A patient has died in a clinical trial evaluating a Rocket Pharmaceuticals gene therapy shortly after complications emerged that led the FDA to pause the study. An inquiry into the fatality is underway, and the initial focus is not on the Rocket gene therapy, RP-A501, but rather a drug administered as part of a treatment regimen that was supposed to improve safety.
RP-A501 had reached a pivotal Phase 2 study in Danon disease, an inherited metabolic disorder that weakens heart muscle, leading to heart failure. Danon patients lack LAMP2B, a protein key to cardiac function. The Rocket gene therapy uses an engineered virus to deliver to cells a functioning version of the gene that codes for this protein.
Earlier results in patients treated with RP-A501 raised concerns that Rocket’s therapy could spark a response from the complement system, a part of the immune system. To mitigate that response, Rocket, with agreement from the FDA, implemented safety measures: excluding patients with end-stage heart failure and adding a drug that inhibits complement system activation.
The focus of Rocket’s inquiry is a C3 inhibitor, a complement inhibitor that was administered before dosing of RP-A501 and afterward, CEO Gaurav Shah said, speaking during a conference call Tuesday. The patient who died had received the pre-treatment regimen in early May. About a week after infusion of the gene therapy, this patient showed signs of capillary leak syndrome. After learning of the adverse event, Rocket voluntarily paused dosing of other patients in the study and informed the FDA. The FDA imposed a clinical hold this past Friday to enable the company to investigate further.
Shah said the patient was stable and doing well enough that the company was cautiously optimistic of recovery. But over the weekend, the patient took a turn for the worse, developing an acute systemic infection “that accelerated his demise,” Shah said.
The unnamed complement inhibitor was administered in combination with other immune-suppressing drugs before and after infusion of the gene therapy. Shah also disclosed that a second patient who received the C3 inhibitor showed signs of capillary leak syndrome. This patient had a reduced course of the immune-suppression regimen and is improving. Shah said these two patients are the only ones that developed capillary leak syndrome, which is why the C3 inhibitor is a focus of Rocket’s inquiry.
“We are considering that as one option, one thought, one idea for root cause,” Shah said. “We’re doing a comprehensive root cause analysis pretty neutrally objectively and this is one idea, so current focus, but just one idea.”
The gene therapy trial was expected to complete dosing in the middle of this year. With the clinical hold in place, Shah said the timeline is uncertain. The study’s targeted enrollment was 12 patients. Shah acknowledged that there are patients remaining who have yet to be dosed, but he declined to specify how many. Asked whether Rocket could proceed without dosing all 12 patients, Shah said that would require more clarity and alignment with the FDA.
Shah emphasized that use of the C3 inhibitor was specific to the Danon gene therapy and does not affect the company’s other programs. As of the end of the first quarter of this year, Rocket reported its cash position was $318.2 million, which the company had expected would be sufficient to fund operations into the fourth quarter of 2026. On Tuesday, The biotech said it is reducing expenditures to extend its cash runway into 2027.
Shares of Rocket plunged more than 60% Tuesday. The drop in price reflects the uncertainty facing the Danon program, which is the most important driver of the company’s stock, Leerink Partners analyst Mani Foroohar wrote in a note to investors. Rocket does have other gene therapies under FDA review for the blood disorders severe leukocyte adhesion deficiency-I (LAD-I) and Fanconi anemia (FA), and approvals could yield priority review vouchers that can be sold to raise money. But Foroohar said the Danon setback, which follows a complete response letter for the LAD-I gene therapy and delays for the Danon and FA programs, undermines credibility of the company’s management and raises questions about the initial rationale for adding a C3 inhibitor to the Danon treatment.
Foroohar said regulatory scrutiny on the Danon program could lead to study design changes, such as increasing enrollment to better define the risk/benefit profile of the therapy and the addition of functional metrics or longer follow-up timelines. The biotech’s shares are “in the penalty box until we have greater clarity on the path forward,” he said.
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