Upcoming events – Clementia and Prometic tackle rare diseases

Welcome to your weekly digest of approaching regulatory and clinical readouts. Clementia is due to report further phase II data with palovarotene, a project for ultra-rare bone disorders, in the second quarter of this year, and after a big IPO last year investors will be watching for the data ahead of the recently started phase III trial.

Meanwhile, by April 14 Prometic Life Sciences could have its first FDA-approved product – Ryplazim, a replacement therapy for congenital plasminogen deficiency. This carries a rare paediatric designation, and a potentially valuable priority review voucher is in the offing.

A bone to pick

Clementia’s phase II open-label extension trial tests its lead project, palovarotene, in fibrodysplasia ossificans progressiva (FOP), a condition characterised by abnormal growth of bone in muscles and connective tissues, known as heterotopic ossification (HO). There are no effective treatments for FOP, but corticosteroids are used to relieve the pain and swelling associated with flare-ups.

The condition is caused by mutations in the ACVR1 gene, leading to an alteration of downstream bone morphogenetic protein signalling, which results in an overgrowth of bone and cartilage. Clementia’s palovarotene, which originated at Roche, is a retinoic acid receptor gamma agonist that aims to inhibit this signalling.

Data are expected soon from part B of Clementia’s phase II trial, which tested 49 subjects given 5mg palovarotene daily for up to 24 months, with an increase in dose in the event of a flare-up. The primary endpoint is the change in new HO volume, assessed every 12 months via whole-body CT scanning; secondary endpoints include the proportion of patients with new HO, and change from baseline in range of motion.

Last year the company reported pooled analysis of a double-blind phase II study and part A of the open-label-extension trial, both testing episodic dosing only. There was a 50% reduction in new HO and in those who formed new HO the mean volumes were reduced by 70% versus placebo. None of the patients required decreased doses or dropped out of the study.

The upcoming part B data are not powered for statistical significance, but Leerink analysts believe that an effect size of 65% or greater would bode well for the recently started phase III trial, which is due to report interim data next year; this also tests chronic dosing with increased dosing for flare-ups. 

Clementia completed its $120m Nasdaq IPO last year. Clinicaltrials.gov shows that the only other clinical asset for FOP is Regeneron’s REGN2477, an activin A antibody in phase II that is a year or two behind palovarotene.

Palovarotene trials
Status Trial ID Details Data
Phase II 201, NCT02190747 Double-blind, placebo-controlled. Episodic dosing: first dose taken within 7 days of flare-up, 6 weeks of drug, 6 weeks without. Reported
Phase II 202, NCT02279095 OLE Part A: episodic dosing, 6 weeks of drug. Reported
Part B: 5mg once-daily chronic dosing, episodic increase in drug dose in response to flare-ups. Duration: 24 months. Due Q2
Part C: Similar to Part B but 36 months' duration. ?
Phase III Move, NCT03312634 Open-label, chronic with episodic increase in drug dose in response to flare-ups. Duration 24 months. Control is untreated patients from natural history study (NCT02322255). Interim data 2019

Replacement therapy

Meanwhile, Prometic could have its first US approval next month with Ryplazim, an intravenous plasminogen replacement therapy for congenital plasminogen deficiency. Plasminogen is vital in wound healing, cell migration, tissue remodelling, angiogenesis and embryogenesis.

The most common condition associated with this deficiency is ligneous conjunctivitis, characterised by thick growths on the conjunctiva that if left untreated can cause corneal damage and blindness. Around 1.6 people in every millon have severe hypoplasminogenaemia or type 1 plasminogen deficiency, and the most serious and life-threatening manifestations of plasminogen deficiency occur most commonly in children.

Plasminogen eyedrops have shown some success in treating ophthalmic lesions in trials, but these are not commercially available and tend to recur once treatment is withdrawn.

The phase II/III study of Ryplazim was a success, with dosing every 2-4 days to 10 patients, four of whom were aged below 17, resulting in all 10 reaching target increase in blood plasma concentration level of plasminogen at 12 weeks, meeting the primary endpoint. Six had had visible conjunctivitis lesions at baseline, and after eight weeks 90% of these had completely resolved. There were also improvements in non-ophthalmic lesions.

Longer-term data have also been positive, with no new lesions, no recurrences of previous lesions, and no safety or tolerability issues after 48 weeks of treatment.

If Ryplazim is approved Prometic will be eligible for a priority review voucher, a potentially valuable commodity, the last of which to sell going for $130m (Snippet roundup: Approvals for Merck/Pfizer and Biom Up, but Shire disappoints, December 22, 2017). 

To contact the writer of this story email Joanne Fagg in London at joannef@epvantage.com or follow @ByJoFagg on Twitter

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