Opinion: Prasad’s FDA exit good for rare diseases but new CBER head must repair eroded trust

FDA CBER Director Exit Spurs Rare Disease Reform Demands

The FDA's Center for Biologics Evaluation and Research (CBER) faces a significant trust problem with industry sponsors, patients, and advocates in the rare disease community, exacerbated by inconsistent regulatory guidance and late-stage reversals of trial designs. This issue is highlighted by the impending departure of CBER director Vinay Prasad. The article emphasizes that a mere leadership transition is insufficient; actual reform requires accountability, transparency, and consistent action, particularly in upholding agreements made during drug development pathways. The case of uniQure's AMT-130 for Huntington's disease, where the FDA reversed its stance on Phase 1/2 data sufficiency, exemplifies the challenges faced by sponsors and patients.

• The FDA's CBER has created a significant trust problem due to inconsistent application of approval pathways, disregarded surrogate endpoints, and late-stage reversals of negotiated trial designs. This has led to patients losing access to therapies and sponsors facing challenges in delivering innovations. The article stresses that the FDA's stated intent matters less than the real-life impact of its decisions on patients with terminal illnesses, necessitating a fundamental shift towards transparency and consistent action to rebuild confidence within the rare disease community.
• The case of uniQure's AMT-130 gene therapy for Huntington's disease serves as a critical example of the FDA's inconsistent guidance. Initially, in June 2025, the FDA agreed that Phase 1/2 data, which later showed a statistically significant 75% slowing of disease progression, would support a BLA. However, by November, the agency reversed its position, demanding a new, sham surgery-controlled Phase 3 trial. This reversal, without documented rationale, highlights the unpredictability sponsors face and the severe implications for patients with a fatal, progressive neurological disease who lose valuable time awaiting treatment.
• To achieve real progress and rebuild trust, the new CBER director must address four essential mandates: publicly respond to Senator Johnson's investigation into Complete Response Letters (CRLs) and share plans for transparent dialogue on review process reforms; provide clearer guidance on surrogate endpoint application; establish and regularly engage a rare disease advisory committee; and commit to consistent application of accelerated approval pathways when criteria are met. These actions are crucial for transforming the regulatory landscape and advancing science for rare diseases.

Key Challenges in Bringing Huntington's Disease Therapies to Patients

Huntington's disease presents significant therapeutic challenges, with no disease-slowing or disease-modifying treatments currently available to patients. While promising experimental approaches are emerging, fundamental gaps in understanding and substantial barriers to clinical translation continue to limit treatment options.

• Absence of disease-modifying therapies - No treatments exist that can slow disease progression or modify the underlying pathology, leaving only symptomatic management options for patients

• Failed neuroprotective strategies - Riluzole showed no neuroprotective or beneficial symptomatic effects in a randomized double-blind trial of 537 patients, with no significant difference between treatment and placebo groups (p = 0.93) over three years

• Incomplete understanding of huntingtin protein function - Despite identification of the HD gene, the normal function of the huntingtin protein remains unknown, limiting rational drug design approaches

• Limited efficacy of experimental cell therapies - Fetal neural transplantation has shown unsatisfactory efficacy in both preclinical and clinical investigations, while stem cell-based therapies face numerous challenges in clinical translation

• Unproven gene therapy modalities - The efficacy and long-term safety profiles of antisense oligonucleotides, siRNAs, zinc finger proteins, and CRISPR-Cas9-based approaches require further verification before clinical implementation

• Lack of rehabilitation guidelines - Few studies exist examining rehabilitation strategies for HD patients, and no established clinical guidelines are available to guide therapeutic interventions

• Research gaps and limited collaboration - Significant underrepresentation of mental health impacts, geographic disparities in research output, and concentration of research within limited countries and author groups constrain comprehensive understanding

• Complex neurosurgical requirements - Promising experimental strategies including deep brain stimulation, neurotrophic factor delivery, and HTT gene silencing require neurosurgical interventions for delivery across the blood-brain barrier, adding procedural complexity and risk

The Shifting Regulatory Demands for uniQure's AMT-130

The clinical development of Huntington's disease therapeutics has involved several key trials with distinct designs and endpoints, providing crucial insights for regulatory strategy. These studies have established important precedents for trial design, biomarker utilization, and endpoint selection that directly inform current regulatory expectations.

Impact of Regulatory Uncertainty on Huntington's Disease Pipeline

The Huntington's disease treatment landscape has undergone significant shifts over the past five years, marked by both promising therapeutic innovations and notable clinical setbacks. Gene therapeutic approaches have emerged as a dominant focus, with multiple strategies targeting the pathological huntingtin gene through antisense oligonucleotides, RNA interference, and CRISPR/Cas9 systems. However, recent clinical trial failures of antisense oligonucleotide candidates have highlighted the gap between promising preclinical data and clinical reality, demonstrating the urgent need for alternative therapeutic approaches. Despite extensive research efforts, no therapies are currently available to modify disease progression, and no FDA-approved medications specifically target key symptoms like irritability in Huntington's disease.

Clinical trial data from the past five years reveals mixed outcomes across various therapeutic modalities. A 2026 randomized controlled trial of dextromethorphan/quinidine (NUEDEXTA) for irritability management showed no significant advantage over placebo, despite both treatments reducing irritability scores. Novel compounds like GLYN122 have demonstrated preclinical efficacy in reducing mutant huntingtin levels and improving motor symptoms in mouse models, while nutraceuticals including curcumin, resveratrol, and Coenzyme Q10 have shown neuroprotective activity in human clinical trials through antioxidant and anti-inflammatory mechanisms. Additionally, advanced delivery systems such as acyclic serinol nucleic acid-modified siRNA have achieved selective silencing of pathological alleles without affecting wild-type counterparts when administered intracerebroventricularly.

The research infrastructure supporting Huntington's disease clinical development has substantially strengthened, with the Enroll-HD platform now operating across 21 countries at 159 clinical sites and recruiting nearly 25,000 participants since 2012. This global database is accelerating research through comprehensive clinical datasets and biosamples. Current research priorities have consolidated around gene therapy, clinical trial optimization, disease modeling, and aggregation clearance therapy. Based on the substantial pipeline of planned, ongoing, and completed clinical trials, several novel gene therapies are anticipated to receive regulatory approval in the near future, potentially transforming the treatment paradigm for this devastating neurodegenerative disorder.

Rebuilding Trust: Navigating Gene Therapy's Regulatory Crossroads

The current climate at the FDA's Center for Biologics Evaluation and Research (CBER) signals a critical juncture for the future of gene therapy, particularly within the rare disease landscape. While the field has celebrated remarkable progress, delivering transformative treatments for conditions like RPE65-related retinal disease, spinal muscular atrophy, and hemophilia B, the path to market remains fraught with challenges. The core issue revolves around a perceived lack of consistent regulatory guidance and late-stage shifts in trial design expectations, which can severely impact drug developers and, ultimately, patients.

For companies pioneering gene therapies, this regulatory unpredictability translates into substantial risk. Investing hundreds of millions into complex modalities, only to face reversals on agreed-upon clinical endpoints or data sufficiency, can derail programs and deter future innovation. The literature highlights that while the FDA has made strides in expediting approvals for rare diseases, some of these accelerated pathways have yielded treatments with minimal clinical benefit or uncertain long-term data. This underscores the need for robust, transparent, and consistent dialogue between sponsors and regulators from the earliest stages of development.

Furthermore, the high cost of gene therapies, exemplified by products like Zolgensma and Hemgenix, presents a significant hurdle for healthcare systems and patient access. While these treatments offer life-changing potential, their multimillion-dollar price tags necessitate innovative funding models, such as outcome-based risk-sharing agreements, to ensure equitable distribution. The requirement for extensive 5-15 year long-term follow-up studies for gene therapy participants also adds a layer of logistical and financial complexity, reflecting ongoing questions about durability and potential late-onset adverse events like hepatotoxicity or even vision loss in some cases. Moving forward, a renewed commitment to clear, predictable regulatory frameworks, coupled with collaborative efforts to address access and long-term data generation, will be essential to fully realize the promise of genomic medicines for rare disease patients globally.