Anifrolumab-FNIA

While AZ has undergone an audit of its Saphnelo datasets to regain the agency’s trust, GSK faces a more daunting challenge: proving that Exdensur actually works in CRSwNP. The FDA is providing more insight into the rejections it recently handed two pharma giants, publishing the complete response letters (CRLs) sent to AstraZeneca and GSK that highlight shortfalls in the data included in their application packages.In a scathing rebuke (PDF) to AstraZeneca, the FDA cited “critical data quality issues that affect key analyses, including the primary endpoint” within a dataset for Saphnelo (anifrolumab) for the drug’s proposed use in systemic lupus erythematosus (SLE). Separately, the agency rejected (PDF) GSK’s Exdensur (depemokimab) for chronic rhinosinusitis with nasal polyps (CRSwNP), ruling that the clinical data failed to provide “adequate evidence” of efficacy, casting doubts on the drug’s potential expansion in that use.The publication of the rejection letters underscores the FDA’s promise of “radical transparency” regarding its drug review process. While AZ has undergone an audit of its Saphnelo datasets to regain the agency’s trust, GSK faces a more daunting challenge: proving that Exdensur actually works in CRSwNP.For AZ, the CRL was issued on Oct. 10, 2025, according to the FDA’s database. But the company didn’t disclose it until Feb. 3, 2026. At that time, the company said it had submitted the information requested by the FDA in the CRL, and that a decision on the updated application was expected in the first half of this year. AZ’s initial submission was based on an interim analysis of the phase 3 Tulip-SC trial, which showed a reduction in disease activity for subcutaneous Saphnelo versus placebo as measured using the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) at week 52. However, in the CRL, the FDA flagged that AZ had submitted a “corrected” dataset for the study late in the review cycle after initially making “errors” in the application.As a result, the FDA asked AZ to provide, among other things, a “corrected interim clinical study report” and corrected raw datasets for both the interim and final analyses, presented in formats standard for regulatory reviews. Additionally, the FDA asked the company to “provide a detailed discussion of what led to the errors in the locked database being found,” as well as “a subject-level listing of all the changes in all the datasets along with the reason for each change.”Two months following the FDA’s rejection, European regulators authorized subcutaneous Saphnelo in SLE. This is not the first time that AZ has found itself dealing with data quality issues in a drug application for a kidney disease treatment. Back in 2021, AZ’s then-partner FibroGen filed for an FDA approval but then admitted to manipulating the safety data of roxadustat in chronic kidney disease-related anemia, data that the two firms unveiled to much fanfare in 2019.Roxadustat has since been rejected by the FDA, and AZ exited the collaboration in the U.S. in 2024. Efficacy questions for GSK Meanwhile, GSK faces a different hurdle for Exdensur, as the FDA has asked for “new evidence” that can demonstrate a treatment effect of greater magnitude to prove that the antibody drug provides a “statistically persuasive and clinically meaningful” benefit to CRSwNP patients. In its CRL to GSK, the FDA acknowledged that the co-primary endpoints of the Anchor-1 and -2 trials were met, showing statistically significant improvements for Exdensur versus placebo on nasal polyp scores and nasal obstruction scores. However, on the nasal obstruction score measure, the FDA found the outcomes were “not robust to sensitivity analyses for missing data and handling of intercurrent events.” The FDA views results from the patient-reported endpoint “especially important for assessing benefit-risk because they are a direct reflection of the clinically meaningful effects for patients.”The magnitude of the effects for both primary endpoints was “numerically small,” so the FDA questioned their clinical meaningfulness.The agency’s review team also looked at secondary endpoints, including additional patient-reported symptom scores, the need for nasal sinus or polyp surgery, and oral corticosteroid use. However, because of the statistical design of the studies, none of those endpoints met statistical significance, despite trends favoring Exdensur.The FDA went on further to suggest that a higher dose than the 100 mg selected by GSK “may provide a greater treatment effect,” faulting GSK for not running phase 2 dose-ranging trials specifically in CRSwNP.To tip the review balance further against GSK, the FDA said the every-half-year dosing—a long-acting feature that GSK has touted—means that non-responders would either have to wait a long time to switch to another drug, or risk any issues from taking two biologic therapies while Exdensur is still present in their bodies. “Given the small effect size for depemokimab with lack of robustness on tipping point analysis, the benefit-risk in the setting of a six-month duration of action is not favorable,” the FDA concluded. While the FDA declined to approve Exdensur in CRSwNP, the agency approved the long-acting IL-5 agent as an add-on maintenance treatment for severe asthma with an eosinophilic phenotype. The drug is approved in the EU for both indications.“We remain confident in the benefit Exdensur could bring for patients with CRSwNP and are continuing discussions with the FDA,” a GSK spokesperson told Fierce Pharma. GSK’s focus in the U.S. is on severe asthma, which affects about two million Americans with more than half uncontrolled on current therapy, as well as chronic obstructive pulmonary disease (COPD), the spokesperson added.Exdensur is a key element of GSK's plan to reach more than 40 billion pounds sterling in annual revenue by 2031, a task that has recently fallen on the shoulders of new CEO Luke Miels. In a more important indication than CRSwNP, GSK is testing Exdensur in three phase 3 trials in COPD.