FDA Rejections, Lilly Concerns & Huntington’s Disease Research Update

Good morning. Recent headlines have been dominated by regulatory challenges facing gene therapies, particularly those targeting Huntington’s disease. A new report in the Readout newsletter highlights the ongoing scrutiny of UniQure’s experimental treatment, as well as broader concerns about the Food and Drug Administration’s decision-making processes. Alongside this, Johnson & Johnson received approval for a novel psoriasis pill, marking a significant advancement in treatment options for the autoimmune condition.

A Complex Landscape for Huntington’s Disease Therapies

The path to new treatments for Huntington’s disease, a devastating inherited neurodegenerative disorder, remains fraught with obstacles. UniQure’s gene therapy candidate, which initially showed promising results in slowing disease progression – with the company reporting a 75% slowing in September 2025 – is now facing a major hurdle. The FDA is requiring a randomized, double-blind, sham surgery-controlled Phase 3 study before considering approval. This decision has sparked debate within the Huntington’s research community.

Ed Wild, a clinician at University College London and an investigator in UniQure’s trial, previously described the initial outcomes as “the result we’ve been waiting for.” However, the FDA’s demand for a more rigorous study signals a need for further evidence to confirm the therapy’s efficacy. The core of the disagreement centers around the design of clinical trials for this complex disease. UniQure has argued that a placebo-controlled trial involving sham surgery is unethical, given the invasive nature of the procedure and the lack of existing effective treatments. A senior FDA official, speaking anonymously to CNBC, countered that the agency needs to be certain the therapy “actually helps people with Huntington’s disease,” suggesting skepticism about the initial trial data.

The Ethical Considerations of Trial Design

The debate over trial design highlights the unique challenges of developing therapies for neurodegenerative diseases. Huntington’s disease is caused by a genetic mutation that leads to the progressive breakdown of nerve cells in the brain. Symptoms typically appear in adulthood and include movement disorders, cognitive decline, and psychiatric problems. Currently, there are no treatments that can halt or reverse the progression of the disease, only manage symptoms.

The FDA’s insistence on a placebo-controlled trial reflects a commitment to rigorous scientific standards. Such trials are considered the gold standard for evaluating the effectiveness of new treatments, as they minimize bias and allow researchers to determine whether the observed effects are truly due to the therapy or simply due to chance. However, in the context of Huntington’s disease, the ethical concerns raised by UniQure are significant. Performing sham surgery carries inherent risks, and denying potentially beneficial treatment to a control group raises questions about fairness and patient welfare.

Broader Concerns About FDA Decision-Making

UniQure’s situation is not isolated. REGENXBIO recently received a complete response letter (CRL) from the FDA for its gene therapy targeting Hunter syndrome, another rare genetic disorder. The rejection was attributed to issues with the study’s population, controls, and the use of surrogate markers to measure efficacy, as reported by BioSpace. These setbacks have fueled concerns among regulatory experts that the FDA’s “circle of trust is shrinking,” leading to decisions that perceive arbitrary and lacking transparency.

Adding to the scrutiny, the FDA’s Center for Biologics Evaluation and Research (CBER) director, Vinay Prasad, is currently under investigation following complaints of fostering a toxic workplace. This internal probe raises questions about the agency’s leadership and its impact on the review process. The biopharmaceutical industry is grappling with the FDA’s recent shift in requiring only one pivotal trial for approval, rather than the traditional two, prompting questions about the rationale behind this change and the potential risks involved.

The Role of Surrogate Markers and Efficacy Measurement

The REGENXBIO case underscores the importance of robust efficacy measurement in clinical trials. Surrogate markers – measurable indicators that are believed to predict clinical benefit – are often used in rare disease trials, where it may be difficult to assess direct clinical outcomes due to modest patient populations and long disease durations. However, the FDA’s rejection of REGENXBIO’s therapy suggests that the agency is becoming more cautious about relying on surrogate markers, particularly when there is limited evidence linking them to meaningful clinical improvements.

This increased scrutiny highlights the need for careful validation of surrogate markers and a clear understanding of their limitations. Researchers must demonstrate a strong correlation between the surrogate marker and the ultimate clinical outcome of interest before relying on it as the primary endpoint in a clinical trial.

What Comes Next for Huntington’s Disease Research

The FDA’s decision regarding UniQure’s gene therapy will have significant implications for the future of Huntington’s disease research. If the agency maintains its demand for a placebo-controlled trial, UniQure will need to invest substantial resources and time to conduct the study. The outcome of this trial will not only determine the fate of UniQure’s therapy but also shape the regulatory landscape for other gene therapies targeting neurodegenerative diseases.

Beyond UniQure’s trial, several other companies are pursuing innovative approaches to treat Huntington’s disease, including therapies that aim to silence the mutant huntingtin gene or protect nerve cells from damage. Ongoing research is also focused on identifying biomarkers that can assist diagnose the disease earlier and track its progression more accurately. The ultimate goal is to develop effective treatments that can slow, halt, or even reverse the course of this devastating illness. The FDA’s evolving stance on gene therapy approvals will undoubtedly influence the trajectory of these efforts.