U.S. patent application number 17/472499 was filed with the patent office on 2022-03-03 for method of providing celiprolol therapy to a patient.
The applicant listed for this patent is Assistance Publique-Hopitaux de Paris (AP-HP). Invention is credited to Michael Frank.
Application Number | 20220062208 17/472499 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-03 |
United States Patent
Application |
20220062208 |
Kind Code |
A1 |
Frank; Michael |
March 3, 2022 |
METHOD OF PROVIDING CELIPROLOL THERAPY TO A PATIENT
Abstract
The present disclosure relates to the field of treatment of an
orphan disease, in particular treatment of vascular Ehlers-Danlos
syndrome (vEDS). More specifically, the present disclosure relates
to novel up-titration dosage regimens (e.g., escalating dosage
regimens) effective for treating vEDS patients with celiprolol.
Inventors: |
Frank; Michael; (Gambais,
FR) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Assistance Publique-Hopitaux de Paris (AP-HP) |
Paris |
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FR |
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Appl. No.: |
17/472499 |
Filed: |
September 10, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16930208 |
Jul 15, 2020 |
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17472499 |
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16184922 |
Nov 8, 2018 |
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16930208 |
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International
Class: |
A61K 31/17 20060101
A61K031/17; A61P 9/00 20060101 A61P009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 21, 2017 |
EP |
17306890.9 |
Claims
1. A method for treating vascular Ehlers-Danlos syndrome,
comprising administering to a patient in need thereof a 80 to 100
mg daily dose of celiprolol, or an equivalent amount of a
pharmaceutically acceptable salt thereof, and increasing the daily
dose to 360 to 440 mg within six months.
2. The method of claim 1, wherein at least a 80 to 100 mg daily
dose increase is made within two months.
3. The method of claim 1, wherein at least a 170 to 210 mg daily
dose increase is made within four months.
4. The method of claim 1, wherein at least a 260 to 310 mg daily
dose increase is made within six months.
5. The method of claim 1, wherein at least a 260 to 310 mg daily
dose increase is made within four months.
6. A method for treating vascular Ehlers-Danlos syndrome,
comprising administering to a patient in need thereof an initial
daily dose of about 91.25 mg celiprolol, or an equivalent amount of
a pharmaceutically acceptable salt thereof, for about 1 month,
followed by administering to the patient a second daily dose of
about 182.5 mg celiprolol, or an equivalent amount of a
pharmaceutically acceptable salt thereof, for about 1 month,
followed by administering to the patient a third daily dose of
about 273.75 mg celiprolol, or an equivalent amount of a
pharmaceutically acceptable salt thereof, for about 1 month,
followed by administering to the patient a fourth daily dose of
about 365 mg celiprolol, or an equivalent amount of a
pharmaceutically acceptable salt thereof.
7. The method of claim 6, wherein the second daily dose is
administered twice daily.
8. The method of claim 7, wherein the fourth daily dose is
administered twice daily.
9. The method of claim 6, wherein the fourth daily dose is
administered for at least 1 year.
10. The method of claim 6, wherein the fourth daily dose is
administered for at least 5 years.
11. The method of claim 1, wherein the patient is 15-years old or
older.
12. The method of claim 1, wherein the treatment is initiated as
soon as vascular EDS is diagnosed, or when the patient is 10 years
old.
13. A method for treating vascular Ehlers-Danlos syndrome,
comprising administering to a patient in need thereof a 90 to 110
mg daily dose of celiprolol hydrochloride and increasing the daily
dose to 360 to 440 mg within six months.
14. The method of claim 13, wherein at least a 90 to 110 mg daily
dose increase is made within two months.
15. The method of claim 13, wherein at least a 180 to 220 mg daily
dose increase is made within four months.
16. The method of claim 13, wherein at least a 270 to 330 mg daily
dose increase is made within six months.
17. The method of claim 13, wherein at least a 270 to 330 mg daily
dose increase is made within four months.
18. A method for treating vascular Ehlers-Danlos syndrome,
comprising administering to a patient in need thereof an initial
daily dose of about 100 mg celiprolol hydrochloride for about 1
month, followed by administering to the patient a second daily dose
of about 200 mg celiprolol hydrochloride for about 1 month,
followed by administering to the patient a third daily dose of
about 300 mg celiprolol hydrochloride for about 1 month, followed
by administering to the patient a fourth daily dose of about 400 mg
celiprolol hydrochloride.
19. The method of claim 18, wherein the initial daily dose is
administered at about 100 mg once daily.
20. The method of claim 18, wherein the second daily dose is
administered at about 100 mg twice daily.
21. The method of claim 18, wherein the fourth daily dose is
administered at about 200 mg twice daily.
22. The method of claim 18, wherein the fourth daily dose is
administered for at least 1 year.
23. The method of claim 18, wherein the fourth daily dose is
administered for at least 5 years.
24. The method claim 13, wherein the patient is 15-years old or
older.
25. The method claim 13, wherein the treatment is initiated as soon
as vascular EDS is diagnosed, or when the patient is 10 years
old.
26. The method of claim 18, the patient has a variant leading to
haplo-insufficiency of the COL3A1 gene. The method of claim 18, the
patient has a pathogenic variant of the COL3A1 gene.
27. The method of claim 18, the patient has a glycine substitution
within the triple helix of the COL3A1 gene.
28. The method of claim 18, the patient has a splice-site variant,
in-frame insertions-deletion or duplication of the COL3A1 gene.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 16/930,208, filed on Jul. 15, 2020, which is a continuation of
U.S. application Ser. No. 16/184,922, filed on Nov. 8, 2018, which
claims the benefit of European Patent Application No. 17306890.9
filed Dec. 21, 2017, the entire content of which is incorporated
herein by reference.
FIELD
[0002] The present disclosure relates to the field of treatment of
an orphan disease, in particular treatment of vascular
Ehlers-Danlos syndrome (vEDS). More specifically, the present
disclosure relates to novel up-titration dosage regimens (e.g.,
escalating dosage regimens) effective for treating vEDS patients
with celiprolol.
BACKGROUND
[0003] Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic
condition secondary to mutation within the COL3A1 gene. Typically,
vEDS has an autosomal dominant inheritance. The most common COL3A1
variants result either in glycine substitutions within the triple
helix encoding type Ill procollagen or in truncating splice-site
variants. Both are responsible for a disruption of proper assembly
of type Ill procollagen into type Ill collagen fibrils with a
dominant negative effect. The amount of mature type Ill collagen is
thus dramatically reduced, which in turn results in an important
loss of mechanical strength of hollow organs, especially arteries
and bowels. Clinically, vEDS is characterized by four major and
nine minor diagnostic criteria (Beighton et al. (1998) Am J Med
Genet, 77:31-37). Vascular EDS is typically clinically silent until
the late teenage years. Acute and spontaneous organ complications
start to occur during early adulthood and repeat at unpredictable
time intervals. Arterial accidents, also referred to as arterial
events, are the most common complications in vEDS (e.g., vascular
ruptures, vascular dissections), followed by bowel perforations and
respiratory accidents (e.g., pneumothorax).
[0004] Life expectancy is reduced in vEDS patients to a median of
51 years due in part to the morbidity associated with this
disorder, especially morbidity associated with arterial accidents
or events. Over the last ten years, awareness of the disease has
significantly increased and patient management has improved,
especially in reducing acute arterial accidents.
[0005] Medical intervention to improve vEDS patient outcome has
made an important step with the publication of the results of the
BBEST trial (Ong et al., (2010) Lancet, 376:1476-1484). In this
trial, a final administration of 200 mg twice a day (BID) of
celiprolol to patients with either a phenotype of vEDS, or with
molecularly proven vEDS, showed a 35% reduction in morbidity and
mortality over a 5-year follow-up. However, due to the fragility of
vEDS patients, and the inability to determine effectiveness of
treatment with celiprolol by a secondary measure such as blood
pressure, in the BBEST trial, treatment was initiated with a daily
dose of 100 mg of celiprolol. The BBEST trial disclosed a dose
up-titration regimen for patients, wherein the patient received an
initial daily dosage of 100 mg celiprolol for the first 6-months;
then the dosage was increased (up-titrated) by an additional 100 mg
celiprolol per day every 6-months, reaching a maximum daily dosage
of 400 mg. Accordingly, reaching a maximum daily dosage of 400 mg
(200 mg BID) was thus only achieved at 18 months. As a result, a
very long up-titration period (e.g., long dose escalation period)
of 18 months was necessary until the target dose was attained. This
very long up-titration period was justified by the risk of adverse
effects and of celiprolol intolerance. However, vEDS is a disease
affecting young adults with a high risk of repeated and
unpredictable arterial accidents (e.g., vascular ruptures, vascular
dissections) who need optimal vascular protection as early as
possible upon vEDS diagnosis, which is not compatible with an
up-titration or dose escalation period of 18 months, as reported in
the BBEST trial.
[0006] Thus there remains an unmet clinical need for improved
treatment strategies and methods of treating a vEDS patient.
SUMMARY
[0007] The present disclosure provides improved treatment
strategies and methods of administering higher doses of celiprolol
to a vEDS patient in a manner that results in improved event-free
survival and overall survival, eliminates or minimizes adverse
events and celiprolol intolerance, by providing shorter
up-titration and dose escalation periods of time.
[0008] The present disclosure provides, inter alia, improved,
optimized dose escalation regimens and up-titration regimens for
the administration of celiprolol to patients having vascular
Ehlers-Danlos syndrome. The dose escalation and up-titration
regimens of the present disclosure provide celiprolol, or a
pharmaceutically acceptable salt thereof, to vEDS patients in an
amount (e.g., an increasing amount) such that a dosage of at least
400 mg per day is reached within three months of initiating
celiprolol treatment. The methods provided herein provide novel
treatment regimens for the treatment of vEDS, resulting in improved
overall survival and event-free survival.
[0009] In one embodiment, the present disclosure provides a method
of providing or administering celiprolol therapy to a vEDS patient
comprising providing or administering to the patient an initial
daily dosage of celiprolol, or a pharmaceutically acceptable salt
thereof, for the duration of a first period of time; followed by
providing to the patient a second daily dosage of celiprolol, or a
pharmaceutically acceptable salt thereof, for the duration of a
second period of time; followed by providing to the patient a third
daily dosage of celiprolol, or a pharmaceutically acceptable salt
thereof, for the duration of a third period of time; and followed
by providing to the patient a fourth daily dosage of celiprolol, or
a pharmaceutically acceptable salt thereof. In some embodiments,
the method further comprises providing to the patent a fifth daily
dosage of celiprolol, or a pharmaceutically acceptable salt
thereof. In some embodiments, the fourth daily dosage, or any daily
dosage beyond the fourth daily dosage, is considered a maintenance
dosage.
[0010] In some embodiments, the initial daily dosage is about 100
mg celiprolol or a pharmaceutically acceptable salt thereof. In
some embodiments, the second daily dosage is about 200 mg
celiprolol, or a pharmaceutically acceptable salt thereof. In some
embodiments, the third daily dosage is about 300 mg celiprolol, or
a pharmaceutically acceptable salt thereof. In some embodiments,
the fourth daily dosage is about 400 mg celiprolol, or a
pharmaceutically acceptable salt thereof. In other embodiments, the
fifth daily dosage is greater than 400 mg celiprolol (e.g., 500 mg
or 600 mg), or a pharmaceutically acceptable salt thereof.
[0011] In some embodiments, the first period of time is about one
month, about 30 days, or about 28 days. In some embodiments, the
second period of time is about one month, about 30 days, or about
28 days. In some embodiments, the third period of time is about one
month, about 30 days, or about 28 days.
[0012] In one embodiment, the present disclosure provides a method
of providing celiprolol therapy to a patient in need thereof in an
initial dose escalation regimen, the method comprising providing or
administering celiprolol, or a pharmaceutically acceptable salt
thereof, to the patient at a daily dosage of about 100 mg for about
one month; followed by providing or administering celiprolol, or a
pharmaceutically acceptable salt thereof, to the patient at a daily
dosage of about 200 mg for about one month; followed by providing
or administering celiprolol, or a pharmaceutically acceptable salt
thereof, to the patient at a daily dosage of about 300 mg for about
one month; and following by providing or administering celiprolol,
or a pharmaceutically acceptable salt thereof, to the patient at a
dosage of about 400 mg.
[0013] In another embodiment, the present disclosure provides dose
escalation regimen for providing celiprolol therapy to a patient
for the treatment of vEDS, wherein the method comprises providing
or administering celiprolol, or a pharmaceutically acceptable salt,
to the patient at a first daily dosage of about 100 mg for about
one month of the dose escalation regimen; followed by providing or
administering celiprolol, or a pharmaceutically acceptable salt, to
the patient at a second daily dosage of about 200 mg for one month
of the dose escalation regimen; followed by providing or
administering celiprolol, or a pharmaceutically acceptable salt, to
the patient at a third daily dosage of about 300 mg for about one
month of the dose escalation regimen; and followed by providing or
administering celiprolol, or a pharmaceutically acceptable salt, to
the patient at a fourth daily dosage of about 400 mg, wherein the
patient is provided or administered celiprolol for the treatment of
vascular Ehlers-Danlos syndrome.
[0014] In one aspect, the disclosure provides methods for treating
vascular Ehlers-Danlos syndrome. The methods include administering
celiprolol, or a pharmaceutically acceptable salt thereof, to a
patient in need thereof, wherein treatment begins with a titration
period wherein celiprolol, or a pharmaceutically acceptable salt
thereof, is administered at a dosage of about 100 mg once daily
during one month and increased by about 100 mg/day every month over
an about 3-month period to reach a dosage of about 400 mg per day.
For example, the patient is administered celiprolol, or a
pharmaceutically acceptable salt thereof, at a dosage of about 100
mg per day for about one month, at least a dosage of about 200 mg
per day for about one month, at least a dosage of about 300 mg per
day for about one month, and at least a dosage of about 360 mg,
such as a dose of at least 400 mg (e.g., about 200 mg twice per
day), from the end of the third month.
[0015] In one aspect, the disclosure provides a method of treating
vascular Ehlers-Danlos syndrome in a patient in need thereof. This
method includes administering an initial dosage of celiprolol, or a
pharmaceutically acceptable salt thereof, of 100 mg per day to the
patient and administering a subsequent dose of celiprolol, or a
pharmaceutically acceptable salt thereof, of at least 400 mg per
day (e.g., 200 mg twice per day) to the patient within 90 days of
the initial dose. In some embodiments, a dosage of at least 200 mg
per day is administered to the patient within 30 days of the
initial dose. In some embodiments, a dosage of at least 300 mg per
day is administered to the patient within 60 days of the initial
dose.
[0016] In one aspect, the disclosure provides a method of treating
vascular Ehlers-Danlos syndrome in a patient in need thereof. This
method includes administering at least 400 mg per day (e.g., 200 mg
twice per day) celiprolol, or a pharmaceutically acceptable salt
thereof, to the patient within 120 days (e.g., within 90 days) of
the initial dosage of celiprolol, or a pharmaceutically acceptable
salt thereof. In some embodiments, the initial dosage of
celiprolol, or a pharmaceutically acceptable salt thereof, is 100
mg per day.
[0017] In one embodiment, the present disclosure provides a method
for treating vEDS in a patient in need thereof, the method
comprising administering celiprolol, or a pharmaceutically
acceptable salt thereof, to the patient at a first daily dosage of
100 mg for one month; followed by administering celiprolol, or a
pharmaceutically acceptable salt thereof, to the patient a daily
dosage of 200 mg for one month; followed by administering
celiprolol, or a pharmaceutically acceptable salt, to the patient a
daily dosage of 300 mg for one month; and followed by providing or
administering celiprolol, or a pharmaceutically acceptable salt
thereof, to the patient a daily dosage of 400 mg, thereby treating
vEDS.
[0018] In one embodiment, the present disclosure provides for the
use of celiprolol, or a pharmaceutically acceptable salt thereof,
for treatment of vEDS, wherein celiprolol, or a pharmaceutically
acceptable salt thereof, is administered to a patient having vEDS
at a first daily dosage of 100 mg for 1 month, followed by a daily
dose of 200 mg for 1 month, followed by a daily dose of 300 mg for
1 month, and followed by a daily dose of 400 mg.
[0019] In some embodiments, the dosage of celiprolol, or a
pharmaceutically acceptable salt thereof, is reduced (e.g., reduced
by 100 mg per day) if any signs of intolerance to the drug (e.g.,
swelling, fatigue, or flu-like symptoms) are experienced by the
patient during up-titration or follow-up.
[0020] In some embodiments, the method further includes
administering a dosage of at least 500 mg per day (e.g., at least
600 mg per day). In some embodiments, the dosage is increased to at
least 500 mg per day after the three-month up-titration or dose
escalation period.
[0021] In some embodiments, the initial daily dosage is about 91.25
mg celiprolol or an equivalent amount of a pharmaceutically
acceptable salt thereof. In some embodiments, the second daily
dosage is about 182.5 mg celiprolol, or an equivalent amount of a
pharmaceutically acceptable salt thereof. In some embodiments, the
third daily dosage is about 273.75 mg celiprolol, or an equivalent
amount of a pharmaceutically acceptable salt thereof. In some
embodiments, the fourth daily dosage is about 365 mg celiprolol, or
an equivalent amount of a pharmaceutically acceptable salt thereof.
In other embodiments, the fifth daily dosage is greater than 365 mg
celiprolol (e.g., about 450 mg or about 550 mg), or an equivalent
amount of a pharmaceutically acceptable salt thereof.
[0022] In some embodiments, the first period of time is about one
month, about 30 days, or about 28 days. In some embodiments, the
second period of time is about one month, about 30 days, or about
28 days. In some embodiments, the third period of time is about one
month, about 30 days, or about 28 days.
[0023] In one embodiment, the present disclosure provides a method
of providing celiprolol therapy to a patient in need thereof in an
initial dose escalation regimen, the method comprising providing or
administering celiprolol, or a pharmaceutically acceptable salt
thereof, to the patient at a daily dosage of about 91.25 mg
celiprolol for one month; followed by providing or administering
celiprolol, or a pharmaceutically acceptable salt thereof, to the
patient at a daily dosage of about 182.5 mg celiprolol for one
month; followed by providing or administering celiprolol, or a
pharmaceutically acceptable salt thereof, to the patient at a daily
dosage of about 273.75 mg celiprolol for one month; and following
by providing or administering celiprolol, or a pharmaceutically
acceptable salt thereof, to the patient at a daily dosage of about
365 mg celiprolol.
[0024] In another embodiment, the present disclosure provides dose
escalation regimen for providing celiprolol therapy to a patient
for the treatment of vEDS, wherein the method comprises providing
or administering celiprolol, or a pharmaceutically acceptable salt,
to the patient at a first daily dosage of about 91.25 mg celiprolol
for one month of the dose escalation regimen; followed by providing
or administering celiprolol, or a pharmaceutically acceptable salt,
to the patient at a second daily dosage of about 182.5 mg
celiprolol for one month of the dose escalation regimen; followed
by providing or administering celiprolol, or a pharmaceutically
acceptable salt, to the patient at a third daily dosage of about
273.75 mg celiprolol for one month of the dose escalation regimen;
and followed by providing or administering celiprolol, or a
pharmaceutically acceptable salt, to the patient at a fourth daily
dosage of about 365 mg celiprolol, wherein the patient is provided
or administered celiprolol for the treatment of vascular
Ehlers-Danlos syndrome.
[0025] In one aspect, the disclosure provides methods for treating
vascular Ehlers-Danlos syndrome. The methods include administering
celiprolol, or a pharmaceutically acceptable salt thereof, to a
patient in need thereof, wherein treatment begins with a titration
period wherein celiprolol, or a pharmaceutically acceptable salt
thereof, is administered at a dosage of about 91.25 mg celiprolol
once daily during one month and increased by about 91.25 mg/day
celiprolol every month over a 3-month period to reach a dosage of
about 365 mg per day celiprolol. For example, the patient is
administered celiprolol, or a pharmaceutically acceptable salt
thereof, at a dosage of about 91.25 mg celiprolol per day for one
month, at least a dosage of about 182.5 mg celiprolol per day for
one month, at least a dosage of about 273.75 mg celiprolol per day
for one month, and at least a dosage of about 330 mg celiprolol,
such as a dose of at least about 365 mg (e.g., about 182.5 mg twice
per day), from the end of the third month.
[0026] In one aspect, the disclosure provides a method of treating
vascular Ehlers-Danlos syndrome in a patient in need thereof. This
method includes administering an initial dosage of celiprolol, or a
pharmaceutically acceptable salt thereof, of about 91.25 mg
celiprolol per day to the patient and administering a subsequent
dose of celiprolol, or a pharmaceutically acceptable salt thereof,
of at least about 365 mg celiprolol per day (e.g., about 182.5 mg
celiprolol twice per day) to the patient within 90 days of the
initial dose. In some embodiments, a dosage of at least about 182.5
mg celiprolol per day is administered to the patient within 30 days
of the initial dose. In some embodiments, a dosage of at least
about 273.75 mg celiprolol per day is administered to the patient
within 60 days of the initial dose.
[0027] In one aspect, the disclosure provides a method of treating
vascular Ehlers-Danlos syndrome in a patient in need thereof. This
method includes administering at least about 365 mg per day (e.g.,
about 182.5 mg twice per day) celiprolol, or an equivalent amount
of a pharmaceutically acceptable salt thereof, to the patient
within 120 days (e.g., within 90 days) of the initial dosage of
celiprolol, or an equivalent amount of a pharmaceutically
acceptable salt thereof. In some embodiments, the initial dosage of
celiprolol is about 91.25 mg per day, or an equivalent amount of a
pharmaceutically acceptable salt thereof.
[0028] In one embodiment, the present disclosure provides a method
for treating vEDS in a patient in need thereof, the method
comprising administering celiprolol, or a pharmaceutically
acceptable salt thereof, to the patient at a first daily dosage of
about 91.25 mg celiprolol for about one month; followed by
administering celiprolol, or a pharmaceutically acceptable salt
thereof, to the patient a second daily dosage of about 182.5 mg
celiprolol for about one month; followed by administering
celiprolol, or a pharmaceutically acceptable salt, to the patient a
third daily dosage of about 273.75 mg celiprolol for about one
month; and followed by providing or administering celiprolol, or a
pharmaceutically acceptable salt thereof, to the patient a fourth
daily dosage of about 365 mg celiprolol, thereby treating vEDS.
[0029] In one embodiment, the present disclosure provides for the
use of celiprolol, or a pharmaceutically acceptable salt thereof,
for treatment of vEDS, wherein celiprolol, or a pharmaceutically
acceptable salt thereof, is administered to a patient having vEDS
at a first daily dosage of about 91.25 mg celiprolol for about 1
month, followed by a second daily dose of about 182.5 mg celiprolol
for about 1 month, followed by a third daily dose of about 273.75
mg celiprolol for about 1 month, and followed by a fourth daily
dose of about 365 mg celiprolol.
[0030] In some embodiments, the dosage of celiprolol, or a
pharmaceutically acceptable salt thereof, is reduced (e.g., reduced
by about 91.25 mg celiprolol per day) if any signs of intolerance
to the drug (e.g., swelling, fatigue, or flu-like symptoms) are
experienced by the patient during up-titration or follow-up.
[0031] In some embodiments, the method further includes
administering a dosage of at least about 456 mg per day (e.g., at
least about 547.5 mg per day) celiprolol. In some embodiments, the
dosage is increased to at least about 456 mg per day celiprolol
after the three-month up-titration or dose escalation period.
[0032] In some embodiments, after the initial about three-month
up-titration or dose escalation period, the patient is provided or
administered a daily dosage of about 365 mg celiprolol or an
equivalent amount of a pharmaceutically acceptable salt thereof for
the treatment of vascular Ehler-Danlos syndrome for at least one
year, two years, three years, four years, five years, five years
and nine months or six years.
[0033] In some embodiments, the celiprolol or pharmaceutically
acceptable salt thereof is celiprolol hydrochloride.
[0034] In some embodiments, the initial daily dosage is about 100
mg celiprolol hydrochloride. In some embodiments, the second daily
dosage is about 200 mg celiprolol hydrochloride. In some
embodiments, the third daily dosage is about 300 mg celiprolol
hydrochloride. In some embodiments, the fourth daily dosage is
about 400 mg celiprolol hydrochloride. In other embodiments, the
fifth daily dosage is greater than 400 mg (e.g., about 500 mg or
about 600 mg) celiprolol hydrochloride.
[0035] In some embodiments, the first period of time is about one
month, about 30 days, or about 28 days. In some embodiments, the
second period of time is about one month, about 30 days, or about
28 days. In some embodiments, the third period of time is about one
month, about 30 days, or about 28 days.
[0036] In one embodiment, the present disclosure provides a method
of providing celiprolol therapy to a patient in need thereof in a
dose escalation regimen, the method comprising providing or
administering celiprolol hydrochloride to the patient at a daily
dosage of 100 mg for one month; followed by providing or
administering celiprolol hydrochloride to the patient at a daily
dosage of 200 mg for one month; followed by providing or
administering celiprolol hydrochloride to the patient at a daily
dosage of 300 mg for one month; and following by providing or
administering celiprolol hydrochloride to the patient at a dosage
of 400 mg.
[0037] In another embodiment, the present disclosure provides dose
escalation regimen for providing celiprolol therapy to a patient
for the treatment of vEDS, wherein the method comprises providing
or administering celiprolol hydrochloride to the patient at a first
daily dosage of about 100 mg (e g., once daily) for about one month
of the dose escalation regimen; followed by providing or
administering celiprolol hydrochloride to the patient at a second
daily dosage of about 200 mg (e g., about 200 mg once daily or
about 100 mg twice daily) for about one month of the dose
escalation regimen; followed by providing or administering
celiprolol hydrochloride to the patient at a third daily dosage of
about 300 mg (e g., about 300 mg once daily, about 150 mg twice
daily or about 100 mg thrice daily) for about one month of the dose
escalation regimen; and followed by providing or administering
celiprolol hydrochloride to the patient at a fourth daily dosage of
about 400 mg (e g., about 400 mg once daily, about 200 mg twice
daily, about 133 mg thrice daily or about 100 mg four times daily),
wherein the patient is provided or administered celiprolol for the
treatment of vascular Ehler-Danlos syndrome.
[0038] In one aspect, the disclosure provides methods for treating
vascular Ehlers-Danlos syndrome. The methods include administering
celiprolol hydrochloride to a patient in need thereof, wherein
treatment begins with a titration period wherein celiprolol
hydrochloride is administered at a dosage of 100 mg per day (e.g.,
once daily) during one month and increased by 100 mg/day every
month over a 3-month period to reach a dosage of 400 mg per day.
For example, the patient is administered celiprolol hydrochloride
at a dosage of 100 mg per day for one month, at least a dosage of
200 mg per day for one month, at least a dosage of 300 mg per day
for one month, and at least a dosage of 360 mg, such as a dose of
at least 400 mg (e.g., 200 mg twice per day), from the end of the
third month.
[0039] In one aspect, the disclosure provides a method of treating
vascular Ehlers-Danlos syndrome in a patient in need thereof. This
method includes administering an initial dosage of celiprolol
hydrochloride of 100 mg per day (e.g., once daily) to the patient
and administering a subsequent dose of celiprolol hydrochloride of
at least 400 mg per day (e.g., 200 mg twice per day) to the patient
within 90 days of the initial dose. In some embodiments, a dosage
of at least 200 mg per day is administered to the patient within 30
days of the initial dose. In some embodiments, a dosage of at least
300 mg per day is administered to the patient within 60 days of the
initial dose.
[0040] In one aspect, the disclosure provides a method of treating
vascular Ehlers-Danlos syndrome in a patient in need thereof. This
method includes administering at least 400 mg per day (e.g., 200 mg
twice per day) celiprolol hydrochloride to the patient within 120
days (e.g., within 90 days) of the initial dosage of celiprolol
hydrochloride. In some embodiments, the initial dosage of
celiprolol hydrochloride is 100 mg per day.
[0041] In one embodiment, the present disclosure provides a method
for treating vEDS in a patient in need thereof, the method
comprising administering celiprolol hydrochloride to the patient at
a first daily dosage of 100 mg for one month; followed by
administering celiprolol hydrochloride to the patient a second
daily dosage of 200 mg for one month; followed by administering
celiprolol hydrochloride to the patient a third daily dosage of 300
mg for one month; and followed by administering celiprolol
hydrochloride to the patient a fourth daily dosage of 400 mg,
thereby treating vEDS.
[0042] In one embodiment, the present disclosure provides for the
use of celiprolol hydrochloride for treatment of vEDS, wherein
celiprolol hydrochloride is administered to a patient having vEDS
at a first daily dosage of about 100 mg for about 1 month, followed
by a second daily dose of about 200 mg for about 1 month, followed
by a third daily dose of about 300 mg for about 1 month, and
followed by a fourth daily dose of about 400 mg.
[0043] In some embodiments, after the initial about three-month
up-titration or dose escalation period, the patient is provided or
administered a fourth daily dosage of about 400 mg celiprolol
hydrochloride for the treatment of vascular Ehler-Danlos syndrome
for at least one year, two years, three years, four years, five
years, five years and nine months or six years.
[0044] In some embodiments, the dosage of celiprolol hydrochloride
is reduced (e.g., reduced by about 100 mg per day) if any signs of
intolerance to the drug (e.g., swelling, fatigue, or flu-like
symptoms) are experienced by the patient during up-titration or
follow-up.
[0045] In some embodiments, the method further includes
administering a dosage of at least 500 mg per day (e.g., at least
600 mg per day) celiprolol hydrochloride. In some embodiments, the
dosage is increased to at least 500 mg per day after the
three-month up-titration or dose escalation period.
[0046] In some embodiments, the patient is a human patient. In some
embodiments, the patient is 15-years old or older. In some
embodiments, the patient is an adult patient. In some embodiments,
the patient is a pediatric patient.
[0047] In some embodiments, the method is initiated as soon as (or
soon after) vEDS is diagnosed. In some embodiments, the method is
initiated when the patient is 15 years old.
[0048] In some embodiments, the patient is diagnosed based on a
phenotype of vEDS, or based on a molecular test vEDS (e.g., the
patient is determined to have vEDS based on one or more genetic
tests such as a test that determines that the patient has a glycine
substitution within the triple helix or a splice-site variant).
[0049] In some embodiments, the patient has a COL3A1 mutation. In
some embodiments, the patient has a glycine substitution within the
triple helix or a splice-site variant. In some embodiments, the
patient has a missense substitutions for glycine in the repeating
(Gly-X-Y)n sequence of the collagen triple helix, or and splice
site variants that lead to in-phase exon-skipping. In some
embodiments, the patient has a glycine substitution within the
triple helix (Group I). In some embodiments, the patient has a
splice-site variant, in-frame insertions-deletion or duplication
(Group II). In some embodiments, the patient has a variant leading
to haplo-insufficiency (Group III).
[0050] In some embodiments, the patient has previously had an acute
vEDS-related event (e.g., an arterial event such as a rupture or
dissection, an intestinal or uterine rupture) prior to the initial
dose of celiprolol, or a pharmaceutically acceptable salt
thereof.
[0051] In some embodiments, methods of the present disclosure as
provided herein result in fewer adverse vascular events (e.g., an
arterial rupture or dissection) in a vEDS patient than prior
methods for providing celiprolol for the treatment of vEDS, such
method including up titrating to a dose of at least 400 mg per day
over 18 months. In some embodiments, methods of the present
disclosure provide greater overall survival (e.g., over a five year
follow up period) compared to the corresponding method which
includes up titrating to a dose of at least 400 mg per day over 18
months.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] FIG. 1: Patient flowchart. Abbreviations: EDS: Ehlers-Danlos
syndrome; Gr I: Group I (Glycine missense); Gr II: Group II
(splice-site variants, insertions/deletions, duplications), Gr III:
Group III (haploinsufficiency); V: follow-up visit with vascular
work-up.
[0053] Kaplan-Meier survival analysis of n=144 vascular EDS
patients treated with celiprolol. FIG. 2A. Overall patient
survival: 71.6%; 95% CI [51.0%; 92.1%]. FIG. 2B. Survival according
to the type of variant (Group I versus Group II versus Group III).
Group I: 65.1%; 95% CI [39.5%; 90.7%] versus Group II: 89.6%; 95%
CI [79.9%; 99.3%] versus Group III: 100%.
[0054] Kaplan-Meier survival analysis of patients with Glycine
missense variants and splice-site variants, deletions, insertions
and duplications (Groups I and n=132 patients), according to
celiprolol treatment. FIG. 3A. Survival according to celiprolol
treatment (treated patients versus not treated patients (i.e. no
treatment, non-adherent, intolerant to celiprolol, celiprolol not
started and patients taking another drug than celiprolol): At the
end of follow-up, survival was 80.7%, 95% CI [67.8%-93.6%] in those
treated with celiprolol versus 48.5%, 95% CI [19.7%-77.4%] in those
not treated. Log Rank: Treated (n=110) versus Not Treated (n=22),
p=0.0002. FIG. 3B. Survival according to daily dose of celiprolol:
At the end of follow-up, survival was 85%, 95% CI [70.5%-99.5%] in
those patients treated by celiprolol 400 mg/day, 62.8%, 95% CI
[39.7%-86.0%] in those taking celiprolol 100-300 mg/day, 40.0% 95%
CI [0.2%-79.8%] in the non-treated group (B). Log rank survival
analysis between the 3 groups: p<0.0001.
[0055] FIG. 4: Evolution of the clinical arterial score throughout
follow-up.
[0056] FIG. 5A. Rate of patients and hospitalizations during the
study. FIG. 5B. Rate of hospitalizations for acute arterial event
before and after the systematic introduction of celiprolol.
DETAILED DESCRIPTION
[0057] The present disclosure provides a method of providing
celiprolol therapy to a patient with vEDS, wherein the method is
associated with an escalating dosage regimen that mitigates adverse
events and intolerance associated with the use of celiprolol, as
well as providing better overall survival and event-free survival,
and better matches the development of tolerance to potentially
adverse effects of the drug with increases in the dosage. Unlike
the use of celiprolol for the treatment of hypertension, wherein
dosage titration and dosage effectiveness can be monitored by
measuring blood pressure changes, the fragility of vEDS patients,
and the inability to determine effectiveness of treatment with
celiprolol by a secondary measure such as blood pressure, has led
to a lack of physiological guidelines for appropriate up-titration
and dose escalation strategies for this patient population. The
present disclosure addresses this with novel up-titration and dose
escalation methods for the effective treatment of vEDS.
[0058] In one embodiment of the present disclosure, a method is
provided for providing or administering celiprolol therapy to a
patient, the method comprising providing or administering an
initial daily dosage of celiprolol (or a pharmaceutically
acceptable salt thereof) to the patient for the duration of a first
period of time; followed by providing or administering a second
daily dosage of celiprolol (or a pharmaceutically acceptable salt
thereof) to the patient for a second period of time; followed by
providing or administering a third daily dosage of celiprolol (or a
pharmaceutically acceptable salt thereof) to the patient for a
third period of time; and followed by providing or administering a
fourth daily dosage of celiprolol (or a pharmaceutically acceptable
salt thereof) to the patient thereafter. The longer dose escalation
periods reported previously are less than optimal for vEDS patient
benefit resulting from the delay in administering a full
therapeutic dosage of 18 months.
[0059] In the dose escalation regimen described herein, the first
daily dosage is about 91.25 mg (e.g., about 91.25 mg once daily)
celiprolol, or an equivalent amount of a pharmaceutically
acceptable salt thereof, during the initial month, the initial 30
days, or the initial 28 days; the second daily dosage is about
182.5 mg (e.g., about 182.5 mg once daily, about 91.25 mg
twice-daily) celiprolol, or an equivalent amount of a
pharmaceutically acceptable salt thereof, during the second month,
the second 30 days, or the second 28 days; the third daily dosage
is about 273.75 mg (e.g., about 273.75 mg once daily, about 136.88
mg twice daily, about 91.25 mg thrice daily) celiprolol, or an
equivalent amount of a pharmaceutically acceptable salt thereof,
during the third month; and the fourth daily dosage is about 365 mg
daily (e.g., about 365 mg once daily, about 182.5 mg twice daily)
celiprolol, or an equivalent amount of a pharmaceutically
acceptable salt thereof. The method of the present disclosure can
further comprise additional steps after the three-month dose
escalation/up-titration period, to further increase the daily dose
of celiprolol administered to the patient. According to a
particular embodiment, one or two additional dosage increases are
performed after the three-month dose escalation/up-titration
period, to reach a daily dosage of greater than 365 mg, such as for
example, about 500 mg or about 600 mg of celiprolol or an
equivalent amount of a pharmaceutically acceptable salt thereof. An
equivalent amount of a pharmaceutically acceptable salt of
celiprolol is the weight amount of the salt that provides the
stated amount of celiprolol. For example, 200 mg of the HCl salt of
celiprolol (celiprolol hydrochloride) provides and is equivalent to
182.5 mg of celiprolol.
[0060] In some embodiments, provided is celiprolol or a
pharmaceutically acceptable salt thereof for use in treating
vascular Ehlers-Danlos syndrome in a patient, wherein treatment
begins with 80 to 110 mg (e.g., about 91.25 mg) daily celiprolol or
an equivalent amount of a pharmaceutically acceptable salt of
celiprolol and increases to 300 to 440 mg (e.g., about 365 mg)
daily celiprolol or an equivalent amount of a pharmaceutically
acceptable salt of celiprolol within six months. In some
embodiments, provided is a method for treating vascular
Ehlers-Danlos syndrome, comprising administering to a patient in
need thereof a 80 to 110 mg (e.g., about 91.25 mg) daily dose of
celiprolol or an equivalent amount of a pharmaceutically acceptable
salt of celiprolol and increasing the daily dose to 300 to 440 mg
(e.g., about 365 mg) within six months. In some embodiments, at
least a 80 to 110 mg daily (e.g., about 91.25 mg) dose increase is
made within two months. In some embodiments, at least a 170 to 210
mg (e.g., about 182.5 mg) daily dose increase is made within four
months. In some embodiments, at least a 260 to 310 mg (e.g., about
273.75 mg) daily dose increase is made within six months. In some
embodiments, at least a 260 to 310 mg (e.g., about 273.75 mg) daily
dose increase is made within four months.
[0061] In some embodiments, provided is celiprolol hydrochloride
for use in treating vascular Ehlers-Danlos syndrome in a patient,
wherein treatment with celiprolol hydrochloride begins with 90 to
110 mg (e.g., about 100 mg) daily and increases to 360 to 440 mg
(e.g., about 400 mg) daily within six months. In some embodiments,
provided is a method for treating vascular Ehlers-Danlos syndrome,
comprising administering to a patient in need thereof a 90 to 110
mg (e.g., about 100 mg) daily dose of celiprolol hydrochloride and
increasing the daily dose to 360 to 440 mg (e.g., about 400 mg)
within six months. In some embodiments, at least a 90 to 110 mg
(e.g., about 100 mg) daily dose increase is made within two months.
In some embodiments, at least a 180 to 220 mg (e.g., about 200 mg)
daily dose increase is made within four months. In some
embodiments, at least a 270 to 330 mg (e.g., about 300 mg) daily
dose increase is made within six months. In some embodiments, at
least a 270 to 330 mg (e.g., about 300 mg) daily dose increase is
made within four months.
[0062] In the dose escalation regimen described herein, the first
daily dosage is about 100 mg during the initial month, the initial
30 days, or the initial 28 days; the second daily dosage is about
200 mg (e.g., 200 mg once daily, 100 mg twice-daily) during the
second month, the second 30 days, or the second 28 days; the third
daily dosage is about 300 mg (e.g., 300 mg once daily, 150 mg twice
daily, 100 mg thrice daily) during the third month; and the fourth
daily dosage is about 400 mg daily (e.g., 400 mg once daily, 200 mg
twice daily). The method of the present disclosure can further
comprise additional steps after the three-month dose
escalation/up-titration period, to further increase the daily dose
of celiprolol administered to the patient. According to a
particular embodiment, one or two additional dosage increases are
performed after the three-month dose escalation/up-titration
period, to reach a daily dosage of greater than 400 mg, such as for
example, 500 mg or 600 mg of celiprolol.
[0063] In the dose escalation regimen described herein, the first
daily dosage is about 100 mg (e.g., about 100 mg once daily)
celiprolol hydrochloride during the initial month, the initial 30
days, or the initial 28 days; the second daily dosage is about 200
mg (e.g., about 200 mg once daily, about 100 mg twice-daily)
celiprolol hydrochloride during the second month, the second 30
days, or the second 28 days; the third daily dosage is about 300 mg
(e.g., about 300 mg once daily, about 150 mg twice daily, about 100
mg thrice daily) celiprolol hydrochloride during the third month;
and the fourth daily dosage is about 400 mg daily (e.g., about 400
mg once daily, about 200 mg twice daily) celiprolol hydrochloride.
The method of the present disclosure can further comprise
additional steps after the three-month dose escalation/up-titration
period, to further increase the daily dose of celiprolol
administered to the patient. According to a particular embodiment,
one or two additional dosage increases are performed after the
three-month dose escalation/up-titration period, to reach a daily
dosage of greater than 400 mg, such as for example, about 500 mg or
about 600 mg of celiprolol hydrochloride.
[0064] Each period of time associated with a particular daily
dosage is about one month. In some embodiments, the period of time
associated with a particular dosage during the up-titration or dose
escalation is about one month, about 30 days, or about 28 days.
[0065] Although the present disclosure exemplifies dose escalation
and up-titration regimens having particular dosage increases over
time, the present disclosure further contemplates additional dose
escalation and up-titration steps in the same amount of time, such
that the daily dosage escalates in smaller steps and more
frequently. Indeed, if desired, each dosage for a particular period
of time can be incrementally larger than the previous dosage, or
the dosage can escalate, for example, every week, every 2-weeks,
every 3-weeks.
[0066] In certain embodiments, the daily dosage of celiprolol is
once daily. In other embodiments, the daily dosage of celiprolol is
twice daily. In yet other embodiments, the daily dosage is thrice
daily (three oral administrations daily).
[0067] According to one embodiment, the present disclosure pertains
to a method of treating vascular Ehlers-Danlos syndrome, comprising
administering celiprolol to a patient in need thereof, wherein
treatment begins with a titration period wherein celiprolol, or a
pharmaceutically acceptable salt thereof, is administered at a
dosage of 100 mg daily during one month and increased by steps of
100 mg/day every month over a 3-month period to reach a dosage of
400 mg per day.
[0068] According to one embodiment, the present disclosure pertains
to a method of treating vascular Ehlers-Danlos syndrome, comprising
administering celiprolol to a patient in need thereof, wherein
treatment begins with a titration period wherein celiprolol, or a
pharmaceutically acceptable salt thereof, is administered at a
dosage of 91.25 mg daily during one month and increased by steps of
91.25 mg/day every month over a 3-month period to reach a dosage of
91.25 mg per day of celiprolol.
[0069] As used herein, the term "comprise" or "include" is intended
to mean that the compositions and methods include the recited
elements, but not excluding others. "Consist essentially of" when
used to define compositions and methods, shall mean excluding other
elements of any essential significance to the combination. For
example, a composition consisting essentially of the elements as
defined herein would not exclude other elements that do not
materially affect the basic and novel characteristic(s) of the
claimed invention. "Consist of" shall mean excluding more than
trace amount of other ingredients and substantial method steps
recited. Embodiments defined by each of these transition terms are
within the scope of this disclosure.
[0070] The term "about" when used before a numerical value
indicates that the value may vary within reasonable range, such as
.+-.10%, .+-.5%, and .+-.1%. The expression "about x" includes the
value "x."
[0071] The singular forms "a" and "the" include plural references
unless the context clearly dictates otherwise. Thus, e.g.,
reference to "the mutation" includes a plurality of mutations.
[0072] As used herein, the terms "treat", "treatment" and
"treating" refer to any reduction of one or more symptom(s)
associated with vascular EDS, such as, for example, a reduction of
the occurrence and/or severity of cardiovascular accidents or
events, and/or an increase in survival that results from the
administration of celiprolol alone or combined with one or more
other therapies.
[0073] Celiprolol (brand names Cardem.RTM., Selectol.RTM.,
Celipres.RTM., Celipro.RTM., Celol.RTM., Cordiax.RTM.,
Dilanorm.RTM., Edsivo.TM.) is a medication in the class of
beta-blockers that is unique from others in its class in both its
pharmacology and clinical applications. Its chemical formula is
N'-(3-Acetyl-4-(3-((1,1-dimethylethyl)amino)-2-hydroxypropoxy)phenyl)-N,
N-diethylurea, its CAS number is 56980-93-9 and Drug Bank number is
DB04846.
[0074] According to an embodiment of the present disclosure,
celiprolol is administered at a dose of 100 mg twice a day during
the second month of treatment.
[0075] When performing any of the above methods of the present
disclosure, signs of celiprolol intolerance can appear, especially
during the titration period. Most often, intolerance leads to
excessive fatigue. According to the present disclosure, the dose of
celiprolol is reduced in case of signs of intolerance during
up-titration or dose escalation, or during any follow-up. According
to a particular embodiment, the dose reduction is a reduction of
100 mg/day (for example, a patient showing signs of intolerance at
a daily dose of 400 mg/day will be given a reduced dose of 300
mg/day, etc.). According to a particular embodiment, the dose
reduction is a reduction of about 91.25 mg/day (for example, a
patient showing signs of intolerance at a daily dose of about 365
mg/day will be given a reduced dose of about 273.75 mg/day, etc.)
celiprolol or an equivalent amount of a pharmaceutically acceptable
salt thereof, for example, the dose reduction is a reduction of
about 100 mg/day (for example, a patient showing signs of
intolerance at a daily dose of about 400 mg/day will be given a
reduced dose of 300 mg/day, etc.) celiprolol hydrochloride.
[0076] The inventors demonstrated that optimal effects of
celiprolol for preventing cardiovascular accidents in vEDS patients
are obtained in patients who take at least 360 mg/day of
celiprolol. According to an embodiment of the present disclosure,
celiprolol is thus administered at a dose at or above 360 mg/day at
the end of the titration period.
[0077] According to an embodiment of the above method, illustrated
in the experimental part below, celiprolol is administered at a
dose of 200 mg twice a day at the end of the three-month titration
period.
[0078] Optionally, the method of the present disclosure can further
comprise additional steps after the three-month titration period,
to further increase the dose of celiprolol administered to the
patient. According to a particular embodiment, one or two
additional dose increases are performed after the three-month
titration period, to reach a daily dose of 500 mg or 600 mg of
celiprolol. Situations that may justify such increases are acute
arterial complications, uncontrolled recurrence of arterial
complications within the same hospitalization, or patient
stabilization after acute arterial complication(s).
[0079] As mentioned above, vascular EDS is typically clinically
silent until the late teenage years. However, in order to better
prevent the risk of arterial accidents or events (e.g., vascular
ruptures, vascular dissections), bowel perforations, and/or
respiratory accidents (pneumothorax) in late teenagers and in young
adults, it is preferable to initiate the treatment as soon as
possible upon diagnosis of vEDS, e.g., when the patient is 10-years
old or older. Hence, according to an embodiment of the method of
the disclosure, the treatment is initiated (i) upon vascular EDS
diagnosis, if the patient is 10 or older, or (ii) when the patient
is 10 years old, if vEDS has been previously diagnosed, or (iii)
upon vascular EDS diagnosis, if the patient is less than 10 with an
history of arterial event.
[0080] In some embodiments, celiprolol is administered in a
pharmaceutical composition comprising celiprolol or a
pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In some embodiments, the
pharmaceutical composition is for oral administration. In some
embodiments, the pharmaceutical composition is a tablet
formulation, such as a film coated tablet. In some embodiments, the
pharmaceutical composition is an immediate release formulation,
such as an immediate release tablet formulation. In some
embodiments, each tablet comprises about 182.5 mg celiprolol or
about 200 mg of celiprolol hydrochloride.
[0081] In some embodiments, the starting dose of celiprolol
administered to the patient is a 1/2 tablet (91.25 mg) once daily,
which is titrated up in 1/2 tablet increments each month to a total
dose of 2 tablets (365 mg) a day. In some embodiments, the daily
dose between a 1/2 tablet and 2 tablets may be adjusted based on
patient tolerance. In some embodiments, the daily dose can be given
once per day or divided into twice a day dosing based on patient
tolerance. For 1/2 tablet dose, the tablet can be split into equal
parts using a tablet splitter.
[0082] In some embodiments, celiprolol is not administered within
one hour of a meal. In some embodiments, celiprolol is not
administered 1 hour before, or 2 hours after a meal.
[0083] In some embodiments, celiprolol is not co-administered with
itraconazole, grapefruit juice, orange juice, chlorthalidone,
hydrochlorothiazide, theophylline, or rifampicin. In some
embodiments, celiprolol is not co-administered with a substrate of
MATE1, MATE2-K, BCRP, or P-gp transporter. In some embodiments,
celiprolol is not co-administered with calcium channel blockers,
such as phenylalkylamine and benzothiazepine, hypotensive agents,
or oral antidiabetic (hypoglycemics) drugs. In some embodiments,
when co-administered with one or more of the agents, such as
itraconazole, the dosage of celiprolol is reduced.
[0084] In some embodiments, celiprolol is not co-administered with
general anesthesia. In some embodiments, anesthesia is not
administered within about 24 hours of the last celiprolol dose. In
some embodiments, anesthesia is not administered within about 48
hours of the last celiprolol dose.
[0085] In some embodiments, celiprolol is not administered to a
patient having one or more of the following conditions: cardiogenic
shock, decompensated cardiac failure, sick-sinus syndrome, heart
block greater than first degree, severe bradycardia, severe renal
impairment with creatinine clearance less than about 15 mL/minute,
hypotension, or hypersensitivity to celiprolol.
[0086] In some embodiments, when treatment with celiprolol is
discontinued, it is discontinued after gradually reducing the
dosage over a period of at least one week, such as one to two
weeks.
[0087] In some embodiments, provided is celiprolol hydrochloride
for use in treating vascular Ehlers-Danlos syndrome in a patient
that is receiving a 360 to 440 mg daily dose of celiprolol
hydrochloride and having a need to cease the treatment, wherein the
daily dose of celiprolol hydrochloride is reduced for no more than
about 100 mg a day. In some embodiments, provided is method for
ceasing the treatment of celiprolol hydrochloride in a patient that
is receiving a 360 to 440 mg daily dose of celiprolol hydrochloride
and having a need to cease the treatment, comprising reducing the
daily dose of celiprolol hydrochloride for no more than about 100
mg a day. In some embodiments, the reduction continues for at least
5 days. In some embodiments, the reduction continues for at least 7
days. In some embodiments, the reduction continues for at least 10
days.
[0088] In some embodiments, provided is
[0089] 1. A method of treating vascular Ehlers-Danlos syndrome,
comprising administering celiprolol, or a pharmaceutically
acceptable salt thereof, to a patient in need thereof, wherein
treatment begins with a titration period wherein celiprolol, or a
pharmaceutically acceptable salt thereof, is administered at a dose
of 100 mg once daily during one month and increased by 100 mg/day
every month over a 3-month period to reach a dose of 400 mg per
day.
[0090] 2. The method of 1 above, wherein during the second month,
celiprolol, or a pharmaceutically acceptable salt thereof, is
administered at a dose of 100 mg twice a day.
[0091] 3. The method of 1 or 2 above, wherein in case of signs of
intolerance during up-titration or follow-up, the dose of
celiprolol, or a pharmaceutically acceptable salt thereof, is
reduced.
[0092] 4. The method of 3 above, wherein the daily dose of
celiprolol, or a pharmaceutically acceptable salt thereof, is
reduced by 100 mg.
[0093] 5. The method of any one 1-4 above, wherein at the end of
the titration period, celiprolol, or a pharmaceutically acceptable
salt thereof, is administered at a dose superior to 360 mg/day.
[0094] 6. The method of any one 1-5 above, wherein at the end of
the titration period, celiprolol, or a pharmaceutically acceptable
salt thereof, is administered at a dose of 200 mg twice a day.
[0095] 7. The method of any one 1-6 above, wherein after the
three-month titration period, one or two additional dose increases
are performed to reach a daily dose of 500 mg or 600 mg.
[0096] 8. The method of any one 1-7 above, wherein the patient is
15-years old or older.
[0097] 9. The method of any one 1-7 above, wherein the treatment is
initiated as soon as vascular EDS is diagnosed, or when the patient
is 10 years old.
[0098] 10. A method for treating vascular Ehlers-Danlos syndrome,
comprising administering to a patient in need thereof a 90 to 110
mg daily dose of celiprolol hydrochloride and increasing the daily
dose to 360 to 440 mg within six months.
[0099] 11. A method of treating vascular Ehlers-Danlos syndrome,
comprising administering celiprolol hydrochloride to a patient in
need thereof, wherein the treatment begins with a titration period
wherein celiprolol hydrochloride is administered at a dose of about
100 mg per day during about one month and increased by about 100
mg/day every month over an about 3-month period to reach a dose of
about 400 mg per day.
[0100] 12. The method of 11 above, wherein during the second month,
celiprolol hydrochloride is administered at a dose of about 100 mg
twice per day.
[0101] 13. The method of 11 or 12 above, wherein in case of signs
of intolerance during up-titration or follow-up, the dose of
celiprolol hydrochloride is reduced.
[0102] 14. The method of 13 above, wherein the daily dose of
celiprolol hydrochloride is reduced by about 100 mg.
[0103] 15. The method of any one of 11-14 above, wherein at the end
of the titration period, celiprolol hydrochloride is administered
at a dose superior to 360 mg/day.
[0104] 16. The method of any one of 11-15 above, wherein at the end
of the titration period, celiprolol hydrochloride is administered
at a dose of about 400 mg per day.
[0105] 17. The method of any one of 11-16 above, wherein after the
three-month titration period, one or two additional dose increases
are performed to reach a daily dose of about 500 mg or about 600
mg.
[0106] 18. The method of any one of 11-17 above, wherein the
patient is 15-years old or older.
[0107] 19. The method of any one of 11-17 above, wherein the
treatment is initiated as soon as vascular EDS is diagnosed, or
when the patient is 10 years old.
[0108] 20. A method for ceasing the treatment of celiprolol
hydrochloride in a patient that is receiving a 360 to 440 mg daily
dose of celiprolol hydrochloride and having a need to cease the
treatment, comprising reducing the daily dose of celiprolol
hydrochloride for no more than about 100 mg a day.
[0109] 21. Celiprolol or a pharmaceutically acceptable salt
thereof, for use in treating vascular Ehlers-Danlos syndrome,
wherein treatment with celiprolol or a pharmaceutically acceptable
salt thereof begins with a titration period during which celiprolol
or a pharmaceutically acceptable salt thereof is administered at a
dose of 100 mg once daily during one month and increased by 100
mg/day every month over a 3-month period to reach a dose of 400 mg
per day.
[0110] 22. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of 21 above, wherein during the second month,
celiprolol or a pharmaceutically acceptable salt thereof is
administered at a dose of 100 mg twice a day.
[0111] 23. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of 21 or 22 above, wherein in case of signs of
intolerance during up-titration or follow-up, the dose of
celiprolol, or a pharmaceutically acceptable salt thereof, is
reduced.
[0112] 24. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of 23 above, wherein the daily dose of
celiprolol or a pharmaceutically acceptable salt thereof is reduced
by 100 mg.
[0113] 25. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of any of 21 to 24 above, wherein at the end
of the titration period, celiprolol or a pharmaceutically
acceptable salt thereof is administered at a dose superior to 360
mg/day.
[0114] 26. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of any of 21 to 25 above, wherein at the end
of the titration period, celiprolol or a pharmaceutically
acceptable salt thereof is administered at a dose of 200 mg twice a
day.
[0115] 27. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of any of 21 to 26 above, wherein after the
three-month titration period, one or two additional dose increases
are performed to reach a daily dose of 500 mg or 600 mg.
[0116] 28. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of any of 21 to 27 above, wherein the patient
is 15-years old or older.
[0117] 29. Celiprolol or a pharmaceutically acceptable salt
thereof, for the use of any of 21 to 28 above, wherein the
treatment with celiprolol or a pharmaceutically acceptable salt
thereof is initiated as soon as vascular EDS is diagnosed, or when
the patient is 10 years old.
[0118] 30. Celiprolol hydrochloride for use in treating vascular
Ehlers-Danlos syndrome in a patient, wherein treatment with
celiprolol hydrochloride begins with 90 to 110 mg daily and
increases to 360 to 440 mg daily within six months.
[0119] 31. Celiprolol hydrochloride for use of 30 above, wherein at
least a 90 to 110 mg daily dose increase is made within two months.
32. Celiprolol hydrochloride for use of 30 or 31 above, wherein at
least a 180 to 220 mg daily dose increase is made within four
months.
[0120] 33. Celiprolol hydrochloride for use of any one of 30 to 32
above, wherein at least a 270-330 mg daily dose increase is made
within six months.
[0121] 34. Celiprolol hydrochloride for use of any one of 30 to 33
above, wherein at least a 270-330 mg daily dose increase is made
within four months.
[0122] 35. Celiprolol hydrochloride for use in treating vascular
Ehlers-Danlos syndrome in a patient, wherein treatment with
celiprolol hydrochloride begins with a titration period during
which celiprolol hydrochloride is administered at a dose of about
100 mg per day during one month and increased by 100 mg/day every
month over an about 3-month period to reach a dose of about 400 mg
per day.
[0123] 36. Celiprolol hydrochloride for the use of 35 above,
wherein during the second month, celiprolol hydrochloride is
administered at a dose of about 200 mg per day.
[0124] 37. Celiprolol hydrochloride for the use of 35 or 36 above,
wherein in case of signs of intolerance during up-titration or
follow-up, the dose of celiprolol hydrochloride is reduced.
[0125] 38. Celiprolol hydrochloride for the use of 37 above,
wherein the daily dose of celiprolol hydrochloride is reduced by
about 100 mg.
[0126] 39. Celiprolol hydrochloride for the use of any one of 35 to
38 above, wherein at the end of the titration period, celiprolol
hydrochloride is administered at a dose superior to 360 mg/day.
[0127] 40. Celiprolol hydrochloride for the use of any one of 35 to
39 above, wherein at the end of the titration period, celiprolol
hydrochloride is administered at a dose of about 400 mg per
day.
[0128] 41. Celiprolol hydrochloride for the use of any one of 35 to
40 above, wherein after the three-month titration period, one or
two additional dose increases are performed to reach a daily dose
of about 500 mg or about 600 mg.
[0129] 42. Celiprolol hydrochloride for the use of any of one 35 to
41 above, wherein the patient is 15-years old or older.
[0130] 43. Celiprolol hydrochloride for the use of any one of 35 to
41 above, wherein the treatment with celiprolol hydrochloride is
initiated as soon as vascular EDS is diagnosed, or when the patient
is 10 years old.
[0131] 44. Celiprolol hydrochloride for the use of any one of 35 to
43 above, wherein the patient is not co-administered
itraconazole.
[0132] 45. Celiprolol hydrochloride for use in treating vascular
Ehlers-Danlos syndrome in a patient that is receiving a 360 to 440
mg daily dose of celiprolol hydrochloride and having a need to
cease the treatment, wherein the daily dose of celiprolol
hydrochloride is reduced for no more than about 100 mg a day.
[0133] 46. Celiprolol hydrochloride for use of 45 above, wherein
the reduction continues for at least 5 days.
[0134] 47. Celiprolol hydrochloride for use of 46 above, wherein
the reduction continues for at least 7 days.
[0135] 48. Celiprolol hydrochloride for use of 46 above, wherein
the reduction continues for at least 10 days.
[0136] Other characteristics of the disclosure will also become
apparent in the course of the description which follows of the
biological assays which have been performed in the framework of the
disclosure and which provide it with the required experimental
support, without limiting its scope.
Examples
[0137] In order to further characterize the protective effect of
celiprolol in vEDS, the inventors performed a follow-up of a large
patient cohort over a 17-year period. The following are examples of
methods of the disclosure. It is understood that various other
embodiments may be practiced, given the general description
provided above.
Methodology
[0138] Patients
[0139] All patients with clinically and molecularly diagnosed vEDS
that were actively followed clinically in the French National
Referral Centre for Rare Vascular Diseases (HEGP, AP-HP, Paris,
France) between January 2000 and March 2017 were screened for
participation. During the initial evaluation of the first affected
family member seeking medical attention for symptoms related to
vEDS (index case), familial medical history was recorded and
investigation performed in the first-degree relatives whenever
possible. A dedicated database for vEDS was created at our
institution in 2011. All relevant clinical data of every vEDS
patient followed by our centre was entered into this database
retrospectively from the year 2000 until 2011, and prospectively
thereafter until Mar. 15, 2017. The database contains all available
medical history related to the pathology before the initial work-up
and obtained during the follow-up either through systematic visits
or those caused by a new clinical event. Thus, the occurrence of
any acute arterial, gastrointestinal, pulmonary and other
vEDS-related events was systematically recorded. In case of death
during follow-up, the time and cause of death were entered into the
database. This study was formally approved by the IDF ethics
committee (IRB registration #00001072) and the database was held in
compliance with French legislation on patient privacy.
[0140] Study Design
[0141] All vEDS patients benefited from standardized whole body
arterial monitoring by Doppler Ultrasound (DUS) and CT angiogram
and/or MRA. Such investigations were performed at baseline (initial
assessment at molecular diagnosis) and was repeated every 12 to 15
months in asymptomatic patients. For arterial events that occurred
before molecular diagnosis, location of arterial segments was
retrieved from hospitalization and imaging reports or examinations,
when available. In case of an acute arterial event, symptomatic
arterial beds/segments were monitored by any necessary diagnostic
and therapeutic means (CT-angiogram, DUS, angiography in case of
embolization). Between routine surveillance work-up, patients were
seen for outpatient visits every 6 to 9 months, except during
molecular diagnosis and celiprolol dose up-titration. For optimized
management of arterial, gastrointestinal, and pulmonary
emergencies, patients were given direct access to the medical team
of our centre.
[0142] Administration of Celiprolol
[0143] Since the publication of the BBest trial in 2011, all
included patients followed by our centre and not already treated
with celiprolol were offered to switch to celiprolol. Patients who
were not part of the trial and who were diagnosed during or since
the termination of the BBest trial were treated with celiprolol
starting at molecular diagnosis. Initial dosing of celiprolol was
100 mg once daily and increased by 100 mg/day every month over a
3-month period to reach the dose of 400 mg/day (200 mg twice daily)
(celiprolol hydrochloride). In case of signs of intolerance
(fatigue, dizziness) during up-titration or follow-up, the dose of
celiprolol was reduced by 100 mg/day until the highest tolerated
dose was reached. Dose adjustments were made whenever necessary
throughout the patient's follow-up if intolerance was suspected. In
accordance with the treatment protocol of the BBEST trial, patients
were up-titrated to a maximum dose of 200 mg twice daily.
[0144] Adherence to medication was verified by open interview of
the patients at each follow-up visit. Low medication adherence was
considered if patients admitted to not taking their medication
regularly at any moment of their follow-up. Patients were
considered intolerant to celiprolol in case of refusal to follow
the prescription even at a minimum dose of 100 mg/day. Patients
taking another beta-blocker were offered to switch to celiprolol
but this change was not mandatory, especially if patients had been
clinically silent until molecular diagnosis while under another
betablocker. If an acute arterial event occurred, patients were
once again offered to switch to celiprolol. To reach significant
numbers to allow comparative analysis, intolerant patients,
patients not taking celiprolol, patients taking another betablocker
and non-adherent patients were merged into one group further
referred to as "not treated".
[0145] Arterial Progression
[0146] In order to assess arterial morbidity over a long timeline
in patients with different follow-up periods, an empirical arterial
score was designed for each subject. Arterial accidents were
weighted as follows: 10 points for arterial ruptures located in the
abdomen/thorax/head/neck or for carotid-cavernous fistulas; 5
points for lower or upper limb arterial ruptures as well as
arterio-venous fistulas, 2 points for symptomatic dissections (any
location) and 1 point for silent dissections, aneurysms and
false-aneurysms when diagnosed during an acute arterial event. The
arterial progression score was calculated for each patient at the
time of the initial work-up hence quantifying history of
symptomatic arterial accidents at baseline. Clinical arterial
events occurring thereafter (i.e. during the follow-up until the
end of the study) were then added to the initial score. According
to their initial score, patients were divided into 4 levels of
clinical progression: very low (score 0-1 point); low (score 2-8
points); medium (score 9-19 points) or high (score 20 points).
[0147] Genetics
[0148] After initial referral and clinical assessment, patients
underwent molecular testing fora COL3A1 variant after written
informed consent. The modalities of molecular analysis have been
reported in detail previously (Frank M et al. Eur J Hum Genet.
2015; December; 23(12):1657-64). After identification of a
pathogenic mutation, patients were staged by type of variant, with
respect to expected differences in outcomes. For this study,
patients were divided into four groups: patients with a glycine
substitution within the triple helix (Group I), patients with
splice-site variants (Group II), patients with variants leading to
haplo-insufficiency (Group III), and patients with variants located
in portions of COL3A1 encoding for the C- and N-Terminal parts of
the protein, as well as non-Glycine substitutions within the triple
helix (Group IV). For this report, we did not take into
consideration the few patients with Group IV variants, since their
causality is only suggested and has not been definitively
proven.
[0149] Statistical Analysis
[0150] Quantitative data were expressed as number, median, first
and third quartiles; qualitative data were expressed as number and
percentage. Qualitative parameters were compared with the
Chi-square test or Fisher's exact test as appropriate. Quantitative
variables were compared with the Wilcoxon-Mann-Whitney or the
Kruskal Wallis tests, as appropriate. Associations between survival
or time until event and compliant patients were examined using the
Kaplan-Meier curve and Log rank test was used to assess the
significance. A Cox proportional hazards model was used to evaluate
predictive factors. Data were censored if a patient was still alive
(or without event) at the end date of data collection (Mar. 15,
2017). All tests were two-sided, and significance was assumed at
p<0.05. Statistical analyses were done with SAS software version
9.2 (Institute INC, Cary, N.C., USA) and XLSTAT software version
2016.4 (Addinsoft).
Results
[0151] Patients
[0152] Between January 2000 and March 2017, n=144 patients with
molecularly confirmed vascular EDS were found eligible for
participation in this study (FIG. 1). A majority (n=90) had glycine
missense mutations (Group I), others had splice variants (n=42,
Group II) and n=12 had variants leading to haplo-insufficiency
(Group III). Patients were followed for a median duration of 5.30
[3.20; 8.45] years. The longest documented follow-up was 20 years,
and half of patients (55.6%) had a follow up >5 years. The
characteristics of patients according to treatment at baseline are
reported in Table 1. As expected, patients were young (34.5 years
at diagnosis) had low body mass index (21.2 Kg/m.sup.2) and normal
blood pressure values. There was a slight female predominance
(60.4%). Almost 2/3.sup.rd of the patients were index cases
typically referred for diagnostic work-up due to unusual vascular
fragility. Thus, overall, many patients (n=98, 68.1%) had
experienced a disease related event before follow-up. More than
half (51.4%) had an arterial event as the first disease-related
complication, whereas a first digestive rupture had occurred in
22.9% of the cases, pneumothorax or hemopneumothorax being less
frequent (n=15; 10.4%) (Table 1). There was no difference in the
initial characteristics of the patients depending on the type of
medical intervention, except those (n=8, age at molecular diagnosis
55.5 years) who were left on medications other than celiprolol,
mainly because of clinical stability on combination drugs at the
time of inclusion in the cohort study.
TABLE-US-00001 TABLE 1 Baseline characteristics of n = 144 patients
with vascular EDS according to treatment. Patient's N = 104 N = 26
characteristics N N = 144 Celiprolol Celiprolol + N = 8 N = 6 P (%)
or median [IQR] All patients alone Another drug Other drugs No
treatment value Sex 0.4201 Female 87 (60.4) 66 (63.5) 12 (46.2) 5
(62.5) 4 (66.7) Male 57 (39.6) 38 (36.5) 14 (53.8) 3 (37.5) 2
(33.3) Age at molecular 34.5 32.5 38.0 55.5 31.0 0.0005 diagnosis
[25.0; 42.5] [24.0; 40.5] [33.0; 45.0] [41.0; 67.5] [15.0; 51.0]
Status 0.0632 Index case 91 (63.2) 67 (64.4) 19 (73.1) 4 (50.0)
1(16.7) Relative 53 (36.8) 37 (35.6) 7 (26.9) 4 (50.0) 5 (83.3)
Type of variant 0.0491 Group I 90 (62.5) 58 (55.8) 22 (84.6) 5
(62.5) 5 (83.3) Group III 42 (29.2) 36 (34.6) 4 (15.4) 1 (12.5) 1
(16.7) Group III 12 (8.33) 10 (9.62) 0 2 (25.0) 0 Baseline
characteristics BMI (kg/m.sup.2) 21.2 21.0 22.9 22.6 20.6 0.2415
[19.0; 23.7] [19.0; 23.0] [20.5; 26.1] [17.3; 28.4] [19.0; 22.5]
SBP (mmHg) 114.0 113.0 120.0 112.5 113.5 0.2145 [106.0; 123.0]
[105.0; 121.0] [112.0; 126.0] [107.0; 131.0] [104.0; 120.0] DBP
(mmHg) 70.0 70.0 74.0 75.0 69.0 0.2837 [65.0; 78.0] [64.0; 76.0]
[65.0; 83.0] [68.0; 85.0] [68.0; 76.0] Heart rate (bpm) 72.0 73.0
71.0 64.5 65.5 0.0920 [64.0; 81.5] [65.0; 83.0] [65.0; 79.0] [57.5;
69.0] [59.0; 76.0] Medical history (Patients with at least one
event) Overall n patients 98 (68.1) 69 (66.3) 21 (80.8) 6 (75) 2
(33.3) 0.1319 n events 227 162 47 14 4 Arterial events n patients
74 (51.4) 50 (48.1) 19 (73.1) 3 (37.5) 2 (33.3) 0.0752 n events 156
105 39 9 3 Gastrointestinal events n patients 33 (22.9) 27 (26.0) 3
(11.5) 3 (37.5) 0 0.1603 n events 47 39 4 4 0 Pulmonary events n
patients 15 (10.4) 11 (10.6) 2 (7.69) 1 (12.5) 1 (16.7) 0.7937 n
events 24 18 4 1 1 Follow-up length 5.30 5.15 7.15 3.55 4.30 0.0123
(year) [3.20; 8.45] [3.10; 8.35] [4.90; 11.3] [2.90; 6.05] [1.30;
5.20] Chi-square test or Fisher exact test(.sup.f) for qualitative
variables and Mann-Whitney test for quantitative variables.
Abbreviations: BMI: body mass index; DBP: diastolic blood pressure;
IQR: interquartile range; SBP: systolic blood pressure Group I:
Glycine missense variants; Group II: splice-site variants,
insertions-deletions, duplications; Group III: variants leading to
haploinsufficiency.
[0153] Medical Intervention
[0154] At the initial work-up, 50% of the patients were not treated
regularly and only 33.3% were taking celiprolol. Other
cardiovascular drugs were also being taken at baseline,
predominantly beta-blockers (12.5%) and/or angiotensin II receptor
blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs)
(6.9%). By the end of the study period, almost all patients (90.3%)
were treated with celiprolol alone or in combination. The
proportion of patients taking ACEIs/ARBs increased with age to a
maximum of 20.1%. Common indications were arterial hypertension and
renal ischemia with reno-vascular hypertension. Once the maximum
tolerated dose of celiprolol was reached, n=90 (62.5%) patients
remained at identical dosage throughout their respective follow-up
periods. Further dose increase was possible in n=32 (22.2%) of
patients. Only n=5 (3.47%) patients required dose reduction due to
fatigue and/or dizziness.
[0155] For patients taking celiprolol, the median treatment
duration for all patients was 5.2 [3.0; 7.3] years (min-max
0.5-13.5). During their respective follow-up, n=120/144 (83.3%)
patients were considered adherent to celiprolol at either 400
mg/day (n=92; 63.9%), or at doses <400 mg/day (n=28; 19.4%). The
median dose of celiprolol throughout follow-up was 400 mg/day [333;
400] in patients at full dose, and 217 mg/day [200; 300] in
patients at lower doses. A minority of patients (n=14; 9.7%) were
reported non-adherent at some point of their follow-up, n=7 (4.9%)
had another beta-blocker, and n=2 (1.4%) declared themselves as
intolerant to celiprolol or refused to take it in fear of
intolerance. Median dose of celiprolol in non-adherent patients was
lower than in adherent patients: 200 mg/day [200; 300] versus 378
mg/day [233; 400], respectively.
[0156] Patient Survival
[0157] During the 17-year timeframe of the study, n=17 (11.8%)
patients died at a relatively young age (35 [26-41]). Arterial
rupture was the most common cause of death (n=12, 70.6%), followed
by bowel perforation (n=2, 11.8%), the three remaining deaths not
being related to vEDS.
[0158] Survival of patients was respectively 98.6% at 1 year, 92%
at 5 years, and 82.7% at 10 years of follow-up. Overall patient
survival was 71.6% 95% CI [51.0%-92.1%] (FIG. 2A). Due to the low
number of deaths, a median age of survival could not be determined.
Patient survival did not significantly differ between groups of
mutations. Notably, no death occurred in patients of Group III
(haplo-insufficiency) (FIG. 2B). Index patients were consistently
more symptomatic over time than relatives.
[0159] Comparison of dead patients with survivors demonstrated a
significant association between celiprolol and survival (Table 2).
Because of the influence of the type of mutation, we restricted our
analysis to the n=132 patients with the Group I and II mutations,
those known as the most severe forms of the disease. This selection
was also justified by the high number of relatives in the group III
(10 relatives vs 2 index cases), their milder phenotype and their
shorter average duration of follow-up (3.2 vs 6.3 years,
p<0.01). On this more homogeneous group of n=132 patients, those
not treated with celiprolol, had a significantly worse outcome than
treated patients (FIG. 3A): survival was 80.7%, 95% CI
[67.8%-93.6%] in those treated with celiprolol versus 48.5%, 95% CI
[19.7%-77.4%] in those not treated (p<0.001). Moreover, in
adherent patients, survival was significantly improved in patients
taking celiprolol at 400 mg/day, when compared to patients with
lower doses or to patients having never been treated with
celiprolol (FIG. 3B). Independent predictors of survival determined
by a Cox stepwise hazards model were an age at molecular diagnosis
<34 years (p<0.0001), treatment duration with celiprolol
>6 years (p=0.01) and celiprolol intake at 400 mg/d (p=0.01)
(Table 3).
TABLE-US-00002 TABLE 2 Characteristics of patients who died during
follow-up compared to surviving patients. Deceased patients Alive N
= 17 N = 127 N (%) or N (%) or median median Patients [Q1;Q3]
[Q1,Q3] P value Sex Male 9 (52.9%) 48 (37.8%) 0.2304 Female 8
(47.1%) 79 (62.2%) Age at the 28.0 35.0 0.0765 beginning of the
[21.0; 38.0] [26.0; 43.0] follow-up Age at death or at 35.0 41.0
the last-follow-up [26.0; 41.0] [33.0; 50.0] Status Index case 13
(76.5%) 78 (61.4%) 0.2268 Relative 4 (23.5%) 49 (38.6%) Type of
variant Group I 13 (76.5%) 77 (60.6%) 0.5802 Group II 4 (23.5%) 38
(29.9%) Group III 0 12 (9.45%) Treatment with Yes 9 (52.9%) 111
(87.4%) celiprolol No 8 (47.1%) 16 (12.6%) Chi square test or
Fisher exact test (.sup.f) for qualitative variables and
Mann-Whitney test for quantitative variables. Bold value indicates
p < 0.05.
TABLE-US-00003 TABLE 3 Multivariate survival analysis adjusted for
prognostic factors (Cox's model) in n = 132 patients (Groups I and
II). Factor Hazard ratio [95% CI] P value Status Relative/Index
0.145 [0.030; 0.700] Gender Male/Female 0.920 [0.260; 3.251] 0.8973
Age at diagnosis .gtoreq.41 years/<25 years 0.001 [0.0001;
0.022] 34-41 years/<25 years 0.001 25-34 years/<25 years
0.039 [0.0001; 0.029] Treatment duration .gtoreq.6 years/<6
years 0.058 [0.010; 0.352] Celiprolol treatment Full dose/No 0.048
[0.009; 0.249] Half dose/No 0.303 [0.071; 1.292] 0.1065 Type of
variant Group II/Group I 0.459 [0.098; 2.148] 0.3224 Stepwise
method Status Relative/Index 0.196 [0.047; 0.814] Age at diagnosis
.gtoreq.41 years/<25 years 0.001 [0.0001; 0.024] 34-41
years/<25 years 0.001 [0.0001; 0.034] 25-34 years/<25 years
0.046 [0.005; 0.405] Treatment duration .gtoreq.6 years/<6 years
0.058 [0.011; 0.314] Celiprolol treatment Full dose/No 0.060
[0.013; 0.277] Half dose/No 0.305 [0.078; 1.184] 0.0862
[0160] Arterial Events
[0161] At the initial work-up, 74 out of the 144 patients (51.4%),
had a history of acute arterial event or arterial lesions detected
at CTA and/or DUS, at a median age of 33.0 years ([27.0; 40.5];
min-max.: 13-70) (Table 1). Almost one-fifth (22.7%) reported two
symptomatic arterial events and n=11 (8.3%) patients presented with
a third arterial event prior to diagnosis. As a consequence of the
recruitment bias mainly based on initial symptoms or complications
for patients with vascular EDS, index cases had a higher history of
previous medical events than their first-degree relatives (82.4% vs
43.4%, p<0.0001) in spite of their younger age (33 vs. 41 years,
p=0.001).
[0162] Combined with secondary arterial defects identified in the
context of these symptomatic arterial events, a total of n=398
arterial lesions were identified in n=74 patients. The most common
were dissections (70.1%), followed by aneurysms and false aneurysms
(20.4%), arterial ruptures (6.0%), and direct spontaneous carotid
cavernous fistula (2.5%). The most common locations of arterial
defects were the abdominal aorta and its branches (digestive and
renal arteries) (37.2%), carotid and vertebral arteries (29.4%),
and iliac and femoral arteries (26.6%). Uncommon locations were the
thoracic aorta, coronary arteries, and peripheral arteries of the
upper and lower limbs.
[0163] During follow-up, all patients of Group III remained
clinically silent. Arterial accidents occurred in patients of
Groups I and II, totaling n=237 new arterial defects in n=66
patients, 87 of them being symptomatic in n=43 patients. Among
these, 15 led to death, others were medically or surgically
treated. To evaluate qualitatively and quantitatively the severity
of arterial lesions, we designed an arterial score taking into
consideration the type, number and locations of arterial lesions
observed on CTA and/or DUS (see methods). The distribution of this
arterial score showed that most patients (73%) were in the lower
group at baseline (FIG. 4). At the end of the follow-up a majority
of patients remained in their respective progression groups: very
low 75% (51/68), low 71.4% (20/28) and medium 70% (20/28),
indicating clinical stability in more than two thirds of
patients.
[0164] Effect of Celiprolol on the Incidence of Acute Arterial
Events
[0165] A total of 87 new arterial events (symptomatic) occurred in
43 patients, i.e. less than 30% of patients. For each of these
patients, we observed 1 to 5 new arterial events, with an average
of 1.7.+-.1.02 events over a 5.3 years follow-up period. At the
time of the occurrence of the new arterial event, 33 out of these
43 patients were treated by celiprolol alone (n=28) or in
combination with another drug (n=5), proportions which were not
different from that of the entire group (104/144 and 26/104,
respectively). It was not possible to assess if the drug had an
effect on the delay these arterial events occurred and/or if it was
associated with a decreased severity or different locations. The
cumulative incidence of a first and second new arterial event
during follow-up was 56.8% (95% CI [45.7; 70.5]) and 29.8% (95% CI
[17.6; 50.4]), respectively. The mean age of occurrence of this
first and second new arterial event was 37 (95% CI[35;42]) years
and 48 (95% CI[42;65]) years, respectively, without identifiable
effect of celiprolol.
[0166] We then looked at the cumulative number of hospitalizations
during the complete survey. The hospitalisations for both
symptomatic arterial accidents and arterial monitoring in
clinically silent patients, paralleled the total number of patients
(FIG. 5A). Interestingly, despite no change in patient monitoring
standards, the hospitalization rates stabilized with the
generalized prescription of celiprolol starting 2011 despite a
constant increase of patients followed by our centre. Notably,
total number of hospitalizations for acute arterial accidents
decreased, as well as recurrent hospitalizations of patients with
repeated symptomatic arterial accidents. We observed a
statistically significant difference between the rate of
hospitalizations for acute arterial event before and after 2011 (OR
1.72, 95% CI [1.0670-2.7620], p=0.0257), suggesting a positive
effect of celiprolol on the occurrence and/or severity of these new
arterial events (FIG. 5B).
[0167] The data show that patients treated with celiprolol had a
better survival than others. The observed reduction in mortality
was dose-dependent, 400 mg/day of celiprolol HCl is better than a
smaller dose administering, and full doses of celiprolol to vEDS
patients with shorter up-titration and dose escalation periods of
about three months provided improved treatment benefits, such as
overall survival, without significant increase in celiprolol
intolerance and side effects.
[0168] Although the foregoing disclosure has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, the descriptions and examples should not be
construed as limiting the scope of the disclosure. The disclosure
of all patent and scientific literature cited herein are expressly
incorporated in their entirety by reference.
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