Death in Rocket Pharmaceuticals gene therapy research brings attention to trial changes aimed at improving safety
A patient died in a clinical trial that evaluated rocket drug gene therapy shortly after the onset of complications, which led to the FDA suspending the study. An investigation into the death is underway, with the initial focus not on rocket gene therapy RP-A501, but rather as part of the treatment regimen that could have improved safety.
RP-A501 has achieved a pivotal Phase 2 study in Danon's disease, a hereditary metabolic disease that weakens the myocardium and leads to heart failure. Danon patients lack LAMP2B, a protein bond that is the heart function. Rocket gene therapy uses engineered viruses to pass on a functional version of the gene coded as the protein encoded.
Early treatment of RP-A501 patients has raised concerns about rocket therapy, which may cause a response to the complement system, which is part of the immune system. To mitigate this response, the Rockets implemented safety measures with the FDA's consent: Excluding patients with end-stage heart failure and adding a drug that inhibits activation of the complement system.
CEO Gaurav Shah said on a conference call on Tuesday that Rocket's inquiry focused on C3 inhibitors, which are complement inhibitors administered before RP-A501, followed by administration of RP-A501. The deceased patient received a treatment regimen in early May. About one week after gene infusion, the patient showed signs of capillary leakage syndrome. After learning of the adverse events, the Rockets voluntarily suspended doses in other patients during the study and informed the FDA. The FDA implemented clinical holdings last Friday to enable the company to investigate further.
Shah said the patients were stable and did a good job, making the company cautiously optimistic about recovery. But over the weekend, the patient got worse and developed an acute systemic infection that “accelerated his demise.”
Unnamed complement inhibitors are used in combination with other immunosuppressive drugs before and after infusion of gene therapy. Shah also revealed that the second patient receiving the C3 inhibitor showed signs of capillary leakage syndrome. The immunosuppressive regimen in this patient has decreased and is improving. Shah said the two patients were the only patients with capillary leakage syndrome, which is why C3 inhibitors are the focus of Rocket's inquiry.
“We think that as an option for root causes, an idea, an idea,” Shah said. “We are doing a comprehensive root cause analysis, it's an idea, it's an idea, so the focus is on the moment, but just an idea.”
Gene therapy trials are expected to be completed by the middle of this year. Shaa said that with clinical retention, the timeline is uncertain. The study targeted enrollment of 12 cases. Shah admits that the remaining patients have not taken it yet, but he refuses to specify how much. Asked if the Rockets could be performed without giving all 12 patients, Shah said it needed to be clearer and consistent with the FDA.
Shah stressed that the use of C3 inhibitors is specific for Danon gene therapy and will not affect the company's other plans. As of the end of the first quarter of this year, Rocket reported its cash position of $318.2 million, which the company expects to be sufficient to fund operating operations through the fourth quarter of 2026. On Tuesday, biotech said it was reducing spending to expand the cash runway into 2027.
On Tuesday, Rockets stocks plunged more than 60%. The price drop reflects the uncertainty facing Danon's plan, the most important driver of the company's stock, Leerink Partners analyst Mani Foroohar wrote in notes to investors. Rocket does carry out other gene therapies for blood diseases in the FDA review, severe leukocyte adhesion deficiency (LAD-I) and acne anemia (FA), and approval can generate a saleable priority review voucher to raise funds. But Foroohar said Danon Setback followed a full response letter for LAD-I gene therapy and delayed delays for Danon and FA programs, undermining the credibility of the company's management and raising questions about the initial justification for adding C3 inhibitors to Danon's treatment.
Foroohar said regulatory review of Danon's program could lead to study design changes, such as increasing enrollment to better define risk/benefit profiles for treatment and increasing functional metrics or longer follow-up schedules. He said.
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