Welcome to your weekly digest of approaching regulatory and clinical readouts. Rigel is awaiting phase II readouts from its dry eye disease project R348 in the third quarter; and after a series of setbacks with other kinase inhibitors it desperately needs a win to improve investor confidence.
Meanwhile Catalyst Pharmaceuticals is expecting phase III data needed for Firdapse's US registration. The orphan drug is on the market in Europe but controversies remain over its approval and pricing – issues that will likely follow it across the pond.
Rigel Pharmaceuticals: R348
The phase II Drops trial is testing two doses of R348 eyedrops in 206 patients with keratoconjunctivitis sicca, also known as dry eye disease. The primary endpoint is change in corneal fluorescein staining score, which shows damaged epithelial cells.
Dry eye disease is an inflammatory disorder that affects the glands that produce tears. Many sufferers also have autoimmune conditions including RA and lupus, and Rigel's project is a Jak-3/Syk inhibitor aimed at reducing inflammation.
The market is dominated by Allergan’s Restasis, an immunomodulator indicated to increase tear production which sold $940m last year, and is forecast to sell $1.7bn by 2020, according to EvaluatePharma.
There are several competitors in the pipeline, but trial success has been hard to find. Shire’s lifitegrast had mixed phase III results, but the company plans to submit its NDA by the first quarter of next year. Pfizer’s Xeljanz, another a Jak-3 inhibitor, was also set to undergo a phase II study in dry eye, but was withdrawn before recruitment, according to Clinicaltrials.gov (Therapeutic focus – Plenty of dry eyes in the house, December 5, 2013).
Rigel desperately needs a win with R348, since after a series of pipeline disappointments last year its shares have fallen 56%. Its biggest letdown was fostamitinib, an oral rheumatoid arthritis project that failed in phase III and to which AstraZeneca returned rights. Last year, Rigel’s asthma candidate R343 also missed primary and secondary endpoints and its lupus agent R333 was abandoned.
Catalyst Pharmaceuticals: Firdapse
Topline data are expected from a pivotal phase III trial testing Firdapse in Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune disease that leads to muscle weakness in the limbs. Around 60% of sufferers have an underlying malignancy, most commonly small cell lung cancer.
Firdapse is a potassium channel blocker and is Catalyst's lead pipeline asset. It has been on the market since 2010 in Europe, where it is promoted by Biomarin; It has orphan designation in US and Europe, and Catalyst holds North America rights.
Last year, Biomarin reported sales of $16m. EvaluatePharma'sconsensus forecasts worldwide 2020 sales of $141m, $113m of which is assigned to Catalyst.
Firdapse is known generically as 3,4-diaminopyridine phosphate (3,4-Dap). It had been used unlicensed in Europe for many years, and Biomarin received approval based on previously published studies with compounded 3,4-Dap.
Two investigator-sponsored trials were considered pivotal, and while these showed improvements in LEMS over placebo they were small and of short duration. Owing to the disease's rarity and the lack of alternatives approval was granted with an additional monitoring requirement.
Firdapse became an orphan drug with a price to match, to the dismay of healthcare professionals.
Across the pond
In the US Firdapse received breakthrough therapy designation last year, and Catalyst started an expanded access programme in April 2014.
The phase III trial has a discontinuation design, with patients treated with Firdapse for at least 91 days and then assigned to continue with Firdapse or placebo for two weeks. Patients then receive open-label Firdapse for a two-year follow-up period. The company has enrolled enough patients to ensure 36 will take part in the discontinuation portion.
This design, compared with trials used for European approval, makes it difficult to predict the outcome of the study.
Controversy around the drug follows it to the US, where Jacobus Pharmaceutical, a private company based in New Jersey, has for the past 20 years been providing 3,4-Dap to LEMS patients for free. When this detail was publicised in a story by The Street last October Catalyst shares fell 27%.
Jacobus has a US phase II trial under way, but is still some way behind Catalyst in terms of securing formal approval.