Kate Therapeutics’ CSO and scientific co-founder, Sharif Tabebordbar, PhD, will present detailed preclinical efficacy and safety results in nonhuman primates (NHPs) on its product pipeline and platform at the ASGCT 2024 Annual Meeting in Baltimore.

tissue slice in muscular dystrophy
The key pathologic change of Duchenne muscular dystrophy is myonecrosis. At an early phase, necrotic fibers appear swollen, homogeneous, and deeply eosinophilic. The disease is caused by mutations of dystrophin, the largest known human gene, located on chromosome Xq21. [Jose Luis Calvo Martin & Jose Enrique Garcia-Maurino Muzquiz/Getty Images]
The results support the best-in-class potential of KateTx’s newest generation of skeletal muscle- and heart-targeted, liver de-targeted engineered MyoAAV capsids and gene regulation technology to treat Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and other devastating genetic skeletal muscle and heart diseases, according to Tabebordbar, who is the recipient of the 2024 Outstanding Investigator Award for contributions to the field of gene therapy.

KateTx debuted less than a year ago with a $51 million Series A round co-led by Westlake Village BioPartners and Versant Ventures, and an exclusive license of KT430 to Astellas Pharmaceuticals for the treatment of X-linked myotubular myopathy. Since that time, the company has used its DELIVER platform to identify a proprietary class of muscle- and heart-targeted, liver de-targeted “MyoAAV-LD” capsids with improved potency and selectivity in NHPs and selected KT809 as a development candidate to treat DMD.

Kevin Forrest, PhD
Kevin Forrest, PhD, co-founder, president, and CEO of KateTx [Kate Therapeutics]
KT809 incorporates MyoAAV-LD 6.1, which is a sixth-generation internally generated and fully owned capsid, as well as a proprietary regulatory element developed to express the transgene in both skeletal muscle and the heart in primates. KateTx expects to select development candidates for additional muscle and cardiac programs in the near term. In addition, Astellas has formally advanced KT430 into IND enablement.

“KateTx has made significant advances over the past 12 months,” said Kevin Forrest, PhD, co-founder, president, and CEO of KateTx. “These ASGCT presentations are a meaningful milestone for the company and demonstrate the potential of our medicines to be the preferred therapies in both DMD and FSHD. We look forward to advancing these differentiated products to patients as quickly as possible.”

Advances in next-generation DMD gene therapy

KateTx will present data on its DMD development candidate showing markedly higher and more uniform expression at lower doses than competing gene therapies in NHPs, noted Tabebordbar.

“First-generation gene therapies for DMD use high doses of naturally occurring capsids that primarily target the liver, and promoters that are more active in skeletal muscle than heart in primates,” said Tabebordbar. “By leveraging our novel capsid and gene regulation technologies, we have developed a DMD gene therapy candidate that potently, uniformly, and selectively expresses high levels of microdystrophin in both skeletal muscle and heart, which are the major affected organs in the disease, while avoiding off-target tissues like the liver.”

Sharif Tabebordbar, PhD
Sharif Tabebordbar, PhD, CSO and scientific co-founder of KateTx [Kate Therapeutics]
In NHPs, KateTx’s product reportedly expressed high levels of microdystrophin uniformly in skeletal and cardiac muscles at a dose three times lower than a surrogate version of an FDA-approved DMD gene therapy. In contrast, microdystrophin expression from the surrogate was barely detectable in skeletal muscles and heart of NHPs at the clinical dose of 1.33E+14 vg/kg. High and uniform levels of microdystrophin protein expression across muscle fibers are required to protect muscles against injury and death in DMD and are important factors affecting DMD gene therapy durability.

KateTx’s DMD development candidate also resulted in 27 times lower vector genomes per nucleus in the liver compared with animals injected with the surrogate. Collectively, these findings support the potential for superior improvements in skeletal muscle strength, cardiac function (largely responsible for mortality in DMD), and safety, according to Tabebordbar.

Preclinical data for the FSHD program

KateTx will also present new preclinical data from its program in FSHD, which is a common muscular dystrophy that results from toxic expression in skeletal muscle of a protein called DUX4. The company says its results show the potential to give a one-time gene therapy that potently suppresses DUX4 whenever it is expressed in skeletal muscles.

In vitro, KateTx’s MyoAAV-LD mediated RNAi gene therapy candidate showed potent knockdown of DUX4 in FSHD patient myotubes with no off-target effects. In mice, the therapy reduced DUX4 target gene expression and led to dose-dependent improvements in muscle function and ultimately protected animals from severe impairment in treadmill time to exhaustion at a low dose.

“Both DMD and FSHD are challenging diseases; they require delivery of therapeutic cargoes to a substantial tissue mass, and expression of significant amounts of protein uniformly and durably across skeletal muscle fibers and cardiomyocytes in the case of DMD, and effective inhibition of toxic DUX4 expression in skeletal muscle in the case of FSHD,” said Katherine A. High, MD, visiting professor at Rockefeller University, professor emerita of pediatrics at the Perelman School of Medicine at the University of Pennsylvania, and member of the KateTx Scientific Advisory Board.

“The clinical evaluation of these novel bioengineered capsids is in my judgment one of the most exciting near-term developments in our field and I look forward to these programs moving into clinical development.”


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