Tolebrutinib

iStock, Yutthana Gaetgeaw Regulatory uncertainty is no longer background noise. It is a material investment risk that reshapes how capital is deployed and pipelines are prioritized. In the more than 40 years I have been in the life science industry, companies and their investors have operated under the assumption that while regulatory review may be rigorous, the rules of the game are generally known. That assumption is now being tested. Changes in leadership at the FDA, less predictable policy signals and evolving approval standards have introduced a new level of uncertainty, one that directly affects development strategy, valuation models and investor appetite for risk. On a positive note, the potential to approve a drug based on a single Phase 3 trial—a change touted by the FDA last year—is explicitly designed to reduce development time and cost, accelerating the time it takes to go from clinical testing to the market. But other recent developments, such as issuing rejections based on unexpected changes to new drug approval criteria, may have far-reaching negative consequences for companies with new products in their pipelines, including affecting how their investors take risk into account in their valuation models. The FDA is not signaling a retreat from innovation, but companies and investors need to weigh the impact these new policies may have on how therapies are developed, financed and ultimately delivered to patients. FDA Moderna’s Outright Flu Refusal Just the Latest Case of Crossed FDA Signals The FDA’s refusal to review Moderna’s mRNA-based flu vaccine is part of a larger communications crisis unfolding at the agency over the past nine months that has also ensnarled Sarepta, Capricor, uniQure and many more. February 13, 2026 · 6 min read · Heather McKenzie Read more Potential Impact of the One-Trial Standard According to FDA Commissioner Marty Makary, the agency plans to move toward requiring a single pivotal clinical study , rather than the traditional two, for many medical products. The stated goal is to accelerate approvals by reducing time and cost, based on the premise that a well-designed trial, supported by robust confirmatory evidence, can provide sufficient statistical confidence. Industry reaction has been cautiously optimistic. Faster paths to approval and greater flexibility in trial design are welcome developments. However, I heard two concerns from executives at the J.P. Morgan Healthcare Conference and Biotech Showcase this year: A single trial default could reduce the breadth and generalizability of clinical evidence. Narrower datasets may lead to weaker labels, negatively affecting physician prescribing behavior and market access. To explore whether the new single-trial standard could indeed increase adoption risk, Litmys , the commercial strategy consulting firm where I work, partnered with Doximity , the largest digital professional network for U.S. healthcare professionals, and physician Nicole Chase to conduct a survey of 100 primary care and family practice physicians. The results were instructive. Physicians were largely indifferent to whether approval was based on one trial or two, provided the product was adequately studied. What mattered most to them was safety pro duration of patient exposure, followed by meaningful endpoints, robustness of clinical benefit and the overall number of study participants. Interestingly, most of the physicians don’t evaluate trial data thoroughly on their own but rely on data summaries, guideline bodies and the experience of KOLs and peers. Specialists may view the issue differently, but these findings suggest that a one-trial standard may not, by itself, be a commercial impediment in primary care. Surprise CRLs: When the FDA Pulls the Rug Out On New Year’s Eve, I received a call from a venture capitalist friend. “What’s going on with Corcept?” he asked. “They hit their endpoint, still got a CRL, and the stock’s down 50%.” On December 31, Corcept Therapeutics announced it had received a complete response letter (CRL) for relacorilant in hypertension secondary to hypercortisolism. While the FDA acknowledged that the pivotal GRACE trial met its primary endpoint and the GRADIENT study provided confirmatory evidence, the agency concluded it could not reach a favorable benefit-risk determination without additional evidence of effectiveness. Just a week earlier, Sanofi received a surprise CRL for tolebrutinib in non-relapsing secondary progressive multiple sclerosis. Despite prior feedback, the FDA determined that even with Risk Evaluation and Mitigation Strategies (REMS), the risk of severe drug-induced liver injury could not be mitigated for any identifiable patient population. These cases followed similar stories from Replimmune, Capricor and Biohaven, and the trouble has continued into 2026. In January, it was Atara Biotherapeutics and Pierre Fabre who received a surprise CRL, this one for Ebvallo, a T cell therapy for EBV-positive post-transplant lymphoproliferative disease. And then in February, the FDA shocked the industry by refusing to even review Moderna’s investigational mRNA-based flu vaccine, despite having agreed to the trial design that supported the application. FDA FDA Reversals Send UniQure, Biohaven, Capricor, More Into a ‘Tailspin’ Since July, several biotechs have been forced to pivot as previous agreements with the FDA around evidence required for approval were reversed, a phenomenon that, according to experts, could portend a more restrictive regulator. November 24, 2025 · 7 min read · Heather McKenzie Read more In each case, sponsors met predefined clinical objectives, yet approval and even review was denied based on evolving benefit-risk interpretations rather than on any new negative data. Industry reaction has been sharply critical and increasingly anxious that the FDA is applying more conservative, less predictable benefit‑risk standards even when pivotal trials meet their primary endpoints. These recent CRLs following seemingly successful Phase 3 trials suggest a tougher, less forgiving interpretation of benefit-risk and higher expectations for trial robustness, safety margins and execution quality. The rejections could also undermine confidence in the value of earlier advice from the agency. For investors and CEOs, these new clinical requirements and their implications for a new drug’s approval challenge a foundational assumption of investors around valuing biotechs. Repricing Regulatory Risk The FDA is signaling a shift toward a greater emphasis on safety and robust real world evidence updates to its benefit-risk framework (BRF). The BRF now directs reviewers to document residual safety uncertainties, therapeutic context and risk management options, making “durable” and well-characterized safety a more visible driver of decisions. The BRF guidance emphasizes that the benefit must outweigh risk given disease severity and unmet need. Uncertainty around long term or off-target safety can block approval even when primary efficacy endpoints are met. Recent CRLs where sponsors hit their prespecified endpoints but FDA cited inability to conclude a favorable benefit-risk balance demonstrate that this framework is being applied more stringently. Valuation models going forward will need to assume a higher probability of CRLs and account for the impact on decisions to conduct a single Phase 3 trial. Will longer and more expensive clinical trials be needed to justify approval? For CEOs, this environment demands both earlier and deeper FDA engagement and greater transparency with investors about agreed-upon endpoints, inclusion criteria and sources of regulatory risk. Notably, recent CRLs show that demonstrating a drug’s incremental clinical value is no longer primarily a post-approval marketing exercise. Sponsors must now establish early and credibly that a product meaningfully improves upon the existing standard of care for a serious disease. This clarity should make the FDA more willing to accept uncertainty, single pivotal trials and narrower safety margins. Regulatory uncertainty is no longer background noise. It is a material investment risk that reshapes how capital is deployed and pipelines are prioritized, and which companies ultimately succeed. Those that integrate regulatory realism into development strategy and investor communication will be better positioned than those that continue to play by the old rules.

Caught in the crossfire of the US's tumultuous and controversial vaccine policy overhaul, Moderna is the latest drugmaker stunned by a negative decision from the FDA that seemed to contradict earlier feedback. The biotech said Tuesday it received a refusal-to-file (RTF) letter from the FDA's Center for Biologics Evaluation and Research (CBER) after using a priority review voucher to speed along its regulatory filing for mRNA-based influenza vaccine candidate mRNA-1010, submitted in January.The letter, signed by CBER Director Vinay Prasad, did not identify any issues with mRNA-1010's safety or efficacy. Instead, the FDA's decision not to review the vaccine's application was based on the company's use of a licensed seasonal flu vaccine comparator in clinical studies. "It should not be controversial to conduct a comprehensive review of a flu vaccine submission that uses an FDA-approved vaccine as a comparator in a study that was discussed and agreed on with CBER prior to starting," Moderna CEO Stéphane Bancel said in a company release.According to Moderna, the letter cited the lack of an "adequate and well-controlled" study with a comparator arm that "does not reflect the best-available standard of care." However, the biotech argued that the RTF letter was "inconsistent with previous written communications from CBER," pointing to feedback it received on its Phase III study protocol.In an April 2024 note, CBER wrote that "it would be acceptable to use a licensed standard dose influenza vaccine as the comparator," though it recommended the drugmaker instead use a vaccine recommended for adults ages 65 and up by the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP), such as Fluzone HD, Fluad or Flublok. The agency concluded that if Moderna proceeded "with using a standard dose influenza vaccine comparator in participants ≥65 years of age, we agree with your plan to include statements in the Informed Consent Form." According to the drugmaker, CBER did not flag any issues with the study protocol before it was launched in September 2024 — but did so after the Phase III efficacy trial had finished and met its agreed-upon primary endpoints. In the study, which recruited 40,817 participants aged 50 and older, mRNA-1010 achieved a relative vaccine efficacy against influenza illness of 26.6% compared to Fluarix, a flu shot marketed by GSK.Following a pre-submission meeting with CBER in August 2025, Moderna said the agency requested that supportive analyses on the comparator be included in the submission, noting that it would be a "significant issue during review of your BLA." The drugmaker did so, and also shared data from a separate Phase III trial that evaluated mRNA-1010's safety and immunogenicity against a licensed high-dose influenza vaccine. In that trial, the mRNA shot demonstrated superior seroconversion rates and geometric mean titre ratios against all strains included in the vaccine."At no time in the pre-submission written feedback or meeting did CBER indicate that it would refuse to review the file," Moderna said. It has requested a Type A meeting with CBER "to understand the basis for the RTF letter." The drugmaker noted that regulators in the EU, Canada and Australia have all accepted its mRNA-1010 application for review, and more global submissions are expected this year. Vaccines in the crosshairs The RTF letter is the latest setback for Moderna since the US began reworking its vaccine policies under the direction of Health and Human Services (HHS) Secretary Robert F. Kennedy Jr., who has shepherded stricter vaccine development guidelines and an overhaul of the CDC's childhood vaccine schedule (see – ViewPoints: 'It's only going to get worse' — Offit's 2026 vaccine outlook).Amidst the flurry of changes in the past year, mRNA technology in particular has come under fire. In August, HHS cancelled funding for 22 mRNA vaccine programmes, including Moderna's experimental mRNA-based bird flu jab. At the time, Kennedy said the wind-down of agency support for the technology was because "the data show these vaccines fail to protect effectively against upper respiratory infections like COVID and flu," though he did not provide any data to support his claim.Increased scrutiny on mRNA-based vaccines also prompted Moderna last year to withdraw its FDA application for mRNA-1083, a combination influenza/COVID-19 candidate, based on a request for additional Phase III flu efficacy data. The biotech had planned to submit a filing for the combo vaccine once the review for mRNA-1010 was under way. Fellow vaccine developer Pfizer also has an mRNA flu shot in late-stage development, though it's unclear whether it will also be hit with an RTF letter. In a Phase III trial, the pharma's jab demonstrated superiority over Fluzone on the study's primary endpoint of relative efficacy.FDA about-faceOutside of the vaccine landscape, other drugmakers have raised concerns with unexpected FDA rejections on products that succeeded in pivotal testing. Most recently, Regenxbio's Hunter syndrome gene therapy received a complete response letter (CRL), though the company asserted on Monday that it had addressed all issues raised "through the submission of additional data and responses to numerous information requests."Regenxbio and Moderna are part of a growing cohort of companies who have called out inconsistent feedback from the FDA.Sanofi's tolebrutinib was rebuffed by the FDA late last year in what it called a "significant and meaningful change in direction from the feedback the agency previously provided." Similarly, Corcept Therapeutics' relacorilant was rejected in December in what the company called a "surprise and disappointment" in the face of a pivotal trial that had met its primary endpoint.For a breakdown on other high-profile rejections from the agency last year — including those handed down to Ultragenyx Pharmaceuticals, Capricor Therapeutics, Atara Biotherapeutics and Replimune — see Vital Signs: The FDA's 2025 report card.