Patient dies after receiving gene therapy for Danon disease

A Phase II clinical trial of an experimental gene therapy for a cardiovascular disease is on hold following the death of a patient.

The US Food and Drug Administration (FDA) placed a formal clinical pause on the trial on 23 May, by which point Rocket Pharma, the biotechnology company developing the treatment, had already voluntarily paused dosing. The patient died from unexpected complications related to capillary leak syndrome, which can cause dangerously low blood pressure as fluid leaks out from blood vessels into surrounding tissues.

'Rocket is working with the FDA, the Independent Data Safety Monitoring Committee, clinical investigators, and scientific experts, and is committed to ensuring the safety of all study patients while resuming the trial as expeditiously as possible,' the company said in a press release.

The incident investigation is focused on the possible role of a new C3 inhibitor immunosuppressant drug given alongside the gene therapy. According to Dr Sami Corwin, a biotechnology and healthcare analyst at William Blair, the drug was recently introduced following two previous non-fatal cases of immune-related blood clotting. A second patient, on the same drug but at a lower dosage, also exhibited early signs of capillary leak syndrome.

'We are inclined to believe the [serious adverse event] was related to the recent addition of the C3 inhibitor to the immunosuppression protocol, given that only reports of [capillary leak syndrome] occurred in the two patients who received it,' Dr Corwin said, but warned that they couldn't yet fully eliminate the possibility the event was related to the investigational gene therapy.

The gene therapy, RP-A501, was developed for Danon disease, an extremely rare X-linked disorder caused by mutations in the lysosome-associated membrane protein (LAMP2) gene which mediates autophagy (cell waste recycling). It can be fatal in young males as lethal accumulation of waste products in cardiac cells triggers heart failure, usually requiring a heart transplant.

The FDA and European Medicines Agency both granted RP-A501 priority designation in 2023. The therapy works by inserting a functional LAMP2 gene directly into cardiac cells via an adeno-associated virus vector, aiming to restore cardiac function as a single-dose intravenous treatment. The Phase II trial was designed to assess the efficacy and safety of RP-A501 in twelve male patients aged eight or older.

'We are heartbroken by this loss and are fully committed to our mission to develop gene therapies that address the underlying cause of devastating diseases like Danon,' Rocket Pharma chief executive officer Dr Gaurav Shah said. 'We are immensely grateful for the patients and families who participate in this important research.'