More than four years after the last of four boys died in a troubled Phase I/II trial of a gene therapy candidate for X-linked Myotubular Myopathy (XLMTM), Astellas Gene Therapies says it remains intent on treating the rare muscle weakening disease through a genetic medicine.
But instead of developing the adeno-associated virus (AAV)-based resamirigene bilparvovec (AT132) on its own, Astellas is now partnering with Kate Therapeutics—acquired in 2024 by Novartis for up to $1.1 billion—to develop a MyoAAV capsid-based gene therapy for XLMTM that the Japanese biopharma believes will be safer than AT132.
The therapy, which Kate calls KT430, is being developed by Astellas through an exclusive license of undisclosed value under the name ASP2957 (MyoAAV3.8-MHCK7-hMTM1). ASP2957 is an investigational, nonreplicating recombinant adeno-associated virus (AAV) with an engineered capsid that contains a DNA sequence of the human MTM1 gene under the control of an MHCK7 muscle-specific promoter. That promoter is only slightly different from the one used in AT132, Wilson said, which makes ASP2957’s capsid its most significant point of differentiation from AT132.
The myoAAV-encapsidated gene therapy encodes the same myotubularin gene that is in AT132.
“ASP2957 uses integrin receptors to increase the affinity and uptake of the viral vector into muscle cells, which allows us to deliver a much, much lower dose,” and thus address the longtime challenge of gene therapy dosing, Richard Wilson, senior vice president, primary focus lead, genetic regulation at Astellas, told GEN in an interview during last week’s J.P. Morgan 44th Annual Healthcare Conference in San Francisco. “The advantage there, we believe, is that on the work that was done by Kate, we could see a dramatic reduction in dose of AAV delivered to achieve the same kind of levels of protein production.”
“We believe that there’s obviously valuable information because you’re delivering the same gene. So once the gene therapy has transduced the muscle cells and formed your epidermal DNA, you’ve got a very, very similar product living in the patient,” Wilson added.
Astellas is now recruiting patients for the Phase I/II VALOR trial (2957-CL-0101, NCT07052929), a first-in-human study designed to assess ASP2957 in XLMTM, Wilson said. In Phase I, small groups of boys will receive lower to higher doses of ASP2957, with each boy receiving a single infusion of the gene therapy, with the aim of finding the most suitable dose of ASP2957 for use in Phase II. In that phase, another small group of young boys will receive a single infusion of ASP2957.
VALOR had an estimated enrollment of nine patients as of January 8, the date of the trial’s most recent update shared via ClinicalTrials.gov.
“We’re basically focusing our energies on starting Valor right now. The sites are active and open, and we’re screening patients,” Wilson said. “We’re hoping to get our first patient dosed in MTM by the end of this fiscal year as well. So, that’s actually a big moment for us. As you can imagine, that’s been a long and challenging road that we feel very strongly about.”
Internal investigation
In pursuing the VALOR trial, Wilson said, Astellas has opted not to resume dosing patients in the troubled Phase I/II ASPIRO trial (NCT03199469) during which the four boys died. An internal investigation of ASPIRO by Astellas has pinpointed two key factors in the deaths of the boys, three of which died in 2020 while the fourth boy passed away in 2021.
One and probably the most critical, according to Astellas, was a previously underappreciated cholestatic tendency that exists within the disease itself, as XLMTM can sometimes present with a liver phenotype that renders patients more susceptible to problems with bile salt transit.
“What we realized was in the setting of a patient who develops that kind of condition with a very high viral load of AAV, we think that tips them into a toxic state. We feel that was the closest we’ve come to finding the mechanistic pathway,” Wilson explained. “We did a lot of preclinical investigations. We candidly could not find a molecular smoking gun that says, here is the mechanism by which we have tipped these patients over into this cholestatic no-go zone. But we feel that at bulk level, it’s about the dose and it’s about understanding that patient population.”
In partnership with patient organizations, Astellas in 2024 launched A Non-Interventional Epidemiological Study of XLMTM and Clinical Expression in the Liver (EXCEL; NCT06581146), an observational study designed to track and map both the prevalence instance and the course of the cholestatic effect within the patient population. Boys under 18 diagnosed with XLMTM are being followed for about a year, with the health of their liver and gallbladder being checked about every six weeks. The study, which has an estimated enrollment of about 50, has an estimated primary completion date of May 31, 2027.
Astellas’ interest in capsids goes beyond using Kate’s myoAAV capsid. Astellas continues to work on developing new capsids through two ongoing collaborations: Astellas has licensed Sangamo Therapeutics’ IV delivered CNS penetrant capsid STAC-BBB for up to five potential neurological disease targets under an up to $1.3 billion ($20 million upfront) license agreement inked in 2024. Three years earlier, Astellas signed an up to $1.6 billion option and license agreement with Dyno Therapeutics to develop next-generation AAV vectors for gene therapy directed to skeletal and cardiac muscle using Dyno’s CapsidMap™ platform.
“Those partnerships are very active. We’ve made a lot of strides in terms of next generation capsids,” Wilson said—without offering details since Astellas cannot publicly discuss the collaborations.
In contrast to ASP2957, AT132 is designed to deliver a functional copy of the MTM1 gene via an AAV serotype 8 vector, in order to transfect and express myotubularin in skeletal muscle cells. It was the lead gene therapy pipeline candidate of Audentes Therapeutics when it was acquired by Astellas for $3 billion, in a deal completed in January 2020.
AT132 received the FDA’s Rare Pediatric Disease, Fast Track, and Orphan Drug designations, as well as the PRIME and Orphan Drug designations of the European Medicines Agency.
Program updates
Wilson also offered updates on several other Astellas wholly owned and partnered gene therapy development programs.
Astellas’ lead genetic medicine candidate is AT845, a gene replacement therapy for low-onset Pompe disease caused by mutations in the gene encoding the lysosomal enzyme alpha-glucosidase (GAA). Wilson said, “We’ve actually completed dosing in our Phase I-II study, and we’re now looking at a proof-of-concept decision by the end of the fiscal year,” Wilson said. Astellas’ current fiscal year ends March 31.
Another is AVB-101, an AviadoBio-discovered AAV-based gene therapy for frontotemporal dementia with progranulin mutations (FTD-GRN), toward which Astellas has committed up to $2.68 billion (including $30 million upfront and a $20 million equity investment) under a collaboration signed in 2024. Astellas has an option to receive a worldwide exclusive license for the development and commercialization rights to AVB-101, which contains a non-mutated version of the GRN gene. AVB-101 is under study in the AviadoBio-run Phase I/II ASPIRE-FTD trial (NCT06064890) expected to read out early biomarker data later this year.
“As the data matures, we’ll be making a decision about potential in-licensing,” Wilson said. “For now, that’s been a very productive collaboration.”
Among Astellas’ preclinical gene therapy programs is AT466, a vectorized, exon skipping/vectorized RNA knockdown for the DMPK gene, targeting myotonic dystrophy 1 (DM1). Like AT132 and AT845, Astellas inherited the discovery phase AT466 when it acquired Audentes.
‘Stay tuned’
Astellas aims to emerge from the several companies now working to develop therapies for DM1, for which there is now no FDA-approved drug on the market. Candidates in the clinic include delpacibart etedesiran (del-desiran™, formerly AOC 1001), an antibody oligonucleotide conjugate or AOC being developed by Avidity Biosciences (set to be acquired by Novartis for approximately $12 billion in H1 2026); and Dyne Therapeutics’ zeleciment basivarsen (DYNE-101), an antisense oligonucleotide targeting the DMPK gene.
Avidity expects to publish 54-week topline data from its global Phase III HARBOR™ trial (NCT06411288) in H2 2026. Last October, Dyne presented additional positive one-year data from its ongoing Phase I/II ACHIEVE trial (NCT05481879) showing clinically meaningful improvements in function and strength at the selected registrational dose.
“We’re seeing great progress with our AT466 program,” Wilson said. “What we’re hoping to be is the first gene therapy, the first one-time treatment. We have reason to believe that there could be more efficacy to be had in the treatment of DM1 than we see with the current late-stage therapies that are in the clinic.”
Astellas is also seeing progress, Wilson said, with its discovery phase program to treat Angelman Syndrome by restoring the UBE3A gene.
Wilson said Astellas is heading towards development of both AT466 and the Angelman candidates, but for now isn’t saying much more: “I would hope you will be hearing us talk more and more about those programs as we go through 2026. But for now, I would say it’s going to have to be a ‘stay tuned’ message.”
