4DMT's 4D-310 Shows Promising Cardiac Improvements in Fabry Disease Trial
核心洞察
4D-310 demonstrated clinically meaningful improvements in cardiac contractility, exercise capacity, and quality of life in Fabry disease (搜索) patients with cardiomyopathy.
Cardiac biopsies showed robust and durable delivery of the GLA gene (搜索) and a reduction in Gb3 substrate within cardiomyocytes.
The therapy was generally well-tolerated, with previously reported cases of atypical hemolytic uremic syndrome fully resolved.
4D Molecular Therapeutics (4DMT) has announced positive interim data from its Phase 1/2 clinical trials of 4D-310 (INGLAXA) for Fabry disease cardiomyopathy (搜索). The data, presented at WORLDSymposium™ 2024, showcased clinically meaningful improvements in cardiac function and a favorable safety profile in treated patients.
The INGLAXA trial evaluated a single intravenous infusion of 4D-310 (1E13 vg/kg) in six adults with Fabry disease cardiomyopathy (搜索). Follow-up data, ranging from 12 to 33 months, revealed improvements in cardiac contractility (echocardiography), peak VO2 (cardiopulmonary exercise testing), and cardiac quality of life (KCCQ) in all five evaluable patients.
Key Findings
- Cardiac Contractility: Improved global longitudinal strain (GLS) was observed in all five evaluable patients by month 12. Two patients with 24 months of follow-up showed clinically meaningful improvements exceeding the minimal detectable difference of -1.5% (-2.8 and -2.9%, respectively).
- Exercise Capacity: Three of four evaluable patients demonstrated clinically meaningful improvement in CPET peak VO2, exceeding the minimal clinically important difference (MCID) of +1.5 at month 12 (+1.8, +2.0 & +7.0). One patient followed for 24 months continued to show meaningful improvement (+7.8).
- Quality of Life: Two patients with low baseline KCCQ scores (<90) experienced clinically meaningful improvements exceeding the MCID of +5. Three patients with baseline values >90 remained stable through 12-24 months.
- Cardiac Biopsies: Biopsies from one patient at weeks 6 and 26 showed robust and durable 4D-310-mediated transgene expression in cardiomyocytes. At week 26, mean Gb3 inclusion body volume per cardiomyocyte was reduced by 15% from week 6 and 61% compared to a historical sample.
Safety and Tolerability
The therapy was generally well-tolerated. Previously reported cases of atypical hemolytic uremic syndrome (aHUS) (n=3) have fully resolved, and no new drug-related adverse events greater than Grade 1 have been reported since the last interim update.
Mechanism of Action
4D-310 utilizes the cardiac-targeted C102 vector to deliver a functional copy of the GLA gene (搜索) to the heart. This is designed to generate high local levels of AGA enzyme directly within heart tissue, aiming to reverse cardiomyopathy in Fabry patients. Fabry disease (搜索), affecting over 50,000 people in the US and EU, results from a deficiency in AGA, leading to the accumulation of globotriaosylceramide (搜索) (Gb3) in vital organs.
Future Directions
4DMT plans to submit data from a non-human primate (NHP) study evaluating 4D-310 with a rituximab/sirolimus immunosuppressive regimen to the FDA in Q2 2024 to address the clinical hold. This study aims to evaluate the safety and biodistribution of 4D-310 with the new immunosuppressive regimen compared to the prior prednisone regimen.
"These promising clinical results continue to validate our Therapeutic Vector Evolution platform, as well as the potential of the C102 vector for targeted IV delivery to cardiomyocytes. Cardiac biopsies also showed robust and durable delivery and transgene expression from 4D-310, and remarkably, a reduction in Gb3 substrate in cardiomyocytes," said David Kirn, M.D., Co-founder and Chief Executive Officer of 4DMT.