US20190192457A1 - Method of providing celiprolol therapy to a patient - Google Patents

Method of providing celiprolol therapy to a patient Download PDF

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US20190192457A1
US20190192457A1 US16/184,922 US201816184922A US2019192457A1 US 20190192457 A1 US20190192457 A1 US 20190192457A1 US 201816184922 A US201816184922 A US 201816184922A US 2019192457 A1 US2019192457 A1 US 2019192457A1
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celiprolol
patient
daily
dose
month
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Michael Frank
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Assistance Publique Hopitaux de Paris APHP
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Assistance Publique Hopitaux de Paris APHP
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Priority to BR112020012095-2A priority Critical patent/BR112020012095A2/pt
Priority to PCT/EP2018/085902 priority patent/WO2019121956A1/en
Priority to CA3083432A priority patent/CA3083432A1/en
Priority to MX2020006351A priority patent/MX2020006351A/es
Publication of US20190192457A1 publication Critical patent/US20190192457A1/en
Assigned to ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (AP-HP) reassignment ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (AP-HP) ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRANK, MICHAEL
Priority to MX2023006765A priority patent/MX2023006765A/es
Priority to US16/930,208 priority patent/US11523997B2/en
Priority to US17/472,499 priority patent/US20220062208A1/en
Priority to US17/985,627 priority patent/US20230142044A1/en
Priority to US18/662,943 priority patent/US20240366541A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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.
  • novel up-titration dosage regimens e.g., escalating dosage regimens
  • vEDS Vascular Ehlers-Danlos syndrome
  • vEDS is a rare genetic condition secondary to mutation within the COL3A1 gene.
  • vEDS has an autosomal dominant inheritance.
  • the most common COL3A1 variants result either in glycine substitutions within the triple helix encoding type III procollagen or in truncating splice-site variants. Both are responsible for a disruption of proper assembly of type III procollagen into type III collagen fibrils with a dominant negative effect. The amount of mature type III 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the method further comprises providing to the patent a fifth daily dosage of celiprolol, or a pharmaceutically acceptable salt thereof.
  • the fourth daily dosage, or any daily dosage beyond the fourth daily dosage is considered a maintenance dosage.
  • the initial daily dosage is about 100 mg celiprolol or a pharmaceutically acceptable salt thereof.
  • the second daily dosage is about 200 mg celiprolol, or a pharmaceutically acceptable salt thereof.
  • the third daily dosage is about 300 mg celiprolol, or a pharmaceutically acceptable salt thereof.
  • the fourth daily dosage is about 400 mg celiprolol, or a pharmaceutically acceptable salt thereof.
  • the fifth daily dosage is greater than 400 mg celiprolol (e.g., 500 mg or 600 mg), or a pharmaceutically acceptable salt thereof.
  • the first period of time is about one month, about 30 days, or about 28 days.
  • the second period of time is about one month, about 30 days, or about 28 days.
  • the third period of time is about one month, about 30 days, or about 28 days.
  • 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.
  • 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 Ehler-Danlos syndrome.
  • 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.
  • 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.
  • 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.
  • 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.
  • a dosage of at least 200 mg per day is administered to the patient within 30 days of the initial dose.
  • a dosage of at least 300 mg per day is administered to the patient within 60 days of the initial dose.
  • 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.
  • the initial dosage of celiprolol, or a pharmaceutically acceptable salt thereof is 100 mg per day.
  • 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.
  • 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.
  • 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.
  • signs of intolerance to the drug e.g., swelling, fatigue, or flu-like symptoms
  • 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.
  • the initial daily dosage is about 91.25 mg celiprolol or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the second daily dosage is about 182.5 mg celiprolol, or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the third daily dosage is about 273.75 mg celiprolol, or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the fourth daily dosage is about 365 mg celiprolol, or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • 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.
  • the first period of time is about one month, about 30 days, or about 28 days.
  • the second period of time is about one month, about 30 days, or about 28 days.
  • the third period of time is about one month, about 30 days, or about 28 days.
  • 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.
  • 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 E
  • 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.
  • 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.
  • celiprolol or a pharmaceutically acceptable salt thereof
  • 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.
  • a dosage of at least about 182.5 mg celiprolol per day is administered to the patient within 30 days of the initial dose.
  • a dosage of at least about 273.75 mg celiprolol per day is administered to the patient within 60 days of the initial dose.
  • 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.
  • the initial dosage of celiprolol is about 91.25 mg per day, or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • signs of intolerance to the drug e.g., swelling, fatigue, or flu-like symptoms
  • 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.
  • 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.
  • the celiprolol or pharmaceutically acceptable salt thereof is celiprolol hydrochloride.
  • the initial daily dosage is about 100 mg celiprolol hydrochloride.
  • the second daily dosage is about 200 mg celiprolol hydrochloride.
  • the third daily dosage is about 300 mg celiprolol hydrochloride.
  • the fourth daily dosage is about 400 mg celiprolol hydrochloride.
  • the fifth daily dosage is greater than 400 mg (e.g., about 500 mg or about 600 mg) celiprolol hydrochloride.
  • the first period of time is about one month, about 30 days, or about 28 days.
  • the second period of time is about one month, about 30 days, or about 28 days.
  • the third period of time is about one month, about 30 days, or about 28 days.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • a dosage of at least 200 mg per day is administered to the patient within 30 days of the initial dose.
  • a dosage of at least 300 mg per day is administered to the patient within 60 days of the initial dose.
  • 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.
  • the initial dosage of celiprolol hydrochloride is 100 mg per day.
  • 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.
  • 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.
  • 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.
  • 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.
  • signs of intolerance to the drug e.g., swelling, fatigue, or flu-like symptoms
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • an acute vEDS-related event e.g., an arterial event such as a rupture or dissection, an intestinal or uterine rupture
  • 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.
  • 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.
  • 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.
  • 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.
  • A. 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.
  • FIG. 4 Evolution of the clinical arterial score throughout follow-up.
  • FIG. 5 A. Rate of patients and hospitalizations during the study. B. Rate of hospitalizations for acute arterial event before and after the systematic introduction of celiprolol.
  • 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.
  • 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.
  • 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-tit
  • a method 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.
  • 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;
  • 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, during
  • 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.
  • 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.
  • 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.
  • 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.
  • a 80 to 110 mg daily (e.g., about 91.25 mg) dose increase is made within two months.
  • at least a 170 to 210 mg (e.g., about 182.5 mg) daily dose increase is made within four months.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • treat refers 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.
  • Celiprolol brand names Cardem®, Selectol®, Celipres®, Celipro®, Celol®, Cordiax®, Dilanorm®, EdsivoTM
  • Celiprolol brand names Cardem®, Selectol®, Celipres®, Celipro®, Celol®, Cordiax®, Dilanorm®, EdsivoTM
  • 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.
  • celiprolol is administered at a dose of 100 mg twice a day during the second month of treatment.
  • the dose of celiprolol is reduced in case of signs of intolerance during up-titration or dose escalation, or during any follow-up.
  • 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.).
  • 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.
  • celiprolol is thus administered at a dose at or above 360 mg/day at the end of the titration period.
  • celiprolol is administered at a dose of 200 mg twice a day at the end of the three-month titration period.
  • 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.
  • 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).
  • vascular EDS is typically clinically silent until the late teenage years.
  • 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.
  • celiprolol is administered in a pharmaceutical composition comprising celiprolol or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is a tablet formulation, such as a film coated tablet.
  • the pharmaceutical composition is an immediate release formulation, such as an immediate release tablet formulation.
  • each tablet comprises about 182.5 mg celiprolol or about 200 mg of celiprolol hydrochloride.
  • 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.
  • the daily dose between a 1 ⁇ 2 tablet and 2 tablets may be adjusted based on patient tolerance.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • treatment with celiprolol 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.
  • 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.
  • 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.
  • the reduction continues for at least 5 days.
  • the reduction continues for at least 7 days.
  • the reduction continues for at least 10 days.
  • 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.
  • celiprolol or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg twice a day.
  • celiprolol or a pharmaceutically acceptable salt thereof, is administered at a dose superior to 360 mg/day.
  • celiprolol or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day.
  • 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.
  • 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.
  • celiprolol hydrochloride is administered at a dose of about 100 mg twice per day.
  • celiprolol hydrochloride is administered at a dose superior to 360 mg/day.
  • celiprolol hydrochloride is administered at a dose of about 400 mg per day.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Celiprolol hydrochloride for the use of any of one 35 to 41 above, wherein the patient is 15-years old or older.
  • 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.
  • Celiprolol hydrochloride for the use of any one of 35 to 43 above, wherein the patient is not co-administered itraconazole.
  • 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.
  • 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.
  • 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.
  • 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).
  • Group I patients with a glycine substitution within the triple helix
  • Group II patients with splice-site variants
  • Group III patients with variants leading to haplo-insufficiency
  • non-Glycine substitutions within the triple helix Group IV
  • 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).
  • the characteristics of patients according to treatment at baseline are reported in Table 1.
  • 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.
  • FIG. 2A 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.
  • 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.

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