FDA committee takes on complex gene therapy safety questions with Novartis' Zolgensma providing lessons learned

Gene therapy biotechs are ready with an arsenal of clinical trials to test the potentially groundbreaking treatments in humans. But an array of complicated safety concerns remain to be addressed—including identifying the correct animal models to use in preclinical research to ensure human testing is safe and determining how to deliver the medicines safely.

That’s the focus of a two-day marathon advisory committee meeting hosted by the FDA this week.  

Two gene therapies were examined in an FDA presentation: Novartis’ Zolgensma for spinal muscular atrophy and Spark Therapeutics’ Luxturna for inherited retinal disease. Both use an adeno-associated virus, or AAV, to deliver a therapeutic gene to patients.

More than 40 therapies using these vectors were submitted to the FDA in 2020 for early consultation ahead of human testing and more than 10 were in consideration for human testing that year. The number of these submissions has been rising.  

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But despite the promise in these gene therapies, the FDA has flagged safety concerns ranging from liver toxicity to kidney injury to a loss of neurons. These issues have long been noted as gene therapies moved toward market and patients died during earlier clinical trials.  

The committee is trying to answer complex questions about the merits and limitations of animal studies to determine the risk of liver toxicity in humans. Which animals should be used in preclinical testing to best model what might happen in humans? How can patients be screened based on their risk of experiencing adverse liver events? What strategies should be used with gene therapy treatment itself to mitigate the risks? Should there be a limit on vector dosing? 

About one-third of the 500 patients who have received Zolgensma since its approval have experienced a liver-related adverse event, including one case of serious liver failure, the FDA documents said. The therapy has a black box warning of the possibility and patients should be treated with systemic corticosteroids. 

The Swiss Big Pharma was the only company to formally present at the advisory committee meeting. The presentation Friday will include details of adverse events that emerged last year during a post-marketing trial for Zolgensma. But even before the committee heard from the company, plenty of discussion was had with the approved gene therapy as a case study on the first day.

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Nine SMA patients out of the 1,400 who have received a dose of Zolgensma to date have experienced thrombotic microangiopathy, a rare disorder that can cause low platelet counts, organ damage and other serious issues, and in some cases death.

One patient who has received the SMA gene therapy died from sepsis, while the rest recovered or were listed as improving. The events led to a revision of Zolgensma’s label, according to the Novartis presentation. 

Novartis also noted that the company is not alone in seeing some of these adverse events during clinical development. The presentation highlighted a Duchenne muscular dystrophy gene therapy developed by an unnamed company that saw four cases of TMA out of nine patients dosed.

Gene therapies tend to treat rare, life-threatening conditions so a patient’s benefit-risk profile needs to be considered when prescribing these medicines, according to Novartis. Patients should be screened for TMA early, given the risk is known, and treatment for the condition should be implemented immediately. The risk should also be added to the drug label for future AAV gene therapies.  

More than 1,000 children have now received Zolgensma since the therapy was approved in 2019, according to advisory committee member Barry Byrne, M.D., Ph.D. He serves as associate chair of pediatrics and director of the Powell Gene Therapy Center at the University of Florida. This presents an opportunity to establish a long-term follow-up study in patients who did not have underlying liver disease before being exposed to a gene therapy.  

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Pfizer gene therapy toxicologist Jing Yuan, Ph.D. argued during a public comment session held Thursday that existing clinical monitoring for liver disease and potential tumors that could be linked to gene therapy treatment “is a reasonable approach and should be adequate during clinical development.”  

These long-term follow-up recommendations “should continue to be adequate,” Yuan said.  

Are standards needed? 

During the discussion on the first day, various experts recommended different ways to tackle the safety concerns.  

“I heard general agreement that animal studies are, in general, problematic with their relationship to humans. Sometimes they show us what is possible and other times, they are not sufficiently representative of the human situation,” said the committee’s chair, Lisa Butterfield, Ph.D., an expert in tumor immunology and VP of the PICI Research Center at the University of California, San Francisco. 

Charles Vite, Ph.D., suggested that dogs may be the best preclinical models for future trials, given the average 10-year life span of the animals and their similarity to humans. Vite is a professor of neurology in the Department of Clinical Sciences at the University of Pennsylvania. 

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“I think it’s possible to get at these questions because the science is so much more advanced in understanding physiology in dogs than in pigs,” Vite said.  

A more formal risk assessment for patients is needed for future trials, according to Theo Heller, M.D. Heller is section chief of translational hepatology in the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.

“We have strong suggestion that pre-existing hepatic conditions may predict the risk of serious liver injury in multiple human models which would make this more important to do carefully,” Heller said.  

Committee member Tabassum Ahsan, Ph.D. argued that it's too early to create general recommendations for preclinical studies. Ahsan serves as the head of analytical development and characterization for therapeutic discovery at MD Anderson Cancer Center. 

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“The technology is still evolving, but we do need to start to drive towards standards, otherwise, we’re really not going to be able to generate the database of information that we need to make informed decisions as we move forward,” Ahsan said. 

Butterfield noted that “there seems to be a strong call for longer assessment” of patients following dosing with a gene therapy.  

Editor's note: This story was updated at 12:20 p.m. ET on Sept. 3, 2021, to clarify the number of patients who have received Zolgensma in clinical trials and since FDA approval.