Phase 3 Randomized, Placebo-Controlled Trial Evaluating Garetosmab Efficacy and Safety in Adult Patients with Fibrodysplasia Ossificans Progressiva

Trial ID: 2023-508350-26-00
Protocol: R2477-FOP-2175
Sponsor: Regeneron Pharmaceuticals Inc.

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Diseases & Conditions

Fibrodysplasia ossificans progressiva

Objectives

The primary objective of this Phase 3 randomized, placebo-controlled study is to evaluate the effect of **garetosmab** versus placebo on the formation of new heterotopic ossification (HO) lesions in patients with **Fibrodysplasia Ossificans Progressiva**. This is determined using low-dose computerized tomography (CT). The primary safety objective is to assess the safety and tolerability of garetosmab compared to placebo. These objectives are clinically relevant as they aim to address the progression of HO lesions, a significant concern in managing Fibrodysplasia Ossificans Progressiva, and to ensure the treatment's safety profile.

Secondary objectives include:

Assessing the effect of garetosmab versus placebo on the number of clinician-assessed flare-up episodes per patient.
Evaluating the effect on the proportion of patients with new HO lesions as determined by CT.
Assessing the effect on the volume of new HO lesions as determined by CT.
Evaluating the occurrence of patient-reported flare-up episodes.
Assessing the long-term safety and efficacy of garetosmab.

These secondary objectives provide a comprehensive evaluation of garetosmab's impact on both clinical and patient-reported outcomes, as well as its long-term safety and efficacy.

Participants

The clinical trial involves a total of **42 participants** diagnosed with **Fibrodysplasia Ossificans Progressiva**. The study population includes both male and female subjects, with an age range encompassing children and adolescents. Participants were selected based on a confirmed clinical diagnosis of Fibrodysplasia Ossificans Progressiva, with documentation of a Type I activin A receptor mutation causing the condition. The trial does not include a vulnerable population. Participants are required to have shown disease activity within one year prior to the screening visit. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants are willing and able to undergo necessary imaging and procedures as outlined in the study protocol.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the safety, tolerability, and efficacy of **garetosmab** in patients with **Fibrodysplasia Ossificans Progressiva** (FOP). The trial is structured to assess the effect of garetosmab versus placebo on the formation of new heterotopic ossification (HO) lesions, as determined by low-dose computerized tomography (CT). The study will also monitor the incidence and severity of treatment-emergent adverse events of special interest (AESIs). The trial is expected to run from November 2022 to September 2026, with a maximum treatment period of 168 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including a clinical diagnosis of FOP and documentation of the Type I activin A receptor (ACVR1) mutation. Following the screening, eligible participants will be randomized to receive either garetosmab or a placebo via intravenous infusion. The study includes multiple follow-up visits to monitor the participants' health, assess the formation of new HO lesions, and evaluate any adverse events. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted.

The expected length of participant involvement is approximately 168 weeks, contingent upon the absence of any conditions that may necessitate early termination from the study. Such conditions include significant adverse reactions or the participant's decision to withdraw consent. The trial's design ensures that all procedures are conducted in accordance with ethical standards and regulatory requirements, providing a comprehensive evaluation of garetosmab's potential benefits and risks in treating FOP.

Treatment

The clinical trial involves the administration of **Garetosmab**, a **human monoclonal antibody against activin A**, developed by Regeneron Pharmaceuticals, Inc. Garetosmab is provided in the form of a **solution for injection** and is administered via **intravenous infusion**. The dosing regimen is based on a milligram per kilogram (mg/kg) basis, although specific dosing amounts are not detailed in the provided data. The maximum treatment period for Garetosmab is 168 days. This investigational medicinal product is classified as an orphan drug, indicating its use in the treatment of a rare condition, specifically **Fibrodysplasia Ossificans Progressiva**. The study aims to evaluate the safety, tolerability, and efficacy of Garetosmab in preventing the formation of new heterotopic ossification (HO) lesions, as assessed by low-dose computerized tomography (CT).

The trial also includes a **placebo** group, which receives a placebo solution that matches the appearance of Garetosmab. The placebo is used as a comparator to assess the efficacy and safety of the investigational drug. The placebo does not contain any active substance and is administered in a manner consistent with the experimental treatment to maintain blinding within the study. The use of a placebo control is essential for determining the true effect of Garetosmab on the progression of Fibrodysplasia Ossificans Progressiva.

Efficacy

The efficacy of Garetosmab in the treatment of **Fibrodysplasia Ossificans Progressiva** will be assessed through a Phase 3 randomized, placebo-controlled clinical trial. The primary efficacy endpoint is the effect of Garetosmab versus placebo on the formation of new heterotopic ossification (HO) lesions, as determined by low-dose computerized tomography (CT). Secondary efficacy endpoints include the number of clinician-assessed flare-ups, occurrence and total volume of new HO lesions, and the number of patient-reported flare-ups. Additional assessments will include changes in joint function using the cumulative analog joint involvement scale (CAJIS), changes in pulmonary function as assessed by spirometry, and changes in disease severity as assessed by the Patient Global Impression of Severity (PGIS), Patient’s Global Impression of Change (PGIC), and Clinician’s Global Impression of Change (CGIC).

Biomarker analysis will involve measuring the concentration of total activin A and Garetosmab in serum over time, as well as the incidence and titer of anti-drug antibodies (ADA) to Garetosmab. The schedule for measuring these parameters will be defined in the study protocol, with specific timepoints for data collection. The trial will utilize validated scales and laboratory tests to ensure the accuracy and reliability of the efficacy assessments. The study is designed to provide comprehensive data on the efficacy of Garetosmab in reducing the progression of HO lesions and improving clinical outcomes in patients with Fibrodysplasia Ossificans Progressiva.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Clinical diagnosis of Fibrodysplasia Ossificans Progressiva (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 Type I activin A receptor (ACVR1) FOP causing mutation.
FOP disease activity within 1 year of screening visit. FOP disease activity is defined as pain, swelling, stiffness, or other signs and symptoms associated with FOP flare-ups; or worsening of joint function, or radiographic progression of HO lesions (increase in size or number of HO lesions) with/without being associated with flare-up episodes.
Willing and able to undergo CT imaging procedures and other procedures as defined in the protocol.
Note: Other protocol defined Inclusion Criteria apply

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Exclusion Criteria

Cumulative Analog Joint Involvement Scale (CAJIS) score at screening >19.
Participant has 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.
Severely impaired renal function defined as estimated glomerular filtration rate <30 milliliter per minute (mL/min) (/1.73 m^2 calculated by the Modification of Diet in Renal Disease equation.
Uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >9% at screening.
History of poorly controlled hypertension, as defined by: a. Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the screening visit b. Systolic blood pressure of 160 mm Hg to 179 mm Hg or diastolic blood pressure of 100 mm Hg to 109 mm Hg at the screening visit, AND a history of end-organ damage (including history of left-ventricular hypertrophy, heart failure, angina, myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease, end-stage renal disease, and moderate-to-advanced retinopathy.
Known history of cerebral vascular malformation.
Cardiovascular conditions such as New York Heart Association class III or IV heart failure, cardiomyopathy, intermittent claudication, myocardial infarction, or acute coronary syndrome within 6 months prior to screening; symptomatic ventricular cardiac arrhythmia.
History of severe respiratory compromise requiring oxygen, respiratory support (eg, bilevel positive airway pressure [biPAP] or continuous positive airway pressure [CPAP]), or a history of aspiration pneumonia requiring hospitalization.
Prior use in the past year and concomitant use of bisphosphonates.
Concurrent participation in another interventional clinical study or a non-interventional study with radiographic measures or invasive procedures (eg, collection of blood or tissue samples).
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.
Women of childbearing potential (WOCBP) who are unwilling to practice highly effective contraception, as defined in the protocol.
Male patients with WOCBP partners who are not willing to use condoms with WOCBP partners to prevent potential fetal exposure, as defined in the protocol.
Note: Other protocol defined Exclusion Criteria apply

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Finland	Not Recruiting	21 Nov 2022	2
France	Not Recruiting	21 Nov 2022	2
Italy	Not Recruiting	21 Nov 2022	13
The Netherlands	Not Recruiting	21 Nov 2022	—
Poland	Not Recruiting	21 Nov 2022	3
Spain	Not Recruiting	21 Nov 2022	1
Netherlands	—	—	3