FOP: three new drug candidates in preclinical development

Ultra-rare, fibrodysplasia ossificans progressiva (FOP) is caused by mutations in the ACVR1 gene, also known as ALK2. This gene encodes the ACVR1 or ALK2 receptor, also called activin A receptor type I or bone morphogenetic protein (BMP) type I receptor.
The mutations involved in FOP are known as “gain-of-function” mutations: the mutated ACVR1 receptor abnormally activates the BMP-Smad1/5/9 signalling pathway. As a result, muscle injury caused by trauma or injection attempts to “repair” itself by producing not muscle tissue, but bone tissue. This formation of bone tissue in abnormal locations, such as muscles, is called “heterotopic ossification”.

Code name RK783

After screening around 140,000 small molecules, an international team of researchers identified one, named RK783, capable of specifically inhibiting the BMP-Smad1/5/9 signalling pathway.

Its efficacy was demonstrated in two mouse models of the disease. Administered orally, RK783 prevented local inflammation as well as cartilage and bone formation in muscles, thereby allowing proper muscle repair following injury induced by injection. Administration twice daily of a high dose of this molecule within two days after the injection expected to trigger muscular ossification prevented it, supporting the potential use of this compound immediately after muscle trauma.

Alpelisib, an already marketed drug

BYL719, also known as alpelisib or Piqray®, could potentially be administered later after injury. This is suggested by additional preclinical results published in June 2025.

Indicated for the treatment of certain breast cancers, alpelisib inhibits an enzyme (PI3Kα) involved in the transformation of cells into tumour cells. A previous study had shown that it could also prevent heterotopic ossification in mouse models of FOP. Through a new study conducted in disease-model cells and mice, the same team confirmed that BYL719 efficiently prevents these ossifications even when administered three to seven days after muscle injury.

Signs of benefit for KTI-2338

Development of KTI-2338 is less advanced. It is a highly selective inhibitor of the ACVR1 (or ALK2) receptor.

A Dutch team tested it on skin cells (fibroblasts) collected from patients with FOP and cultured in conditions promoting their transformation into bone-producing cells. KTI-2338 reduced markers of this transformation and inhibited the Smad1/5/9 pathway, which is abnormally activated in FOP. This new molecule could therefore prevent the formation of new bone tissue. Further studies will be needed.

Sources
A new BMP type 1 receptor kinase inhibitor for safe and efficient oral treatment to prevent genetically induced heterotopic ossification in mice.
Yang J, Pan H, Sekimata K et al.
Bone. 2025 Jun 18;199:117565

PI3Kα inhibition blocks osteochondroprogenitor specification and the hyper-inflammatory response to prevent heterotopic ossification.
Valer JA, Deber A, Wits M et al.
Elife. 2025 Jun 17;12:RP91779

Compound KTI-2338 Inhibits ACVR1 Receptor Signaling in Fibrodysplasia Ossificans Progressiva.
Rosenberg NM, Zhytnik L, Wisse LE et al.
Pharmaceutics. 2025 Dec 10;17(12):1590.