FDA Asks Gene Therapy Biotech to Run Clinical Trial That Might Be Impossible

One challenge of developing a drug for a disease with no approved therapies is that there isn’t an established clinical trial roadmap to follow. Taysha Gene Therapies hoped the trial design for its gene therapy for a rare neuromuscular disease would put it on the path to a regulatory submission. FDA questions about the study mean that the path forward is almost certainly longer, and might not even be possible.

After meeting with FDA to discuss data from a small, open-label study for its gene therapy for giant axonal neuropathy (GAN), Taysha said the agency has asked the company to conduct a randomized and placebo-controlled clinical trial to further evaluate the therapy, TSHA-120. The rarity of GAN poses several challenges for such a trial, according to CEO Sean Nolan. The low numbers people affected by the disease is whittled down even further when applying eligibility criteria for a clinical trial, he explained. Statistical analysis on such small numbers becomes challenging.

“We are questioning the feasibility of this kind of study,” said Nolan, speaking during a Tuesday evening conference call. “If you don’t have the right number of patients and the right stats, doing the study really wouldn’t be a worthwhile endeavor.”

GAN is caused by mutations in the gene that codes for gigaxonin, a protein important to neuron function. Mutated versions of that protein lead the axons on neurons to become abnormally large and dysfunctional. Affects the peripheral and central nervous systems, GAN leads to walking difficulty among other muscle problems. It also causes vision and hearing problems. The prevalence of GAN is unknown but only about 50 affected families have been described in medical literature.

With TSHA-120, Taysha aims to replace the gigaxonin gene. The National Institutes of Health is evaluating the therapy in a Phase 1/2 clinical trial with a targeted enrollment of 21 patients; Taysha acquired the rights to the therapy in 2021. Patients in the study are being evaluated according to Motor Function 32 (MFM32), a 32-item scale for assessing motor function in those who have neuromuscular diseases. Nolan said this endpoint was proposed based on its use for regulatory approvals in other neuromuscular diseases.

Last year, Taysha reported that those given the highest dose showed a slowing of disease progression that was similar to what was achieved in the lower dose groups—results that the company considered a sign of disease modification. Those results were the main discussion topic during a Dec. 13 meeting with the FDA.

According to Nolan, the FDA said that assessing patients according to GAN may have introduced bias due to the subjective nature of MFM32. The FDA’s remedy was to recommend a randomized and placebo-controlled clinical trial. While Nolan declined to discuss specific details of the meeting, he said the FDA’s focus was on MFM32 because that test accounted for most of the available data.

Taysha President and Head of R&D Sukumar Nagendran said In addition to MFM32, Taysha is also evaluating the effect of the gene therapy on retina and optic nerve. The potential to show a change in vision could be part of a comprehensive data package that provides the FDA with additional information. Nagendran, who did not attend the December meeting because he was not employed by Taysha at the time, said he hopes future discussion with the agency can span the totality of data.

The meeting was attended by Astellas. Last November, the Japanese pharmaceutical company made an equity investment in Taysha that also gave it options on the biotech’s gene therapy candidates for GAN and Rett syndrome, a rare neurodevelopmental disorder with no FDA-approved therapies. Nolan said Astellas was involved in the planning for the meeting is aware of what the company is doing with its gene therapies. He added that there is no formal timeline to getting feedback from the FDA but he expects the company will be able to provide an update later in the current quarter.

In a research note sent to investors, William Blair analysts Sami Corwin and Raju Prasad wrote that the FDA recommendation for a placebo-controlled study was “the worse-case scenario outcome for Taysha’s Type B meeting.” They said this feedback was perplexing given previous draft guidance suggesting the potential for expedited development of gene therpaies for monogenic disorders, such as GAN, that have well-characterized natural histories.

Corwin and Prasad echoed Taysha’s sentiments that a placebo-controlled, randomized study for TSHA-120 would not be logistically, financially, or statistically feasible. But the analysts added that clinical development of the Rett program may be more important for the company. The first adult patient is expected to be dosed in the first half of this year. An application to begin a clinical trial in the U.K. enrolling pediatric Rett patients is on track for a mid-year submission, followed by an investigational new drug application filing with the FDA in the second half of 2023.

“Furthermore, while the TSHA-120 update is disappointing, our investment thesis has always predominantly hinged on TSHA-102, given its large [total addressable market], and we continue to believe that clinical update from the company’s Rett syndrome program will be key catalysts over the next 12 months. Last, we continue to view the strategic investment by Astellas positively as it provides opportunities for Taysha to receive additional nondilutive capital (if the TSHA-102 or TSHA-120 options are exercised) or be outright acquired by Astellas.”

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