B5 - Neurologic Diseases (excluding Ophthalmic and Auditory Diseases)
627: Clinical Safety and Efficacy of EXG001-307 in SMA Type 1 Patients: A Next-Generation AAV-Based Gene Therapy
Type: Poster Session
Poster Board Number: 627
Presentation Details
Session Title: Wednesday Posters: Neurologic Diseases
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that leads to progressive muscular weakness and hypotonia. Gene therapy for SMA has been successfully developed, and the commercialized medicine Onasemnogene abeparvovec (Zolgensma), which was approved by FDA in 2019 as a one-time administration to SMA patients below the age of 2 years, demonstrated significant clinical benefits including prolonged survival and motor milestone achievement . However, current gene therapy faces various challenges including insufficient expression of the SMN1 gene in the target organs/tissues and off-target organ toxicity such as liver failure. Thus, there is a need for improved gene therapies for SMA with tissue specific SMN1 expression and reduced off-target toxicity. We developed an AAV-based gene therapy, EXG001-307, favoring neuronal transgene expression. Nonclinical studies have demonstrated that EXG001-307 improved the survival rate, further enhanced the motor function, and significantly reduced toxicity in the SMA mouse model. Moreover, our clinical trial demonstrated an excellent safety and efficacy profile for EXG001-307.
The IND for EXG001-307 was approved by the National Medical Products Administration (NMPA) in China and an open-label, multicenter, single-arm, non-randomized, single-dose escalation clinical trial to evaluate the safety and efficacy of a single IV injection of EXG001-307 in patients with type 1 SMA is ongoing and patients enrollment for the Phase 1have been completed. Main inclusion criteria are: 1) SMA is diagnosed with bilateral allelic SMN1 mutations (deletions or point mutations) and 2 copies of the SMN2 gene; 2) On the day of administration, the age of the subject shall not exceed the 180th day after birth; 3) The clinical history and physical signs are consistent with the symptoms of type 1 SMA. Six patients have been enrolled, and two doses have been studied, 1.1x1014 vg/kg and 1.5x1014 vg/kg. EXG001-307 were well tolerated in both groups, with the most common test article related adverse events (AEs) as fever, transient sinus tachycardia; mild elevation of aspartate aminotransferase (AST), troponin I, creatine kinase-MB (CK-MB), activated partial thromboplastin time (APTT) and prothrombin activity; and a reduction trend in platelet, lymphocyte and white blood cell counts. No occurrence of dose-limiting toxicity (DLT), or test article related >Grade 2 serious AEs (SAEs), or ≥ Grade 2 elevation of transaminases or cardiac enzymes in the trial has been reported. All patients achieved significant increase in CHOP-INTEND scores. All three patients in 1.1x1014 vg/kg group achieved head control in 3-6 months post dose, while all three patients in 1.5x1014 vg/kg group achieved head control in 1-2 months post dose. The first patient in 1.1x1014 vg/kg dose group has achieved sitting without assistance around 10 months post dose. In summary, while first-generation gene therapies like Zolgensma have shown substantial benefits for SMA patients, challenges persist in achieving sufficient SMN1 gene expression in the target organs and avoiding off-target toxicity. Our AAV-based gene therapy, EXG001-307, tackles these issues by favoring neuronal transgene expression. Positive outcomes in our clinical trial, including patients reaching significant milestones with well-tolerated responses, highlight the potential of EXG001-307 as a promising next generation treatment for SMA. Ongoing research in this direction aims to advance EXG001-307, providing targeted SMN expression and minimizing off-target effects for improved outcomes in SMA patients.
Plain Language Summary
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that leads to progressive muscular weakness and hypotonia. We developed an AAV-based gene therapy, EXG001-307, favoring neuronal transgene expression. Nonclinical studies have demonstrated that EXG001-307 improved the survival rate, further enhanced the motor function, and significantly reduced toxicity in the SMA mouse model.
In a Phase I clinical study, six patients received 1.1x1014 vg/kg or 1.5x1014 vg/kg doses of EXG001-307 and showed good tolerability with no dose-limiting toxicity or > grade 2 serious adverse events (SAEs). All patients achieved significant motor milestones, suggesting EXG001-307 as a next-generation SMA treatment for improved patient outcomes.
Zhenhua Wu1, Chunjuan Song1, Wenhui Li2, Xiaojing Li1, Xiaomei Zhu2, Hui Li2, Meijia Yang1, Wenshu Yang1, Rui Ji1, Kuan Lu1, Yanna Zhang1, Haifeng Li3, Lijun Wang1, Guo-jie Ye1, Qiang Shu3, Yi Wang2
1Exegenesis Bio Inc., Spring House, PA,2Children’s Hospital of Fudan University, Shanghai, China,3The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China"
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