Clementia Pharmaceuticals Inc. delighted Wall Street with news that the company would file an NDA in the second half of 2019 – a full year earlier than previously planned – based on data from the completed phase II trial with its lead candidate, oral retinoic acid receptor gamma agonist palovarotene in the ultra-rare bone disease fibrodysplasia ossificans progressiva (FOP).

Shares of the Montreal-based firm (NASDAQ:CMTA) rose 40.2 percent or $4.16 to close Wednesday at $14.50. Designated as a breakthrough therapy, the drug was the subject of a type B meeting Tuesday with the FDA, which agreed that results in preventing heterotopic ossification (HO) are good enough to file for approval in adult and pediatric patients with flare-up symptoms of FOP.

Clementia's ongoing 90-patient phase III trial called Move continues to evaluate a dosing regimen of palovarotene that includes a chronic 5-mg daily dose along with the episodic 20/10-mg dose at the time of a flare-up. If Move data pan out, they could provide the basis for a supplemental NDA for another treatment regimen option in FOP. The study is expected to finish in November 2020.

A spokesperson for Clementia said officials were "fully booked" and the company could not be reached, but Leerink analyst Joseph Schwartz called the move-up in filing "a big win for the company, with revenues now anticipated to come in 2020 – previously 2021 – and further de-risking this program (probability of success [rising] to 90 percent from 65 percent). With a cash runway guided to take the company through the major remaining milestones in 2019 and out to 2020, we believe Clementia is favorably positioned to be the first-to-market in FOP," he wrote in a report. The company will ask for a label that allows for episodic treatment with palovarotene in the event of patient flare-ups, which typically precede the excessive formation of bone.

The updated regulatory strategy is based on 12-week flare-up data from the phase II program. Data showed a greater than 70 percent reduction in mean new bone volume at that time point vs. control in patients treated with palovarotene at the time of a flare-up. Those treated episodically with the 20/10-mg dosing regimen (20 mg for four weeks starting at the time of a flare-up followed by 10 mg for eight weeks), turned up a significant reduction (p=0.02) in mean new bone volume. The outcome "sets a high bar for other companies vying for a piece of the FOP market," in Schwartz's view. The phase II findings were presented at the American Society for Bone and Mineral Research annual meeting last month in Orlando, Fla. Ninety-two palovarotene-treated flare-ups in 62 patients across three different dosing regimens were evaluated compared to 46 placebo or untreated flare-ups in 41 patients from the company's natural history study.

FOP is a rare genetic condition characterized by progressive extraskeletal ossification leading to cumulative and severe disability. The disease has "an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger," noted an article in the International Journal of Molecular Sciences (IJMS) in March. The gene to blame is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic protein (BMP). Affecting about one person in every two million, FOP is "characterized by the presence of a peculiar congenital malformation of the great toes and progressive extraskeletal ossification leading to cumulative and severe disability. Other skeletal malformations and signs may be variably associated with the phenotype, such as the fusion of cervical vertebrae, thumb malformation, presence of osteochondromas, etc."

BMP pathway singled out early

The IJMS paper by Serena Cappato from the department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health at the University of Genoa in Italy, and others, finds hope in the ongoing research. "So far, there is no effective and specific treatment to cure this terrible disease. However, in the last 10 years since the discovery of the causative gene, research on the pathogenic mechanisms underlying this condition has progressed impressively. Most importantly, it has provided several druggable targets to attack the disease by identifying the dysregulated pathways involved, their cross-talk with other signals, the key molecular and cellular processes that might create a favorable environment for the derailment of the tissue repair process leading to HO," the paper concludes.

Nearest to Clementia in that race is Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. with phase II-stage garetosmab (REGN-2477), an activin A antibody. The Lumina-1 study, which is expected to enroll 40 patients, bears an estimated completion data of August 2020. But the drug is intravenously given, as opposed to the oral route with Clementia's prospect, which also is "positively differentiated by demonstrating safety in children, namely the selective inhibition of pathological bone growth alongside the preservation of normal bone development."

Among other players is Biocryst Pharmaceuticals Inc., of Research Triangle Park, N.C., with ALK2 inhibitor candidates BCX-9250 and BCX-9499, and Cambridge, Mass.-based Blueprint Medicines Inc., which expects an IND filing for preclinical ALK2 kinase-targeting BLU-782 by the end of this year. In July 2017, Blueprint said it would "evaluate opportunities to advance its rare disease discovery program in FOP" after Alexion Pharma Holding, of Dublin, ended their deal as part of a pipeline review.

La Jolla Pharmaceutical Co., of San Diego, has early stage LJPC-6417, a BMP type-1 receptor antagonist.

Even before researchers singled out the ACVR1 gene as FOP's culprit, the BMP pathway was under suspicion. In vivo experiments had shown that implants of BMP-embedded matrigel in mouse skeletal muscles induced the formation of ectopic ossicles through cartilage intermediately after an early phase of tissue damage and inflammation, the IJMS paper noted. Also, ectopic bone formation was also described in transgenic mice overexpressing BMP4 under the control of the NSE promoter, which told clinicians that hyperactivation of such signaling may hijack normal tissue repair process.