having a target dose such as 48 mg
per day or 54 mg per day) if ambulatory; if the subject having a
weight greater 50 kg is non-ambulatory, the fixed dose of
deflazacort administered may be 54-96 mg per day (e.g., including
an alternative range of 54-90 mg per day, 60-90 mg per day, 66-84
mg per day or 72-96 mg per day, or having a target dose such as 54
mg or 66 mg per day).
[0009] In another aspect, the subject is a child (i.e., less than
or equal to 11 years of age) and is ambulatory and may be
administered a fixed dose of 6-18 mg of deflazacort per day (e.g.,
including alternative ranges of 6-12 mg or 12-18 mg per day, or
having a target dose such as 18 mg per day). In another aspect, the
subject is a child and is non-ambulatory, and may be administered a
fixed dose of 12-30 mg of deflazacort per day (e.g., including
alternative ranges of 12-18 mg, 12-24 mg, 18-24 mg or 18-30 mg per
day, or having a target dose such as 18 mg or 24 mg per day). In
another aspect, the subject is an adolescent (i.e., greater than 11
years of age) and is ambulatory and may be administered a fixed
dose of 30-60 mg of deflazacort per day (e.g., including
alternative ranges of 30-36 mg, 30-48 mg, 36-54 mg, 36-54 mg, 36-60
mg, 42-60 mg, 48-54 mg or 48-60 mg, per day, or having a target
dose such as 36 mg per day). In another aspect, the subject is an
adolescent and is non-ambulatory, and may be administered a fixed
dose of 36-72 mg of deflazacort per day (e.g., including
alternative ranges of 36-54 mg, 36-60 mg, 36-66 mg, 42-54 mg, 42-60
mg, 42-66 mg, 42-72 mg, 48-54 mg, 48-60 mg, 48-66 mg or 48-72 mg,
per day, or having a target dose such as 36 mg or 42 mg per day).
In another aspect, the subject is an adult (i.e., greater than 18
years of age) and is ambulatory and may be administered a fixed
dose of 36-72 mg of deflazacort per day (e.g., including
alternative ranges of 36-54 mg, 36-60 mg, 42-60 mg, 42-66 mg, 42-72
mg, 48-54 mg, 48-72 mg, 54-60 mg, 54-66 mg or 54-72 mg per day, or
having a target dose such as 42 mg per day). In another aspect, the
subject is an adult and is non-ambulatory, and may be administered
a fixed dose of deflazacort of 48-96 mg per day (e.g., including
alternative ranges of 48-54 mg, 48-60 mg, 48-72 mg, 54-60 mg, 54-72
mg or 54-96 mg per day, or having a target dose such as 54 mg, or
66 mg).
[0010] In any of the aspects described herein, the deflazacort
therapy may comprise administering the fixed dose daily, on
alternative days, two consecutive days per week, or for a period of
time followed by a dosing reprieve (e.g., administering the fixed
dose each day for ten days, not administering deflazacort for the
following ten days, then optionally resuming administration). When
dosing on alternative days, the deflazacort fixed dose is about the
same as the daily dose or is double (two-times; 2.times.) the daily
dose for the aspects described herein. When dosing two days per
week, the deflazacort fixed dose is three to ten times (e.g., six
times; 6.times.) the daily dose in any of the aspects described
herein. For example, when deflazacort is administered only two days
per week (e.g., "high dose weekend"), the deflazacort therapy may
comprise administering a fixed dose of 24-360 mg per day for two
days followed by a five day dosing reprieve. When deflazacort is
given for a period of time followed by a dosing reprieve of similar
length (e.g., administered for ten days, then not administered for
ten days), the dose is about the same or optionally up to three
times higher than the daily dose of any of the aspects described
herein.
[0011] In one aspect, the disclosure further provides a deflazacort
therapy that may be administered to a subject suffering from DMD,
comprising increasing the dosage administered to the subject when
the subject loses ambulation. In another aspect, the therapy
comprises increasing the dosage by about 6 mg to about 24 mg (e.g.,
about 6 mg to about 12 mg or about 12 mg to about 24 mg) per
administration (e.g., administration per day). In another aspect,
the therapy comprises increasing the dosage in the subject by 1.2
fold or 1.4 fold. Put another way, the fixed deflazacort dose for a
non-ambulatory subject is 1.2 to 1.4 times higher than an
ambulatory subject with the same weight.
[0012] In one aspect, the deflazacort therapy comprises
administering to a subject in need a therapeutically effective
amount of deflazacort and avoiding, discontinuing, or
contraindicating administration of a cytochrome P450 3A (CYP3A)
(e.g., CYP3A4) inducer. In another aspect, the deflazacort therapy
comprises increasing the dosage of deflazacort administered to the
subject during concomitant administration of a CYP3A (e.g., CYP3A4)
inducer. In another aspect, the deflazacort therapy to a subject in
need thereof comprises decreasing the dosage of deflazacort
administered to the subject during concomitant administration of a
CYP3A (e.g., CYP3A4) inhibitor. Such aspects contemplate that the
CYP3A4 inducer may be a moderate CYP3A4 inducer, or a strong CYP3A4
inducer; and that the CYP3A4 inhibitor may be a moderate CYP3A4
inhibitor, or a strong CYP3A4 inhibitor.
[0013] The disclosure further provides a deflazacort therapy for
the treatment of a subject suffering from DMD, such as a subject 18
years or younger. In some aspects, the deflazacort therapy is
administered as a fixed dose (e.g., any of the fixed doses
disclosed herein). In other aspects, the fixed dosage of
deflazacort is increased when the subject loses ambulation. In
certain aspects, a therapeutically effective amount of deflazacort
is administered and administration of a CYP3A inducer is avoided.
In certain aspects, the fixed dosage of deflazacort administered to
the subject is increased during concomitant administration of a
CYP3A inducer. In certain aspects, a therapeutically effective
amount of deflazacort is administered and administration of a CYP3A
inhibitor is avoided. In certain aspects, the fixed dosage of
deflazacort administered to the subject is reduced during
concomitant administration of a CYP3A inhibitor.
DESCRIPTION OF THE FIGURES
[0014] FIG. 1 is a line graph illustrating mean plasma 21-desDFZ
(active deflazacort metabolite) concentration (ng/mL; y-axis) vs.
time (hours; x-axis) overlaid by study population on Day 8 (linear
scale; circles=adolescent; triangles=child). Children (ages 5-11,
inclusive) and adolescents (ages 12-16, inclusive) were
administered the weight-based regimen of 0.9 mg/kg/day deflazacort
orally once daily for 8 days. Blood samples were collected through
eight hours post-dose. Blood samples were processed to plasma and
concentrations of 21-desDFZ were measured using validated
bioanalytical assays. The difference in mean plasma concentration
of 21-desDFZ resulting from weight-based dosing in children and
adolescents is demonstrated in the first four hours following
administration. At about one hour following administration,
children exhibit only 67% of the mean plasma concentration observed
in adolescents.
[0015] FIG. 2 is a boxplot comparing 21-desDFZ clearance (CL/F and
CLss/F) by day and study population with individual values included
(linear scale). There were no differences in the clearance values
(CL/F) of 21-desDFZ calculated after a single oral dose of
deflazacort and at steady-state between children and
adolescents.
[0016] FIG. 3 is a boxplot comparing 21-desDFZ volume of
distribution (Vz/F and Vzss/F) by day and study population with
individual values included (linear scale). There were no
differences in the volume of distribution (Vd/F) of 21-desDFZ
calculated after a single oral dose of deflazacort and at
steady-state between children and adolescents.
[0017] FIG. 4 is a line graph correlating mean dose-normalized
21-desDFZ concentration (ng/mL; y-axis) and time (hours) by study
population (triangles=adolescent; circles=child). The figure
illustrates data from Day 8. Corrected for dose, there are
negligible differences in the concentration-time profiles of
21-desDFZ between children and adolescents.
[0018] FIG. 5 is a scatter plot of 21-desDFZ AUC as a function of
dose on Day 8 based on data from a deflazacort pharmacokinetic
study in child DMD subjects (aged 5 to 11 years old) and adolescent
DMD subjects (aged 12 to 16 years old). The scatterplot of AUC
(h*ng/mL; y-axis) vs. dose (mg; x-axis) demonstrate a tight linear
relationship regardless of the subject population, with exposures
in both child and adolescent subjects increasing in a similar
manner as shown by comparable regression slopes. These data suggest
a trend toward increasing exposure (C.sub.max and AUC) with
increasing age that may be better explained as a function of actual
dose administered rather than age alone. In other words, regardless
of patient subpopulation (children or adolescent), dose-normalized
total exposures to 21-desDFZ as measured by AUC correlate with the
total weight based dose actually received and are not complicated
by age or maturation of metabolizing enzymes. Accordingly, these
data clearly show that, with a target dose regimen of 0.9
mg/kg/day, child subjects were consistently under-dosed compared to
adolescent subjects.
[0019] FIG. 6 is a histogram of the predicted AUC after deflazacort
0.9 mg/kg and 1.2 mg/kg as simulated in patients with DMD from
clinical efficacy studies with deflazacort. The clinical simulation
pharmacokinetic modeling data derived from pharmacokinetic and
pivotal clinical efficacy studies indicate substantial overlap in
estimated exposures to the 21-desDFZ metabolite using the SOC
dosing regimen of 0.9 and 1.2 mg/kg/day, where the 10th and 90th
percentiles for each dose are highlighted. The bars with arrows
above the graph show the doses that were assumed for given
exposures.
[0020] FIG. 7 is a box plot showing the Week 12 change in muscle
strength by various fixed-dose regimen treatment arms, assuming 50
subjects per arm with doses not dependent on ambulatory status
after 10,000 clinical trial simulations. The box represents the
25th and 75th percentiles, with the median, while the 5th and 95th
percentiles are depicted by a thin line and outliers are
represented by dots. The vertical dotted line represents the median
results using the Current Dosing Table (0.9 mg/kg). The treatment
arms are given in the following order: placebo, prednisone, Current
Dosing Table, two (2) Age groups, two (2) Age groups High Dose, two
(2) Weight groups, two (2) Weight groups High Dose, three (3)
Weight groups, four (4) Weight groups, and 54 mg to all.
[0021] FIG. 8 is a box plot showing the Week 52 change in muscle
strength by various fixed dose regimen treatment arms, assuming 50
subjects per arm with doses not dependent on ambulatory status
after 10,000 clinical trial simulations. The box represents the
25th and 75th percentiles, with the median, while the 5th and 95th
percentiles are depicted by a thin line and outliers are
represented by dots. The vertical dotted line represents the median
results using the Current Dosing Table. The treatment arms are
given in the following order: prednisone, Current Dosing Table, two
(2) Age groups, two (2) Age groups High Dose, two (2) Weight
groups, two (2) Weight groups High Dose, three (3) Weight groups,
four (4) Weight groups, and 54 mg to all.
[0022] FIG. 9 is a box plot showing the Week 52 Non-ambulatory FVC
(Forced Vital Capacity) by Responders by various fixed-dose
treatment arms, assuming 50 subjects per arm after 10,000 clinical
trial simulations with doses not dependent on ambulatory status.
The box represents the 25th and 75th percentiles, with the median,
while the 5th and 95th percentiles are depicted by a thin line and
outliers are represented by dots. The vertical dotted line
represents the median results using the Current Dosing Table. The
treatment arms are given in the following order: prednisone,
Current Dosing Table, two (2) Age groups, two (2) Age groups High
Dose, two (2) Weight groups, two (2) Weight groups High Dose, three
(3) Weight groups, four (4) Weight groups, and 54 mg to all.
[0023] FIG. 10 is a box plot showing the Week 52 Proportion of
Subjects with Weight Gain by various fixed-dose treatment arms,
assuming 50 subjects per arm after 10,000 clinical trial
simulations with doses not dependent on ambulatory status. The box
represents the 25th and 75th percentiles, with the median, while
the 5th and 95th percentiles are given with the thin line and
outliers are represented by dots. The vertical dotted line
represents the median results using the Current Dosing Table. The
treatment arms are given in the following order: prednisone,
Current Dosing Table, two (2) Age groups, two (2) Age groups High
Dose, two (2) Weight groups, two (2) Weight groups High Dose, three
(3) Weight groups, four (4) Weight groups, and 54 mg to all.
[0024] FIG. 11 is a box plot showing the Week 52 Proportion of
Subjects with Cushingoid Syndrome by various fixed-dose treatment
arms, assuming 50 subjects per arm after 10,000 clinical trial
simulations with doses not dependent on ambulatory status. The box
represents the 25th and 75th percentiles, with the median, while
the 5th and 95th percentiles are given with the thin line and
outliers are represented by dots. The vertical dotted line
represents the median results using the Current Dosing Table. The
treatment arms are given in the following order: prednisone,
Current Dosing Table, two (2) Age groups, two (2) Age groups High
Dose, two (2) Weight groups, two (2) Weight groups High Dose, three
(3) Weight groups, four (4) Weight groups, and 54 mg to all.
[0025] FIG. 12 is a box plot showing the Week 12 change in muscle
strength by various fixed-dose treatment arms, assuming 50 subjects
per arm after 10,000 clinical trial simulations with doses
dependent on ambulatory status. The box represents the 25th and
75th percentiles, with the median, while the 5th and 95th
percentiles are given with the thin line and outliers are
represented by dots. The vertical dotted line represents the median
results using the Current Dosing Table. The treatment arms are
given in the following order: placebo, prednisone, Current Dosing
Table, two (2) Age groups (Amb and Non-Amb), two (2) Weight groups
(Amb and Non-Amb), three (3) Weight groups (Amb and Non-Amb), and
four (4) Weight groups (Amb and Non-Amb).
[0026] FIG. 13 is a box plot showing the Week 52 change in muscle
strength by various fixed-dose treatment arms, assuming 50 subjects
per arm after 10,000 clinical trial simulations with doses
dependent on ambulatory status. The box represents the 25th and
75th percentiles, with the median, while the 5th and 95th
percentiles are given with the thin line and outliers are
represented by dots. The vertical dotted line represents the median
results using the Current Dosing Table. The treatment arms are
given in the following order: Prednisone, Current Dosing Table, two
(2) Age groups (Amb and Non-Amb), two (2) Weight groups (Amb and
Non-Amb), three (3) Weight groups (Amb and Non-Amb), and four (4)
Weight groups (Amb and Non-Amb).
[0027] FIG. 14 is a box plot showing the Week 52 FVC Responders by
various fixed-dose treatment arms, assuming 50 subjects per arm
with after 10,000 clinical trial simulations doses dependent on
ambulatory status. The box represents the 25th and 75th
percentiles, with the median, while the 5th and 95th percentiles
are given with the thin line and outliers are represented by dots.
The vertical dotted line represents the median results using the
Current Dosing Table. The treatment arms are given in the following
order: prednisone, Current Dosing Table, two (2) Age groups (Amb
and Non-Amb), two (2) Weight groups (Amb and Non-Amb), three (3)
Weight groups (Amb and Non-Amb), and four (4) Weight groups (Amb
and Non-Amb).
[0028] FIG. 15 is a box plot showing the Week 52 Proportion of
Subjects with Weight Gain by various fixed-dose treatment arms,
assuming 50 subjects per arm after 10,000 clinical trial
simulations with doses dependent on ambulatory status. The box
represents the 25th and 75th percentiles, with the median, while
the 5th and 95th percentiles are given with the thin line and
outliers are represented by dots. The vertical dotted line
represents the median results using the Current Dosing Table. The
treatment arms are given in the following order: prednisone,
Current Dosing Table, two (2) Age groups, two (2) Weight groups
(Amb and Non-Amb), three (3) Weight groups (Amb and Non-Amb), and
four (4) Weight groups (Amb and Non-Amb).
[0029] FIG. 16 is a box plot showing the Week 52 Proportion of
Subjects with Cushingoid Syndrome by various fixed-dose treatment
arms, assuming 50 subjects per arm after 10,000 clinical trial
simulations with doses not dependent on ambulatory status. The box
represents the 25th and 75th percentiles, with the median, while
the 5th and 95th percentiles are given with the thin line and
outliers are represented by dots. The vertical dotted line
represents the median results using the Current Dosing Table. The
treatment arms are given in the following order: prednisone,
Current Dosing Table, two (2) Age groups (Amb and Non-Amb), two (2)
Weight groups (Amb and Non-Amb), three (3) Weight groups (Amb and
Non-Amb), and four (4) Weight groups (Amb and Non-Amb).
[0030] FIG. 17 is a table summarizing simulations of fixed dosing
regimens (regardless of ambulatory status). The mean change in
muscle strength at 12 weeks, the mean change in muscle strength at
52 weeks, the proportion of 52 week forced vital capacity (FVC)
responders, the proportion of subjects with weight gain at 52
weeks, and the proportion of subjects with Cushingoid Syndrome at
52 weeks are presented for each dosing regimen, assuming 50
subjects per arm.
[0031] FIG. 18 is a table summarizing simulations of fixed dosing
regimens (by ambulatory status). The mean change in muscle strength
at 12 weeks, the mean change in muscle strength at 52 weeks, the
proportion of 52 week FVC responders, the proportion of subjects
with weight gain at 52 weeks, and the proportion of subjects with
Cushingoid Syndrome at 52 weeks are presented for each dosing
regimen, assuming 50 subjects per arm.
DETAILED DESCRIPTION
[0032] The disclosure provides an improved deflazacort therapy for
administration to subjects in need thereof. Features of the therapy
are described below. Section headings are for convenience of
reading and not intended to be limiting per se. The entire document
is intended to be related as a unified disclosure, and it should be
understood that all combinations of features described herein are
contemplated, even if the combination of features are not found
together in the same sentence, or paragraph, or section of this
document. It will be understood that any feature of the therapy
described herein can be deleted, combined with, or substituted for,
in whole or part, any other feature described herein.
[0033] Deflazacort, also known as (11.beta.,
16.beta.)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16--
d]oxazole-3,20-dione, is a glucocorticoid (GC) used as an
anti-inflammatory and immunosuppressive agent. Pharmacologically,
it is a pro-drug which is metabolized rapidly and completely in the
plasma by esterases to the active drug 21-desacetyldeflazacort
(21-desDFZ). After oral administration, GCs such as deflazacort or
prednisone are readily absorbed into the bloodstream. GCs diffuse
through cell membranes to the cytoplasm to bind soluble steroid
hormone receptors that dimerize and translocate to the nucleus. In
the nucleus, the receptor complex directly binds promoter elements
that modulate gene transcription. The intracellular GC receptor
(GR) binds GC Response Elements (GREs) in target gene promoters
that can activate or inhibit transcription of a variety of genes.
Downstream effects of GCs include increase in myoblast growth and
stabilization of muscle fiber membranes, followed by reduction in
muscle necrosis. GCs can also suppress the inflammatory process by
inhibiting production of inflammatory mediators, such as
arachidonic acid metabolites, cytokines, interleukins, adhesion
molecules, and enzymes, and by affecting B cell activity.
[0034] The American Academy of Neurology (AAN) and Center for
Disease Control (CDC) guidelines recommend glucocorticoids
(including prednisone or deflazacort) as first line therapy at the
time of DMD diagnosis, typically ages 4-5. Treatment is generally
aimed at controlling the symptoms and modifying certain aspects of
the disease to sustain and maximize muscle function and improve
quality of life. Results from multiple studies presented in Manzur
et al. (2008) showed that glucocorticoids improve muscle strength,
which was maximal at 3 months and maintained up to 18 months.
Increases in muscle strength were paralleled by significant
improvements in functional testing and muscle mass, as measured by
urinary creatinine excretion.
[0035] Applicants observed that deflazacort improves muscle
strength in both ambulatory and non-ambulatory patients as early as
six weeks after treatment initiation, that improvements in muscle
strength are preserved during long-term treatment up to 24-months,
that increases in muscle strength are paralleled by significant
improvements in functional testing and muscle mass (as measured by
urinary creatinine excretion), and also by improvements in
pulmonary function testing.
[0036] Standard of Care (SOC) dosing of corticosteroids to DMD
patients has been based on patient weight (mg/kg), regardless of
the dosing schedule (daily; alternate day; 10 days on, 10 days off;
high-dose weekends only; etc.), age, ambulatory status, use of CYP
inducers or inhibitors and the like. The recommended SOC dose of
deflazacort in DMD patients has been selected from 0.9 mg/kg or 1.2
mg/kg. In various aspects, the therapeutic dose is 0.9 mg/kg/day.
In various aspects of the present disclosure, the therapeutically
effective amount is other than 0.9 mg/kg or 1.2 mg/kg. The
recommended dose is based on clinical data from randomized,
blinded, placebo-controlled trials with additional supportive
evidence obtained from the global literature, as well as clinical
standard of care guidelines for treatment. The widespread adoption
and acceptance of weight-based (mg/kg) dosing is highlighted by
Bello et al. (2015), where the authors published findings from a
long-term observational, natural history study of boys with DMD
treated with prednisone/prednisolone or deflazacort. In 340
participants, there were fourteen different weight-based (mg/kg)
dosing regimens recorded.
[0037] In one aspect, the dosing schedule comprises, a scheduled
period selected from administering the fixed dose daily; or,
administering twice the daily fixed dose on alternate days; or,
administering thrice the daily fixed dose on each of 10 days
followed by 10 days with no fixed dose administration; or,
administering thrice to five times the daily fixed dose on each of
2 days followed by 5 days with no fixed dose administration.
[0038] In another aspect, the dosing schedule comprises,
administering the fixed dose for a plurality of scheduled periods.
In another aspect, the fixed dose may be reduced by 6 mg for each
period until a lower fixed dose of deflazacort is being
administered or until deflazacort therapy has been completely
discontinued. In this aspect, the lower fixed dose or
discontinuance of deflazacort therapy may be required due to
development of intolerability or adverse events. In another aspect,
the fixed dose reduction by 6 mg for each period may continue until
the intolerability or adverse events are mitigated; whereupon,
therapy may continue at a lower fixed dose.
Fixed Dose Regimen
[0039] Surprisingly, an investigation of the pharmacokinetics of
21-desDFZ after oral administration of deflazacort to children and
adolescents with DMD (see, Griggs, et al) revealed that the
standard-of-care weight-based (mg/kg) dosing is not optimal for
children whose age inherently correlates with a lower weight (for
whom the Current Dosing Table does not provide any coverage) and
adolescents who have become non-ambulatory (for whom the Current
Dosing Table also does not provide any coverage). We have
discovered that young patients (those having an age less than or
equal to 11 years old) and non-ambulatory adolescents (those having
an age greater than 11 years old and less than or equal to 18 years
old) are at risk for the greatest variance in total dose
administered in relation to the weight-based SOC target dose shown
in the Current Dosing Table (see Table 1c). Analysis of the total
doses of deflazacort administered to the youngest children with DMD
(those of which are also predisposed to having the lowest weight)
demonstrated that a considerable number of patients in this
subpopulation were under-dosed (FIG. 1 and FIG. 5). While plasma
concentrations were lower in such children (regardless of
ambulatory status) compared to adolescents (regardless of
ambulatory status) receiving deflazacort using a weight-based
dosing regimen of 0.9 mg/kg once daily for 8 days, the dose
normalized plasma concentrations were similar for the absolute dose
the subjects received (FIG. 4). The clinical trial simulations
described herein were conducted to extrapolate the 21-desDFZ
concentrations from the actual clinical data, showing that exposure
is unexpectedly more dependent on a fixed dose than on either the
current standard of care weight-based dosing regimen or even a
theoretical weight-based (mg/kg) dose administered. Using the area
under the plasma concentration time curve during a dosing interval
(AUC) corrected for dose and subject body weight (FIG. 6), the AUC
could be predicted for a weight-based deflazacort 0.9 mg/kg and 1.2
mg/kg dose, as administered in the pivotal, efficacy and safety
clinical trial. In contrast to dose response studies suggesting a
difference in plasma concentration between 0.9 mg/kg and 1.2 mg/kg,
there is actually a substantial overlap in exposure between these
two doses (FIG. 6). However, these doses are unexpectedly
relatively equivalent when concentrations are normalized to the
actual deflazacort dose administered (in mg) to each subject (FIG.
6).
[0040] Thus, a fixed dose of deflazacort has the potential for
reducing the complexity of the Current Dosing Table 1c used
presently by physicians, while enhancing efficacy and providing a
more appropriate/effective dose when multiple factors (other than
just weight) are considered. The modeling data used to derive the
fixed-dose ranges suggest that in addition to weight, the subject
age, ambulatory status and CYP inducer/inhibitor usage must also be
considered as factors in patient population subgroups to determine
an effective fixed dose regimen (as shown in Table 1).
[0041] The clinical trial simulations were conducted assuming the
efficacy and safety of different fixed doses of deflazacort as
compared to weight-based dosing of prednisone 0.75 mg/kg/day and
placebo, along with the original results from weight-based dosing
of deflazacort 1.2 mg/kg/day and deflazacort 0.9 mg/kg/day, to
develop simpler fixed dose regimens that would produce similar
efficacy and safety to the Current Dosing Table currently used by
physicians. The fixed dose regimen and other aspects described
herein were developed based on these clinical trial simulations.
The disclosure provides, in these aspects, a simplified, fixed-dose
regimen that provides more appropriate exposures to the active
metabolite of deflazacort, 21-desDFZ, in children, adolescents, and
adults, while employing a simpler dosing regimen. This disclosure
also provides, in other aspects, differential dosing for ambulatory
adolescents as the loss of ambulation accelerate at around age 15
due to progressive muscle degeneration and loss of muscle tissue.
Data from simulated clinical trials revealed that the fixed dose
for a non-ambulatory adolescent should be increased as the loss of
ambulation accelerates and continued post-ambulation, rather than
"capped" or reduced as is current, clinical practice.
[0042] Other aspects of the deflazacort therapy described herein
comprise administering to a subject suffering from Duchenne
muscular dystrophy (DMD) a fixed dose of deflazacort. The term
"fixed dose" is meant to describe a dosage that is not calculated
by a daily weight-based formula (i.e., as mg/kg/day or according to
the Current Dosing Table). The particular fixed dose of deflazacort
to be administered is selected based on at least one or more of a
plurality of factors, e.g., age of the subject, weight of the
subject, ambulation status, and CYP inducer/inhibitor usage. While
each of these factors may have some overlapping pharmacokinetic
effect with each other based on certain subject phenotypes, they
are connected such that an effect on one has a multiplied effect on
others. For example, depending on the amount of body fat present
and height, subject weight will affect body surface area (which
affects cardiac output and liver volume, liver weight and the
amount of microsomal protein in milligrams per gram of liver, thus
affecting intrinsic liver clearance). At the same time, subject age
affects height and the corresponding amount of body fat (which
affects body surface area and corresponding liver volume and liver
weight), as well as the amount of microsomal protein in milligrams
per gram of liver (thus affecting intrinsic liver clearance),
cardiac output and serum creatinine levels. Categorizing subjects
based on other factors besides weight alone for selecting and
administering a deflazacort therapy using a fixed dosage regimen is
a departure from the Current Dosing Table daily weight-based dosing
(at 0.9 mg/kg/day or 1.2 mg/kg/day), the standard of care used in
deflazacort treatment regimens. In other aspects of the fixed dose
deflazacort therapy described herein, subjects in a particular
weight class are administered a fixed dosage, which does not
require recalculation of dose (at 0.9 mg/kg/day or 1.2 mg/kg/day)
each time a subject's weight incrementally changes. Based on the
clinical trial simulation modeling data described herein, a fixed
dose regimen has the advantage of providing a more appropriate
21-desDFZ exposure to a child or npn-ambulatory adolescent.
[0043] In one aspect, the fixed dose of deflazacort is preferably
100 mg or less (e.g., 72 mg or less) per administration (e.g., per
day). In certain aspects wherein the subject is a child (i.e., less
than or equal to 11 years of age, having an age in a range such as
2-11 years or 4-11 years), the fixed dose of deflazacort to be
administered is preferably 6-36 mg per day (e.g., including
alternative ranges of 6-12 mg, 18-24 mg, 6-30 mg, 12-24 mg, 20-36
mg, 24-36 mg, or having a target dose such as 24 mg per day). In
other aspects, the subject is an adolescent (i.e., having an age in
a range such as greater than 11-18 years of age), and the fixed
dose of deflazacort to be administered is 30-72 mg per day (e.g.,
including alternative ranges of 36-72 mg, 42-66 mg, 48-54 mg, or
having a target dose such as 48 mg, or 42 mg per day). In other
aspects, the subject is an adult (i.e., having an age greater than
18 years of age), and the fixed dose of deflazacort to be
administered is 36-96 mg per day (e.g., including alternative
ranges of 36-72 mg, 54-96 mg, 60-90 mg, 66-84 mg, 72-96 mg, or
having a target dose such as 48 mg, 54 mg, 60 mg, or 66 mg).
[0044] In another aspect, the subject to be administered
deflazacort therapy has a weight that is 30 kg or less, and the
fixed dose of deflazacort to be administered is 6-36 mg per day
(e.g., including alternative ranges of 16-36 mg, 18-24 mg, 24-36
mg, or having a target dose such as 18 mg, or 24 mg). In other
aspects, the population of subjects 30 kg or less can be stratified
into two subpopulations based on weight: (i) subjects having a
weight less than or equal 16 kg may be administered a fixed dose of
6-18 mg (e.g., including alternate ranges of 6-12 mg, 12-18 mg, or
having a target dose such as 12 mg) of deflazacort per day; and
(ii) subjects having a weight greater than 16 kg and less than or
equal to 30 kg may be administered a fixed dose of 18-36 mg (e.g.,
including an alternate range of 18-24 mg, 24-30 mg, 24-36 mg, or
having a target dose such as 24 mg or 30 mg) per day.
[0045] In another aspect, the subject has a weight that is greater
than 30 kg, and the fixed dose of deflazacort to be administered is
24-96 mg per day (e.g., including alternative ranges of 24-72 mg,
24-48 mg, having a target dose such as 36 mg, or 42 mg). In other
aspects, the population of subjects greater than 30 kg can be
further stratified to generate two subpopulations based on weight:
(i) subjects having a weight greater than 30 kg and less than or
equal to 50 kg may be administered a fixed dose of 24-66 mg per day
(e.g., including alternative ranges of 24-54 mg, 24-48 mg, 30-42
mg, 36-54 mg, or having a target dose such as 36 mg) of
deflazacort, and (ii) subjects having a weight greater than 50 kg
may be administered a fixed dose of 48-96 mg per day (e.g.,
including alternative ranges of 48-72 mg, 54-66 mg, or having a
target dose such as 48 mg, 54 mg, or 54 mg) of deflazacort.
[0046] In one aspect, the deflazacort therapy for administration to
a subject that is suffering from Duchenne muscular dystrophy (DMD)
comprises, determining a fixed target dose range of deflazacort to
be administered to the subject using one or more factors selected
from the subject's age, weight and ambulatory status; wherein the
subject's age is selected from an age less than or equal to 11
years of age, an age greater than 11 years to less than or equal to
18 years of age or an age greater than 18 years of age, wherein the
subject's weight is selected from a weight less than or equal to 30
kg, a weight greater than 30 kg to less than or equal to 50 kg or a
weight greater than 50 kg, wherein the subject's ambulatory status
is selected from ambulatory or non-ambulatory, and wherein the
selection of factors determine the fixed target dose range to
administer; administering a target dose from the fixed target dose
range; and measuring a treatment, amelioration or prevention of DMD
symptoms selected from improved muscle strength, response time to a
timed function test and improvement in pulmonary function in the
subject.
[0047] In another aspect, the subject age range is less than or
equal to 11 years of age and the fixed target dose range of
deflazacort is 6-36 mg per day, having a target dose of 18 or 24 mg
per day; or, the age range is greater than 11 years of age and less
than or equal to 18 years of age and the fixed target dose range of
deflazacort is 30-72 mg per day, having a target dose of 36, 42 or
48 mg per day; or, an age range of greater than 18 years of age and
the fixed target dose range of deflazacort is 36-72 mg per day,
having a target dose of 36, 42, 48, 54, 60 or 66 mg per day.
[0048] In another aspect, the fixed target dose range of
deflazacort for a subject less than or equal to 11 years of age is
selected from 6-18 mg per day, having a target dose of 18 mg per
day for an ambulatory subject or, 12-30 mg per day, having a target
dose of 18 or 24 mg per day for a non-ambulatory subject; or,
wherein the fixed target dose range of deflazacort for a subject
greater than 11 years of age and less than or equal to 18 years of
age is selected from 30-60 mg per day, having a target dose of 36
mg per day for an ambulatory subject or, 36-72 mg per day, having a
target dose of 36 or 42 mg per day for a non-ambulatory subject;
or, wherein the fixed target dose range of deflazacort for a
subject greater than 18 years of age is selected from 36-72 mg per
day, having a target dose of 42 mg per day for an ambulatory
subject or, 48-96 mg per day, having a target dose of 54 or 66 mg
per day for a non-ambulatory subject.
[0049] In another aspect, the subject weight range is less than or
equal to 30 kg and the fixed target dose range of deflazacort is
6-36 mg per day, having a target dose of 18 or 24 mg per day; or,
the subject weight range is greater than 30 kg and less than or
equal to 50 kg and the fixed target dose range of deflazacort is
24-66 mg per day, having a target dose of 36 mg per day; or, the
subject weight range is greater than 50 kg and the fixed target
dose range of deflazacort is 42-96 mg per day, having a target dose
of 48, 54 or 60 mg per day.
[0050] In another aspect, the fixed target dose range of
deflazacort for a subject weight range less than or equal to 30 kg
is selected from 12-36 mg per day, having a target dose of 18 mg
per day for an ambulatory subject or, 18-54 mg per day, having a
target dose of 24 mg per day for a non-ambulatory subject; or,
wherein the fixed target dose range of deflazacort for a subject
weight range greater than 30 kg and less than or equal to 50 kg is
selected from 24-60 mg per day, having a target dose of 36 mg per
day for an ambulatory subject or 30-72 mg per day, having a target
dose of 42 mg per day for a non-ambulatory subject; or, wherein the
fixed target dose range of deflazacort for a subject weight range
greater than 50 kg is selected from 48-72 mg per day, having a
target dose of 48 mg per day for an ambulatory subject or, 54-96 mg
per day, having a target dose of 54 mg per day for a non-ambulatory
subject.
[0051] In another aspect, the target dose selected from a fixed
target dose range of deflazacort for a subject less than or equal
to 11 years of age and having a subject weight range less than or
equal to 30 kg is selected from 18 mg per day for an ambulatory
subject or, 24 mg per day for a non-ambulatory subject; or, wherein
the target dose selected from a fixed target dose range of
deflazacort for a subject greater than 11 years of age and less
than or equal to 18 years of age and having a subject weight range
greater than 30 kg and less than or equal to 50 kg is selected from
36 mg per day for an ambulatory subject or, 42 mg per day for a
non-ambulatory subject; or, wherein the target dose selected from a
fixed target dose range of deflazacort for a subject greater than
18 years of age and having a subject weight range greater than 50
kg is selected from 48 mg per day for an ambulatory subject or, 54
mg per day for a non-ambulatory subject.
[0052] In addition to providing fixed dose regimens for subjects
based on age or weight classification, the disclosure provides for
improved regimens based on ambulatory status, depending on use of a
CYP inducer or inhibitor. Ambulatory status and usage of CYP
inducers or inhibitors are described further below. Exemplary fixed
dose regimens are provided in Table 1, which is provided merely to
illustrate various aspects of the disclosure and is not meant to be
limiting. In the various aspects shown in Table 1 and described
herein, an exemplary dose range, alternative range and target dose
are provided for each subject classification based on age or
weight, these classifications are further stratified based on
ambulatory (Amb) or non-ambulatory (Non-Amb) status, having a
corresponding dose range, alternative range and target dose for
each; and, when fixed dose deflazacort therapy is administered in
the presence of a CYP inhibitor (CYP Inh), the dose range and
target dose represent a 3-4 fold decrease in the dose range and
target dose for each classification, where applicable; or, when
therapy is administered in the presence of a CYP inducer (CYP Ind),
the dose range and target dose represent a 3-4 fold increase in the
dose range and target dose for each classification, where
applicable.
TABLE-US-00001 TABLE 1 Age (years old) Weight (kg) Dose (mg)
.ltoreq.11 >11-18 >18 .ltoreq.16 >16-.ltoreq.30 .ltoreq.30
>30 >30-.ltoreq.50 >50 Exemplary 6-36 30-72 36-72 6-18
18-36 6-36 24-96 24-66 42-96 24-48, 24-72, 36-48, 24-48, 36-54,
36-54, 24-54, 30-36, 36-60, 36-60, 30-42, 30-48, 42-60, 36-72,
36-48, 42-60, 30-54, 42-66, 6-12, 36-96, 36-54, 42-66, 36-54,
42-72, 6-18, 42-60, 36-60, 42-72, 36-60, 48-54, 6-30, 42-66, 36-66,
48-54, 36-72, 48-72, 12-18, 42-72, 42-54, 48-66, 6-12, 42-60,
54-60, 12-24, 42-96, 42-60, 48-72, 6-30, 42-66, 54-66, 18-24,
48-54, 42-66, 48-96, 12-24, 42-72, 54-72, 18-30, 48-72, 48-54,
54-60, 18-24, 48-54, 60-66, 18-24, 18-36, 48-96, 48-66, 54-66,
Alternative 20-36, 48-72, 60-72, 6-12, 24-30, 24-30, 54-72, 54-60,
54-72, Range 24-36 54-72 66-72 12-18 24-36 24-36 54-96 54-66 54-96
36, 42, 48, Target 18, 24 36, 42, 48 54, 60, 66 12 18, 24, 30 18,
24 36, 42, 48 36 48, 54, 60 Amb Range 6-18 30-60 36-72 6-18 18-30
12-36 24-60 24-54 48-72 24-48, 24-54, 36-54, 30-42, 36-60, 36-48,
30-36, 42-60, 36-54, 24-48, 30-48, 42-66, 36-60, 30-42, 30-54,
42-72, 12-24, 36-66, 36-48, 48-54, 36-54, 48-54, 12-30, 42-54,
36-54, 48-60, 36-60, 48-72, 18-24, 42-60, 36-66, 48-66, 42-60,
54-60, 18-30, 48-54, 42-54, 54-60, Alternative 6-12, 48-54, 54-66,
6-12, 18-24, 18-36, 48-60, 42-60, 54-66, Range 12-18 54-60 54-72
12-18 24-30 24-36 54-60 48-54, 54-72 Amb Target 18 36 42 12 24 18
36 36 48, 54 Non-Amb Range 12-30 36-72 48-96 12-24 24-36 18-54
30-72 30-66 54-96 30-36, 36-54, 30-42, 36-60, 30-48, 30-36, 36-66,
30-54, 30-60, 42-54, 36-48, 36-54, 42-60, 36-54, 36-60, 42-66,
48-54, 18-24, 36-72, 42-54, 42-72, 48-60, 18-30, 42-54, 42-60,
12-18, 48-54, 48-72, 18-36, 42-60, 42-66, 54-90, 12-24, 48-60,
54-60, 24-36, 42-66, 48-54, 60-90, Alternative 18-24, 48-66, 54-72,
12-18, 24-30, 24-48, 48-54, 48-66, 66-84, Range 18-30 48-72 54-96
18-24 30-36 24-54 54-72 54-66 72-96 Non-Amb Target 18, 24 36, 42
54, 66 18 30 24 42 42 54, 66 CYP Inh Range Exemplary 6-12 12-24
12-32 6-12 6-12 6-12 12-32 12-32 12-32 Target 6 12 18 6 6 6 18 18
18 Amb Range 6-12 6-18 12-24 6-12 6-12 6-18 6-18 6-18 12-24 Amb
Target 6 12 18 6 6 12 12 12 18 Non-Amb Range 12-18 12-24 54-96 6-12
6-12 6-12 6-18 6-12 18-24 Non-Amb Target 12 18 54 12 12 12 12 12 18
CYP Ind Range Exemplary 18-108 90-216 108-288 18-54 54-108 18-108
72-288 72-198 126-288 Target 66 162 198 36 84 66 180 138 210 Amb
Range 18-48 90-162 108-216 18-48 18-48 54-72 72-108 108-144 144-192
Amb Target 24 90 126 24 42 66 90 126 168 Non-Amb Range 36-90 90-216
144-288 36-72 60-96 72-96 96-126 126-168 162-216 Non-Amb Target 66
162 216 66 78 84 114 150 192
[0053] In any of the aspects described herein, the therapy may
comprise administering a fixed dose daily, on alternative days, on
two consecutive days per week (e.g., weekends only), or for a
period of time followed by a dosing reprieve of similar length
(e.g., administering the fixed dose each day for ten days, not
administering deflazacort for the following ten days, then
optionally resuming administration). When dosing on alternative
days, the deflazacort fixed dose would be about the same or about
double (Two-Fold; 2.times.) the daily doses for the aspects
described herein. For example, in one aspect, wherein the subject
is aged 4-11 years and is ambulatory, and a fixed daily dose of 18
mg is selected, a dose of 36 mg would be selected for dosing on
alternative days. When dosing two days per week, the deflazacort
fixed dose would be about three to about ten times (e.g., six
times, 6.times.) the daily doses described in the aspects provided
herein. In one example, the subject is aged >11-18 years, weighs
more than 75 kg and is non-ambulatory, a daily dose of 66-96 mg may
be selected. In another example, the subject is aged 4-11 years,
weighs more than or equal to 16 kg and less than 30 kg, and is
ambulatory, a daily dose of 18 mg is selected. For the same dose
taken twice weekly, dosing optionally is selected from 54-180 mg
per administration (e.g., 114 mg per administration). When
deflazacort is given for a period of time followed by a dosing
reprieve of similar length, the dose would be similar to or up to
three times higher than the daily doses in the aspects described.
Any route of administration appropriate for deflazacort delivery is
appropriate for use in the context of the invention, including oral
or parenteral (e.g., intramuscular or intravenous) routes of
administration.
[0054] In addition to providing fixed dose regimens for subjects
based on age or weight class, the disclosure provides for improved
regimens based on ambulatory status and CYP usage. Ambulatory
status and CYP usage are described further below. Exemplary fixed
dose regimens are provided in Table 1, which is provided merely to
illustrate various aspects of the disclosure and is not meant to be
limiting. In various aspects of the invention, subject
classifications based on age or weight class are further stratified
based on ambulatory status.
[0055] In another aspect, deflazacort therapy comprises,
administering a fixed daily dose of deflazacort based on patient
weight, ambulatory status and CYP inhibitor or inducer usage
according to the regimen shown in Table 1a.
TABLE-US-00002 TABLE 1a Ambulatory/ Non-Ambulatory/ CYP-Inhibitor/
CYP-Inhibitor/ CYP-Inducer CYP-Inducer Weight (mg/day) (mg/day)
.ltoreq.30 kg 18/6/54-72 24/6-12/72-96 mg/day 30 kg-.ltoreq.50 kg
36/12/108-144 mg/day 42/6-12/126-168 mg/day >50 kg
48/12-18/144-192 mg/day 54/18-24/162-216 mg/day
[0056] In another aspect, deflazacort therapy comprises,
administering a fixed daily dose of deflazacort based on patient
weight and ambulatory status according to the regimen shown in
Table 1b.
TABLE-US-00003 TABLE 1b Weight Ambulatory Non-Ambulatory .ltoreq.30
kg 18 mg/day 24 mg/day >30 kg-.ltoreq.50 kg 36 mg/day 42 mg/day
>50 kg 48 mg/day 54 mg/day
[0057] In another aspect, Table 1c compares the weight based,
standard-of-care (SOC) Current Dosing Table with a fixed dose
deflazacort therapy.
[0058] In this aspect, the rows in Table 1c that are shaded and
repeated represent those narrow weight ranges in the Current Dosing
Table where they bridge the broader fixed dose deflazacort therapy
weight ranges. Based on the factors considered in the clinical
simulations described herein, the differences in ambulatory status
(wherein Amb represents an Ambulatory subject and Non-Amb
represents a Non-Ambulatory subject, each at a dose in mg/day) show
that a higher dose is recommended for a Non-Ambulatory subject
compared to an Ambulatory subject. In one example comparing Table 1
and Table 1c, for an ambulatory subject having an age less than or
equal to 11 years of age and a weight less than or equal to 16 kg,
Table 1 suggests an Ambulatory Range (Amb Range) dose of from 6 to
18 mg/day, which is lower than the Table 1 Exemplary Dose of from 6
to 36 mg/day, not covered in the Table 1c Current Dosing Table and
inclusive (at the higher end) of the claimed fixed dose therapy.
The result of clinical trial simulations shown in FIG. 6 and
exemplified in FIG. 17, however, predict that the lower dose for
the Table 1 Ambulatory Range will be, in the long term, an
efficacious therapeutic dose while reducing the amount of adverse
events compared to the 0.9 mg/kg/day dose of the Current Dosing
Table and retaining muscle strength longer compared to the 1.2
mg/kg/day dose of the Current Dosing Table. Table 1c shows that the
fixed dose therapy provides a single, comparatively lower daily
dose, replacing the SOC total dose for both the 0.9 mg/kg/day and
1.2 mg/kg/day doses with a less complicated regimen that addresses
the effect of ambulatory status and other factors while maintaining
efficacy and enhancing safety.
[0059] In other words, while the dose ranges in Table 1 for the
age, weight, ambulation and CYP classes are based on the
simulations, they are all expected long-term to mitigate
under-dosing and provide higher doses for non-ambulatory subjects
while balancing safety issues compared to the Current Dosing Chart
shown in Table 1c. It is to be understood by those skilled in the
art that the fixed doses compared in Table 1c with the Current
Dosing Table represent only one example of therapeutic ranges
determined by the clinical simulations to balance long-term
efficacy and safety. It is also to be understood that the fixed
doses exemplified in Table 1c are considered optimal in comparison
to the Current Dosing Chart because they are based on the optimal
three (3) Weight Group simulation results discussed herein.
[0060] For oral administration, deflazacort is, optionally,
formulated as a tablet or an oral suspension. Deflazacort tablets
are supplied at 6 mg, 18 mg, 30 mg or 36 mg strength tablets.
Additional components of a tablet may include, for instance,
colloidal silicon dioxide, lactose monohydrate, magnesium stearate,
and pre-gelatinized corn starch. Deflazacort oral suspension is
supplied at 22.75 mg/mL, as 13 mL in a 20 mL bottle. An oral
suspension may comprise, for example, acetic acid, aluminum
magnesium silicate, benzyl alcohol, carboxymethylcellulose sodium,
polysorbate 80, purified water, and sorbitol. One of ordinary skill
will appreciate that these are merely examples of excipients and
inactive components suitable for oral administration, and
additional or alternative formulations may be used.
[0061] In one aspect, the pharmaceutical composition for use in
providing a fixed dose deflazacort therapy to a subject that is
suffering from Duchenne muscular dystrophy (DMD) comprises, oral
administration of the composition formulated as an oral dosage form
selected from a tablet or an oral suspension.
[0062] In another aspect, the tablet contains an amount of
deflazacort selected from 6 mg, 18 mg, 30 mg or 36 mg in admixture
with excipients selected from colloidal silicon dioxide, lactose
monohydrate, magnesium stearate, and pre-gelatinized corn
starch.
[0063] In another aspect, the oral suspension contains 22.75 mg/mL
of deflazacort in a suspension with acetic acid, aluminum magnesium
silicate, benzyl alcohol, carboxymethylcellulose sodium,
polysorbate 80, purified water, and sorbitol.
[0064] In another aspect, the deflazacort oral suspension contains
13 mL of the suspension in a 20 mL bottle.
Clinical Trial Pharmacokinetic Analysis/Exposure Simulations
[0065] Pharmacokinetic analysis was performed as part of an open
label, Phase 1 single-period study. Twenty-six (26) male DMD
subjects were enrolled, consisting of children (ages 4 up to 12)
and adolescents (ages 12 to 16, inclusive) with at least 12
subjects between the ages of 4 and 12 (children). The primary
objective of the study was characterization of the single-dose and
steady-state PK of deflazacort and its active deflazacort
metabolite (21-desDFZ). The characterization of the PK of the
21-desDFZ metabolite 6.beta.-OH-21-desDFZ was included as a
secondary outcome. A total of 24 subjects (16 children and 8
adolescents) received deflazacort tablets (0.9 mg/kg/day) for 8
days. Blood samples for PK profiles were collected on Days 1 and 8.
All 24 subjects who completed the study had sufficient data to use
in the PK analysis. Plasma 21-desDFZ concentrations were
quantifiable by the time of the first post-dose sample collection
(0.5 hours) in all children and adolescents on Days 1 and 8. Plasma
21-desDFZ concentrations remained above the limit of quantification
in most subjects over the 8-hour sampling window on both study
days.
[0066] On Days 1 and 8, 21-desDFZ exposure parameters were slightly
higher for adolescents compared to children (data not shown).
However, the geometric mean Cmax for adolescents was almost double
that in children on Day 1 and 1.5 fold that in children on Day 8
(FIG. 1). Moreover, the geometric mean AUClast and AUCinf values in
adolescents were roughly 1.5- to 1.6-Fold that in children on Days
1 and 8. The geometric mean terminal elimination half-life values
were also similar between study populations at 1.17 hours in
children and 1.34 hours in adolescents on Day 1.
[0067] There was a trend toward increasing exposure (Cmax, AUClast,
and AUCinf, or AUCtau) with increasing age; however, the child
plasma concentration was consistently below the norm compared to
the adolescent plasma concentration (FIG. 5). This pharmacokinetic
trend was better explained as a function of dose received rather
than age alone (FIG. 5). The dose normalized exposure parameters
(FIG. 4) and the dose dependent parameters: clearance (FIG. 2) and
volume of distribution (FIG. 4), though, were consistent between
children and adolescents.
[0068] Plasma 6.beta.-OH-21-desDFZ (primary, inactive metabolite of
21-desDFZ) concentrations were quantifiable by the time of the
first post-dose sample collection (0.5 hours) in all children and
adolescents on Days 1 and 8. Plasma 6.beta.-OH-21-desDFZ
concentrations remained above the limit of quantification in most
subjects over the 8-hour sampling window on both sampling days. On
Days 1 and 8, 6.beta.-OH-21-desDFZ exposure parameters were
slightly higher for adolescents compared to children. The geometric
mean Cmax for adolescents was roughly 1.25-Fold that in children on
Day 1 and 1.30-Fold that in children on Day 8. Geometric mean
AUClast and AUCinf values in adolescents were roughly 1.25-Fold
that in children on Days 1 and 8. The geometric mean terminal
elimination half-life values were also similar between study
populations at 1.63 hours in children and 1.72 hours in adolescents
on Day 1.
[0069] Children and adolescents in the study were administered the
same doses for 7 days, 0.9 mg/kg/day; however, the exposures to
21-desDFZ after administration of deflazacort on Days 1 and 8 were
markedly decreased in children compared to adolescents (See FIG. 1
for Day 8 plasma concentration-time curves, Day 1 data not shown).
However, these differences were more a function of total dose
received (FIG. 4) rather than differences between patient
populations as the dose-dependent parameters, CL and Vd were
similar between children and adolescents (FIGS. 2 and 3). Simulated
plasma exposures to 21-desDFZ after a 0.9 mg/kg/day dose of
deflazacort and a 1.2 mg/kg/day dose of deflazacort resulted in
nearly equivalent plasma exposures (FIG. 6). The pharmacokinetic
data from this patient population showed that the youngest patients
are at risk for the greatest variance in total dose administered in
relation to the target, weight-based dose of 0.9 mg/kg/day. Review
of the total doses of deflazacort administered to the youngest
children with DMD (of lowest weight) demonstrated a considerable
number of patients were under-dosed. The clinical pharmacokinetic
data of 21-desDFZ after oral administration of deflazacort showed
that children clear 21-desDFZ to the same extent as adolescents and
similar to adults (FIGS. 1-5).
[0070] These data support the use of a simplified, fixed-dose
regimen to more appropriately administer a deflazacort therapy to
subjects with DMD, particularly subjects 11 years of age and
younger. Based on the properties of deflazacort within the child
and adolescent populations, a simplified, fixed dose regimen
provides more appropriate exposures of the active 21-desDFZ
deflazacort metabolite across age groups.
Clinical Trial Simulations
[0071] Exposure-response clinical trial simulations, modeling both
efficacy and safety endpoints, were employed to identify fixed dose
regimens of deflazacort treatment to children and adolescents with
DMD to maximize exposure to the active metabolite and manage
potential adverse side effects.
[0072] First, for each subject, a random sample was taken from the
Dose-normalized AUC from a clinical trial and multiplied by a
random sample of the body weight from the CDC height and weight
charts for children and by the dosing regimen proposed (e.g.,
Current Dosing Table or each fixed dose). Second, depending on the
AUC, the subject was assumed to have efficacy and safety similar to
deflazacort 0.9 mg/kg, deflazacort 1.2 mg/kg, or placebo as
illustrated in FIG. 6. Third, each subject was given values for the
change in muscle strength at 12 or 52 weeks (FIG. 7 and FIG. 8,
respectively), and allocated as a non-ambulatory FVC responder at
52 weeks (yes/no) (FIG. 9), experiencing weight gain at 52 weeks
(yes/no) (FIG. 10), and experiencing Cushingoid Syndrome at 52
weeks (yes/no) (FIG. 11). This was achieved by randomly selecting
from distributions (developed from previous study results plus
uncertainty). Fourth, steps 1-3 were conducted assuming 50
subjects/arm for placebo, prednisone and 10 different fixed-dose
schemes of deflazacort. Fifth, 10,000 clinical trials were
simulated, and safety and efficacy were summarized.
[0073] The dosing regimens shown in FIGS. 7-16 were simulated
according to the clinical trial treatment arm classifications:
Placebo, Prednisone, Current Dosing Table, Age Group Dosing, Weight
Group Dosing, Combined Ambulatory Status and Age Group Dosing,
Combined Ambulatory Status and Weight Group Dosing and Positive
Control High Dosing, where simulated data in each Figure shows
results as follows according to the groupings:
[0074] [A] Current Dosing Table currently used to approximate 0.9
mg/kg;
[0075] [B] Dosing based on age groups: [0076] Two (2) Age Groups
(Lower Doses): .ltoreq.11 yr=18 mg, >11 yr=36 mg; [0077] Two (2)
Age Groups (Higher Doses): .ltoreq.11 yr=24 mg, >11 yr=42
mg;
[0078] [C] Dosing based on weight groups: [0079] Two (2) Weight
Groups (Lower Doses): .ltoreq.30 kg=18 mg, >30 kg=36 mg; [0080]
Two (2) Weight Groups (Higher Doses): .ltoreq.30 kg=24 mg, >30
kg=42 mg; [0081] Three (3) Weight Groups: .ltoreq.30 kg=18 mg,
30-.ltoreq.50 kg=36 mg, >50 kg=48 mg; [0082] Four (4) Weight
Groups: .ltoreq.16 kg=12 mg, 16-.ltoreq.30 kg=24, 30-.ltoreq.50
kg=42, >50 kg=54 mg;
[0083] [D] Dosing based on ambulatory status (Amb or Non-Amb) and
two (2) Age Groups: [0084] Amb & .ltoreq.11 yr=18 mg, [0085]
Amb & .gtoreq.11 yr=36 mg, [0086] Non-Amb & .ltoreq.11
yr=24 mg, [0087] Non-Amb & .ltoreq.11 yr=42 mg;
[0088] [E] Dosing based on ambulatory status (Amb or Non-Amb) and
two to four (2-4) Weight Groups: [0089] Two (2) Weight Groups:
[0090] Amb & .ltoreq.30 kg=18 mg, [0091] Amb & .gtoreq.30
kg=36 mg; [0092] Non-Amb & .ltoreq.30 kg=24 mg, [0093] Non-Amb
& .gtoreq.30 kg=42 mg; [0094] Three (3) Weight Groups: [0095]
Amb & .ltoreq.30 kg=18 mg, [0096] Amb & 30-.ltoreq.50 kg=36
mg, [0097] Amb & >50 kg=48 mg; [0098] Non-Amb &
.ltoreq.30 kg=24 mg, [0099] Non-Amb & 30-.ltoreq.50 kg=42 mg,
[0100] Non-Amb & .gtoreq.50 kg=54 mg; [0101] Four (4) Weight
Groups: [0102] Amb & .ltoreq.16 kg=12 mg, [0103] Amb &
16-.ltoreq.30 kg=24 mg, [0104] Amb & 30-.ltoreq.50 kg=42 mg,
[0105] Amb & .gtoreq.50 kg=60 mg; [0106] Non-Amb &
.ltoreq.16 kg=18 mg, [0107] Non-Amb & 16-.ltoreq.30=30 mg,
[0108] Non-Amb & 30-.ltoreq.50 kg=48 mg, [0109] Non-Amb &
.gtoreq.50 kg=66 mg.
[0110] The overall results for dosing regimens not related to
ambulatory status are described in FIG. 17 and illustrated in FIGS.
7-11. In general, most dosing regimens yield similar changes in
muscle strength, FVC, weight gain, and Cushingoid Syndrome. While
still acceptable in certain aspects, there may be a loss of
efficacy with two (2) Age Groups (Lower Doses) and two (2) Weight
Groups (Lower Doses) (for both muscle strength and FVC) and an
increase in the incidence of weight gain and Cushingoid Syndrome
with two (2) Age Groups (Higher Doses), two (2) Weight Groups
(Higher Doses), and four (4) Weight Groups.
[0111] As shown in FIG. 17, clinical trial simulation results
(n=10,000) of the control arms and the recommended simplified
dosing regimen using the overall DMD population are presented. It
is important to note that there were only very small differences
seen among the various simplified dosing regimens. Simulations
replicating results from the pivotal Griggs study showed that 1.2
mg/kg/day SOC dose regimen had a greater average change in muscle
strength than the 0.9 mg/kg/day SOC dose regimen at 12 weeks (0.310
vs 0.185, respectively), a slightly greater proportion of FVC
responders at 52 week (0.636 vs 0.626, respectively), but a
slightly lower average change in muscle strength at 52 weeks (0.369
vs 0.424, respectively). The proportion of subjects with weight
gain or Cushingoid Syndrome adverse events (AEs) was higher for the
1.2 mg/kg/day dose group than the 0.9 mg/kg/day dose group at 52
weeks (weight gain:0.328 vs 0.286, respectively, and Cushingoid
Syndrome AEs: 0.687 vs 0.600, respectively). Because all of the
deflazacort dosing simulations were randomly sampled from these
distributions, these values define the range of the deflazacort
simulation results for each simplified dosing regimen. Placebo data
was only available for the 12-week change in muscle strength, and
as expected, the results showed a slight decline in muscle strength
(average change of -0.072). Efficacy predictions for prednisone
ranked it much lower than the deflazacort 0.9 mg/kg/day for the 52
week change in muscle strength (mean change of 0.212 and 0.424 for
prednisone and deflazacort 0.9 mg/kg/day, respectively) and FVC
responders (response rate of 0.365 and 0.626, respectively), but
higher than the 0.9 mg/kg/d deflazacort for 12-week change in
muscle strength (mean change of 0.278 and 0.185, respectively).
Prednisone was also predicted to have a higher proportion of
subjects with weight gain or Cushingoid Syndrome AEs than
deflazacort 0.9 mg/kg/day.
[0112] FIG. 17 shows that results from the clinical trial
simulations using the Current Dosing Table were within the ranges
defined by the replicated results from the deflazacort 0.9
mg/kg/day SOC dose regimen, but were slightly lower for the average
52 week change in muscle strength (0.396 and 0.424 for the fixed
dose regimen and 0.9 mg/kg/day for the SOC regimen, respectively)
and the 52 week FVC responders (0.600 and 0.626, respectively). The
results of the positive control (54 mg deflazacort to all subjects)
predicted higher 12-week change in muscle strength and FVC
responders, but both regimens predicted a higher proportion of
subjects with AEs. These results indicate the clinical trial
simulation methodology (including assumptions) was functioning as
expected. The simplified dosing regimen (not taking ambulatory
status into account) that optimally balanced efficacy and safety
was based on dosing deflazacort using the three (3) Weight Groups
(.ltoreq.30 kg=18 mg, >30<50 kg=36 mg, >50 kg=48 mg)
regimen. This regimen predicted slightly less (4%) efficacy to the
Current Dosing Table (0.205 vs 0.214) for 12 week change in muscle
strength, but comparable efficacy at 52 weeks (0.397 vs 0.396) for
52 week change in muscle strength, and 0.598 vs 0.600 for FVC
responders, respectively), while predicting comparable or slightly
lower AEs (0.290 vs 0.293 for weight gain, and 0.607 vs 0.613 for
Cushingoid Syndrome AEs, respectively). Comparing this dosing
regimen with replicated results from the SOC deflazacort 0.9
mg/kg/day and deflazacort 1.2 mg/kg/day dosing regimen suggests
that the proportion of subjects with weight gain or Cushingoid
Syndrome AEs would be comparable to deflazacort 0.9 mg/kg/day
(within 1%) while producing changes in muscle strength better than
deflazacort 1.2 mg/kg/day at 12 weeks, but slightly (about 6-7%)
less than 0.9 mg/kg/day at 52 weeks and slightly (<6%) lower FVC
responder rates.
[0113] The results for dosing regimens which are dependent on
ambulatory status are described in FIG. 18 and illustrated in FIGS.
12-16. In general, most dosing regimens yield similar changes in
muscle strength, FVC, weight gain, and Cushingoid Syndrome. Four
(4) Weight Groups by ambulatory status resulted in greater efficacy
and greater incidence of weight gain or Cushingoid Syndrome.
[0114] Simulation results of the control arms and the recommended
simplified dosing regimens for the DMD population stratified by
ambulation status are shown in FIG. 18. Once again, there were only
very small differences seen among the various dosing regimens.
Because clinical trial simulations stratified by ambulatory status
randomly sampled efficacy and safety results and weight
distributions from simulations based on ambulatory status, the
absolute values of the endpoints in FIG. 18 for the simulated
clinical trial arms (Current Dosing Table, Placebo and prednisone)
are different from those described in FIG. 17. Therefore, the
simplified fixed dose regimen simulations by ambulatory status
should only be interpreted relative to the Current Dosing Table
shown in Table 1c. Results of the clinical trial simulations
stratified by ambulatory status revealed that using simplified
dosing regimens based on ambulatory status and two (2) Weight
Groups, or three (3) Weight Groups both yielded comparable results
to each other and the Current DFZ Dosing Table.
Conclusions from Clinical Trial Pharmacokinetic Analysis/Exposure
Simulations
[0115] Clinical trial simulations were conducted to assess whether
a simplified fixed dose deflazacort regimen would produce
comparable safety and efficacy to the Current Dosing Table as well
as comparable results from Phase 3 studies using the SOC 0.9
mg/kg/day regimen in pediatric patients with DMD. The concepts from
the FDA's Exposure-Response Guidance (2003) were used in the
analyses. There have been numerous examples where modeling and
simulation have led to approved doses not studied in a Phase 3
clinical study, including: pasireotide in Cushings' disease (Yu
2016), mirabegron in the treatment of overactive bladder (Huang
2013, Astellas 2015) and clevidipine in the treatment of
hypertension (Lee 2011), among others. Because both exposure and
response were not available in the same subjects receiving
deflazacort, the clinical trial simulations show how utilizing
safety and efficacy data from pivotal studies can be linked to dose
normalized PK data to predict safety and efficacy outcomes for a
simplified fixed dose regimen.
[0116] The first important finding from the analysis was that there
was substantial overlap in the predicted 21-desDFZ AUC following
administration of deflazacort 0.9 mg/kg/day and 1.2 mg/kg/day (FIG.
6). This large overlap between doses is the fundamental reason for
similar efficacy and safety results from clinical trial simulations
of numerous dosing paradigms, with only minor differences predicted
between regimens actually used. Therefore, there is no real
clinical need for an extensive dosing table (as exemplified by the
Current Dosing Table) to target deflazacort 0.9 mg/kg/day, which
may introduce errors in dosing because of its complexity.
[0117] To determine the optimal simplified dosing regimen, a number
of simplified dosing regimens describe herein were assessed.
Whether or not ambulatory status was taken into account, the
results of the simulations honed in on a simplified dosing regimen
using three (3) weight groups to provide an optimal balance of
efficacy and safety comparable to the results using the Current
Dosing Table. While the results for the dosing regimen based on
ambulatory status and two (2) weight groups (Amb & .ltoreq.30
kg=18 mg, Non-Amb & .ltoreq.30 kg=24 mg, Amb & >30 kg=36
mg, Non-Amb & >30 kg=42 mg) were very similar to the dosing
regimen based on ambulatory status and three (3) weight groups, use
of the three (3) weight groups better accounts for the fact that
DMD patients are more likely to live into adulthood and require
continued treatment. With regards to doses administered to
non-ambulatory subjects, the current clinical practice maintains or
reduces the deflazacort dose to patients after they become
non-ambulatory. However, these simulations show that modestly
increasing the dose administered to non-ambulatory patients is
likely to increase efficacy (muscle strength and/or pulmonary
function). Thus, the clinical trial simulations suggest that a
change in clinical practice of dosing deflazacort to non-ambulatory
patients should be considered.
[0118] Another important finding of the clinical trial simulations
is that a simplified dosing regimen using three (3) Weight Groups
are predicted to have a lower probability of exceeding the
exposures simulated for clinical use than dosing according to the
Current Dosing Table (7.91% vs 11.4% not accounting for ambulatory
status; 11.5% vs 16.1% by ambulatory status). This finding suggests
that simplifying the dosing regimen is unlikely to result in
differences in safety compared to the Current Dosing Table. Thus,
like the examples of mirabegron (Huang 2013; Astellas 2015),
clevidipine (Lee 2011) and pasireotide (Yu 2016), modeling and
simulation has identified more reasonable dosing regimens that
improve the benefit/risk profile of deflazacort, without exposing
subjects to higher exposures of deflazacort and increased risk.
Accordingly, the clinical trial simulation data described herein
demonstrate that a fixed-dose regimen (mg/day) based on three (3)
weight groups and consideration of ambulatory status to provide a
more consistent, simplified deflazacort dosing regimen than the
Current Dosing Table.
CYP3A Inducers and Inhibitors
[0119] This disclosure further provides a deflazacort therapy
comprising, administering to a subject in need thereof a
therapeutically effective amount of deflazacort and avoiding
administration of an inducer or inhibitor of cytochrome P450 3A
(CYP3A), such as CYP3A4 (EC 1.14.13.97). The cytochrome P450 family
of proteins comprises monooxygenases involved in drug metabolism
and synthesis of biomolecules. In various aspects, the CYP3A4
inducer may be a moderate or strong CYP3A4 inducer. For CYP
enzymes, the FDA generally defines a "strong inducer" as one that
caused a .gtoreq.80% decrease in plasma AUC in clinical
evaluations. Examples of strong inducers identified by the FDA
include, e.g., avasimibe, carbamazepine, phenytoin, rifampin, and
St. John's wort. U.S. Food and Drug Administration, Development and
Drug Interactions: Table of Substrates, Inhibitors and Inducers,
available at
www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInt-
eract ionsLabeling/ucm093664.htm. The FDA generally defines a
"moderate inducer" as one that caused a 50-80% decrease in AUC in
clinical evaluations. Examples of moderate inducers include, but
are not limited to, bosentan, efavirenz, etravirine, modafinil, and
nafcillin. Other examples of CPY3A inducers include, but are not
limited to, phenobarbital, primidone, aminoglutethimide, phenytoin,
oxcarbazepine, nevirapine, quercetin, capsaicin, bexarotene,
dexamethasone, fosphenytoin, griseofulvin, rifabutin, and
rifapentine.
[0120] In various aspects, the CYP3A4 inducer is a rifamycin
antibiotic. Rifamycins are well characterized in the art, and have
been proposed to act via inhibition of DNA-dependent RNA polymerase
in bacteria. Examples of rifamycin antibiotics include, e.g.,
rifampin (also known as rifampicin), rifabutin, rifapentine, and
rifaximin. In one aspect, the therapy comprises administering to a
subject in need thereof a therapeutic amount of deflazacort and
avoiding rifampin administration. In various aspects of the
disclosure, the subject is in need of antibiotic therapy, such as a
subject suffering from infection, e.g., a respiratory infection,
which is a common complication of muscular dystrophy.
[0121] A "subject in need thereof" is a subject suffering from a
disorder or condition responsive to deflazacort, such as DMD. In a
particular aspect, the disorder or condition responsive to
deflazacort is DMD. The subject is optionally 18 years or less in
age. In various aspects, the subject also is in need of treatment
with a CYP3A4 inducer or inhibitor. The term "therapeutically
effective amount" refers to an amount of deflazacort sufficient to
treat, ameliorate, or prevent an identified disease or condition
that is responsive to deflazacort, or to exhibit a detectable
therapeutic, prophylactic, or inhibitory effect on symptoms. For
example, in patients suffering from DMD, a therapeutic effective
amount is that which delays the onset of proximal muscle weakness
of the legs and pelvis, loss of muscle mass, or fibrosis, or
maintains the subject's ability to sit, stand independently, and
walk. In various aspects, the therapeutically effective amount is
determined using a combination of one or more factors selected from
subject age, weight, ambulatory status and the presence or absence
of an inducer or inhibitor of cytochrome P450 3A (e.g.,
CYP3A4).
[0122] An exemplary dose range based on age may be selected from
6-36, 30-72 or 36-72 mg/day; having alternative dose ranges
selected from 6-12, 6-30, 12-24, 18-24, 20-36, 24-36, 30-36, 30-48,
30-54, 36-54, 36-60, 36-72, 42-60, 42-66, 42-72, 48-54, 48-72,
54-60, 54-66 or 54-72 mg/day; and, having target doses selected
from 18, 24, 36, 42, 48, 54, 60 or 66 mg/day; or, an ambulatory
dose range based on age may be selected from 6-18, 30-60 or 36-72
mg/day; having alternative dose ranges selected from 6-12, 12-18,
30-36, 30-48, 30-54, 36-54, 36-60, 42-60, 42-66, 42-72, 48-54,
48-72, 54-60, 54-66 or 54-72 mg/day; and, having target doses
selected from 18, 36 or 42 mg/day; or, a non-ambulatory dose range
based on age may be selected from 12-30, 30-54 or 48-96 mg/day;
having an alternative dose range selected from 12-18, 12-24, 18-24,
18-30, 30-36, 30-42, 36-54, 42-54, 48-54, 48-60, 48-72, 54-60,
54-72 or 54-96 mg/day; and, having target doses selected from 18,
24, 36, 42, 54 or 66 mg/day.
[0123] An exemplary dose range based on weight may be selected from
6-18, 6-36, 18-36, 24-66, 24-96 or 42-96 mg/day; having alternative
dose ranges selected from 6-12, 6-18, 6-30, 12-18, 12-24, 18-24,
18-30, 18-36, 24-30, 24-36, 24-48, 24-54, 24-72, 30-42, 36-48,
36-54, 36-60, 36-66, 36-72, 36-96, 42-54, 42-60, 42-66, 42-72,
48-54, 48-66, 48-72, 48-96, 54-60, 54-66, 54-72 or 54-96 mg/day;
and, having target doses selected from 12, 18, 24, 30, 36, 42, 48,
54 or 60 mg/day; or, an ambulatory dose range based on weight may
be selected from 6-18, 12-36, 18-30, 24-60, 24-54 or 48-72 mg/day;
having alternative dose ranges selected from 6-12, 12-18, 12-24,
12-30, 18-24, 18-30, 18-36, 24-30, 24-36, 24-48, 24-54, 30-42,
36-48, 36-54, 36-60, 36-66, 42-54, 42-60, 48-54, 48-60, 48-66,
54-60, 54-66 or 54-72 mg/day; and, having target doses selected
from 12, 18, 24, 36, 48 or 54 mg/day; or, a non-ambulatory dose
range based on weight may be selected from 12-24, 18-54, 24-36,
30-66, 30-72, or 54-96 mg/day; having alternative dose ranges
selected from 12-18, 18-24, 18-30, 18-36, 24-30, 24-36, 24-48,
24-54, 30-36, 30-42, 30-48, 30-54, 30-60, 36-48, 36-54, 36-60,
36-72, 42-54, 42-60, 42-66, 48-54, 48-66, 54-66, 54-90, 60-90,
66-84, or 72-96 mg/day; and, having target doses selected from 18,
24, 30, 42, 54 or 66 mg/day.
[0124] In alternative aspects, the therapeutically effective amount
is any of the fixed dosages described herein. It will be
appreciated that the instant disclosure provides a therapy for
treating DMD in an appropriate subject by administering a
corresponding fixed dose referenced herein, as appropriate for any
particular aspect. Use of deflazacort in a method of treatment
(e.g., a method of treating DMD), and use of any of the dosages of
deflazacort referenced herein in the preparation of a medicament
also is provided.
[0125] In various aspects of the disclosure, the therapy comprises
avoiding administration of CYP3A inducer (such as a CYP3A4 inducer,
e.g., rifampin) or a CYP3A inhibitor (such as a CYP3A4 inhibitor).
"Avoiding" is used in accordance with its customary meaning to
mean, e.g., "refraining from." In some aspects, the therapy
comprises discontinuing administration of the CYP3A inducer
throughout the entire course of treatment with deflazacort. For
example, the CYP3A inducer (e.g., rifampin) is discontinued at the
time that administration of deflazacort begins. In other aspects,
the CYP3A inducer is discontinued within at least three days to 1
month prior to or after starting deflazacort therapy. Avoiding
co-administration of deflazacort and the CYP3A inducer (i.e.,
avoiding administration of the two agents within 24 hours of each
other) also is contemplated. When the administration regimen
includes a dosing reprieve (e.g., ten days of deflazacort treatment
followed by ten days of no deflazacort administration), the CYP3A4
inducer is optionally administered during the period of
reprieve.
[0126] The deflazacort therapy administered to a subject in need
thereof can be improved by, for example, advising the subject that
co-administration of deflazacort with a CYP3A4 inducer can alter
the therapeutic effect of deflazacort. In some aspects, the subject
is advised that a CYP3A4 inducer, such as a CYP3A4 inducer (e.g.,
rifampin) should be avoided or discontinued. Avoiding a CYP3A4
inducer, e.g., avoids reduced (decreased) exposure to the active
metabolite of deflazacort, 21-desDFZ, or the potential for reduced
exposure to 21-desDFZ.
[0127] The disclosure also provides a deflazacort therapy
comprising, administering to a subject in need thereof a
therapeutically effective amount of deflazacort and avoiding
administration of an inhibitor of CYP3A, such as CYP3A4. For CYP
enzymes, the FDA generally defines a "strong inhibitor" as one that
causes a >5-Fold increase in the plasma AUC values or more than
80% decrease in clearance of CYP substrates (not limited to
sensitive CYP substrate) in clinical evaluations. The FDA generally
defines a "moderate inhibitor" as one that causes a >2-Fold but
<5-Fold increase in the AUC values or 50-80% decrease in
clearance of sensitive CYP substrates when the inhibitor is given
at the highest approved dose and the shortest dosing interval in
clinical evaluations. Examples of strong CYP3A inhibitors
identified by the FDA include, for example, boceprevir,
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole,
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and
voriconazole. Examples of moderate CYP3A inhibitors identified by
the FDA include, for example, amprenavir, aprepitant, atazanavir,
ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin,
fluconazole, fosamprenavir, imatinib, and verapamil.
[0128] In various aspects of the disclosure, the therapy comprises
discontinuing administration of a CYP3A4 inducer or inhibitor prior
to starting deflazacort therapy. In some aspects, the CYP3A4
inducer or inhibitor is discontinued within one month prior to
starting deflazacort therapy, within three weeks, within two weeks,
or within one week prior to starting deflazacort therapy, or at the
same time as starting deflazacort therapy. In other aspects, the
CYP3A4 inducer or inhibitor is discontinued in response to starting
deflazacort therapy and is discontinued within one week after
starting deflazacort therapy.
[0129] In one aspect, the selection of factors used to determine
the effective fixed target dose to be administered includes the
presence or absence of an inducer or inhibitor of cytochrome P450
3A (CYP3A), in particular, concomitant administration of a CYP3A4
inducer, concomitant administration of a CYP3A4 inhibitor or
concomitant administration of a P-glycoprotein (Pgp) inhibitor.
[0130] In another aspect, the CYP3A4 inducer is a moderate or
strong CYP3A4 inducer.
[0131] In another aspect, the CYP3A4 inducer is a moderate CYP3A4
inducer and the dosage of deflazacort is increased about Two-Fold
to about Three-Fold.
[0132] In another aspect, the CYP3A4 inducer is a strong CYP3A4
inducer and the dosage of deflazacort is increased about Four-Fold
to about Six-Fold.
[0133] In another aspect, the CYP3A4 inhibitor is a moderate or
strong CYP3A4 inhibitor.
[0134] In another aspect, the CYP3A4 inhibitor is a moderate CYP3A4
inhibitor and the dosage of deflazacort is reduced about Two-Fold
to about Three-Fold.
[0135] In another aspect, the CYP3A4 inhibitor is a strong CYP3A4
inhibitor and the dosage of deflazacort is reduced about Three-Fold
to about Four-Fold.
[0136] In another aspect, the fixed dose of deflazacort is reduced
about Three-Fold to about Four-Fold during concomitant
administration of a Pgp inhibitor.
Dosage Modifications
[0137] The disclosure further provides an improved deflazacort
therapy involving dose modifications based on other factors not
generally considered until applied in the therapy described herein.
Previously, clinicians generally did not consider ambulatory status
when determining deflazacort dosage in DMD patients; dosage was
selected only based on weight to achieve a daily mg/kg dose. When
ambulatory status was considered, clinicians generally reduced the
dose of deflazacort or cycled the patient off the drug. Contrary to
previous regimens, the present disclosure provides a deflazacort
therapy to a subject suffering from DMD comprising, increasing the
dosage administered to the subject when the subject loses
ambulation. The terms "loses ambulation" or "becomes
non-ambulatory" refer to the loss of the ability to walk, i.e., the
subject requires a wheel chair. Loss of ambulation status has been
defined a number of ways, but generally its definition includes,
but is not limited to: the inability to walk independently or
without support, a shifting of Grade 1 to Grade 0 on the North Star
Ambulatory Assessment, the ability to perform the 6 minute walk
test, among others. In various aspects, the dosage is increased by
about 6 mg to about 12 mg per day (e.g., 6 mg or 12 mg per day) for
subjects 18 years and under, and up to 24 mg (e.g., 6-24 mg) in
subjects greater than 18 years of age. In various aspects, the
therapy comprises increasing the dosage in the subject at risk of
losing ambulation by 1.2 fold or 1.4 fold.
[0138] For example, in various aspects, when the subject is 30 kg
or less and is ambulatory, the fixed dose is 12-36 mg per day
(e.g., 12-24 mg per day, or 18 mg per day), whereas if the subject
is non-ambulatory, and the fixed dose is 18-54 mg per day (e.g.,
18-36 mg per day, 24-54 mg per day, or 24 mg per day). For various
aspects of the therapy wherein the subject is greater than 30 kg,
the fixed dose of deflazacort for an ambulatory subject is 24-60 mg
per day (e.g., 36 mg per day), whereas the fixed dose for a
non-ambulatory subject is 30-72 mg per day (e.g., 42 mg per day).
For subjects greater than 30 kg and less than or equal to 50 kg,
the fixed dose of deflazacort is optionally 24-54 mg per day (e.g.,
24-48 mg per day, or 36 mg per day) for an ambulatory subject,
whereas it is optionally 30-66 mg per day (e.g., 42 mg per day) for
a non-ambulatory subject. In various aspects wherein the subject is
greater than 50 kg, the fixed dose of deflazacort is optionally
48-72 mg per day (e.g., 54 mg per day or 60 mg per day) if
ambulatory; if the subject is non-ambulatory, the fixed dose of
deflazacort is 54-96 mg per day (e.g., 66 mg per day).
[0139] In various aspects, the deflazacort therapy administered to
a subject in need thereof (e.g., a subject suffering from DMD)
comprises, increasing the dosage of deflazacort administered to the
subject during concomitant administration of a CYP3A inducer (e.g.,
a CYP3A4 inducer). Put another way, optionally, when a treatment
regimen comprises administration of both deflazacort and a CYP3A
inducer, the subject is administered a therapeutically effective
amount of the CYP3A inducer and a dosage of deflazacort that is
increased relative to the dose taken in the absence of the CYP3A4
inducer. In various aspects, the therapy comprises, increasing the
dosage of deflazacort (e.g., any of the fixed doses set forth
herein) about Two-Fold to about Six-Fold during concomitant
administration of a CYP3A4 inducer (e.g., a CYP3A4 inducer such as,
but not limited to, rifampin). For example, in one aspect, the dose
of deflazacort is increased about Two-Fold to about Three-Fold
during concomitant administration of a moderate CYP3A inducer.
Alternatively, the therapy comprises increasing the dosage of
deflazacort about Four-Fold to about Six-Fold during concomitant
administration of a strong CYP3A inducer. To illustrate, in one
aspect, a subject suffering from DMD is being treated with the
strong CYP3A inducer rifampin, the therapy disclosed herein
comprises, increasing the SOC weight-based dose of deflazacort (0.9
mg/kg) to about 3.2-6.4 mg/kg.
[0140] The disclosure further provides a deflazacort therapy
administered to a subject in need thereof (e.g., a subject
suffering from DMD) comprising, reducing the dosage of deflazacort
administered to the subject during concomitant administration of a
CYP3A inhibitor (e.g., CYP3A4 inhibitor). Put another way,
optionally, when a treatment regimen comprises administration of
both deflazacort and a CYP3A inhibitor, the subject is administered
a therapeutically effective amount of the CYP3A4 inhibitor and a
dosage of deflazacort that is reduced relative to the dose taken in
the absence of the CYP3A4 inducer. In various embodiments, the
therapy comprises reducing the dosage of deflazacort (e.g., any of
the fixed doses set forth herein) about Two-Fold to about
Three-Fold during concomitant administration with a CYP3A4
inhibitor. Alternatively, the therapy comprises reducing the dosage
of deflazacort (e.g., any of the fixed doses set forth herein)
about Three-Fold to about Four-Fold during concomitant
administration with a CYP3A4 inhibitor. To illustrate, in one
embodiment, a subject suffering from DMD is being treated with,
e.g., clarithromycin, and the therapy comprises reducing the SOC
weight-based dose of deflazacort (0.9 mg/kg) to about 0.3-0.45
mg/kg. Alternatively, for example, a 36 mg per day dose would be
reduced to a 12 mg per day dose.
[0141] The disclosure further provides a deflazacort therapy to a
subject in need thereof (e.g., a subject suffering from DMD)
comprising, reducing the dosage of deflazacort administered to the
subject during concomitant administration of a P-glycoprotein (Pgp)
inhibitor. In various embodiments, concomitant use of moderate or
strong Pgp inhibitors is avoided. If concomitant use of a moderate
or strong Pgp inhibitor is not avoided, i.e., when a treatment
regimen comprises administration of both deflazacort and a Pgp
inhibitor, the subject is administered a therapeutically effective
amount of the Pgp inhibitor and a dosage of deflazacort that is
reduced relative to the dose taken in the absence of the Pgp
inducer. In various embodiments, the therapy comprises reducing the
dosage of deflazacort (e.g., any of the fixed doses set forth
herein) about Two-Fold to about Three-Fold during concomitant
administration with a Pgp inhibitor. Alternatively, the therapy
comprises reducing the dosage of deflazacort (e.g., any of the
fixed doses set forth herein) about Three-Fold to about Four-Fold
during concomitant administration with a Pgp inhibitor. An
inhibitor of Pgp is, for example, an agent that increases the area
under the curve (AUC) of digoxin to .gtoreq.1.25-fold. Pgp
inhibitors include, for example, Cyclosporine, Elacridar
(GF120918), Ketoconazole, Quinidine, Reserpine, Ritonavir,
Tacrolimus, Valspodar (PSC833), Verapamil, Zosuquidar (LY335979),
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole,
lapatinib, lopinavir, propafenone, quinidine, ranolazine,
saquinavir, telaprevir, and tipranavir.
[0142] "Concomitant administration" is understood to be
interchangeable with concurrent administration or
co-administration. Thus, the term is understood to encompass
administration of two agents simultaneously, or at different times,
and by the same route or by different routes, as long as the agents
are given in a manner that allows both agents to be affecting the
body at the same time. In some embodiments, the subject is already
being administered the CYP3A inducer or inhibitor or Pgp inhibitor.
In other embodiments, the subject is already being administered
deflazacort, CYP3A inhibitor or CYP3A inducer or Pgp inhibitor
therapy is instituted, and the dose of deflazacort is adjusted as
described herein. In related embodiments, the dosage of deflazacort
is increased prior to administration of the CYP3A inducer, or
decreased prior to administration of the CYP3A inhibitor or Pgp
inhibitor.
[0143] The disclosure further provides a method of discontinuing
deflazacort therapy, the method comprising reducing the daily dose
of deflazacort administered to a subject undergoing deflazacort
therapy by no greater than 6 mg every two weeks. Put another way, a
subject administered a first daily dose of deflazacort is
administered a second daily dose of deflazacort for a treatment
period of two weeks, wherein the second daily dose is lower than
the first daily dose, and the reduction in dosage between the first
and second daily doses is no more than 6 mg. The subject optionally
is administered a third daily dose for a second treatment period of
two weeks, wherein the third daily dose is lower than the second
daily dose, and the reduction in dosage between the second and
third daily doses is no more than 6 mg. The two week step-down is
optionally performed until the dosage reaches 0 mg (i.e., treatment
withdrawal is complete).
[0144] All publications, patents and patent applications cited in
this specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference.
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