Efficacy and Safety Evaluation of INCB000928 in Fibrodysplasia Ossificans Progressiva: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this Phase 2, randomized, double-blind, placebo-controlled study is to determine the efficacy of **INCB000928** for the prevention of new heterotopic ossification (HO) in participants with **Fibrodysplasia Ossificans Progressiva** (FOP). This is clinically relevant as FOP is a rare and debilitating condition characterized by the abnormal development of bone in soft tissues, leading to severe mobility restrictions and complications.

Secondary objectives include:

• To further evaluate the efficacy of INCB000928 in the reduction of flares and improvement in flare-related symptoms.
• To evaluate the safety and tolerability of INCB000928 in participants with FOP.
• To further evaluate the efficacy of INCB000928 in participants with FOP.
• To confirm the efficacy of INCB000928 at Week 48 in participants randomized to placebo during the double-blind period.
• To characterize the pharmacokinetics (PK) of INCB000928 in participants with FOP.

The clinical trial involves a total of **42 participants** diagnosed with **Fibrodysplasia Ossificans Progressiva** (FOP). The study population includes both male and female subjects, with an age range starting from 12 years and above, encompassing adolescents and adults. Participants were selected based on their clinical diagnosis of FOP, which includes congenital malformation of the great toes, episodic soft-tissue swelling, and/or progressive heterotopic ossification (HO). The trial population is characterized by their ability to swallow and retain orally administered tablets or receive them via a feeding tube, and their willingness to comply with study procedures, including low-dose whole-body computed tomography (WBCT) imaging. Participants are required to avoid pregnancy or fathering children during the study. The trial includes a vulnerable population, indicating special considerations for the participants' health and safety. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, and tolerability of **INCB000928** in participants with **Fibrodysplasia Ossificans Progressiva** (FOP). The trial aims to determine the efficacy of INCB000928 for the prevention of new heterotopic ossification (HO) in participants with FOP. The study involves the administration of INCB000928, an ALK2 inhibitor, in the form of film-coated tablets, with a maximum daily dose of 100 mg. The trial is expected to last until January 21, 2028, with recruitment having started on April 12, 2022.

Participants will be randomly assigned to receive either INCB000928 or a placebo, with the study being double-blind to ensure neither the participants nor the investigators know which treatment is being administered. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and collect data, and an end-of-study visit to assess the overall outcomes. The primary endpoint is the total volume of new HO as assessed by low-dose whole-body computed tomography (WBCT) at Week 24. Secondary endpoints include the total number of new flares, the proportion of participants with clinically meaningful improvement in flare-related symptoms, and the frequency and severity of adverse events (AEs) and serious adverse events (SAEs).

Participant involvement is expected to last up to 48 weeks, with the possibility of early termination if certain conditions arise, such as non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events. The study requires participants to be willing and able to comply with all study procedures, including the ability to swallow and retain orally administered tablets or receive them via a feeding tube. Participants must also be willing to avoid pregnancy or fathering children during the study period. The trial is not a low-intervention study and is categorized as a Phase II study, focusing on a rare disease condition.

The clinical trial involves the administration of **INCB000928**, a chemical compound developed by Incyte Corporation, as the experimental medication. INCB000928 is formulated as a **film-coated tablet** and is classified as an ALK2 inhibitor. The medication is administered orally with a maximum daily dose of 100 mg. The treatment period for participants is set at a maximum of 60 days. The primary objective of the trial is to evaluate the efficacy of INCB000928 in preventing new heterotopic ossification in participants diagnosed with **Fibrodysplasia Ossificans Progressiva**. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the experimental medication in appearance but does not contain any active pharmaceutical ingredients. The use of a placebo allows for the assessment of the true efficacy and safety profile of INCB000928 by providing a baseline for comparison. Participants are randomly assigned to receive either the experimental medication or the placebo, ensuring that the study's findings are robust and scientifically valid.

The efficacy of INCB000928 in the treatment of **Fibrodysplasia Ossificans Progressiva (FOP)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the total volume of new heterotopic ossification (HO) as measured by low-dose whole-body computed tomography (WBCT), excluding the head, at Week 24. Secondary endpoints include the total number of new flares (annualized) from baseline to Week 24, the proportion of participants with a clinically meaningful improvement in flare-related symptoms as assessed by the FOP-PROMPT at Week 24, and the frequency and severity of adverse events (AEs) and serious adverse events (SAEs). Additional secondary endpoints involve the proportion of participants with new HO over the 24-week period, the total number of new HO lesions as assessed by low-dose WBCT from baseline to Week 24, and the total volume of new HO from Week 24 to Week 48 compared to baseline to Week 24 in participants randomized to placebo during the double-blind period.

Measurements will be conducted at specified timepoints, including baseline, Week 24, and Week 48, using validated imaging techniques and patient-reported outcomes. The FOP-PROMPT tool will be utilized to assess flare-related symptoms. Pharmacokinetic parameters of INCB000928, such as Cmax, tmax, Cmin, and AUCt, will also be evaluated in plasma and/or saliva. The analysis will focus on comparing the efficacy of INCB000928 against placebo in preventing new HO and reducing flare frequency and severity, thereby providing comprehensive insights into the therapeutic potential of the investigational drug in managing FOP.