The scientific committee of the European Medicines Agency (EMA) has issued a positive opinion of the type II variation application of filgotinib (Jyseleca, Galapagos NV) based on testicular function safety data from the MANTA and MANTA-RAy studies, a company press release indicates.
Filgotinib is a small molecule that selectively inhibits Janus kinase (JAK) type 1. It is approved in the European Union for treating adults with moderate to severe RA and adults with moderately to severely active ulcerative colitis.
The type II variation regulatory application was submitted to EMA in June 2022 in an effort to amend the European label of filgotinib based on data from the MANTA study in men with ulcerative colitis and Crohn’s disease and the MANTA-RAy study in men with active rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, or nonradiographic axial spondylarthritis. Both studies are investigating the potential effect of filgotinib use on semen parameters and sex hormones.
“This positive CHMP (Committee for Medicinal Products for Human Use) opinion marks a key milestone for Jyseleca and provides important information for patients and physicians, given [filgotinib] is the only anti-inflammatory drug that has been evaluated in a robust large-scale, placebo-control trial program for the potential effect on male reproduction,” Galapagos Chief Medical Officer Walid Abi-Saab, MD, said in a statement.
“We will now work to update all relevant label information and materials with the aim to increase access to Jyseleca so that European patients who may benefit from the treatment are able to receive it.
Following assessment of the interim data from MANTA, CHMP concluded that the data did not reveal a difference between treatment groups in the proportion of patients who had a 50% or more decrease from baseline in semen parameters at either week 13 or at week 26. At week 13, the pooled primary endpoint occurred in 6.7% of patients treated with filgotinib, compared with 8.3% of placebo controls.
Moreover, CHMP concluded that the interim MANTA data did not show any relevant changes in sex hormone levels or change from baseline in semen parameters across treatment groups. Overall, CHMP concluded that these clinical data were not suggestive of any filgotinib-related treatment effects on testicular function.
The design of the MANTA and MANTA-RAy studies were published in Advances in Therapy in June 2022. Both are phase 2 studies and include men between 21 and 65 years of age. Semen parameter values were sampled at baseline and included semen volume, total sperm/ejaculate count, sperm concentration and motility, and normal sperm morphology.
Each trial was initially carried out as a 13-week, randomized, double-blind, placebo-controlled period during which the effects of filgotinib 200 mg on semen parameters were compared with that of placebo. The study designs diverged owing to disease-specific consideration from week 13 onward, but all subjects with a 50% or greater decrease in sperm parameters will continue on until reversibility is shown or up to a maximum of 52 weeks, with standard of care as treatment.
Following the positive CHMP opinion, the language in the section of the special warnings and precautions will be removed from the Summary of Product Characteristics and the MANTA and MANTA-RAy studies will be removed from the Risk Management Plan.
In a review of currently available data, results from a phase 3 study in which patients with moderate to severe ulcerative colitis were treated with filgotinib showed that treatment is both effective and has a reassuring safety profile. Furthermore, treatment was not associated with a greater risk of thrombosis or herpes zoster infections, compared with other JAK inhibitors.
On the other hand, review authors did point out that preclinical studies reported impaired spermatogenesis and histopathologic effects on male reproductive organs in animals exposed to filgotinib, making it necessary to further explore this aspect of potential safety issue in human studies.
Galapagos is planning to publish the results of the MANTA and MANTA-RAy studies in a peer-reviewed journal next year.