Rare disease ushered in a new milestone!

February 9, 2022 / eMedClub News / -- Recently, Astellas announced positive interim data from a Phase 1/2 clinical trial of its AAV gene replacement therapy AT845, which provides functional alpha-glucosidase ( GAA) gene for the treatment of late-onset Pompe disease (LOPD)
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Pompe disease, also known as type II glycogen storage disease, is a rare autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA)
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Dysfunction or lack of functional GAA results in toxic accumulation of glycogen in lysosomes, skeletal and cardiac muscles, the tissues primarily affected by disease
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The disease process of Pompe disease is progressive, and it is divided into infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (IOPD) according to the age of onset, disease progression and degree of organ involvement.
LOPD)
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Incidence is related to ethnicity and clinical type, with a global incidence of 1:40,000-1:200,000
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The only currently approved treatment for Pompe disease is enzyme replacement therapy (ERT), a chronic treatment usually given as an intravenous infusion every two weeks
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Despite the availability of ERT, there is still a large unmet medical need, mainly due to ERT's inability to penetrate critical tissues affected by disease and the immunogenicity of ERT
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AAV Gene Therapy for Pompe Disease Astellas Gene Therapies (formerly Audentes, later acquired by Astellas) is developing AT845, a novel gene replacement investigational therapy that addresses ERT by targeting muscle tissue, the primary tissue affected in Pompe disease limitations
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Using a muscle-directed approach and the AAV8 capsid serotype, AT845 is being investigated for its effectiveness in delivering a functional GAA gene that is efficiently transduced to express GAA directly in disease-affected tissues, including skeletal and cardiac muscle
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At the same time, targeted gene delivery therapy using a relatively low-dose adenovirus type 8 vector is beneficial to increase immune immunity to GAA
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A stable GAA enzyme secretion has been detected in the blood of GAA knockout mice using this treatment method, and similar gene therapy methods have also successfully treated hemophilia
B.

FORTIS is an ongoing multicenter, open-label, escalating-dose Phase 1/2 clinical trial to evaluate the safety and tolerability of AT845 in adults with LOPD
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The trial's primary endpoints were safety and tolerability, as well as efficacy measures, including changes from baseline in muscle GAA protein expression and enzymatic activity
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Secondary endpoints assessed improvements in measures of breathing, endurance, and quality of life
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As of December 3, 2021, four subjects have been enrolled in FORTIS, two at a dose of 3 x 10^13vg/kg (cohort 1) and two at a dose of 6x10^13vg/kg (cohort 1) 2)
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Data reported include an interim safety and tolerability assessment, as well as up to 24 weeks of follow-up for two participants in cohort 1 and preliminary data for two participants in cohort 2
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Results showed an encouraging safety profile for AT845 during the 24-week follow-up period after dosing
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More importantly, none of the four subjects reported serious adverse events after dosing
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Astellas Gene Therapies will continue to recruit patients for this clinical trial
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Safety is still the top priority of gene therapy.
Gene-targeted therapy overcomes the shortcomings of long treatment period and frequent injections of ERT, and can effectively increase the enzyme content and enhance muscle strength
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However, immune induction therapy may have associated risk factors that increase the chance of infection and cancer
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Despite analyst optimism, there are ample signs that the FDA remains cautious about the safety of gene therapy
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Risk factors emerging in gene therapy trials have been the reason the FDA has suspended clinical trials for the past two years
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For example, a study testing spinal injections of Novartis-approved spinal muscular atrophy therapy Zolgensma had its clinical trials suspended for more than 18 months due to signs of neurological inflammation in animal testing
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Meanwhile, some gene therapies being developed by UniQure and Bluebird bio were briefly suspended after reports of cancer in trial subjects
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After the investigation, the relevant R&D companies said that there may not be a necessary link between their gene therapy and cancer, and that gene therapy is not the cause of cancer
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Scientists in basic research and drug development are working to understand the link between gene therapy and these types of serious side effects
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Meanwhile, regulators have not reduced or limited clinical testing, and the FDA has said on multiple occasions that they expect to approve 10 to 20 cell and gene therapies a year by 2025
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With the introduction of the concept of precision medicine, the precise treatment of various rare diseases at the gene level has become the focus of current medical research, and the development of the AAV vector platform has also entered the fast lane.
Patients bring hope
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References: 1.
https:// -pompe-disease/