Rocket Pharmaceuticals acknowledged the death of a patient in a pivotal trial assessing its Danon disease gene therapy candidate RP-A501, a study that the FDA has placed on clinical hold.
The patient, whose age was not disclosed, suffered an unexpected serious adverse event (SAE) that involved clinical complications related to a capillary leak syndrome (CLS), following dosing with RP-A501 in early May, Rocket’s CEO Gaurav Shah, MD, told analysts on a conference call.
“Our thoughts are with the patient’s family, caregivers, and the treating clinical team. This is a deeply tragic loss, and we are committed to fully understanding the circumstances surrounding it objectively and neutrally,” Shah stated. “We are also immensely grateful to the family for their contribution to this important clinical research, and their commitment to helping advance science for the broader Danon community.”
Shah said Rocket is investigating the cause of the event, which has prompted the company to voluntarily pause further dosing in the pivotal Phase II study (NCT06092034). During the conference call, Shah said the patient experienced signs of CLS about a week after receiving RP-A501 in early May.
RP-A501 consists of a recombinant adeno-associated serotype 9 (AAV9) capsid containing a full-length, wild-type version of the human LAMP2B transgene (AAV9.LAMP2B), which, when inserted into heart cells harboring mutations in the endogenous LAMP2 gene, is designed to fully restore cardiac function at its root.
RP-A501 is a single-dose treatment administered as an intravenous infusion. In preclinical and clinical studies, AAV9.LAM2B has been shown to target cardiac cells (cardiomyocytes) and deliver the functional LAMP2B gene to heart tissue, which ultimately leads to improved cardiac structure and function in patients. In 2023, the FDA granted RP-A501 its regenerative medicine advanced therapy designation, while the European Medicines Agency granted PRIority MEdicines (PRIME) eligibility to the gene therapy candidate.
“Rocket is conducting a comprehensive root cause analysis and remains in active dialogue with the FDA and other key stakeholders,” the company also stated.
Rocket is focusing its investigation on its recent introduction of a novel immune suppression agent to the pre-treatment regimen that had been implemented to mitigate complement activation observed in some patients. The agent was specific to its AAV9-Danon program, Rocket said.
“Rocket is carefully evaluating whether a mechanism related to the new agent may have influenced immune responses in an unexpected or paradoxical way,” Shah added. “While the clinical hold remains in place, the company is unable to provide guidance on the anticipated timing for completion of the Phase II trial.” Its primary completion date had been set for September.
The patient’s death comes at a time when researchers across industry and academia are seeking less toxic alternatives to busulfan as a bone conditioning regimen, a crucial component of cell and gene therapy protocols.
“We view the patient death and subsequent clinical hold as unfortunate; however, we believe the pausing of dosing is necessary given CLS is a safety event not previously observed with RP-A501 or other AAV gene therapies, to our knowledge,” Sami Corwin, PhD, a biotechnology-focused healthcare analyst with Willilam Blair, wrote in a research note. She reiterated her firm’s “Outperform” rating on Rocket shares.
Corwin noted Rocket’s disclosure on the call that the patient who died had received a marketed C3 complement inhibitor as a part of an amended immunosuppression protocol that was enacted following at least two cases of thrombotic microangiopathy (TMA) during the trial.
“Regarding the TMA events, one case was linked to a genetic mutation that confers complement sensitivity, and the company has implemented a revised protocol to exclude patients who are genetically predisposed to increased risk for complement activation,” Corwin reported. “Importantly, the patients that did develop TMA earlier in the trial are doing well now from a safety perspective.”
Needham senior analyst Gil Blum, PhD, however, downgraded Rocket’s shares from “Buy” to “Hold” and removed its 12-month price target of $42 on the company’s shares, citing increased uncertainty for RP-A501.
Mani Foroohar, MD, a senior research analyst with Leerink Partners focused on genetic medicines, commented in a research note that Rocket executives will need to clearly explain the course of the SAE and contemplated changes to the protocol to establish patient safety.
“This news is foremost a tragedy for the patient and family, and implications for the Danon program are potentially disastrous,” Foroohar wrote. “Given already poor market sentiment on gene therapy, reassuring investors on a path off clinical hold and to approvability (if
one is available) will be a tremendous challenge.”
The C3 inhibitor was given pre- and post-RP-A501 treatment in combination with the enhanced prophylactic immunosuppressive regimen of sirolimus, rituximab (marketed as Rituxan® by Genentech, a member of the Roche Group, and Biogen), and prednisone. A second patient also received the modified immunosuppression regimen, including the C3 inhibitor, and also exhibited early signs of CLS but had a reduced course of the C3 inhibitor, which, according to Rocket, further supports its hypothesis that the compound played a role in the development of CLS.
“While we cannot fully eliminate the possibility that the SAE was associated with the AAV9 vector, we are inclined to believe the SAE was related to the recent addition of the C3 inhibitor to the immunosuppression protocol, given that only reports of CLS occurred in the two patients who received it,” Corwin added.
Investors punished Rocket’s stock with a selloff that caused the company’s share price to plummet $2.30 at the opening bell, from Friday’s closing price of $6.27. After bouncing back to $2.79, Rocket shares slid backward to $2.22 before closing at $2.33, for a total one-day plunge of 63%.
Rocket said it will prioritize spending on its AAV platform “while assessing ways to optimize value for the rest of the pipeline,” something the company said will translate into reduced overall cash spending.
Rocket finished the first quarter with cash, cash equivalents, and investments of $318.2 million, which the company said will be enough to fund its operations into 2027, excluding any potential proceeds from the sale of Priority Review Vouchers that could follow the approval of therapies from its hematology portfolio.
The Phase II pivotal trial is a global, single-arm, multi-center study designed to assess the efficacy and safety of RP-A501 in 12 patients with Danon disease, including a two-patient pediatric safety run-in, and a dose level of 6.7 x 1013 GC/kg. All patients are males ages 8 years and older. To support accelerated approval, the study is also assessing the efficacy of RP-A501 as measured by a biomarker-based co-primary endpoint consisting of improvements in LAMP2 protein expression and reductions in left ventricular mass.
A global natural history study is running concurrently with the pivotal trial, whose key secondary endpoint is change in troponin. Additional secondary endpoints include natriuretic peptides, Kansas City Cardiomyopathy Questionnaire, New York Heart Association class, event-free survival to 24 months, and treatment-emergent safety events. Rocket reasons that those endpoints could support a full approval with longer-term follow-up.
Danon disease is a rare X-linked inherited disorder caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP-2), an important mediator of autophagy. This results in accumulation of autophagosomes and glycogen, particularly in cardiac muscle and other tissues, which ultimately leads to heart failure, and for male patients, frequent death during adolescence or early adulthood. Between 15,000 and 30,000 patients in the United States and Europe are estimated to have Danon disease.
“Rocket extends our deepest sympathies to the patient’s family, caregivers, and the treating clinical team,” the company stated in announcing the patient’s death. “Rocket also continues its longstanding collaboration with the Danon Foundation, whose commitment to research, advocacy, and patient support remains integral to advancing the field and improving outcomes for individuals affected by Danon disease.”
The post Danon Disease Patient Dies in Rocket Gene Therapy Trial appeared first on GEN - Genetic Engineering and Biotechnology News.
The patient, whose age was not disclosed, suffered an unexpected serious adverse event (SAE) that involved clinical complications related to a capillary leak syndrome (CLS), following dosing with RP-A501 in early May, Rocket’s CEO Gaurav Shah, MD, told analysts on a conference call.
“Our thoughts are with the patient’s family, caregivers, and the treating clinical team. This is a deeply tragic loss, and we are committed to fully understanding the circumstances surrounding it objectively and neutrally,” Shah stated. “We are also immensely grateful to the family for their contribution to this important clinical research, and their commitment to helping advance science for the broader Danon community.”
Shah said Rocket is investigating the cause of the event, which has prompted the company to voluntarily pause further dosing in the pivotal Phase II study (NCT06092034). During the conference call, Shah said the patient experienced signs of CLS about a week after receiving RP-A501 in early May.
RP-A501 consists of a recombinant adeno-associated serotype 9 (AAV9) capsid containing a full-length, wild-type version of the human LAMP2B transgene (AAV9.LAMP2B), which, when inserted into heart cells harboring mutations in the endogenous LAMP2 gene, is designed to fully restore cardiac function at its root.
RP-A501 is a single-dose treatment administered as an intravenous infusion. In preclinical and clinical studies, AAV9.LAM2B has been shown to target cardiac cells (cardiomyocytes) and deliver the functional LAMP2B gene to heart tissue, which ultimately leads to improved cardiac structure and function in patients. In 2023, the FDA granted RP-A501 its regenerative medicine advanced therapy designation, while the European Medicines Agency granted PRIority MEdicines (PRIME) eligibility to the gene therapy candidate.
“Rocket is conducting a comprehensive root cause analysis and remains in active dialogue with the FDA and other key stakeholders,” the company also stated.
Focus on suppression agent
Rocket is focusing its investigation on its recent introduction of a novel immune suppression agent to the pre-treatment regimen that had been implemented to mitigate complement activation observed in some patients. The agent was specific to its AAV9-Danon program, Rocket said.
“Rocket is carefully evaluating whether a mechanism related to the new agent may have influenced immune responses in an unexpected or paradoxical way,” Shah added. “While the clinical hold remains in place, the company is unable to provide guidance on the anticipated timing for completion of the Phase II trial.” Its primary completion date had been set for September.
The patient’s death comes at a time when researchers across industry and academia are seeking less toxic alternatives to busulfan as a bone conditioning regimen, a crucial component of cell and gene therapy protocols.
“We view the patient death and subsequent clinical hold as unfortunate; however, we believe the pausing of dosing is necessary given CLS is a safety event not previously observed with RP-A501 or other AAV gene therapies, to our knowledge,” Sami Corwin, PhD, a biotechnology-focused healthcare analyst with Willilam Blair, wrote in a research note. She reiterated her firm’s “Outperform” rating on Rocket shares.
Corwin noted Rocket’s disclosure on the call that the patient who died had received a marketed C3 complement inhibitor as a part of an amended immunosuppression protocol that was enacted following at least two cases of thrombotic microangiopathy (TMA) during the trial.
“Regarding the TMA events, one case was linked to a genetic mutation that confers complement sensitivity, and the company has implemented a revised protocol to exclude patients who are genetically predisposed to increased risk for complement activation,” Corwin reported. “Importantly, the patients that did develop TMA earlier in the trial are doing well now from a safety perspective.”
Needham senior analyst Gil Blum, PhD, however, downgraded Rocket’s shares from “Buy” to “Hold” and removed its 12-month price target of $42 on the company’s shares, citing increased uncertainty for RP-A501.
Mani Foroohar, MD, a senior research analyst with Leerink Partners focused on genetic medicines, commented in a research note that Rocket executives will need to clearly explain the course of the SAE and contemplated changes to the protocol to establish patient safety.
“This news is foremost a tragedy for the patient and family, and implications for the Danon program are potentially disastrous,” Foroohar wrote. “Given already poor market sentiment on gene therapy, reassuring investors on a path off clinical hold and to approvability (if
one is available) will be a tremendous challenge.”
The C3 inhibitor was given pre- and post-RP-A501 treatment in combination with the enhanced prophylactic immunosuppressive regimen of sirolimus, rituximab (marketed as Rituxan® by Genentech, a member of the Roche Group, and Biogen), and prednisone. A second patient also received the modified immunosuppression regimen, including the C3 inhibitor, and also exhibited early signs of CLS but had a reduced course of the C3 inhibitor, which, according to Rocket, further supports its hypothesis that the compound played a role in the development of CLS.
“While we cannot fully eliminate the possibility that the SAE was associated with the AAV9 vector, we are inclined to believe the SAE was related to the recent addition of the C3 inhibitor to the immunosuppression protocol, given that only reports of CLS occurred in the two patients who received it,” Corwin added.
Stock price plunge
Investors punished Rocket’s stock with a selloff that caused the company’s share price to plummet $2.30 at the opening bell, from Friday’s closing price of $6.27. After bouncing back to $2.79, Rocket shares slid backward to $2.22 before closing at $2.33, for a total one-day plunge of 63%.
Rocket said it will prioritize spending on its AAV platform “while assessing ways to optimize value for the rest of the pipeline,” something the company said will translate into reduced overall cash spending.
Rocket finished the first quarter with cash, cash equivalents, and investments of $318.2 million, which the company said will be enough to fund its operations into 2027, excluding any potential proceeds from the sale of Priority Review Vouchers that could follow the approval of therapies from its hematology portfolio.
The Phase II pivotal trial is a global, single-arm, multi-center study designed to assess the efficacy and safety of RP-A501 in 12 patients with Danon disease, including a two-patient pediatric safety run-in, and a dose level of 6.7 x 1013 GC/kg. All patients are males ages 8 years and older. To support accelerated approval, the study is also assessing the efficacy of RP-A501 as measured by a biomarker-based co-primary endpoint consisting of improvements in LAMP2 protein expression and reductions in left ventricular mass.
A global natural history study is running concurrently with the pivotal trial, whose key secondary endpoint is change in troponin. Additional secondary endpoints include natriuretic peptides, Kansas City Cardiomyopathy Questionnaire, New York Heart Association class, event-free survival to 24 months, and treatment-emergent safety events. Rocket reasons that those endpoints could support a full approval with longer-term follow-up.
Danon disease is a rare X-linked inherited disorder caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP-2), an important mediator of autophagy. This results in accumulation of autophagosomes and glycogen, particularly in cardiac muscle and other tissues, which ultimately leads to heart failure, and for male patients, frequent death during adolescence or early adulthood. Between 15,000 and 30,000 patients in the United States and Europe are estimated to have Danon disease.
“Rocket extends our deepest sympathies to the patient’s family, caregivers, and the treating clinical team,” the company stated in announcing the patient’s death. “Rocket also continues its longstanding collaboration with the Danon Foundation, whose commitment to research, advocacy, and patient support remains integral to advancing the field and improving outcomes for individuals affected by Danon disease.”
The post Danon Disease Patient Dies in Rocket Gene Therapy Trial appeared first on GEN - Genetic Engineering and Biotechnology News.