Marlin Study Aims to Assess Fertility Outcomes in Risdiplam-Treated Males With Spinal Muscular Atrophy

Travis Dickendesher, PhD

At the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, investigators presented an outline of a phase 4 observational study, dubbed Marlin, that collects and describes fertility-related outcomes in adult males with spinal muscular atrophy (SMA) who have received risdiplam (Evrysdi; Genentech).¹

Risdiplam, an FDA approved survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier, is one of 3 approved products for patients with SMA. In Marlin, investigators will primarily assess whether adults males with SMA exposed to risdiplam can conceive, while exploratory end points include characterization of confounding factors that may impact fertility, fertility-related healthcare resource utilization, management and fertility treatment decisions, and pregnancy outcomes.

Lead author Travis Dickendesher, PhD, principal medical science director at Genentech, and colleagues, noted that the real-world study is expected to include 30 males with the disease. Enrolled males actively trying to conceive will provide data via questionnaire at baseline and annually for 3 years, with an option for their sexual partner/surrogates/gestational carriers to also complete questionnaires. If the partner/surrogate/gestational carrier is pregnant at the end of the 3-year time frame, 1 additional annual questionnaire to capture the pregnancy outcome will be administered.

The questionnaire categories cover general health and medical history, which includes examples like SMA type, risdiplam treatment dates, other medical conditions, history and type of medication use, and family history of fertility difficulties. In addition to capturing standard demographic information of age, ethnicity, and race, the questionnaire will also ask about social history and environmental exposures, as well as relationship and sexual history, and fertility journey. Examples of fertility journey include methods for attempted conception, fertility testing, fertility treatment, and history and outcome of positive pregnancy tests.

Marlin will exclude those who are using/used donor sperm for conception, as well as individuals who are using/used their own cryopreserved sperm that was not exposed to risdiplam for conception. The study investigators noted that the trial will be limited by the use of participant-reported questionnaires, as well as the fact that female partner/surrogate/gestational carriers may introduce confounding factors related to conception; however, their participation in the study is optional and these factors may not be collected.

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Marlin aims to gather more information about the effects of SMN2 splicing modifiers on the human male reproductive system. A parallel, second study, led by Natan Bar-Chama, MD, a urologist at Mount Sinai, is also evaluating the impact of SMA on sperm concentration/quality and male productive hormone levels.

At MDA 2024, Bar-Chama presented a poster of the study, highlighting the design and the goals for it. The study features 75 men between the ages 18-50 years old with a diagnosis of SMA who are not on disease-modifying therapies. Participants will complete online questionnaires that will assess SMA diagnosis and disease burden, medical and surgical history, medication usage, and fertility status and perspectives. The male fertility evaluation will be achieved by obtaining 2 baseline semen analyses, a serum reproductive hormonal profile, and a sperm DNA fragmentation assay.²

In May 2022, the FDA approved an expanded indication for risdiplam to include the treatment of presymptomatic babies under 2 years old with SMA, making it the first approved treatment administered at home for this patient group.³ The decision to expand risdiplam’s indication was based off interim efficacy and safety data from the RAINBOWFISH study (NCT03779334), which showed that, following 12 months of treatment with risdiplam, a majority of presymptomatic babies met key milestones of healthy babies. This included sitting, standing, and walking, in addition to maintaining the ability to swallow.

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REFERENCES
1. Dickendesher T, Bar-Chama N, Fulton GW, et al. Observational study of fertility in risdiplam-treated adult male patients with spinal muscular atropy (SMA). Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; Orlando, FL. POSTER T392
2. Bar-Chama N. A new clinical study: the assessment of fertility in men with spinal muscular atrophy. Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; Orlando, FL. POSTER S112.
3. FDA approves Genentech’s Evrysdi (risdiplam) for use in babies under two months with spinal muscular atrophy (SMA). News release. Genentech. May 31, 2022. Accessed March 6, 2024. https://www.biospace.com/article/releases/fda-approves-genentech-s-evrysdi-risdiplam-for-use-in-babies-under-two-months-with-spinal-muscular-atrophy-sma-/?s=85