In this interview, we speak with Nathalie Dubois-Stringfellow, Chief Development Officer at Sangamo Therapeutics, about the FDA’s accelerated approval pathway and its impact on rare disease treatments, focusing on Fabry disease. We discussed the benefits and challenges of surrogate endpoints, post-approval trials, and ethical considerations for patient access.

Moe Alsumidaie: How does the FDA’s accelerated approval pathway impact gene therapy strategies for rare diseases like Fabry?

Nathalie Dubois-Stringfellow: The FDA’s accelerated approval program is crucial for early drug approval in serious conditions with unmet needs, especially for rare diseases like Fabry. This pathway allows for earlier patient access, potentially preventing disease progression. Despite standard care, Fabry patients often experience severe symptoms, making this pathway vital. It also helps companies avoid abandoning programs due to potential lengthy and costly trials  in rare diseases with limited patient numbers. We are motivated to secure a partner for Fabry commercialization to address this unmet need swiftly. Peter Marks at the FDA is keen on bringing transformational treatments to patients, aligning with our goal to expedite the availability of our gene therapy for Fabry patients.

Nathalie Dubois-Stringfellow, Chief Development Officer at Sangamo Therapeutics

Moe Alsumidaie: What are the benefits and limitations of using eGFR slope as a surrogate endpoint for accelerated approval in this therapy?

Nathalie Dubois-Stringfellow: Renal issues like proteinuria and decreased eGFR occur early in Fabry patients, leading to renal failure and early death. eGFR is a key clinical measurement of renal function, and the FDA considers it an acceptable efficacy endpoint for Fabry disease. Our data from 18 patients treated with ST-920 showed a statistically significant positive mean annualized eGFR slope, which is remarkable compared to the negative slope seen with approved therapies. The FDA agreed to use this endpoint for accelerated approval. Patients have expressed challenges with current treatments, such as side effects and logistical issues with bi-weekly infusions, which our single-infusion gene therapy aims to address. Existing therapies like enzyme replacement therapy (ERT) improve eGFR values but still result in a negative overall slope, highlighting the potential of ST-920 to offer a more effective solution.

Moe Alsumidaie: What challenges should be anticipated in designing post-approval confirmatory trials for ST-920 in Fabry patients?

Nathalie Dubois-Stringfellow: We plan to discuss post-approval requirements with the FDA in a pre-BLA meeting, before filing a BLA for accelerated approval in the second half of 2025. We do not anticipate needing additional trials beyond the STAAR study, which simplifies the path to full approval and emphasizes the robustness of our current data. The FDA has advised that eGFR slope at 104 weeks from the Phase 1/2 STAAR study may be assessed to verify clinical benefit, which we will have in mid- 2026. This approach allows us to focus on gathering comprehensive data from our existing trial, ensuring we meet regulatory requirements efficiently.

Moe Alsumidaie: How does ST-920’s mechanism compare to current enzyme replacement therapies and other emerging treatments for Fabry?

Nathalie Dubois-Stringfellow: ST-920 is a one-time intravenous gene therapy infusion that delivers a healthy copy of the GLA gene to the liver, producing the alpha-Gal enzyme to clear toxins. Our trial shows patients achieving and maintaining physiological levels of this enzyme, with the longest follow-up over four years. This constant enzyme level contrasts with enzyme replacement therapy’s (ERT) peaks and troughs. Additionally, we see a significant reduction or disappearance of antibodies against alpha-Gal in patients who started the trial with preexisting antibodies. This is an important point as antibodies against alpha-gal can affect ERT efficacy. This suggests a potential for immune tolerization brought by the gene therapy treatment, which is extraordinary and highlights the potential of ST-920 to offer a more consistent and effective treatment option for Fabry patients.

Moe Alsumidaie: What ethical considerations should be addressed to ensure equitable patient access to ST-920, given the high costs of gene therapies?

Nathalie Dubois-Stringfellow: Addressing affordability and economic barriers is crucial. High costs can exclude uninsured or underinsured patients and burden families and healthcare systems. Strategies like outcome-based pricing and reimbursement agreements can help, as well as subscription-based models, to manage upfront costs. Geographical disparities also need addressing, with investments in infrastructure and telemedicine to ensure access in rural areas. We are committed to educating stakeholders and engaging with patient advocacy groups to address access needs. Collaboration across the healthcare ecosystem, including payers, regulators, and patient advocacy groups, is essential to develop innovative solutions that ensure broad access to our potentially life-changing therapy. We believe that working together can overcome these challenges and make ST-920 accessible to all who need it.

Moe Alsumidaie: How might the FDA’s decision to use the accelerated approval pathway influence future regulatory approaches for other gene therapies?

Nathalie Dubois-Stringfellow: The accelerated approval pathway supports companies in developing treatments for rare diseases with high unmet needs. With only 5% of the 10,000 rare diseases having approved treatments, this pathway provides hope for previously untreatable conditions. The FDA’s support is crucial in advancing genomic medicine, and we hope it will be a game-changer, encouraging other companies to follow. Good data and safety can reduce the need for lengthy trials, vital for rare diseases. We are grateful for the FDA’s willingness to consider this pathway for our product and believe it could unlock opportunities for other companies to develop treatments for rare diseases. This approach could revolutionize how we address rare diseases, providing new hope for patients worldwide.

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Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.