Peter Marks' departure after a decade as the director of the FDA's Center for Biologics Evaluation and Research left some worried about the future of cell and gene therapies.
The sudden resignation of Peter Marks, M.D., Ph.D., from the FDA branch that regulates biological products for humans laid bare the vaccine skepticism underpinning Robert F. Kennedy Jr.’s new leadership in the federal healthcare system.“If you’re going to be a biotech company right now, don’t be a vaccine company,” Leerink Partners analyst Mani Foroohar, M.D., said in a recent interview.But there’s another field of human medicines managed under Marks’ previous leadership that could face significant disruptions—cell and gene therapies. To many in this realm of the biopharma industry, Marks’ exit means losing a seasoned regulator and key ally.Marks played a pivotal role in ushering in the modern era of cell and gene therapies. A year after he became the director of the Center for Biologics Evaluation and Research (CBER) in 2016, his department approved the very first CAR-T cell therapy, Novartis’ Kymriah, opening up a drug class that offers the hope of a potential cure for patients with once difficult-to-treat blood cancers. That same year, the FDA cleared the U.S.’ first gene therapy, Roche’s Luxturna.In a landmark approval by Marks’ CBER at the end of 2023, Vertex and CRISPR Therapeutics’ Casgevy became the first treatment based on the Nobel Prize-winning CRISPR gene-editing system. And last year, Marks oversaw the go-ahead of Iovance Biotherapeutics’ Amtagvi, the first cell therapy for solid tumors.Amid all of these developments, Marks wasn’t just a bystander but rather an outspoken champion of novel technologies and an advocate of regulatory flexibility to accelerate approvals.“We want to lean into accelerated approval whenever we can, particularly in the rare disease space, because if you have patients in need, getting something to them a year or two sooner can make the difference,” Marks said at the 2024 DIA Global Forum.The former CBER chief also worked to streamline the interactions between the agency and developers of cell and gene therapies. He introduced INTERACT meetings, which offer sponsors of advanced biological therapies the opportunity to gain early guidance from the FDA on a product development plan. He was also instrumental in the idea of a platform designation to significantly slash development timelines and regulatory work around follow-on therapies based on reproducible technology.Marks wasn’t the first senior FDA leader to exit under the new administration. His counterpart at the Center for Drug Evaluation and Research (CDER), Patrizia Cavazzoni, M.D., had left in January. But Marks’ departure was more poignantly felt by the industry, partly because of the duration of his leadership and “how he has really changed the character of—and approach at—CBER during his tenure,” Foroohar said.While small molecule drug regulations are well established, CBER requires more regulatory handholding because of the novelty and complexity of advanced technologies, Foroohar added.As Foroohar put it, Marks “was a driver of a lot of acceleration” for the cell and gene therapy space.Now, with Marks’ departure—plus a massive workforce reduction at the FDA—that trajectory looks to be under threat. Plus, any government-related hits would serve as a double whammy for an industry that’s already undergoing a serious crisis marked by pipeline discontinuations, layoff rounds, business closures, funding challenges, commercialization struggles and a Big Pharma retreat. Interpreting the impactFollowing news of Marks’ sudden departure, investors in vaccine and cell & gene therapy biotechs hit the exit, too.On Monday, besides the widely reported selloffs at Moderna and Novavax, CRISPR Therapeutics’ stock was down 8%, while share prices for base editing specialists Beam Therapeutics and Verve Therapeutics each dropped 12%. And allogeneic cell therapy leader Allogene Therapeutics also lost about 6% in market value.After the initial shock, industry watchers were left parsing through the implications for biopharma companies. Some within the industry are openly worried about the future of cell and gene therapies, even though Marks’ high-profile resignation was focused overwhelmingly on disagreements around vaccine regulations.“We MUST get Dr. Marks reinstated within the next 30 days,” Nicole Paulk, Ph.D., CEO of gene therapy startup Siren Biotechnology, posted on X on March 29.“We MUST protect Dr. Verdun at all costs,” she continued, referring to Nicole Verdun, M.D., director of CBER’s all-important Office of Therapeutic Products (OTP), which more directly evaluates cell and gene therapies. “What we do in the next 30 days may well dictate the future of #GeneTherapy #CellTherapy #Vaccines #GeneEditing for the next 100 years. We must act NOW!”Still, given how harshly Marks criticized RFK Jr. in his resignation letter (PDF), it seems “fairly unlikely” that Marks will be reinstated, Foroohar said. Besides Paulk, many others in the biopharma industry have expressed concern at Mark’s departure. Talking about the bigger biopharma sector, trade group Biotechnology Innovation Organization CEO John Crowley said in a Saturday statement: “We are deeply concerned that the loss of experienced leadership at the FDA will erode scientific standards and broadly impact the development of new, transformative therapies to fight diseases for the American people.”Some, however, are more optimistic.Stephen Majors, VP of global communications at the Alliance for Regenerative Medicine, is hopeful that cell and gene therapies won’t land in RFK Jr.’s crosshairs. Majors pointed to positive comments in the HHS secretary’s written testimony to Sen. Tim Scott during this confirmation hearing, as well as from Trump’s White House on the establishment of the Make America Healthy Again Commission, which brought up gene therapies for sickle cell disease as a noteworthy achievement.“I’ve spoken before on the future of gene therapies and the potential for developing technologies, like CRISPR-Cas9, to one day provide treatments for rare diseases like sickle cell,” RFK Jr. said in his response to Sen. Scott. “I am so excited that sickle cell disease patients now have two potential one-time cures, one developed with the CRISPR technology.”From Wall Street’s perspective, Citi analysts in a Monday note said they do not believe that Marks’ departure “will usher in a new period of regulatory uncertainty or questionable approvals.” Still, the analysts recognized Marks’ key role in regulatory policies toward cell and gene therapies.The analysts argued that it’s natural to have leadership turnover at federal agencies in a new administration, and that the FDA knows how to uphold continuity of approval standards.Similarly, a Jefferies team led by analyst Andrew Tsai also struck a positive note in a Saturday report to clients.Pointing to Marks’ comments in his resignation letter, Tsai concluded that “we do not see increased regulatory risk for sponsors currently working with CDER/CBER on some form an expedited pathway for rare diseases.”Marks highlighted the “unwavering commitment to public health priorities” that CBER has applied to “the development of cell and gene therapies to address both hereditary and acquired rare diseases.” CBER staffers are committed to “increased communication” with product developers and have been “exploring the dramatic transformation of our regulatory approach to expedite the delivery of directly administered genome editing products,” he wrote.However, whether those efforts will continue under Marks’ replacement—or face major disruptions—remains an open question. Two potential outcomesDepending on Marks’ potential successor, Foroohar envisioned the twin possibilities of relative stability or turmoil for cell and gene therapies. Until the agency provides comments, Foroohar is not favoring any scenario because “we don’t even have tea leaves yet.” That was on Monday.Tuesday afternoon, the FDA announced the appointment of Scott Steele, Ph.D., as acting director of CBER. Steele holds a Ph.D. in molecular biology from Princeton and has been a full-time senior adviser at CBER since late 2022. And outdated resume (PDF) of Steele’s on the FDA’s website shows he received predoctoral training in genetics at the National Institutes of Health until 1998.In Foroohar’s two scenarios, promoting an internal CBER leader would be “a strong indication that the status quo, philosophically, is going to continue for cell and gene therapy.”Despite the positive sign, Steele is at least for now only filling the role on an interim basis. Even among traditional institutionalists, Marks “had a more forceful view in favor of regulatory flexibility” and “a more high-touch regulatory approach with cell and gene therapy in particular,” Foroohar said. This suggests Marks’ stance toward these novel technologies appeared to be more favorable than many of his FDA colleagues.Marks brought to light his openness—particularly toward gene therapies—in his controversial decisions on Sarepta Therapeutics’ Duchenne muscular dystrophy treatment Elevidys. The former CBER chief stepped in to overrule objections from internal FDA reviewers twice for Elevidys’ initial accelerated approval and a traditional approval last year despite the failure of a confirmatory trial.“When we are on the leading-edge of science, we’re going to make mistakes sometimes, and we may not have the rock-solid evidence always,” Marks said during the Fierce Cell & Gene virtual event last fall. “But I think our commitment is that we will do our best to weigh the benefits, risks and uncertainty and wrap that up in terms of the other available potential therapies to make the best decision we can.”Elevidys may have been an isolated event, but it’s possible at a CBER without Marks that cell and gene therapies are forced to contend with more stringent rules, William Blair analysts said in a Monday note.The other scenario in Foroohar’s modeling could be more chaotic.“If we see someone whose background is much less technical than one would expect, more of a political appointee, doesn’t have direct regulatory experience, perhaps someone who doesn’t have a lot of direct scientific drug development experience, you would start to worry that that is a case where you’re going to see a lot more destruction,” Foroohar said.In this scenario, things could go bad for cell and gene therapies in two divergent ways, he figured.A political appointee could be more skeptical of the biopharmaceutical industry as a whole, adopting a stricter approach to accelerated approvals and making clinical development more difficult and costly.Alternatively, an FDA outsider could come with much greater regulatory flexibility than even Marks, falling closer to the “right to try” camp, Foroohar explained. There were advocates for that ideology under President Trump’s first term, he noted.That approach may come as a near-term positive for the cell and gene industry. But less scientific rigor would eventually be harmful to the health of the industry, Foroohar argued.“There’s a risk that if you have a very flexible regulatory profile, you start to have products that are approved with labeled indications and datasets that don’t clearly differentiate clinical data,” Foroohar said.As a result, payers would balk at reimbursement even for approved agents, which Foroohar views would be a “more profound long-term challenge to the industry.” A greater concernAlthough a trailblazer and a visible leader, Marks is just one person. To Foroohar, a potential bigger FDA issue threatening the growth of cell and gene field is the likely loss of talented staff at CBER.“The greater concern is that you’ll see a bleeding away either from headcount reductions or from […] voluntary departures of reviewers, CMC staff, etc., the boots on the ground […] as you see people struggle with working under a leadership […] in an agency where they feel like the mission is not respected or they don’t have support from the administration.”Lola Fashoyin-Aje, M.D., an FDA veteran who was tapped in early 2024 to lead CBER’s office of clinical evaluation focused on cell and gene therapies, left the agency a few weeks ago. Before CBER, Fashoyin-Aje worked at the FDA’s Oncology Center of Excellence, where she formed and served as the program lead of Project Equity, an initiative designed to promote racial diversity in clinical trials. Her departure came shortly after the Trump administration banned diversity programs at federal agencies.“There’s going to be a lot of departures behind Peter [Marks],” former FDA commissioner Scott Gottlieb, M.D., said Monday on CNBC’s “Squawk Box.”“If you pull bricks high up off the tower, it can be very obvious, and you can draw a lot of attention and also be unlikely to implode the entire structure,” Foroohar said, drawing an analogy between the FDA staffing situation and the game Jenga. “But if you start pulling all the blocks out from the middle and the bottom, you can pretty quickly collapse the infrastructure and make it wobbly very quickly.”As to the headcount reduction, RFK Jr.’s massive layoff round targeting 3,500 FDA employees—out of 10,000 for the entire HHS—appears to have affected industry-facing staffers even though core drug reviewers have been spared.Nearly the entire FDA team involved with negotiating industry user fees has been terminated, Politico’s AgencyIQ reported Tuesday, citing several sources close to the situation. The FDA and the biopharma industry need to agree on user fee programs, including the Prescription Drug User Fee Act (PDUFA) that governs the evaluation of drugs, to ensure that the agency has enough resources to provide predictable timelines for its review process.RFK Jr. has in the past expressed skepticism toward user fee programs—which are considered a bedrock of FDA operations—out of concerns of undue industry influence.“An FDA reviewer needs the support of others,” Leerink’s Foroohar said. “There’s all kinds of other infrastructure necessary for them to allow a reviewer to do their job.”And it’s not as if CBER is overstaffed, at least according to Marks and Foroohar. The FDA’s struggle to hire and retain talent to handle the influx of complicated cell and gene therapy programs in the past few years has been no secret among industry watchers.“I suspect we’re going to need more headcount in that area very soon,” Marks said last April during an Alliance for a Stronger FDA webinar. At that time, the agency was still hiring up and evaluating the resources necessary to “really make the transformation to a very high performing organization,” he said.“Don’t be surprised if, as we move through the next year or so, we come up with some asks,” Marks said during the webinar. A regulatory retreat?Now, instead of bulking up, the FDA is slimming down.The current headcount reduction at the FDA is reportedly targeting communications, policy and operations functions. But some FDA operations that are critical to the industry beyond specific product reviews may be dependent on those staffers. “We’re advocating for OTP to be able to continue in its work, and part of that is maintaining the ability to have these early communications with companies,” Majors at the Alliance for Regenerative Medicine said. “Those early interactions are very, very important in terms of being able to move programs along quickly.”For example, on the policy side, the FDA in May 2024 laid out a draft guidance on a new platform designation, which aims to provide an expedited pathway for the development of novel therapies that utilize the same reproducible technology, such as a gene-editing system. The platform would save the FDA a figurative “three billion visits” by drug developers every time they try to use the same technology to edit a disease gene, Marks said at the American Society of Gene and Cell Therapy meeting last year.During the Fierce Cell & Gene event last year, Marks also said that his department was re-evaluating the class-wide boxed warnings about secondary cancers that it had previously slapped on existing commercial CAR-T therapies for blood cancers. Companies are closely following the FDA’s decision on the warning as they try to develop CAR-T products for more prevalent conditions, such as autoimmune diseases, which entail entirely different benefit-risk calculations from cancers.At the Alliance for a Stronger FDA webinar last year, Marks touted the Support for clinical Trials Advancing Rare disease Therapeutics (START) pilot program. It offers constant communication and clinical development guidance for companies developing treatments for rare disease to shorten their development timeline.“If we can show even a 10% decrease in time that translates into a sufficiently large number of dollars across different rare disease programs, that one could potentially easily justify staffing up and the number of reviewers that would need to be brought on board to make this a regular procedure,” Marks said of the pilot.Whether the personnel changes would delay the formal rollout of those initiatives remains to be seen.“Every signal that we have is that they are supportive of cell and gene therapy,” Majors said of the Trump administration. “We just want to make sure that […] even if CGT was not the target, that there isn’t collateral damage based on the actions they’re taking with vaccines, specifically, and then, more broadly, with everything they’re doing in the reorganization of FDA.”
