Clementia in innovating 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.
We have conducted a Phase 2 program which evaluated four different palovarotene dosing regimens in FOP. Based on the efficacy and safety data available from the completed Phase 2 clinical program, which showed a statistically significant reduction in mean new HO volume, or bone volume, associated with flare-ups of FOP at 12 weeks as compared to placebo or untreated flare-ups, Clementia is preparing for a New Drug Application (NDA) which we intend to submit to the U.S. Food and Drug Administration (FDA) in the second half of 2019.
We also completed enrollment in the Phase 3 MOVE Trial in FOP in August 2018. The MOVE Trial is evaluating chronic daily dosing, in addition to episodic flare-up dosing, and is expected to report final results in 2020 with three planned interim read-outs. We believe that, if successful, the data from the MOVE Trial may provide the basis for a supplemental NDA (sNDA) for an additional treatment regimen option for patients with FOP. Learn more about the MOVE Trial.
Palovarotene has received Orphan Drug designation for FOP from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). 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.
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.
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 Reduces New Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva [Poster presentation at the ASBMR 2018 Annual Meeting]
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) and the European Medicines Agency (EMA).
MO is caused by mutations in either exostosin (EXT) 1 or 2 which are needed for adding heparin sulfate to cell surface proteins. Deficiency in heparin sulfate is associated with increased BMP and Smad1/5/8 signaling, local cartilage growth and OC development. In 2017, a team led by Dr. Maurizio Pacifici reported for the first time that BMP inhibitors can inhibit osteochondroma formation in a MO animal model, further supporting the rational for using palovarotene to treat MO. Palovarotene has been shown to inhibit BMP signaling and OC formation in a MO mouse model. The effect of palovarotene on OC formation in humans is currently being tested in clinical trials. It is hoped that this approach can reduce OC formation, deformity and functional disability in children with MO.
Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice. PLoS Genet. 2017; 13, e1006742, Pacifici, M. et al.
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 initiated a clinical trial of a palovarotene ophthalmic solution in 2018.
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.