Clementia in innovating new treatments for ultra-rare bone disorders and other diseases

 

Our expertise is focused on translating science into medicine and delivering innovative treatments to under-served patients. We are developing our lead product candidate, palovarotene, an oral, highly-selective retinoic acid receptor gamma (RARγ) agonist, for the treatment of fibrodysplasia ossificans progressiva (FOP) and multiple osteochondromas (MO), two ultra-rare and disabling bone diseases, and we are investigating other conditions that may benefit from RARγ therapy.

Our team is committed to leveraging our talents and capabilities to advance our science, and ultimately develop a pipeline of innovative and effective treatment options for patients who currently have none.

Palovarotene Mechanism of Action

Palovarotene for FOP

FOP is an ultra-rare and severely disabling condition characterized by heterotopic ossification (HO), the abnormal growth of bone in muscles, tendons and ligaments for which there are currently no treatments. The formation of HO is often preceded by an inflammatory event called a flare-up. Palovarotene has been shown to inhibit secondary messenger systems in the bone morphogenetic protein (BMP) pathway that promotes bone formation. Preclinical studies demonstrated that palovarotene blocked bone formation in abnormal places.

Clementia has initiated patient enrollment in our pivotal Phase 3 MOVE trial, a multicenter, single treatment arm study evaluating the safety and efficacy of palovarotene in FOP. Learn more about the MOVE trial.

We have also conducted a Phase 2 program, which evaluated four different palovarotene dosing regimens. Findings from this adaptive clinical program have informed the chronic dosing regimen of our Phase 3 trial. In addition, we are conducting a natural history study, which will serve as the external control for our Phase 3 program.

Palovarotene has received Orphan Drug designation for FOP from the U.S. Food and Drug Administration (FDA). In addition, palovarotene has been granted Fast Track and Breakthrough Therapy designations for FOP from the FDA, and orphan status for the treatment of FOP in the EU.

 

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FOP is caused by a mutation in the ACVR1 gene that encodes for the ACVR1/ALK2 receptor. This receptor is part of the bone morphogenetic protein (BMP) signaling pathway and is critical in the regulation of cartilage and bone development and growth. The mutation leads to increased activity of the ACVR1/ALK2 receptor. The mutated, overactive receptor leads to excess phosphorylation of Smads 1/5/8 and enhanced signals to the nucleus to form heterotopic bone. Palovarotene, a selective RARγ agonist decreases the phosphorylation and levels of Smad 1/5/8 proteins, repressing excess BMP signaling which may prevent the formation of abnormal new bone.

Studies of RARγ selective agonists in preclinical models of FOP have shown:

  • Inhibition 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;
  • No rebound when RARγ agonists were withdrawn, meaning inhibition of bone formation lasted beyond the treatment period; and,
  • RARγ agonist treatment appeared to revert induced mesenchymal stem cells (skeletal cells traditionally found in the bone marrow) to non-skeletal soft tissue.

Supporting Publications:

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.

Efficacy and Safety of Palovarotene in Fibrodysplasia Ossificans Progressiva (FOP): A Randomized, Placebo-Controlled, Double-Blind Study [Poster presentation at 2017 American Society for Bone and Mineral Research (ASBMR) Annual Meeting]

Assessment Tools of Physical and Functional Disability in Fibrodysplasia Ossificans Progressiva (FOP) [Poster presentation at 2017 American Society for Bone and Mineral Research (ASBMR) Annual Meeting]

Efficacy and Safety of Palovarotene in Fibrodysplasia Ossificans Progressiva: A Randomized, Placebo-Controlled, Double-Blind Study [Poster presentation at the 13th meeting of the ISDS, 2017]

Palovarotene for MO

Clementia also is advancing palovarotene clinical development in patients with multiple osteochondromas (MO), an ultra-rare genetic musculoskeletal condition in which multiple benign bone tumors, also known as osteochondromas (OCs) or osteocartilaginous exostoses, develop on bones. There are currently no approved medicinal therapies for MO. Surgical excision is currently the only treatment available for symptomatic OCs. However, surgery carries the risk of serious complications.

Clementia initiated a Phase 2 multicenter, randomized, placebo-controlled global trial, the MO-Ped Trial, in 2018. The objective this study is to evaluate the efficacy and safety of palovarotene in MO patients with confirmed EXT1 or EXT2 gene mutations. Learn more about the MO-Ped Trial.

Palovarotene has received Orphan Drug designation for MO from the U.S. Food and Drug Administration (FDA).

MO is caused by mutations in either exostosin (EXT) 1 or 2 which are needed for adding heparin sulfate to cell surface proteins. The resultant deficiency in heparin sulfate caused increased BMP bioactivity with increased Smad1/5/8 signaling to cause the local growth of cartilage and OC development. Palovarotene has been shown to inhibit BMP signaling and OC development in a mouse model of MO. Thus palovarotene could potentially reduce deformity and functional disability by inhibiting OC growth.

Publications:

Efficacy of Palovarotene Oral Treatment on Prevention of Osteochondroma Formation in the Fsp1-Ext1CKO Mouse Model of Multiple Osteochondromas [Oral Presentation at 2017 American Society for Bone and Mineral Research (ASBMR) Annual Meeting]

Efficacy of palovarotene on prevention of osteochondroma formation in the Fsp1-Ext1 conditional knockout mouse model of Multiple Osteochondromas (MO) [Poster presentation at the 13th meeting of ISDS, 2017]

Inubushi T, Nozawa S, Matsumoto K, Irie F, Yamaguchi Y. Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice. JCI Insight. 2017;2(15). doi:10.1172/jci.insight.90049

Palovarotene for Dry Eye Disease

Dry eye disease, one of the most common eye diseases, is a condition in which the eye does not adequately produce tears. Currently available treatment options for dry eye disease do not treat the underlying disease but rather the associated symptoms. These treatments include artificial tears, lubricants, anti-inflammatory drugs (including topical steroids), topical cyclosporine (generic), Restasis® (cyclosporine emulsion), Xiidra® (lifitegrast ophthalmic solution), tear retention devices (plug lacrimal puncta preventing tear drainage), topical antihistamines and mast cell stabilizers.

Scientific insights on the role of RARγ receptors for mediating anti-fibrotic effects in the eye, our own in vivo studies with palovarotene, as well as the historical evidence supporting the clinical benefits of retinoids in dry eye disease, all provide a strong rationale for the development of a palovarotene eye drop formulation for the treatment of dry eye disease. We plan to initiate clinical trials for palovarotene in dry eye disease in 2018.

Publications:

Efficacy of a RARγ selective agonist eye drop formulation on improvement of tear production and corneal fluorescein staining in the BTX-B mouse model of dry eye disease [Poster presentation at EVER 2017]

Other RARγ Agonists

We believe that RARγ agonists represent a class of compounds with broad therapeutic potential comparable to other hormones such as corticosteroids. Our plans are to fully exploit this potential internally and in partnership with others.

Our work in FOP, MO, and eye disorders, as well as research designed to elucidate RARγ agonist biology in a variety of cell systems, have provided us with unique insights into the biological effects of RARγ agonists and their potential therapeutic applications. We believe that selective RARγ agonists have substantial untapped therapeutic potential because of their potential anti-fibrotic, tissue regeneration and repair activities, as well as their safety profile.

Under an agreement with Galderma, we have licensed several novel, next-generation RARγ agonists from their portfolio that may be applicable in different diseases. RARγ agonists may also have therapeutic potential in other indications, such as those characterized by excessive fibrosis or scarring, which we are exploring in preclinical studies.