Nivolumab

iStock, mpalis Amid an unprecedented turnover in leadership at the FDA and mass layoffs of staff, communication has crumbled and uncertainty runs rampant, leaving small and medium biopharma companies without a clear path forward for their therapies. Change is hard—especially when a new administration comes in gung-ho to overhaul the entire system. For Health Secretary Robert F. Kennedy Jr., this has meant slashing some 10,000 jobs at the Department of Health and Human Services and overseeing an extensive turnover of leadership at the highest levels . At the FDA, Commissioner Marty Makary has announced plans to speed drug reviews through avenues such as the Commissioner’s National Priority Voucher , expedite rare disease therapies through a yet-to-be-defined conditional approval pathway and ban pharmaceutical representatives from some advisory committees. With all this upheaval, many biopharma companies have gotten caught up in the confusion. Ironically, many of them are seeking approval for rare disease therapies. Capricor Therapeutics, Ultragenyx and Replimune have expressed surprise at recent rejections in Duchenne muscular dystrophy (DMD) cardiomyopathy , Sanfilippo syndrome type A and melanoma , respectively. Meanwhile, three deaths stemming from Sarepta’s gene therapy platform—two of which were associated with its DMD therapy Elevidys—prompted the FDA to request the company halt all shipments of the approved therapy. Amidst these developments, Center for Biologics Evaluation and Research Director Vinay Prasad suddenly left his role , only to return less than two weeks later. With rumors swirling of his direct involvement in some regulatory decisions, his temporary ouster only adds to the uncertainty some biotechs are facing. “These companies who don’t have a lot of cash at hand, they’re actually looking to create these treatments for rare diseases,” Rahul Gupta, president of AI/ML company GATC Health, who served as head of the White House Office of National Drug Control Policy under former President Joe Biden, told BioSpace . “They need a very clear framework, a blueprint of what’s acceptable, what’s not acceptable, and how things will go so they’re not feeling like they’re gambling with their limited amount of funds every time they go up to the FDA.” Here, BioSpace unpacks the journeys of five biotechs that have tangled with the new FDA over the past six months. Sarepta’s Summer Saga Like it or not, the biopharma story of the summer belongs to Sarepta Therapeutics. The Massachusetts-based biotech had a difficult spring, with two nonambulatory teenage patients taking Elevidys succumbing to acute liver injury. It appeared that Sarepta was managing the risks, adding a black box warning to Elevidys’ label for acute liver injury and acute liver failure. But after the death of a third patient —a 51-year-old nonambultory man who had been participating in a Phase I study of Sarepta’s SRP-9004 for limb-girdle muscular dystrophy (LGMD), which used the same underlying technology as Elevidys—the FDA acted, requesting that Sarepta stop all shipments of the gene therapy in the U.S. and pause all LGMD clinical trials. The agency also revoked the platform designation the biotech had previously been granted for its viral vector technology. Initially, Sarepta stood its ground, refusing the FDA’s request. Notably, in its July 18 statement, the company said, “We first heard of this potential request earlier in the day at the same time the public and our patient communities did, through media reports.” The company noted in the same press release that it had alerted the FDA to the death on July 3. The agency later confirmed this to be true but told STAT News that the report had been lost in the bureaucracy and that it had, in fact, only learned of the death with the rest of the world when BioCentury reported it . The FDA further stated it had always planned to take action if a third death occurred. Sarepta ultimately relented to the FDA’s request to halt Elevidys shipments, setting off a week of action for patient groups eager to regain access to the treatment. That action apparently worked. On July 28, the FDA did a 180 and recommended that the voluntary hold on Elevidys be lifted for ambulatory patients. The following day, Prasad was out as CBER director —a development multiple sources suggested was connected to the Sarepta saga. The “unprecedented” FDA leaks were “missteps” on the part of CBER that sowed confusion for both Sarepta and patients, BMO Capital Markets’ Kostas Biliouris wrote to investors on July 30. Capricor Communication Kerfluffle Capricor has also reportedly been caught on the carousel of FDA change. The rejection of the company’s cell therapy deramiocel in July “was unexpected given the trajectory of positive [FDA] interactions,” CEO Linda Marbán said during the company’s second-quarter earnings call on Aug. 11. Drama reportedly predated the rejection, however. Nicole Verdun, the former director of the FDA’s Office of Therapeutic Products, and her deputy, Rachael Anatol, were allegedly “put on administrative leave because of an argument about our file, and that Prasad wanted to [reject] us and Nicole was fighting it,” Marbán told BioSpace in an earlier interview, attributing the information to a STAT reporter who’d contacted her after receiving a tip from an agency insider. After Prasad stepped aside from his role on July 29, Marbán expressed optimism about the company’s chances of fighting the rejection. Speaking again with BioSpace after his return less than 10 days later, she said: “My initial reaction was of great surprise. It was pretty clear that he was asked to leave . . . but I think what it showed is that Makary has tremendous faith in him. We all understand the ramifications of that, that there’s not a lot of ladders you can go up besides the Prasad ladder.” Nevertheless, Capricor is full speed ahead with its resubmission plans for deramiocel. The biotech met with the FDA on Aug. 13 for a type A meeting to discuss a path forward, but Marbán said she would appreciate an audience with Prasad, who did not attend the meeting. “We’ve never had any direct communication from or with him. We would like that very much, but nothing so far.” Ultragenyx’s Unread Responses Also on July 11, the FDA declined to approve Ultragenyx’s investigational in vivo gene therapy UX111, which the biotech is proposing for Sanfilippo syndrome type A—an ultrarare disease that leads to neurological symptoms including language and developmental delays and progressive intellectual disability. On the July 17 edition of STAT News ’ podcast, The Readout Loud , Ultragenyx CEO Emil Kakkis said that a number of issues were raised during the CMC inspection process, which the company was in the process of addressing. Ultragenyx had sent the FDA “a number of very large responses,” Kakkis said. However, at the time of the complete response letter (CRL), “they hadn’t actually read or completed review of the last four responses we had given them. They issued the CRL before they had fully reviewed those responses.” Ultragenyx “believes that these [CMC] observations are readily addressable and many have already been addressed,” Kakkis said in a prepared statement on July 11. Ultragenyx plans to resubmit an approval application and anticipates another six-month review period for UX111. Replimune’s Surprise Rejection In contrast to the other three companies on this list, Replimune can apparently thank a legacy FDA leader for the rejection of its candidate. According to reporting by multiple news outlets, Richard Pazdur , director of the FDA’s Oncology Center of Excellence (OCE) and acting director of the Office of Oncologic Diseases, directly intervened to issue the CRL for Replimune’s advanced melanoma drug, RP1. Pazdur has been the agency’s chief cancer strategist for more than 25 years . An unnamed FDA official told STAT News on Aug. 4 that CBER “mishandled the RP1 review from the beginning,” compelling Pazdur and his team to get involved. The situation was exacerbated, the individual added, by the leadership upheaval within CBER. In Replimune’s announcement of the CRL, CEO Sushil Patel expressed surprise with the decision. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews,” he said in a prepared statement. “Additionally, we had also aligned on the design of the confirmatory study. We strongly believe that RP1 in combination with nivolumab [Bristol Myers Squibb’s Opdivo] can bring substantial benefit to advanced melanoma patients.” On Aug. 5, 22 experts who designed and ran RP1’s Phase III trial issued an open letter responding to several issues outlined in the CRL and urging the FDA to “re-review” Replimune’s application. This decision has had further reverberations as well. Late last month, Krystal Biotech discontinued a Phase I/II study of its investigational intratumoral therapy KB707, which it is developing for solid tumors. Speaking with STAT, Stéphane Paquette, Krystal’s vice president for corporate development, said “heightened uncertainty regarding potential accelerated approval pathways” for KB707 following the FDA’s rejection of RP1 contributed to the biotech’s decision. Novavax’s Delay When the FDA missed its deadline to issue a decision regarding the 2024–2025 formulation of Novavax’s COVID-19 vaccine on April 1, concern circulated about what it could mean for the broader vaccines space. While the Maryland-based company did ultimately secure a narrow nod for Nuvaxovid, the approval process represented a potential “harbinger” of a threat to the FDA’s integrity, former FDA associate commissioner Peter Lurie told BioSpace in June. On April 2, Politico reported that deputy FDA commissioner Sara Brenner directly intervened in the review of Novavax’s vaccine application. A few days later, Kennedy said the delay reflected HHS’ “shifting [its] priorities to multiple-antigen vaccines,” causing the company’s shares to drop by 24%. The influence of both Brenner and Kennedy is a significant deviation from normal protocols, Lurie and three other former government officials wrote in an op-ed published in the Journal of the American Medical Association in June. On May 16, the FDA approved Nuvaxovid for all seniors aged 65 years and older and people 12 through 64 years of age at high risk for severe outcomes from COVID-19. Similar restrictions have now also been applied to the three other vaccines marketed in the U.S.—Pfizer and BioNTech’s Comirnaty and Moderna’s Spikevax and mNEXSPIKE—in line with the FDA’s new risk-based approach to COVID-19 vaccination introduced in May.

Combining Summit Therapeutics and Akesos closely watched cancer drug with chemotherapy didnt help people with lung cancer live longer than chemo alone in a late-stage study, raising doubts whether the Food and Drug Administration will agree to review it for potential approval.The final analysis of the Harmoni trial, released Sunday at the World Conference on Lung Cancer in Spain, was the first data from a global Phase 3 study for ivonescimab or any drug in its class, which block both the immune pathway PD-1 and the blood vessel-building protein VEGF.Drugmakers have invested heavily in the PD-1-VEGF class, looking to build on the success of PD-1-blocking drugs like Keytruda and Opdivo. More than a dozen are in development, with Merck & Co. and BioNTech notably among the big-name drugmakers that have bought into the field.The Harmoni data will likely make many take a closer look, however. Summit teased the possibility of a positive outcome in May, when results from the trial, which tested the ivonescimab-chemo combination in people with an EGFR mutation and PD-1 expression who already progressed on a VEGF inhibitor, showed the combination reduced the risk of death or progression by 48% compared with chemo plus placebo.At that point, the trial was unable to prove the combination extended survival, as the reported 21% relative reduction in the risk of death failed to achieve statistical significance. Summit said it wanted to do a final analysis with longer follow-up from people from Western countries enrolled in the trial. Without a statistically significant overall survival benefit, the FDA wouldnt approve the drug, the company said at the time.The data released Sunday didnt help its case. The analysis showed that trial participants from North America and the EU, when assessed, together, had only a 16% relative reduction in the risk of death. People enrolled in North America, when analyzed separately from Europe, had a 30% relative risk reduction.Summit executives acknowledged the timing of the survival readouts and their conflicting findings might cast doubt on ivonescimabs effectiveness. [We] knew this was going to be a problem, said Jack West, Summits vice president of clinical development, in a call with Wall Street analysts.However, he said critics should also listen to physicians who have seen the drugs benefits.Some of the conversations I've had just in the last few hours are with people who have actually used ivonescimab, who are extremely committed to it, who have participated in this trial, he said. They've seen what they've come to conclude are really good results as well. And so there's nothing like that clinical experience.Summit shares fell 24% in morning trading.Leerink Partners analyst Daina Graybosch wrote in a note to clients that following the data she believes the FDA wont approve ivonescimab nor will Summit be able to achieve a licensing deal at the substantial valuation expected by investors.Evercore ISI analyst Cory Kasimov, meanwhile, wrote its possible Summit executives could re-open negotiations with the FDA and file on this data. However, its probably better for the company to wait until it has data from trials in a first-line setting, according to his note. '