With increasing insurance coverage and AveXis’ plans to broaden access to older spinal muscular atrophy (SMA) patients, the U.S. Food and Drug Administration (FDA) remains “very confident” in the use of Zolgensma despite preclinical data concerns, according to an official from the agency.
Cure SMA hosted a recent webinar with representatives from the FDA and AveXis — the company that originally developed Zolgensma, now owned by Novartis — which addressed these concerns and other topics, including updates on access, insurance coverage, and future plans for the therapy.
Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, briefly went over Zolgensma’s clinical development, from the “very promising“ Phase 1 data (NCT02122952) to the “quite remarkable” Phase 3 findings in the STR1VE trial (NCT03306277).
AveXis submitted the request for Zolgensma’s approval in October 2018, and the therapy was granted priority review two months later. The FDA reviewed all information, including the treatment’s science, toxicology, manufacturing, and clinical testing, and on May 24, it approved Zolgensma to treat patients younger than 2 with SMA of any type via intravenous infusion.
About a month later, on June 28, AveXis notified the FDA about data irregularities, which prompted an investigation. The issue regarded an animal test conducted prior to July 2018 to compare an early version of the therapy used in Phase 1 with the version used in Phase 3 and now being marketed.
In particular, the assay was aimed at determining how equivalent the two were and, according to Cure SMA, whether Zolgensma (then AVXS-101) had the “strength and potency” to advance to clinical trials.
The FDA then started looking at all data to make sure other parts of the application were not affected. It decided that new facility inspections were necessary and conducted those between July 24 and Aug. 2. The agency concluded that Zolgensma was still safe, and there were no concerns about leaving it on the market.
A summary of the agency’s findings was released on Aug. 6. Ultimately, it found no other issues besides the problematic animal assay, in agreement with AveXis’ earlier conclusions that the issue did not affect safety, efficacy or quality, according to Dave Lennon, president of the company.
“Looking at what we now know,” Marks said, “we still came out the same place that the product … is safe and is effective for its intended use.”
“We are very comfortable having patients continue to get treated,” and “in this particular case, we think that the benefits of having this product remain on the market far outweigh the risks of having a potentially transformative therapy removed … and not available to patients,” he said, adding that the FDA “would not allow” Zolgensma to stay on the market if it had any concerns for patients.
“We apologize for this situation and for any concerns that it may have caused,” Lennon said. “I want to reinforce that we take the matter very seriously, and we are committed to ensuring the highest levels of transparency and integrity.”
Lennon further said that the past few weeks have shown that physicians and caregivers “continue to believe in the promise of Zolgensma, and babies in need continue to get treated.”
As it did with Rett syndrome gene therapy candidate AVXS-201, the company is implementing a quality improvement plan. The recent appointment of Page Bouchard — formerly with Novartis — to oversee preclinical development at AveXis is part of the plan to improve procedures, Lennon says.
Regarding the impact of these issues on future submissions, Marks said the agency has reinforced to all companies the importance of “accurate, truthful, and complete” information and regards it as “a commitment to patients.”
The FDA “would like to believe this was an isolated incident” and does not foresee significant delays in the availability of important therapies, including any future submissions to broaden the use of Zolgensma.
“That is something we are very pleased to hear,” said Kenneth Hobby, president of Cure SMA.
The FDA’s Office of Regulatory Affairs is currently investigating possible action against AveXis and Novartis. In general, the FDA does not take these matters lightly, and both civil and criminal penalties are considered, Marks said. Still, the agency is “encouraged” that Novartis is willing to do the “right thing” moving forward, while Lennon reiterated the ongoing cooperation with the FDA to address any additional quality gaps.
Insurance coverage expanding
Updated data show that 44 sites across 24 U.S. states and Washington, D.C., are dosing or ready to dose Zolgensma. Thirty-one commercial plans and 31 Medicaid programs already have policies to provide coverage.
This is “a good, rapid development” for “a very new technology,” Hobby said.
Coverage denials are expected at such an early stage of a therapy’s approval, he said. He advises these patients to not get discouraged, to inform Cure SMA, and to appeal to set a precedent that helps expand coverage. But even with restrictive policies, Lennon says, there have been patients getting Zolgensma based on medical exception. Only one final denial decision has not been overturned, because the child was older than 2, he added.
“It takes time to set up the agreements with commercial- and government-based health plans” for such as an “innovative one-time gene therapy,” Lennon said, noting AveXis’ work to “accelerate coverage decisions that support access.”
As shared previously, he said, the company is offering the possibility to pay for Zolgensma over up to five years through a third party to ease budget constraints, which includes an outcomes-based agreement also of up to five years.
Patients and caregivers are advised to discuss all data with their neurologist, and not to wait for a future therapy or trial if they already have an option. Working closely with the healthcare team is also essential, added Mary Schroth, MD, Cure SMA’s chief medical officer.
Lennon also mentioned the importance of AveXis’ OneGene program to help connect with resources along the treatment journey.
Hobby noted that although some policies cover Zolgensma after treatment with Biogen’s Spinraza (nusinersen), in most cases, patients need to first stop treatment with Spinraza before receiving Zolgensma and a combination approach is a rather remote possibility at this time.
Zolgensma is still being tested in a vast clinical program, which includes the STRONG Phase 1 trial (NCT03381729) of intrathecal (spinal canal) delivery in type 2 children ages 6 months to 5 years. This study is still enrolling for one of its groups and currently has 51 participants at 11 U.S. sites.
Other ongoing studies included STR1VE’s counterparts in Europe (NCT03461289) and Asian Pacific countries (NCT03837184), as well as the SPR1NT Phase 3 trial (NCT03505099) in presymptomatic infants. Similar to STRONG, these three trials are enrolling. For more information, click on their respective identifying numbers.
Overall, ongoing work will determine whether Zolgensma’s use is expanded to older patients. “We know this is a priority for the SMA community, and we remain extremely positive about the data we have seen to date in older kids,” Lennon said.
This year, the company will start discussions with the FDA about having intrathecal delivery approved for older patients, he added.