Pfizer has paused enrollment in a Phase III trial assessing its Duchenne muscular dystrophy (DMD) gene therapy candidate fordadistrogene movaparvovec after acknowledging the sudden death of a young boy who received the treatment last year.

The boy, whose age was not disclosed, was among patients dosed with the gene therapy in the Phase II DAYLIGHT trial (NCT05429372), which is evaluating fordadistrogene movaparvovec in 10 boys ages two to less than four years old. Initial dosing was completed last year in DAYLIGHT, as well as in the Phase III CIFERO trial (NCT04281485), which is studying the gene therapy in boys ages four to less than eight years old.

Pfizer said it has paused dosing associated with the crossover portion of the placebo-controlled, randomized CIFFREO trial, in which patients who originally received placebo are crossed over to the gene therapy, while the company reviews data with regulators and the study’s independent External Data Monitoring Committee.

Fordadistrogene movaparvovec is a recombinant adeno-associated virus, serotype 9 (AAV9) carrying a mini-dystrophin or truncated human dystrophin gene under the control of a muscle-specific promoter. The gene therapy is a mini-dystrophin because the human dystrophin gene is too large to fit in the AAV9 capsid.

“On behalf of everyone at Pfizer, we extend our sympathies to his family, friends, and those closest to his care,” Pfizer’s DMD gene therapy team wrote in a May 7 letter that was posted on the website of Parent Project Muscular Dystrophy (PPMD), a nonprofit organization solely focused on DMD. “We do not yet have complete information and are actively working with the trial site investigator to understand what happened.”

“We are working with regulators and the independent external Data Monitoring Committee as we learn more about this event. Other than this pause in dosing, trial activities are continuing as scheduled,” Pfizer stated.

The pause does not apply to other ongoing trials of fordadistrogene movaparvovec. These include a Phase III long term safety study (NCT05689164) designed to follow up on patients dosed in previous trials for 10 years after the end of their previous study; and an observational study (NCT04543357) investigating male and female participants who live or work in the same household as a patient in one of the other fordadistrogene movaparvovec studies.

“We are devasted to learn of this heartbreaking loss and our hearts are with the boy’s family during this unimaginably difficult time. This tragic event painfully reminds us of the stakes of our mission and the importance of ensuring the utmost safety in all clinical trials,” said Debra Miller, founder and CEO of CureDuchenne, which advances research and advocacy in DMD. “We recognize the tremendous courage of this family—and all families that participate in clinical trials—as we offer the support of the whole Duchenne community.”

“Fatal serious adverse event”

In a statement to Reuters, Pfizer added through a spokesperson: “A fatal serious adverse event was reported as cardiac arrest for a participant in the Phase II DAYLIGHT study.”

DAYLIGHT is a single-arm, non-randomized, open-label study that includes boys who are at least two years old and less than four years old (including three-year-olds up until their fourth birthday). All boys in the study needed to be negative for neutralizing antibodies against AAV9, as measured by the test done for the study as part of screening.

The trial’s primary analysis is planned after all participants have completed visits through Week 52 (or withdrawn from the study prior to Week 52). All participants will be followed in the study for five years after treatment with gene therapy, according to Pfizer. The trial’s estimated primary completion date is December 27 of this year, with full completion estimated for January 2029.

Speaking with analysts last year on Pfizer’s third-quarter 2023 earnings call in October 2023, Mikael Dolsten Pfizer’s CSO and president of research & development, defended fordadistrogene movaparvovec as showing “a very consistent effect across biomarkers and functional endpoints.”

“What has differentiated it so far is that when you look at the functional data we have reported, it has been given encouraging signals in both the younger and the slightly older boys,” Dolsten said. “I remain, as earlier, very positive about looking forward to the readout and letting the data tell you the story. But of course, this makes our gene therapy, in a way, the main game in town.”

Second death

The death is the second to be associated with fordadistrogene movaparvovec during a clinical study.

In December 2021, the FDA imposed a clinical hold on a Phase Ib trial (NCT03362502) assessing the gene therapy candidate, then called PF-06939926, after Pfizer acknowledged the death of a young male participant in the open-label study. The FDA lifted the clinical hold in April 2022, allowing dosing to resume in the first-in-human/first-in-patient, multi-center, non-randomized, ascending dose, safety, and tolerability study.

“The safety and well-being of the patients in our clinical trials remains our top priority, and we are committed to sharing more information with the medical and patient community as soon as we can,” Pfizer’s DMD gene therapy team wrote. “We are also aware that many in the patient community are hopeful about the potential benefit of fordadistrogene movaparvovec for the treatment of DMD, and we will continue to collect data from our trials to evaluate its ability to address this disease.”

Pfizer is among companies working in recent years to develop DMD gene therapies. The first DMD gene therapy reached the market after Sarepta Therapeutics won FDA accelerated approval in June 2023 for Elevidys® (delandistrogene moxeparvovec-rokl), an AAV-based gene therapy for the treatment of ambulatory pediatric patients aged four through five years with DMD with a confirmed mutation in the DMD gene. Elevidys generated $200.4 million in net product revenues last year.

Pfizer is not alone among drug developers in experiencing the death of young patients in gene therapy trials.

In 2022, Novartis acknowledged that two patients died of acute liver failure following treatment with its Zolgensma® (onasemnogene abeparvovec-xioi), a one-time gene therapy indicated for some forms of spinal muscular atrophy (SMA). The patients were later acknowledged to be children, and Novartis revised Zolgensma’s label to specify that fatal acute liver failure had been reported.

Between 2020 and 2021, Astellas Pharma acknowledged the deaths of four boys in its Phase I/II ASPIRO trial (NCT03199469), assessing the company’s AAV gene therapy candidate resamirigene bilparvovec (AT132) in patients with X-linked Myotubular Myopathy (XLMTM).

Astellas’ ASPIRO trial was put on its first clinical hold after the first three boys died in 2020. That hold was lifted in December 2020 when Astellas eliminated the higher of two original doses, and agreed to dose patients at the lower dose. The second clinical hold was imposed in September 2021 when the fourth boy died, and remains in effect.

“This journey is not without its challenges, and yet, it is also instilled with resilience, determination, and unwavering hope. In the face of adversity, we find the courage to persevere, fueled by the knowledge that every step forward brings us closer to our shared goal of ending Duchenne,” Pat Furlong, PPMD’s Founding President and CEO, worte on the group’s website.

“We grieve this loss. There are no words to describe the unjust nature of a tragedy like this,” Furlong added. “Let us come together in this time of mourning, holding this Duchenne community near and dear as our hearts feel hollow and our minds search for answers.”

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