A Study to Assess the Effectiveness and Safety of 2 Dosage Regimens of Oral Fidrisertib (IPN60130) for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP).

Study Overview
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Brief Summary
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Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by the presence of bone in soft tissue where bone normally does not exist, known as Heterotopic Ossification (HO). It is often associated with painful, recurrent episodes of soft tissue swelling (flare-ups) that lead to abnormal stiffening and immobility (ankyloses) of major joints with cumulative and irreversible loss of movement and disability. This study will evaluate the efficacy of 2 dosing regimens of IPN60130 in inhibiting new HO volume compared with placebo (a dummy treatment) in adult and paediatric participants with FOP. It will be assessed by a scan (provides internal images of the body) called low dose Whole Body Computed Tomography (WBCT), excluding head. Adults and participants 5 years of age or older are also eligible for a sub study to evaluate HO lesions assessed by another type of scan, Fluorine-18-labelled natrium fluoride Positron Emission Tomography-Computed Tomography ([18F]NaF PET-CT ).

Official Title
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A Phase 2 Study to Assess the Efficacy and Safety of 2 Dosage Regimens of Oral Fidrisertib (IPN60130) for the Treatment of Fibrodysplasia Ossificans Progressiva in Male and Female Paediatric and Adult Participants.

Conditions
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Fibrodysplasia Ossificans Progressiva

Intervention / Treatment
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* Drug: IPN60130
* Drug: IPN60130
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants must be at least 5 years of age, to be confirmed (entry for younger paediatric participants <15 years of age will only be once safety in adult and older paediatric participants ≥15 years of age has been established) at the time of signing the informed participant/parent consent and, for participants who are minors, age-appropriate assent. Participants must be at least 15 years of age at the time of signing the informed participant/parent consent for the main study and, for participants who are minors, age-appropriate assent Participants must be clinically diagnosed with FOP, with the R206H ACVR1 mutation or other FOP variants associated with progressive HO. Participants must have disease progression in the preceding year of the screening visit. Participants who have participated in a prior clinical study using another investigational product for the treatment of FOP may be enrolled after a washout of at least 5 half-lives of the other investigational product. Participants with prior treatment such as, but not limited to, imatinib, isotretinoin, garetosmab, or palovarotene may be enrolled 30 days after discontinuation or after washout of at least 5 half-lives, whichever is longer. Washout period for palovarotene is 30 days Washout period for garetosmab is 4 months Participants must be able to perform pulmonary function tests adequately and reliably. Participants must be able to have an adequate echocardiography assessment at screening for evaluation of left ventricular structure and function as defined by the protocol. Participants must be accessible for treatment and follow-up and be able to undergo all study procedures. Participants living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all on-site follow-up visits. Participants must be able to undergo low-dose WBCT (excluding head) without sedation. Body weight ≥10 kg. Abstinent or using two highly effective forms of birth control. Females must also have a negative blood or urine pregnancy test prior to administration of study drug. Participants must be capable of giving written, signed, and dated informed participant/parent consent; and for participants who are minors, age-appropriate assent and/or legal guardian consent (performed according to local regulations) Key Exclusion Criteria: Participants with complete heart block and left bundle branch block on screening electrocardiogram. Participants with screening echocardiography showing septal or left ventricular free wall thickness >12 mm for adult participants or a z-score >3 compared with population norms for children and adolescent participants or left ventricular ejection fraction (LVEF) <50%. Participants with severe mitral or tricuspid regurgitation on echocardiography at screening. Participants with significant underlying lung disease requiring supplementary oxygen or forced vital capacity <35% of predicted at screening. Participants with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or another significant disease as judged by the investigator. Participants with severe hepatic impairment. Concomitant medications that are strong inhibitors (including grapefruit juice) or inducers (including St John's Wort) of cytochrome P450 (CYP) 3A4 activity; or kinase inhibitors such as imatinib. Prior use in the past year and concomitant use of bisphosphonates for participants in the PET-CT sub study. Concurrent participation in another interventional clinical study, or a noninterventional study with radiographic measures or invasive procedures (e.g. collection of blood or tissue samples). Amylase or lipase >2× the upper limit of normal (ULN) or with a history of chronic pancreatitis. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5×ULN. Participants with hematologic abnormalities: Hgb<10g/dL Platelets<75,000/mm3 WBC<2000/mm3 Participants with coagulation test measurements outside of the normal range at screening.

Ages Eligible for Study
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Minimum Age: 5 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: IPN60130 high dosage<br>Oral capsule, swallowed whole or sprinkled onto food, once daily | Drug: IPN60130<br>* Immediate-release capsule containing high dose of the drug substance.<br>* Other names: Fidrisertib;|
| Experimental: IPN60130 low dosage<br>Oral capsule, swallowed whole or sprinkled onto food, once daily | Drug: IPN60130<br>* Immediate-release capsule containing low dose of the drug substance.<br>* Other names: Fidrisertib;|
| Placebo Comparator: Placebo<br>Oral capsule, swallowed whole or sprinkled onto food, once daily | Drug: Placebo<br>* Placebo will be supplied as powder filled hard capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized change in HO volume as assessed by low-dose WBCT (excluding the head) in treated participants receiving IPN60130 compared with placebo. |  | From baseline to 12 months | 
| Incidence of Adverse Events / Serious Adverse Events (AEs/SAE) |  | From baseline until the end of study (63 months) | 
| Change from baseline in clinically significant abnormal values in laboratory parameters (haematology, biochemistry, and urinalysis) | Percentage of participants with clinically significant change in laboratory parameters (biochemistry, hematology and urinalysis) will be reported. The clinical significance will be graded by the investigator. | From baseline until the end of study (63 months) | 
| Change from baseline in physical examination findings | Percentage of participants with clinically significant changes in physical examination findings will be reported. The clinical significance will be graded by the investigator. | From baseline until the end of study (63 months) | 
| Change from baseline in clinically significant vital signs | Percentage of participants with clinically significant changes in Vital Signs will be reported. The clinical significance will be graded by the investigator. | From baseline until the end of study (63 months) | 
| Change from baseline in clinically significant Electrocardiogram (ECG) readings | Percentage of participants with clinically significant changes in ECG readings will be reported. The clinical significance will be graded by the investigator. | From baseline until the end of study (63 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HO volume of new HO lesions as detected by WBCT in participants receiving IPN60130 compared with placebo recipients |  | From baseline up to 12 months | 
| Change in number of HO lesions by WBCT in participants receiving IPN60130 compared with placebo recipients |  | From baseline up to 12 months | 
| Flare-up rate and number of flare-up days in participants receiving IPN60130 compared with placebo recipients | The rate and the number of flare-up days, the flare-up being confirmed by the Investigator, will be compared between participants treated with IPN60130 and those treated with Placebo at Month 12 | From baseline up to 12 months | 
| The number of body regions with new HO in participants receiving IPN60130 compared with placebo recipients |  | From baseline up to 12 months | 
| Change in pain intensity | Assessed in participants ≥13 years old with the Numeric pain rating scale (NRS) and in participants <13 years old with Wong Baker Faces Pain Scale (FPS) | From baseline up to 12 months | 
| The proportion of participants with any new HO in participants receiving IPN60130 compared with placebo recipients |  | From baseline up to 12 months | 
| Change from baseline in HO volume as detected by WBCT in participants receiving IPN60130 compared with placebo recipients and with participants receiving the standard of care in the Natural history study (NHS) |  | From baseline up to 60 months | 
| Change from baseline in Cumulative Analogue Joint Involvement Scale for FOP (CAJIS) by treatment arm compared with placebo recipients and participants receiving the standard of care in the NHS across all available timepoints |  | From baseline up to 60 months | 
| Change in the FOP Physical Function Questionnaire (FOP-PFQ) by treatment arm compared with placebo recipients and participants receiving the standard of care in the NHS from baseline across all available timepoints |  | From baseline up to 60 months | 
| Pharmacokinetic (PK) parameter: Cmax of IPN60130 | Cmax is defined as the maximum observed concentration of IPN60130 | From baseline up to Month 24 | 
| PK parameter: AUC of IPN60130 | AUC is defined as the concentration of drug over time. | Every 6 months up to Month 24 | 
| PK parameter: Ctrough of IPN60130 | Ctrough is defined as the plasma concentration at the end of the dosing interval. | Every 6 months up to Month 24 | 
| PK parameter: Cmin of IPN60130 | Cmin is defined as the minimum observed concentration of IPN60130 | Every 6 months up to Month 24 | 
| Assessment of the exposure-response relationship | The exposure-response relationship will be assessed by modelling using relevant efficacy and safety parameters | From baseline up to 60 months |