Giant Axonal Neuropathy

Astellas Pharma is spreading its bets in neurodegenerative disorders, committing $50 million to AviadoBio for the opportunity to license its lead program, an experimental gene therapy for a type of dementia with no FDA-approved drugs. The sum breaks down to a $20 million equity investment and up to $30 million in upfront payments. The deal announced Tuesday grants Astellas an exclusive option to license global rights to the London-based startup’s AVB-101, which is currently in early clinical development as a potential treatment for a certain form of frontotemporal dementia (FTD). FTD is a type of early-onset dementia that leads to rapid decline in functions such as attention control, working memory, and problem solving. It typically causes death within three to 13 years of diagnosis, according to AviadoBio. The company aims to specifically treat this dementia when it is driven by a mutation to the gene that encodes progranulin (PGN), a protein that regulates immune activity in the brain. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health AVB-101 delivers to the central nervous system a functioning copy of the gene that provides instructions for making progranulin. The goal of the one-time treatment is to bring levels of that protein into the range of normal. Administered into the thalamus of the brain, AviadoBio’s therapy is transported to its cellular targets aboard an adeno-associated virus (AAV), an engineered virus widely as a delivery vehicle for genetic medicines. AviadoBio’s science is based on research from King’s College London. The startup emerged from stealth in 2021, backed by $80 million in Series A financing. In preclinical research conducted with progranulin-deficient mice, AviadoBio has reported its experimental FTD-PGN therapy led to expression of progranulin in the brain and a reduction in disease pathology. A Phase 1/2 ascending-dose clinical trial treated its first patient earlier this year. The open-label study has a targeted enrollment of nine participants. There are other efforts underway to try and restore progranulin levels as a way to treat FTD-PGN. Passage Bio’s PBFT02 is a gene therapy intended to boost levels of the key protein in the central nervous system. This program has reached Phase 1/2 testing. Alector is taking a different approach with AL100, an antibody drug designed to bind to a protein that leads to degradation of progranulin. This program has reached Phase 3 testing under a partnership with GSK, which has rights to share in the development and commercialization of this experimental therapy. Gene therapy is one of the areas Astellas has identified for growth, Richard Wilson, the company’s senior vice president for genetic regulation, told MedCity News last year. Within gene therapy, the company is focusing on neuromuscular disorders, central nervous system conditions, and ophthalmology. Astellas’s gene therapy division formed from the 2020 acquisition of Audentes Therapeutics, which brought a pipeline of gene therapies in various stages of development for rare inherited disorders. presented by Health Tech What’s Keeping Healthcare CIOs Up at Night: How to Improve Patient Satisfaction by Handling Calls More Efficiently Health systems have spent billions on portals while investments in modernizing the voice channel — the dominant preference of healthcare consumers — have taken a backseat. By Stephanie Baum Some of the Audentes programs have encountered setbacks. The FDA in 2021 placed a clinical hold on an experimental gene therapy for the enzyme deficiency Pompe disease. That hold was lifted in early 2023. Three gene therapy programs for Duchenne muscular dystrophy were terminated in 2022 based on preclinical data. A gene therapy for the rare neuromuscular disorder X-linked myotubular myopathy was placed under a clinical hold in 2020 following three patient deaths. Though it later was cleared to resume, a fourth patient death in 2021 led to another clinical hold that is still in place. Astellas has prior experience with option deals for gene therapies. Two years ago, Astellas made an equity investment in Taysha Gene Therapies, securing exclusive options to license gene therapies for the rare neurodegenerative disorders giant axonal neuropathy (GAN) and Rett syndrome. Following the report of Phase 1/2 data for the GAN gene therapy last year, Astellas said it would not exercise its option on that program. A key Rett study is ongoing and the option for this program remains open. Astellas has struck other deals to fill its gene therapy pipeline. Last year, the company licensed a preclinical Kate Therapeutics gene therapy in development for X-linked myotubular myopathy. Following that deal, Astellas licensed the rights to use a 4D Molecular Therapeutics AAV vector for ophthalmic diseases. The option agreement with AviadoBio covers the application of AVB-101 to FTD-GRN and other indications. The trigger for the option and the option exercise period were not disclosed. But if Astellas exercises it, AviadoBio could receive up to $2.18 billion in license fees and milestone payments, plus royalties from sales of a commercialized product. “As we complete dosing of the first cohort of patients in our Phase 1/2 ASPIRE-FTD trial of AVB-101, we are excited about the potential of this collaboration to help address the unmet need that exists today in frontotemporal dementia,” AviadoBio CEO Lisa Deschamps said in a prepared statement. “This strategic collaboration will combine our promising gene therapy candidate for FTD-GRN and delivery expertise with Astellas’s global capabilities in development and commercialization of gene therapies.” Public domain image by Flickr user SciTechTrend

Pictured: Man climbing a DNA double helix/iStock, Moor Studio Taysha Gene Therapies touted positive early-stage data last month for its gene therapy to treat Rett syndrome, which has become the company’s main focus after cutting other programs and laying off 35% of its staff. If successful, the candidate for Rett syndrome has the capability to put Taysha in a billion-dollar market. The early-stage data only show the results of four Rett patients from a Phase I/II trial on Taysha’s AAV9 gene transfer therapy TSHA-102, however. Taysha’s focus on Rett comes after a patient death was recorded in 2022 for its experimental gene therapy for Sandhoff and Tay-Sachs diseases. While the death was not attributed to the therapy itself, it still drove down the company’s stock price, and eventually, Taysha abandoned the program, throwing its resources into Rett. If TSHA-102 does go the distance, the market could be a lucrative play for the Dallas-based biotech. With an estimated 16,600 to 25,800 patients in the U.S., the market totals an estimated $2.5 billion, according to an analyst report from Bank of Montreal Capital Markets. If everything goes according to plan, Taysha may have a solid opportunity to carve out a good slice of the Rett market—to the tune of around $1 billion at peak revenues in 2035, experts told BioSpace. “There’s a clear need for something better that could give these patients a real chance at having a more normal life,” said Maury Raycroft, an equity analyst at Jefferies. Taysha’s Push in Rett Syndrome After the patient death in 2022, Taysha announced it would focus on targeting Rett and giant axonal neuropathy (GAN) but pause work on its other R&D efforts, and axed 35% of its workforce. In 2023, further setbacks hit Taysha as the FDA requested more patient dosing to support a Biological License Application for its GAN therapy, TSHA-120. Finally, after a Type C meeting later that year, the company chose to halt all development of TSHA-120 and focus entirely on TSHA-102. The trial data reported in June was split into two cohorts. The pediatric patients showed improvements in motor skills, communication, and a reduction in the rates of seizure, among other observations. The adults in the trial had similar results, with one patient having normal sleep for the first time in 20 years. No serious adverse events occurred during the trial, according to Taysha. However, the results are not only early stage but involve a very small number of patients, Raycroft reminded BioSpace. In addition, investors’ feedback noted that the scales Taysha used did not show “clear trends” or clear consistency. Raycroft said that these scales are based on caregiver and clinician assessments, however, and he puts more weight on the clinicians’ findings. He sees this as a positive start for Taysha and believes that higher dose data should be available in the year’s second half. “I think the adult data is potentially even more meaningful, based on this update, because we’re seeing data after one year for one patient, and then half the year for the other patient, and both of those patients seem durable, at a minimum.” The Future for Taysha For smaller biotechs like Taysha, culling programs and eliminating employees may be necessary to preserve capital to get a product on the market, Raycroft said. He noted that the Rett candidate is Taysha’s best opportunity to get a product across the finish line, and it ultimately makes sense to prioritize and focus on it. He noted that Reata Therapeutics made a similar play with Friedreich’s ataxia drug Skyclarys, which was approved by the FDA last year and eventually acquired by Biogen. The company previously discontinued other programs in its pipeline, including its candidate for chronic kidney disease, choosing to focus solely on getting Skyclarys across the finish line. With its recent results, Taysha is looking to net more funds, recently announcing a public offering of over 14 million shares, which the company expects to bring around $75 million. In SEC documents, Taysha highlighted that the funds from the public offering would go toward the clinical, regulatory and manufacturing development of TSHA-102. With Taysha, Raycroft said, “they’re focused on reducing their expenses. And making sure that every dollar they spend will be more relevant to advancing this Rett syndrome program because this is their best option at reaching that pinnacle.” Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

Rett syndrome is characterised by loss of communication, slowing or regression of development, and motor and respiratory impairment. Credit: designer491 via Getty Images. Taysha Gene Therapies has received a regenerative medicine advanced therapy (RMAT) designation for its gene therapy candidate TSHA-102 from the US Food and Drug Administration (FDA) to treat Rett syndrome. TSHA-102 is a gene therapy that involves using an AAV9 virus to deliver the MECP2 gene directly into the central nervous system to treat the underlying cause of Rett syndrome, a rare genetic disorder caused by mutations in the MECP2 gene that affects brain development. It primarily occurs in girls and results in severe mental and physical disability. The RMAT designation programme is intended to expedite the development and review of regenerative therapies to treat, modify, reverse, or cure a serious condition. The FDA’s decision to grant the designation to Taysha is supported by initial results from the ongoing Phase I/II REVEAL clinical trials in adults (NCT05606614), and paediatric (NCT06152237) patients. The FDA reviewed safety and efficacy data from the first three patients dosed with the low dose of TSHA-102 across the two trials. Initial safety and efficacy data from the high-dose cohorts from both trials is expected in the second half of 2024, as per a 29 February update. In October 2022, Astellas announced plans to make a strategic investment to back the development of Taysha’s development programmes for Rett syndrome and giant axonal neuropathy (GAN). The pharma giant gained an exclusive option for licensing two clinical-stage programmes of Taysha—TSHA-102 and TSHA-120 for the treatment of GAN. See Also: Vertex Pharmaceuticals gets grant for treatment of alpha-1 antitrypsin deficiency with compound of formula (i) BioCryst Pharmaceuticals gets grant for inhibitors of the complement system for disease treatment Things however did not go to plan as about a year later, Taysha discontinued its TSHA-120 development programme following a Type C meeting with the US Food and Drug Administration (FDA), where the agency suggested the company conduct a placebo-controlled study and do a long-term follow-up trial. Following this, Astellas chose not to exercise its right to obtain an exclusive licence for the drug. After this, Taysha said that it would shift its focus to the TSHA-102 programme. According to GlobalData’s Pharma Intelligence Center, TSHA-102 is forecast to generate $650m in sales in 2030. GlobalData is the parent company of Pharmaceutical Technology. In the announcement accompanying the designation, Taysha’s president and head of R&D Sukumar Nagendran said: “We believe receiving RMAT designation reinforces the high unmet medical need in Rett syndrome and the therapeutic potential of TSHA-102 to change the treatment paradigm.” In April 2023, Acadia commercialised the first US Rett syndrome drug Daybue (trofinetide). The drug deactivates certain brain cells to prevent further neurodegeneration, thus preventing injury-induced seizures. Still, there is currently no disease-modifying treatment that treats the genetic root of the disease.