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Palovarotene for the Potential Treatment of FOP

Clementia is rapidly developing its lead product candidate, palovarotene, as an oral therapy for fibrodysplasia ossificans progressiva (FOP) and other diseases. Palovarotene is an investigational retinoic acid receptor gamma (RARγ) agonist that holds the potential to prevent the abnormal growth of bone in people with FOP. FOP is an extremely rare and severely disabling myopathy characterized by heterotopic ossification (HO), the abnormal growth of bone in muscles, tendons and ligaments. The formation of HO is often preceded by an inflammatory event called a flare-up. The drug has been shown to inhibit secondary messenger systems in the bone morphogenetic protein (BMP) pathway that promotes bone formation. Nonclinical studies demonstrated that palovarotene blocked abnormal bone formation in animal models.

Clementia licensed the compound from Roche Pharmaceuticals, which previously investigated palovarotene as a possible treatment for chronic obstructive pulmonary disease (COPD) and evaluated its safety in more than 800 healthy volunteers and patients.

We are currently investigating palovarotene in Phase 2 clinical trials for adults and children as young as six years old with FOP to evaluate the impact of different doses on new heterotopic bone formation during and after a flare-up. The Phase 2 trials will also continue to evaluate the safety of palovarotene in people with FOP.

In 2014, palovarotene became the first compound with the potential to treat FOP to receive Orphan Drug Designation from the FDA and Orphan Medicinal Product Designation from the European Medicines Agency (EMA). Palovarotene also received Fast Track designation from the U.S. Food and Drug Administration (FDA), which facilitates development and expedites review of medications intended to treat a life-threatening condition and fill an unmet medical need, and in July 2017 the FDA granted Breakthrough Therapy Designation to palovarotene for the prevention of HO in patients with FOP, which allows for intensive guidance on efficient drug development, organizational commitment involving senior management, and rolling review of our application. There are currently no treatments for FOP.

Mechanism of Action

In people with FOP, the ACRV1/ALK2 receptor involved in the BMP pathway, which controls bone growth and development, is overactive resulting in a cascade of events that induces the characteristic heterotopic bone formation. RARγ agonists, such as palovarotene, may prevent the formation of abnormal new bone by inhibiting secondary messenger systems in the BMP pathway.

RARγ agonists have completely blocked new bone formation in both an injury-induced mouse model of heterotopic ossification (HO) and a genetically modified biological mouse model of FOP containing a continuously active ACVR1/ALK2 receptor. In these models:

  • Researchers observed a lack of new bone formation when treatment was started as late as 6 days post-injury, suggesting a window of opportunity for therapeutic intervention post-flare-up initiation
  • There was no rebound when RARγ agonists were withdrawn, meaning inhibition of bone formation lasted beyond the treatment period
  • RARγ agonists appeared to revert induced mesenchymal stem cells – skeletal cells traditionally found in the bone marrow – to non-skeletal soft tissue

Learn more about RARy agonist research:

Shimono et. al. Potent Inhibition of Heterotopic Ossification by Nuclear Retinoic Acid Receptor γ Agonists. Nat Med. 2011 Apr; 17(4): 454–460.

Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nature Medicine 2011;17(4):420-421.

Palovarotene is an investigational therapy with the potential to prevent extra-skeletal bone growth.

Palovarotene est un traitement expérimental qui pourrait potentiellement prévenir la formation osseuse extra squelettique

Palovaroteno: um possível tratamento para a FOP sob investigação

Palovaroteno: un posible tratamiento de la FOP bajo investigación

References

IL Dahiru et al. Fibrodysplasia Ossificans Progressiva: A Rare, Crippling and Disabling Disorder. Nigerian Journal of Orthopedics and Trauma. 2012; Vol 2. No 1

International Fibrodysplasia Ossificans Progressiva Association. FOP Fact Sheet. Accessed June 10, 2015 via http://www.ifopa.org/fop-fact-sheet.html

Winkler et. al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003 Dec 1; 22(23): 6267–6276.