The Food and Drug Administration cleared the first two gene therapies for inherited diseases in short order, with just a year and a half separating historic approvals for the blindness treatment Luxturna and the spinal muscular atrophy drug Zolgensma.
Since the May 2019 OK for Zolgensma, however, another year and a half has now passed without an addition to the ranks of approved gene therapies, despite a broad and growing pipeline. A recent spate of regulatory setbacks, including a surprise rejection for BioMarin Pharmaceutical's hemophilia treatment Roctavian, have spurred questions about whether the agency is enforcing a tougher line on new candidates.
One sign of increasing scrutiny is delays involving cell and gene therapy manufacturing. Over the past two months, Sarepta Therapeutics, Voyager Therapeutics, Iovance Biotherapeutics and, most recently, Bluebird bio, have been forced to reset development timelines as the FDA has requested more information about production processes.
"It's in part due to the general evolution of the field," said Timothy Cripe, hematology and oncology division chief at Nationwide Children's Hospital and an early stage gene therapy researcher. "The technology is improving and the methodology is improving for measuring purity and potency and genome copy numbers," he added, referring to assessments of manufacturing quality.
"This is increasing [the FDA's] bar a bit, as would naturally occur," Cripe said.
Manufacturing-related delays, however, have come in addition to clinical trial pauses for Solid Biosciences and Astellas Pharma's Audentes division due to safety concerns, most notably the death of three participants in a trial of an Audentes gene therapy.
"That also gives the agency pause. That gives us all pause. We're asking, 'Are we dosing the kids appropriately? Is dosing by kilogram appropriate?'" Cripe said.
FDA officials, for their part, say the delays and holds aren't related to any change in policy, but rather are a reflection of the agency's increasing workload as more gene therapies are tested in humans.
"I think what you're seeing is the increase in activity in the field," Wilson Bryan, director of FDA's Office of Tissues and Advanced Therapies, said in a session of the virtual Biopharma Congress held by the analyst group Prevision Policy.
"We have over 1,000 active [Investigational New Drug applications]," Bryan said. "As we get more and more active INDs more and more bad things are going to happen. What gets attention are the bad things."
That view is shared by Patricia Zettler, an associate law professor at Ohio State University and a former associate chief counsel at the FDA. "It's more likely that there just have been some bumps along the road," she said. "It would be more surprising if no gene therapies ever encountered those kinds of bumps in the road."
Some of the "bumps" may also be the product of gene therapies moving out of academic labs, where many of the ones furthest along were birthed, and into large-scale clinical or commercial production at big pharmaceutical companies. A data manipulation scandal over animal testing for Zolgensma, for example, was blamed on this type of handover.
Successful reviews of manufacturing data or sites, meanwhile, may not be the sort of event that companies disclose to their investors.
"If you're a company like BioMarin and you put out a press release that said, 'We had an FDA inspection and everything is fine,' investors would be calling up and asking what is wrong," said Jacob Sherkow, a University of Illinois professor who is an affiliate of the university's Carl R. Woese Institute for Genomic Biology.
Current setbacks aside, the two approvals and a review, albeit eventually rejected, of a third show an agency much more open to considering gene therapies than it was after safety scares two decades ago, most notably the death of teenager Jesse Gelsinger in a clinical trial. So too do new guidelines for developers and FDA officials' predictions of a near future with many more cell and gene therapies approved.
"[Gene therapy] was the third rail of FDA policies for a long time," Sherkow said. "They're a lot more open now. We have actual guidance about how to do this, how to do a clinical trial and what endpoints you should use."
Cripe, at Nationwide Children's, agreed the FDA's comfort with the risk-benefit balance of gene therapy has shifted. "With Zolgensma and with Luxturna and reports of successful trials in muscular dystrophy, the benefit part of that equation is becoming more clear," he said.
One variable potentially at play as more gene therapies go under FDA review is the relative urgency for approval when other therapies exist. Luxturna, for example, treats an otherwise incurable form of blindness, while, at the time of Zolgensma's approval for spinal muscular atrophy, only one alternative treatment existed for the disabling and often fatal neuromuscular disorder.
BioMarin's Roctavian, on the other hand, treats hemophilia A, a bleeding condition that while potentially severe has multiple treatments that can limit or prevent spontaneous bleeds in most patients.
Treatment availability could given FDA reviewers more leeway to carefully consider the risks and benefits of experimental gene therapies, including controversial questions like the durability of benefit.
While Bryan did not directly address the rejection of Roctavian at the Biopharma Congress, he said the agency wants gene therapies to represent substantial improvements over existing treatments, if they exist.
"Sometimes people look at gene therapy and [talk about] the advantages: it could be a one-time treatment versus the drugs that are out there that may require repeated administrations, or it might replace a more invasive administration," he said. "We don't take that into account so much."
More and more gene therapies for inherited diseases with few or no treatments are advancing, however, while second-generation therapies for more common diseases are under study as well.
"Cell and gene therapy," Bryan said, "is a growth industry."