4DMT Aligns with FDA on Plan to Lift Clinical Hold on Fabry Disease Cardiomyopathy Trial

Rare Daily Staff

4D Molecular Therapeutics reported alignment with the U.S. Food and Drug Administration on a plan to lift the clinical hold on the phase 1/2 INGLAXA clinical trial in the United States for the gene therapy 4D-310 for Fabry disease cardiomyopathy.

“We have shared with the FDA the totality of the most up to date clinical activity and safety data already generated from INGLAXA trials, as of August 2023, and look forward to progressing this critical work on behalf of all patients with Fabry disease,” said David Kirn, co-founder and CEO of 4DMT.

In January 2023, the company said it would pause enrollment in both the United States and Asia-Pacific trials after observing instances of atypical hemolytic uremic syndrome (aHUS). Consistent with the company’s plans, the FDA subsequently notified 4DMT of a clinical hold in the U.S. The Asia-Pacific clinical trial program was not placed on clinical hold by any regulatory agency.

4DMT’s plan includes a single non-clinical study, currently underway, that will evaluate the safety and biodistribution in non-human primates (NHPs) of IV 4D-310 with the R/S immunosuppressive regimen compared to the prior prednisone regimen. 4DMT expects to submit the results to the FDA in the second quarter of 2024. In addition, the INGLAXA clinical trial protocol has been amended to minimize the risk of aHUS following IV 4D-310 dosing, including requiring the R/S immunosuppressive regimen.

In February 2023, the Company presented positive interim clinical activity data of 4D-310 from 3 patients with 12 months of follow-up, which demonstrated improvements in multiple FDA-recommended cardiac endpoints along with selective and widespread transgene expression within approximately 50 percent of cardiomyocytes in a cardiac biopsy. Additional interim cardiac biopsy and clinical efficacy data, with follow-up of at least 12 -18 months for all 6 patients dosed with 4D-310 from the INGLAXA clinical trials, is expected to be presented in the first quarter of 2024.

Clinical investigators have previously demonstrated that the R/S immunosuppressive regimen is well-tolerated and is able to prevent the development of aHUS following IV administration of AAV gene therapeutics.

Affecting more than 50,000 people in the United States and European Union, Fabry disease is a genetic disorder of the GLA gene that results in the body’s inability to produce AGA, causing accumulation of the substrate globotriaosylceramide (Gb3) in critical organs, including the heart, kidney, and blood vessels. Cardiomyopathy is the leading cause of death in the Fabry disease patient population. Such substrate accumulation can lead to life-threatening hypertrophic cardiomyopathy, heart failure, arrhythmias, various degrees of kidney dysfunction and cerebrovascular stroke. Significant unmet medical needs remain for these patients despite enzyme replacement therapy (ERT), the current standard of care. ERT requires biweekly intravenous dosing which markedly decreases patients’ quality of life. In addition, while benefit has been demonstrated in the kidney, ERT has not been shown to clearly benefit the heart.

4D-310 utilizes the cardiac targeted and evolved C102 vector to efficiently deliver a functional copy of the GLA gene (encodes for AGA enzyme) to the heart after a single low dose IV administration. The product candidate is designed to generate high local levels of AGA directly within heart tissue, as well as other affected organs, with the goal of reversing the cardiomyopathy in Fabry patients.

Photo: David Kirn, co-founder and CEO of 4D Molecular Therapeutics