A Study to Examine the Safety, Tolerability and Effects on Abnormal Bone Formation of REGN2477 in Patients With Fibrodysplasia Ossificans Progressiva

NCT03188666 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: R2477-FOP-16232016-005035-33
• Study Type: interventional
• Target: 44
• Locations: 8 countries
• Sites: 11

Brief Summary

This is a three period study design consisting of a 6-month, randomized, double-blind placebo-controlled treatment (period 1) followed by a 6-month, open-label treatment (period 2) and a follow-up treatment period (period 3). Primary safety objective of the study is to assess the safety and tolerability of REGN2477 in male and female patients with fibrodysplasia ossificans progressiva (FOP). Primary efficacy objective of the study is to assess the effect of REGN2477 versus placebo on the change from baseline in heterotopic ossification (HO) in patients with FOP, as determined by 18-NaF uptake in HO lesions by positron emission tomography (PET) and in total volume of HO lesions by computed tomography (CT). Key Secondary objectives are:

• To compare the effect of REGN2477 versus placebo on pain due to FOP, as measured by the area under the curve (AUC) for pain based on daily pain numeric rating scale (NRS) scores
• To assess the effect of REGN2477 versus placebo on the change from baseline in HO, as determined by the number of new HO lesions identified by 18F-NaF PET or by CT
• To assess the effect of REGN2477 versus placebo on the change from baseline in 18F-NaF standardized uptake value maximum (SUVmax) of individual active HO site(s) by PET
• To assess the effect of REGN2477, between week 28 and week 56, on the number, activity, and volume of HO lesions identified by 18F-NaF PET or by CT in patients who switch from placebo to REGN2477 at week 28 versus the same patients between baseline and week 28
• To assess the effect of REGN2477 versus placebo on the change from baseline in biochemical markers of bone formation
• To characterize the concentrations of total activin A at baseline and over time following the first dose of study drug
• To characterize the concentration-time profile (pharmacokinetics \[PK\]) of REGN2477 in patients with FOP
• To assess the immunogenicity of REGN2477

Conditions

Fibrodysplasia Ossificans Progressiva

Outcome Measures

Primary Outcomes (7)

• Period 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

  Treatment-emergent adverse events (TEAEs) are adverse events not present at baseline or represent the exacerbation of a pre-existing condition during the on-treatment period. A serious TEAE was defined as any untoward medical occurrence that resulted in any of following outcomes not present at baseline or represent the exacerbation of a pre-existing condition during the on-treatment period: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. Number of participants with TEAEs and Serious TEAEs are reported.

  Up to Week 28

• Period 1: Number of Participants With TEAEs by Severity

  Severity of TEAEs were graded as follows: Mild: Does not interfere in a significant manner with the participant's normal functioning level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms but may be given because of personality of the participants. Moderate: Produces some impairment of functioning but is not hazardous to health. It was uncomfortable or an embarrassment. Treatment for symptom may be needed. Severe: Produces significant impairment of functioning or incapacitation and was a definite hazard to the participant's health. Treatment for symptom may be given and/or participants hospitalized. Number of participants with TEAEs by severity is reported.

  Up to Week 28

• Period 1: Time-Weighted Average (Standardized Area Under the Curve [AUC]) of the Percent Change From Baseline in Total Lesion Activity by Fluorine-18-labeled Sodium Fluoride (18^F-NaF) Positron Emission Tomography (PET) at Week 28 (AHO)

  18\^F-NaF PET is used to assess lesion and disease activity. Time-weighted average (standardized area under the curve \[AUC\]) of the percent change from baseline in total lesion activity by 18\^F-NaF PET up to Week 28 in AHO analysis set is reported.

  Baseline and Week 28

• Period 1: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by Computed Tomography (CT) at Week 28 (AHO)

  CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Percent change from baseline in the total volume of HO lesions as assessed by CT during Period 1 at Week 28 is reported.

  Week 28

• Period 2: Number of New HO Lesions as Assessed by CT at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)

  CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. HO detectable by CT that developed after baseline are referred to as "new HO lesions." Number of new HO lesions as assessed by CT at Week 56 relative to Week 28 scan is reported.

  Week 28, Week 56

• Period 1: Time-weighted Average (Standardized AUC) of the Percent Change From Baseline in Total Lesion Activity Assessed by 18^F-NaF PET at Week 28 (AHOC)

  18\^F-NaF PET is used to assess lesion and disease activity. Time-weighted average (Standardized AUC) of the percent change from baseline in total lesion activity as assessed by 18\^F-NaF PET in Active HO Classic ACVR1 Mutation (AHOC) analysis set up to Week 28 is reported.

  Week 28

• Period 1: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by CT at Week 28 (AHOC)

  CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Percent change from baseline in the total volume of HO lesions was assessed by CT at Week 28 in AHOC analysis set is reported.

  Week 28

Secondary Outcomes (36)

• Period 1: Time-weighted Average (Standardized AUC) of the Change From Baseline in Daily Pain Due to Fibrodysplasia Ossificans Progressiva (FOP) Assessed by Daily Numeric Rating Scale (NRS) at Week 28 (AHO)

  Week 28

• Period 1: Time-weighted Average (Standardized AUC) of the Change From Baseline in Daily Pain Due to FOP, Assessed by Daily NRS at Week 28 (AHOC)

  Week 28

• Period 1: Percent Change From Baseline in 18^F-NaF SUVmax of Individual Active HO Site(s) Assessed by 18^F-NaF PET at Week 8 (AHOC)

  Week 8

• Period 1: Percent Change From Baseline in 18^F-NaF SUVmax of Individual Active HO Site(s) as Assessed by 18^F-NaFPET at Week 8 (AHO)

  Week 8

• Period 1: Change From Baseline in Number of HO Lesions as Assessed by 18^F-NaF PET at Week 28 (AHOC)

  Week 28

Study Arms (2)

REGN2477

EXPERIMENTAL

Drug: REGN2477

Placebo

EXPERIMENTAL

Drug: Matching placebo

Interventions

REGN2477 DRUG

Pharmaceutical form: liquid product for injection/infusion; Route of administration: Intravenous (IV); Administered during treatment periods 1 and 2.

REGN2477

Matching placebo DRUG

Pharmaceutical form: Liquid product for injection/infusion; Route of administration: Intravenous (IV); Administered during treatment period 1 only.

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Men and women 18 to 60 years of age at screening.
• Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft tissue swelling, and/or progressive heterotopic ossification (HO)).
• Confirmation of FOP diagnosis with documentation of any ACVR1 mutation.
• FOP disease activity within 1 year of screening visit. FOP disease activity is defined as pain, swelling, stiffness, and other signs and symptoms associated with FOP flare-ups; or worsening of joint function, or radiographic progression of heterotopic ossifications (increase in site or number of HO lesions) with/without being associated with flare-up episodes.
• Willing and able to undergo PET and CT imaging procedures and other procedures as defined in this study.

You may not qualify if:

• Significant concomitant illness or history of significant illness such as, but not limited to cardiac, renal, rheumatologic, neurologic, psychiatric, endocrine, metabolic or lymphatic disease, that in the opinion of the study investigator might confound the results of the study or pose additional risk to the patient by their participation in the study.
• Previous history or diagnosis of cancer.
• Use of bisphosphonate within 1 year of screening.
• Concurrent participation in another interventional clinical study, or a non-interventional study with radiographic measures or invasive procedures (e.g. collection of blood or tissue samples). Participation in the FOP Connection Registry or other studies in which participants complete study questionnaires are allowed.
• Treatment with another investigational drug, denosumab, imatinib or isotretinoin in the last 30 days or within 5 half-lives of the investigational drug, whichever is longer.
• Pregnant or breastfeeding women.
• Male and women of childbearing potential participants who are unwilling to practice highly effective contraception.

Sponsors & Collaborators

• Regeneron Pharmaceuticals: lead

Study Sites (11)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Vanderbilt University

Nashville, Tennessee, 37240, United States

Location

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

Hopital Cochin

Paris, 75014, France

Location

Hopital Lariboisiere,Hospitalier Universitaire Nord

Paris, 751010, France

Location

Giannina Gaslini Institute

Genova, 16147, Italy

Location

VU University Medical Center

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Szpital Wojewodzki Nr 2

Rzeszów, 35-301, Poland

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Royal National Orthopaedic Hospital, Brockley Hill

Stanmore, Middlesex, HA7 4LP, United Kingdom

Location

Related Publications (4)

• de Ruiter RD, Botman E, Teunissen BP, Lammertsma AA, Boellaard R, Raijmakers PG, Schwarte LA, Nieuwenhuijzen JA, Gonzalez Trotter D, Eekhoff EMW, Yaqub M. Performance of simplified methods for quantification of [18F]NaF uptake in fibrodysplasia ossificans progressiva. Front Nucl Med. 2024 Jul 22;4:1406947. doi: 10.3389/fnume.2024.1406947. eCollection 2024.

  PMID: 39381032 DERIVED

• Di Rocco M, Forleo-Neto E, Pignolo RJ, Keen R, Orcel P, Funck-Brentano T, Roux C, Kolta S, Madeo A, Bubbear JS, Tabarkiewicz J, Szczepanek M, Bachiller-Corral J, Cheung AM, Dahir KM, Botman E, Raijmakers PG, Al Mukaddam M, Tile L, Portal-Celhay C, Sarkar N, Hou P, Musser BJ, Boyapati A, Mohammadi K, Mellis SJ, Rankin AJ, Economides AN, Trotter DG, Herman GA, O'Meara SJ, DelGizzi R, Weinreich DM, Yancopoulos GD, Eekhoff EMW, Kaplan FS. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med. 2023 Oct;29(10):2615-2624. doi: 10.1038/s41591-023-02561-8. Epub 2023 Sep 28.

  PMID: 37770652 DERIVED

• Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M, Herman G, Davis JD. Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study. J Clin Pharmacol. 2020 Nov;60(11):1424-1431. doi: 10.1002/jcph.1638. Epub 2020 Jun 18.

  PMID: 32557665 DERIVED

• Aykul S, Corpina RA, Goebel EJ, Cunanan CJ, Dimitriou A, Kim HJ, Zhang Q, Rafique A, Leidich R, Wang X, McClain J, Jimenez J, Nannuru KC, Rothman NJ, Lees-Shepard JB, Martinez-Hackert E, Murphy AJ, Thompson TB, Economides AN, Idone V. Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop. Elife. 2020 Jun 9;9:e54582. doi: 10.7554/eLife.54582.

  PMID: 32515349 DERIVED

MeSH Terms

Conditions

Myositis Ossificans

Condition Hierarchy (Ancestors)

Myositis; Muscular Diseases; Musculoskeletal Diseases

Results Point of Contact

• Title: Clinical Trials Administrator
• Organization: Regeneron Pharmaceuticals, Inc

clinicaltrials@regeneron.com

844-734-6643

Study Officials

• Clinical Trial Management

  Regeneron Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2017
• First Posted: June 15, 2017
• Study Start: February 26, 2018
• Primary Completion: September 16, 2019
• Study Completion: September 16, 2021
• Last Updated: December 2, 2022
• Results First Posted: December 2, 2022

Record last verified: 2022-11

Locations

ES (1); PL (1); FR (2); GB (1); NL (1); CA (1); US (3); IT (1)