GAN

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.” Image: koto_feja, Getty Images

Jason Armond/Los Angeles Times/Getty Images The FDA asked Taysha Gene Therapies to dose more patients in a double-blinded, placebo-controlled trial for its Biological License Application for its giant axonal neuropathy (GAN) candidate TSHA-120, the company announced Tuesday. This regulatory recommendation follows a Type B end-of-Phase II meeting, wherein the FDA acknowledged that Taysha’s plans to use the 32-item Motor Function Measure (MFM-32) assessment as a study endpoint was acceptable. In an investor call Tuesday, Sukumar Nagendran, M.D., president and head R&D at Taysha, said the FDA acknowledged the moderate efficacy of TSHA-120. However, since the MFM-32 may have subjective bias, a blinded trial is needed for better data integrity. In response to the FDA’s recommendations, Taysha submitted follow-up questions to clarify details about the proposed study design and the totality of data required for the BLA. The company is awaiting further feedback and guidance from the FDA, Nagendran said. Taysha’s shares fell around 6% in post-market trading Tuesday in reaction to the news. TSHA-120 is a vector-delivered gene therapy being developed for GAN, an ultra-rare autosomal recessive disease of the central and peripheral nervous systems characterized by numbness and muscle weakness, which progress to seizures, loss of control over the body and gradual mental decline. GAN is caused by mutations that render the gigaxonin gene inactive. TSHA-120 works by delivering a full-length and functional copy of this gene. During the investor call, Nagendran said that all data generated so far for TSHA-120 “are encouraging and support a disease-modifying potential” of the candidate. Taysha is developing TSHA-120 in collaboration with Tokyo-based Astellas. In October 2022, Astellas bought 15% of Taysha’s outstanding common stock for $50 million. Astellas has the exclusive option to license TSHA-120 and TSHA-102, another clinical-stage asset for Rett syndrome. Corporate Updates Alongside the FDA’s regulatory recommendations, Taysha announced Tuesday it has implemented a comprehensive strategic review to improve business execution. This review kicked off in December 2022, when Nagendran and Sean Nolan, chairman and newly appointed CEO, Taysha, joined the company. Since then, company leadership has implemented operational, structural and personnel changes “to enhance information flow, coordination, decision-making and execution.” These changes included modifying governance structures, adjusting the cadence of meetings and forming cross-functional teams, Nolan said. Taysha implemented a similar strategic reorientation in March 2022, when it suspended all other clinical R&D activities to focus on its GAN and Rett syndrome programs. Along with this pivot, the company laid off 35% of its staff.

Astellas and Taysha Gene Therapies (Taysha) have announced a strategic investment to support the advancement of Taysha’s adeno-associated virus (AAV) gene therapy development programmes for the treatment of Rett syndrome and giant axonal neuropathy (GAN). Under the terms of the agreement, the Japanese firm will invest a total of $50m to acquire 15% of the outstanding common stock of Taysha and to receive an exclusive option to license two of Taysha’s clinical stage programmes: TSHA-102 for Rett syndrome and TSHA-120 for GAN. Rett Syndrome and GAN are monogenic diseases of the central nervous system. Rett Syndrome results from a mutation in the MECP2 gene on the X chromosome and causes a broad spectrum of symptoms, including loss of speech, mobility and muscle tone and breathing issues. GAN is caused by an abnormality in a gene that encodes for the gigaxonin protein found on chromosome 16. The disorder also impacts mobility and motor abilities and can cause seizures and skeletal abnormalities. The deal gives Astellas the future option to apply its global research and development, manufacturing and commercialisation capabilities in gene therapy to Taysha’s AAV gene therapy development programmes, creating the opportunity for both companies to enhance the development of novel treatment options for patients with Rett syndrome and GAN, who have serious unmet medical needs. “Taysha is an industry leader in central nervous system gene therapies and this partnership fits strategically with our long-term vision of expanding Astellas’ gene therapy capabilities, allowing the company to impact the lives of a broader range of patients with urgent unmet medical needs,” said Naoki Okamura, chief strategy officer, at Astellas. Also commenting on the deal, RA Session II, Taysha’s chief executive officer, said: “We are excited to enter this strategic investment with Astellas, a premier biopharmaceutical company with global R&D, manufacturing and commercial capabilities. “We believe this investment not only further validates the potential of our technology platform, but also reinforces the therapeutic and market opportunity of our two lead clinical assets.” The deal is the latest of Astellas’ efforts to build its capability in gene therapy, following a $1.6bn research collaboration with Dyno Therapeutics in December 2021, as well as its $3bn acquisition of Audentes – now Astellas Gene Therapies, California – in January 2020.