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

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.

Time frame: Up to Week 28

Population: The safety analysis set included all randomized participants who received any study drug and was analyzed as treated.

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.

Time frame: Up to Week 28

Population: The safety analysis set included all randomized participants who received any study drug and was analyzed as treated.

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.

Time frame: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline was based on the treatment allocated (as randomized).

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.

Time frame: Week 28

Population: AHOC analysis set included all randomized participants with the classic ACVR1 \[R206H\] mutation and who had at least one AHO at baseline, as defined by 18\^F-NaF PET positivity; and was based on the treatment allocated (as randomized). Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Baseline and Week 28

Population: Baseline-active heterotopic ossification analysis set (AHO) included all randomized participants who had at least one active HO lesion at baseline; and was based on the treatment allocated (as randomized).

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.

Time frame: Week 28

Population: AHOC analysis set included all randomized participants with the classic ACVR1 \[R206H\] mutation and who had at least one AHO at baseline, as defined by 18\^F-NaF PET positivity; and was based on the treatment allocated (as randomized). Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

Change from baseline in number of HO lesions was assessed by 18\^F-NaF PET in AHO analysis set is reported.

Time frame: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized).

Change from baseline in number of HO lesions was assessed by 18\^F-NaF PET at Week 28 in AHOC analysis set is reported.

Time frame: Week 28

Population: AHOC analysis set included all randomized participants with the classic ACVR1 \[R206H\] mutation and who had at least one AHO at baseline, as defined by 18\^F-NaF PET positivity; and was based on the treatment allocated (as randomized). Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized).

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.

Time frame: Week 28

Population: AHOC analysis set included all randomized participants with the classic ACVR1 \[R206H\] mutation and who had at least one AHO at baseline, as defined by 18\^F-NaF PET positivity; and was based on the treatment allocated (as randomized). Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Week 8

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized).

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.

Time frame: Week 8

Population: AHOC analysis set included all randomized participants with the classic ACVR1 \[R206H\] mutation and who had at least one AHO at baseline, as defined by 18\^F-NaF PET positivity; and was based on the treatment allocated (as randomized). Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized). Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Week 28

Population: AHOC analysis set included all randomized participants with the classic ACVR1 \[R206H\] mutation and who had at least one AHO at baseline, as defined by 18\^F-NaF PET positivity; and was based on the treatment allocated (as randomized). Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Week 28 up to Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Data were planned to be collected and analyzed only for participants switching to REGN2477 in period 2 for this outcome measure.

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.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

Number of new HO lesions as assessed by 18\^F-NaF PET at Week 56 Relative to Week 28 Scan is reported.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

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.

Time frame: Baseline, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 only (Placebo/REGN2477) as planned.

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.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who receive a treatment in Period 2 for whom at least 1 post-Week 28 scan is collected and the period between any consecutive doses is less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

Percentage of participants with flare-ups starting between week 28 and week 56 as assessed by participant E-diary is reported.

Time frame: Week 28 to Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Data were planned to be collected and analyzed only for participants switching to REGN2477 in period 2 for this outcome measure.

Percentage of participants with investigator-assessed flare-ups were reported.

Time frame: Week 28 to Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Data were planned to be collected and analyzed only for participants switching to REGN2477 in period 2 for this outcome measure.

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.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

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.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

Percent change from baseline in 18\^F-NaF PET SUVmax to week 56

Time frame: Baseline, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

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.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

Percent change from baseline in TLA as assessed by 18\^F-NaF PET to week 56 were reported.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

Percent Change from Week 28 to Week 56 is reported.

Time frame: Week 28 to Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

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.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

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.

Time frame: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

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

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan is collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

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.

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

Difference of Percent Change from Week 28 to Week 56 versus from Baseline to Week 28 is reported

Time frame: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Overall number of participants analyzed are the participants who were evaluable for this outcome measure.

Concentration of total activin A in serum over time is reported.

Time frame: Week 28, Week 56, Week 76

Population: The PK analysis set included all treated participants who received any study drug and who had at least 1 non-missing drug concentration following the first dose of study drug. (Number Analyzed equals number of participants evaluable at that time point)

Concentrations of REGN2477 capable of target binding were measured (functional drug).

Time frame: Week 28, Week 56, Week 76

Population: The PK analysis set included all treated participants who received any study drug and who had at least 1 non-missing drug concentration following the first dose of study drug. (Number Analyzed equals number of participants evaluable at that time point)

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.

Time frame: Up to Week 76

Population: The Anti-Drug Antibody (ADA) analysis set included all participants who received study drug and had at least 1 non-missing ADA result following the first study dose. Overall number of participants analyzed are the participants who were evaluable for this outcome measure.