DUBLIN – Ipsen SA is on track for an NDA filing for palovarotene in fibrodysplasia ossificans progressiva (FOP), an ultra-rare disease characterized by the gradual replacement of skeletal muscle and connective tissue with bone, following an interim analysis of phase III data which indicates that the drug may have a substantial effect on the disease process.

Paris-based Ipsen looks to have put the statistical quandary that bedevilled this program behind it, as its clinical collaborators are now reporting a mean 62% reduction in the annualized volume of new heterotrophic ossification (HO) formation in patients who received the drug as compared with untreated participants in a natural history study. Those on drug (n=97) experienced an annualized mean of 8,821 mm3 of new HO formation, as assessed by whole-body computed tomography (excluding the head) whereas those in the natural study gained a mean of 23,318mm3 of new HO. The data will be formally reported in an oral presentation at the American Society for Bone and Mineral Research annual meeting on Sept. 12.

It does come with considerable side effects, however, particularly in younger patients. It caused skeletal abnormalities - premature physeal closure (n=18) and epiphyseal disorder (n=1) – in 19 of 70 trial participants who were skeletally immature at baseline.

The data still appear to represent a dramatic turnaround for a program that was on the skids earlier this year. In January, Ipsen suspended dosing patients on the phase III MOVE study when a prespecified futility analysis indicated that palovarotene, a retinoic acid receptor gamma agonist, would not confer any benefit. Additional post hoc statistical analyses suggested the drug may provide benefit, however, and the company, at the suggestion of the Independent Data Monitoring Committee, amended the trial protocol to include additional statistical analysis methods. With the agreement of the FDA and regulators in the U.K., France, Italy, Sweden, Argentina and Canada, it restarted dosing patients aged fourteen years and older in March.

How this maneuver will play out when the drug is undergoing regulatory assessment is still unclear. Major protocol amendments are, for good reason, generally treated with disdain as they raise suspicions that developers are attempting to fit the data to any clinical hypothesis rather than prospectively testing their original hypothesis. At the same time, the unmet medical need in FOP is so extraordinarily high – there are no approved therapies and, notwithstanding the interruption, Ipsen is still the standard bearer in the FOP field. If the drug truly offers patients a useful treatment option, it would be unconscionable to abandon it at this point.

The highly deleterious autosomal dominant condition arises from mutations in the gene encoding activin receptor type-1 (ACVR1; also called ALK2), a member of the bone morphogenetic type I receptor family involved in controlling bone growth, including the replacement of cartilage by bone during skeletal development. The most common causative mutation, a single amino-acid substitution at position 206, causes constitutive activation of the receptor in the absence of its activating physiological ligands bone morphogenetic protein and activin-A. This leads to the unrelenting build-up of a second skeleton, which progressively restricts joint movement and mobility. Flare-ups resulting in additional spurts of HO formation can be triggered by numerous sources, including inflammation, immunization, viral illness, surgery, dental procedures, trauma or soft tissue injury. Median life expectancy is about 40 years. Only about 800 cases have been confirmed globally.

A number of other programs are at an earlier stage of development. Tarrytown, NY-based Regeneron Pharmaceuticals Inc. is in phase II trials with garetosmab (REGN2477), an antibody that targets activin-A. The Amsterdam University Medical Center, in The Netherlands, has received funding from the Innovative Medicines Initiative to conduct a phase II trial of saracatinib, a Bcr/Abl kinase inhibitor which Cambridge, U.K.-based Astrazeneca plc previously tested unsuccessfully in cancer. The molecule inhibits the kinase signaling activity of ALK2 and has achieved a 50% reduction in ectopic bone formation in a murine FOP model. In Japan, Kyoto University is undertaking a phase II study of rapamycin, a drug with anti-proliferative and immunosuppressive properties, which has slowed FOP progression in animal models.

Keros Therapeutics, Inc., of Lexington, Mass., has completed administration of KER-047, another ALK2 inhibitor, to all dose cohorts in phase I study in healthy volunteers. Ipsen has done likewise with BLU-782, which it in-licensed from Cambridge, Mass.-based Blueprint Medicines Corp. Biocryst Pharmaceuticals, Inc., of Durham, N.C., is in phase I with BCX9250, another ALK2 inhibitor.

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