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

FOP is characterized by episodic soft tissue oedema (flare-ups) and the
progressive replacement of skeletal muscle and connective tissue by heterotopic
bone. The International FOP Association, a US-based patient group organization,
reports approximately 800 confirmed cases of FOP globally. The prevalence is
estimated at 1.36 per million individuals in the Americas and 1.58 per million
in West Europe, with no geographic, ethnic, racial, or gender preference. FOP
is misdiagnosed in approximately 80% of patients often resulting in harm to
the patient.
FOP is a genetic condition caused by single gain-of-function mutation in the
ALK2 (also known as activin A receptor type I, or ACVR1) gene, which encodes
ALK2, a bone morphogenetic protein (BMP) type-1 receptor. This ALK2
gain-of-function mutation aberrantly activates the BMP Smad1/5/8 signalling
pathway, diverting normal connective tissue (muscle, tendons and ligaments)
injury repair mechanisms away from tissue regeneration by promoting
chondrogenesis and heterotopic bone formation. In FOP, HO (or myositis
ossificans) proceeds in 2 phases: a catabolic phase of inflammation and tissue
destruction followed by an anabolic phase of tissue formation ultimately
leading to HO. Most patients with FOP (approximately 97%) have the same point
mutation, R206H, although other FOP variants are associated with progressive
HO.
Progressive HO is severely disabling and ultimately becomes life-threatening
due to thoracic insufficiency syndrome. Lesions begin in early childhood and
lead to progressive ankyloses of major joints with resultant loss of movement.
Individuals with FOP appear normal at birth except for the pathognomonic
malformation of the great toes, which are typically short (lack a phalange) and
deviated in hallux valgus. The majority of patients with FOP are confined to a
wheelchair in their twenties and require caregiver assistance to perform daily
living activities. Thoracic insufficiency syndrome leads to a markedly
shortened survival (Kaplan-Meier median survival estimate, 56 years) with
cardiorespiratory failure and pneumonia the most common causes of death.
Presently there are no approved medical treatment options to prevent the
formation of heterotopic bone in FOP, although several are under clinical
investigation. Available treatments are aimed at the symptomatic management of
the disease. Removal of heterotopic bone and other trauma are avoided, as
surgical trauma to tissues is likely to induce additional bone formation.
Several other triggers may lead to flare ups and ensuing HO such as
intramuscular immunizations, blocks for dental work, muscle fatigue, blunt
muscle trauma from bumps, bruises, or falls, or influenza-like viral illnesses.
Falls in particular are a severe form of trauma. In one survey of FOP patients,
flare-ups were induced in two-thirds of falls and resulted in permanent loss of
movement in 93% of patients.
Glucocorticoids are used to manage symptoms of flare-ups affecting major joints
of the appendicular skeleton and jaw, especially when used immediately after
the onset of a flare-up. Nonsteroidal anti-inflammatory agents,
cyclooxygenase-2 inhibitors, mast cell stabilizers, and leukotriene inhibitors
manage chronic pain and ongoing disease progression. Although some patients
experience clinical benefit from one of these treatments, treatment for the
condition itself is ineffective, FOP usually progresses, or intolerance to
these therapies hinders effective treatment. Managing symptoms is the only
course of treatment for patients with FOP. Therefore, there is a great unmet
medical need for new therapeutic treatments that can help improve clinical
outcomes for patients with FOP.

This study has been transitioned to CTIS with ID 2024-511469-13-00 check the CTIS register for the current data.

Main objective:
• Evaluate the efficacy of IPN60130 monotherapy compared with placebo
recipients in inhibiting new HO volume in adult and paediatric participants
with FOP as assessed by low-dose WBCT (excluding the head)
• Evaluate the safety of IPN60130 in adult and paediatric participants with FOP

Secondary objectives:
• Change in HO volume of new HO lesions over time by WBCT at M12.
• Number of new HO lesions by WBCT at M12.
• Rate and number of flare-up days at M12
• The number of body regions with new HO at M12.
• To evaluate the effect of IPN60130 on pain intensity over time through M12.
• Proportion of participants with new HO by WBCT
• Change in HO volume over time as detected by WBCT.
• To evaluate the effect of IPN60130 on ROM as evaluated by CAJIS over time.
• To evaluate the effect of IPN60130 on physical function as evaluated by
FOP-PFQ overt time.

Pharmacokinetic
• From the PK interim analysis, to evaluate the plasma pharmacokinetics of low
and high doses of IPN60130.
• From the overall study, to evaluate the plasma PK of low and high doses of
IPN60130.

Exposure-Response
• To evaluate the exposure-response relationship, if feasible.

Study 60130-452 is a Phase 2 study to evaluate the efficacy, safety, and
tolerability of IPN60130 as a monotherapy in adult and paediatric participants
with FOP comprising 2 parts.

• Part A will be a 12-month, randomised, placebo-controlled, parallel-group,
3-arm, double-blind treatment period. Participants will be randomised with a
ratio 1:1:1 to weight-based IPN60130 high dosage arm , low dosage arm, or
placeboarm (summarized in protocol section 6.1). Participants aged >=15 years
will be enrolled first with the first 12 participants included in a sentinel
cohort. Younger paediatric participants (5 to <15 years of age) will start to
be enrolled if the DMC deems favourable the 6-month safety and cardiac safety
profiles of the sentinel cohort of 12 participants aged >=15 years (protocol
section 8.2).

• Part B will be a 12-month, double-blind treatment period during which
participants will receive high or low weight-based dosages of IPN60130. On
entering Part B, placebo recipients from Part A will be randomized to one of
the IPN60130 dosage arms with a 1:1 ratio, whereas participants receiving
IPN60130 in Part A will remain in their initially assigned dosage arms.

The primary objective will be to compare the efficacy of IPN60130 monotherapy
with placebo (protocol section 2.2.1) in inhibiting new HO as assessed by
low-dose WBCT (excluding the head) in adult and paediatric participants with
FOP. The proposed primary endpoint is the annualized change from baseline in HO
volume as assessed by low-dose WBCT (excluding the head) in participants
receiving IPN60130 through Month 12 compared with placebo. In addition, an
imaging substudy will explore the utility of [18F]NaF PET-CT for assessing HO
lesion activity. Participation in the substudy will be open to adults and older
paediatric participants >=15 years of age.

During Part A, a PK interim analysis of IPN60130 will be performed by an
independent clinical pharmacometrics team when PK data are available from at
least 12 IPN60130-treated participants (approximately 6 in each of the low and
high dose arms) at Month 1 (approximately 18 participants randomized). The
interim analysis is performed to confirm PK exposure in FOP participants to
achieve targeted exposures for safety and efficacy based on PK data at Day 1
and Month 1 of treatment.

All participants will undergo the procedures and assessments summarized in the
SoA (protocol table 1 and table 2). Imaging with WBCT and [18F]NaF PET-CT for
the exploratory substudy will occur at screening and at clinic visits every 6
months. To ensure consistent interpretation of the acquired images, a central
imaging laboratory will perform blinded reads of all images obtained in this
study as well as blinded re-reads of those obtained from the NHS (untreated
control group for secondary endpoints) using standardized procedures that will
be documented in Image Acquisition Guidelines and an Independent Review Charter.

Individuals with FOP will learn about this Phase 2 study through their
participation in the NHS and through the FOP community (physicians, patient
support groups, and other contacts). The total duration of study participation
(from informed consent) will be approximately 26 months if participants
complete all study parts.

Study intervention for Part A will include 3 double-blind arms comprising
weight-based 120 or 60 mg IPN60130 once daily or placebo. The total duration of
Part A will be up to 13 months, consisting of screening that may occur up to 35
days prior and a 12-month treatment period. Part B will include 2 double-blind
dosage arms of weight-based 120 or 60 mg IPN60130 once daily over 12 months
followed by 1 month of follow-up and an end of study visit for a total duration
of 13 months.

Should a participant experience a flare-up during the study, they will remain
on the same dosage and receive the standard of care treatment for a flare-up,
which may include systemic corticosteroid. There will be no dosage escalation
during a flare-up. The daily dosage may be reduced during the study should
tolerability become an issue until adverse events (AEs) are stabilized or
resolved. Dose modifications should be captured in the e-CRF and dosing diary.

Please refer to section 6. *What side effects could you experience?* and
section 7. *What are the pros and cons if you take part in the study?* in the
Subject Information For Participation In Medical Research Form for an overview
of the risks and side effects.