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

Study Overview
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Brief Summary
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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

Official Title
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A Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effects on Heterotopic Bone Formation of REGN2477 in Patients With Fibrodysplasia Ossificans Progressiva

Conditions
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Fibrodysplasia Ossificans Progressiva

Intervention / Treatment
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* Drug: REGN2477
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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. Key Exclusion Criteria: 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. Note: Other protocol defined Inclusion/Exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REGN2477<br> | Drug: REGN2477<br>* Pharmaceutical form: liquid product for injection/infusion; Route of administration: Intravenous (IV); Administered during treatment periods 1 and 2.<br>|
| Experimental: Placebo<br> | Drug: Matching placebo<br>* Pharmaceutical form: Liquid product for injection/infusion; Route of administration: Intravenous (IV); Administered during treatment period 1 only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | The pain NRS is a patient reported outcome (PRO) used by participants to rate their pain associated with FOP. Participants were asked to rate their pain on a scale that ranges from 0 (no pain) to 10 (worst possible pain), where the highest score indicated worst outcome. Time-weighted average (Standardized AUC) of the change from baseline in daily pain due to FOP assessed by daily NRS at Week 28 in AHO analysis set is reported. | 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) | The pain NRS is a PRO used by participants to rate their pain associated with FOP. Participants were asked to rate their pain on a scale that ranges from 0 (no pain) to 10 (worst possible pain), where the highest score indicated worst outcome. Time-Weighted average (standardized AUC) of the change from baseline in daily pain due to FOP assessed by daily NRS at Week 28 in AHOC analysis set is reported. | 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) | Standardized uptake value max (SUVmax) was a measurement of the maximum radiopharmaceutical uptake within the volume of interest. Relative accuracy of a particular radiotracer in a particular tissue is determined by expressing the absolute accuracy (obtained in the primary outcome measure) in terms of percent difference between SUVmax values obtained from PET/CT. Percent Change in 18^F-NaF SUVmax of Individual Active HO Site(s) assessed by 18^F-NaF PET in AHOC analysis set is reported. | 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) | Percent change in 18^F-NaF SUVmax of individual active HO site(s) as assessed by 18^F-NaF PET at Week 8 in AHO analysis set is reported. | Week 8 | 
| Period 1: Change From Baseline in Number of HO Lesions as Assessed by 18^F-NaF PET at Week 28 (AHOC) | Change from baseline in number of HO lesions was assessed by 18^F-NaF PET at Week 28 in AHOC analysis set is reported. | Week 28 | 
| Period 1: Change From Baseline in Number of HO Lesions as Assessed by 18^F-NaF PET at Week 28 (AHO) | Change from baseline in number of HO lesions was assessed by 18^F-NaF PET in AHO analysis set is reported. | Week 28 | 
| Period 1: Change From Baseline in Number of HO Lesions Detectable 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. Change from baseline in number of HO lesions was detectable by CT using AHOC analysis set is reported. | Week 28 | 
| Period 1: Change From Baseline in Number of HO Lesions Detectable by 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. Change from baseline in number of HO lesions detectable by CT at Week 28 in AHO analysis set is reported. | Week 28 | 
| Period 2: Number of New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT) | Number of new HO lesions as assessed by 18^F-NaF PET at Week 56 Relative to Week 28 Scan is reported. | Week 28, Week 56 | 
| Period 2: Percentage of Participants With 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. Percentage of participants with new HO lesions as assessed by CT at week 56 relative to week 28 scan is reported. | Week 28, Week 56 | 
| Period 2: Percentage of Participants With New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT) | 18^F-NaF PET is used to assess lesion and disease activity. Percentage of participants with new HO lesions as assessed by 18^F-NaF PET at week 56 relative to week 28 scan is reported. | Week 28, Week 56 | 
| Period 2: Number of New HO Lesions as Assessed by CT Only 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 Only: Computed Tomography (CT) assessment without reference to positron-emission tomography (PET). Number of new HO lesions as assessed by CT only at week 56 relative to week 28 scan is reported. | Week 28, Week 56 | 
| Period 2: Percentage of Participants With New HO Lesions as Assessed by CT Only 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 Only: Computed Tomography (CT) assessment without reference to Positron-Emission Tomography (PET). Percentage of participants with new HO lesions as assessed by CT only at week 56 relative to week 28 scan is reported. | Week 28, Week 56 | 
| Period 2 vs. Period 1: Change From Week 28 in Number of Active HO Lesions as Assessed by 18^F-NaF PET to Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (AHO COVID-19 mITT) | 18^F-NaF PET is used to assess lesion and disease activity. Difference of Change from Week 28 to Week 56 as assessed by 18^F-NaF PET versus from Baseline to Week 28 | Week 28, Week 56 | 
| Period 2 vs. Period 1: Change From Week 28 in Number of Active HO Lesions as Assessed by CT Scan at Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (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. Difference of Change from Week 28 to Week 56 as assessed by CT Scan versus from Baseline to Week 28 is reported | Week 28, Week 56 | 
| Period 2: Number of New HO Lesions as Assessed by CT at Week 56 Relative to Baseline (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. Number of new HO lesions as assessed by CT at week 56 relative to baseline. | Baseline, Week 56 | 
| Period 2: Number of New HO Lesions as Assessed by CT Only at Week 56 Relative to Baseline (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 Only: Computed Tomography (CT) assessment without reference to Positron-Emission Tomography (PET); Number of new HO lesions as assessed by CT only at week 56 relative baseline is reported. | Week 56 | 
| Period 2: Percentage of Participants With New HO Lesions as Assessed by CT at Week 56 Relative to Baseline (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. Percentage of participants with new HO lesions as assessed by CT at week 56 relative to baseline were reported. | Week 56 | 
| Period 2: Number of New HO Lesions as Assessed by 18^F-NAF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT) | 18^F-NaF PET is used to assess lesion and disease activity. Number of new HO lesions as assessed by 18^F-NAF PET at week 56 relative to baseline is reported. | Week 56 | 
| Period 2: Percentage of Participants With New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT) | 18^F-NaF PET is used to assess lesion and disease activity. Percentage of participants with new HO lesions as assessed by 18^F-NaF PET at week 56 relative to baseline. | Week 56 | 
| Period 2: Total Volume 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. Total volume of new HO lesions as assessed by CT at Week 56 relative to Week 28 scan. | Week 28, Week 56 | 
| Period 2: Total Lesion Activity (TLA) Assessed by 18^F-NaF PET in New HO Lesions at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT) | TLA is a measure of participant-level cumulative burden of metabolically active HO. Activity of individual HO lesions was calculated as the product of mean standard uptake value (SUVmean) and the PET volume of the active HO lesion. TLA was derived for each participant at each time point as the sum of HO lesion activity of individual target and new active HO lesions. | Week 28, Week 56 | 
| Period 2 vs. Period 1: Percent Change From Week 28 in TLA as Assessed by 18^F-NaF PET to Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (AHO COVID-19 mITT) | Difference of Percent Change from Week 28 to Week 56 versus from Baseline to Week 28 is reported | Week 28, Week 56 | 
| Period 2 vs. Period 1: Percent Change From Week 28 in the Total Volume of HO Lesions as Assessed by CT to Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (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. Difference of Percent Change from Week 28 to Week 56 versus from Baseline to Week 28 is reported. | Week 28, Week 56 | 
| Period 2: TLA in New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT) | Total Lesion Activity (TLA) is a measure of participant-level cumulative burden of metabolically active HO. TLA in New (Relative to Baseline) Lesions at Week 56 is reported. | Week 56 | 
| Period 2: Total Volume of New HO Lesions as Assessed by CT Only at Week 56 Relative to Baseline (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 Only: Computed Tomography (CT) assessment without reference to Positron-Emission Tomography (PET); Total volume of new HO lesions as assessed by CT only at week 56 relative to baseline is reported. | Week 56 | 
| Period 2: Percent Change From Baseline in TLA as Assessed by 18^F-NaF PET to Week 56 (AHO COVID-19 mITT) | Percent change from baseline in TLA as assessed by 18^F-NaF PET to week 56 were reported. | Week 56 | 
| Period 2: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by CT to Week 56 (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. Percent change from baseline in the total volume of HO lesions as assessed by CT to Week 56 were reported. | Week 56 | 
| Period 2: Percent Change From Week 28 in SUVmax as Assessed by 18^F-NaF to Week 56 (AHO COVID-19 mITT) | Percent Change from Week 28 to Week 56 is reported. | Week 28 to Week 56 | 
| Period 2: Percent Change From Baseline in 18^F-NaF PET SUVmax to Week 56 (AHO COVID-19 mITT) | Percent change from baseline in 18^F-NaF PET SUVmax to week 56 | Baseline, Week 56 | 
| Period 2: Daily Average Pain Due to FOP Measured Using the Daily NRS | The pain NRS is a patient reported outcome used by participants to rate their pain associated with FOP. Participants were asked to rate their pain on a scale that ranges from 0 (no pain) to 10 (worst possible pain), where the highest score indicated worst outcome. | Week 28 up to Week 56 | 
| Period 2: Percentage of Participants With Flare-ups Assessed by Participant E-diary | Percentage of participants with flare-ups starting between week 28 and week 56 as assessed by participant E-diary is reported. | Week 28 to Week 56 | 
| Period 2: Percentage of Participants With Investigator-assessed Flare-ups | Percentage of participants with investigator-assessed flare-ups were reported. | Week 28 to Week 56 | 
| Periods 1, 2, and 3: Concentration of Total Activin A in Serum | Concentration of total activin A in serum over time is reported. | Week 28, Week 56, Week 76 | 
| Periods 1, 2, and 3: Concentrations of Functional REGN2477 in Serum | Concentrations of REGN2477 capable of target binding were measured (functional drug). | Week 28, Week 56, Week 76 | 
| Periods 1, 2, and 3: Number of Participants With Clinical Impact of Treatment-Emergent Anti-drug Antibodies (ADA) to REGN2477 | Immunogenicity was characterized by ADA responses & titers. Responses categories: Negative - ADA negative response at all time points, regardless of missing samples; Pre-existing immunoreactivity - ADA positive response at baseline with all post first dose negative results or positive response at baseline with all post first dose ADA responses < 9-fold over baseline titer levels; Treatment-boosted response - positive response in the assay post first dose, >= 9-fold over baseline titer levels, when baseline results are positive; Treatment-emergent response - ADA positive response in the REGN2477 ADA assay post first dose when baseline results = negative or missing. | Up to Week 76 |