The FDA has provided further insight into recent rejections submitted to two major pharmaceutical companies, releasing complete response letters (CRLs) sent to AstraZeneca and GSK, highlighting gaps in data included in the application packages.
In a scathing rebuke (PDF) to AstraZeneca, the FDA cited “significant data quality issues impacting key analyzes including the primary endpoint” in the dataset for Safnero (anifrolumab), which is proposed for use in systemic lupus erythematosus (SLE).
Separately, the agency rejected GSK’s Exdensur (depemokimab) for chronic sinusitis with nasal polyps (CRSwNP) (PDF), ruling that clinical data failed to provide “sufficient evidence” of efficacy and cast doubt on the drug’s potential for expanded use.
The publication of the rejection letter underscores FDA’s commitment to “radical transparency” regarding the drug review process. While AZ is undergoing an audit of the Saphnelo dataset in a bid to regain the agency’s trust, GSK faces the more difficult challenge of proving that Exdensur is indeed working in CRSwNP.
According to FDA’s database, in the case of AZ, the CRL was issued on October 10, 2025. However, the company did not disclose it until February 3, 2026. At the time, the company said it had submitted the FDA-requested information to CRL and that a decision on the updated application was expected in the first half of this year.
AZ’s initial submission is based on an interim analysis of the Phase 3 Tulip-SC study, which showed a reduction in disease activity with subcutaneous Safnero compared to placebo, as measured at week 52 using the British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA).
However, in the CRL, FDA warned that AZ submitted a “revised” dataset for the study late in the review cycle after initially making “errors” in its application.
As a result, FDA required AZ to provide, among other things, a “revised interim clinical study report” and revised raw data sets for both interim and final analyzes presented in a standard format for regulatory review.
Additionally, FDA asked the company to provide “a detailed explanation of why the error was found in the locked database” and “a subject-level list of all changes in all data sets and the reason for each change.”
Two months after the FDA’s rejection, European regulators approved subcutaneous administration of Safnero for SLE.
This is not the first time AZ has dealt with data quality issues in a kidney disease drug application. In 2021, AZ’s then-partner Fibrogen filed for FDA approval, but later admitted to manipulating safety data for roxadustat in chronic kidney disease-related anemia. This data was announced extensively by both companies in 2019.
Roxadustat was subsequently rejected by the FDA, and AZ withdrew from the U.S. partnership in 2024.
Questions regarding effectiveness against GSK
Meanwhile, GSK faces another hurdle for Exdensur. The FDA is seeking “new evidence” that can demonstrate greater therapeutic efficacy to prove that antibody drugs provide “statistically convincing and clinically meaningful” benefits for patients with CRSwNP.
In the CRL for GSK, the FDA acknowledged that the joint primary endpoints of the Anchor-1 and Anchor-2 trials were met, demonstrating statistically significant improvements between Exdensul and placebo on nasal polyp scores and nasal obstruction scores.
However, regarding the nasal obstruction score measurement, the FDA found that the results were “not robust to sensitivity analysis of missing data or treatment of concurrent events.” FDA considers patient-reported endpoint results to be “particularly important in assessing benefit-risk because they directly reflect clinically meaningful effects for patients.”
The effect sizes for both primary endpoints were “numerically small,” leading the FDA to question their clinical significance.
The agency’s review team also considered secondary endpoints such as additional patient-reported symptom scores, need for sinus or polyp surgery, and use of oral corticosteroids. However, due to the statistical design, In the study, none of these endpoints met statistical significance, despite a trend in favor of Exdensur.
The FDA also specifically criticized GSK for not conducting a Phase 2 dose-ranging study with CRSwNP, suggesting that doses higher than the 100 mg chosen by GSK “may have greater therapeutic effect.”
Further tipping the balance of the review against GSK, the FDA said that semiannual dosing (a long-acting feature that GSK has touted) means patients who don’t respond will have to wait a long time before switching to another drug, or risk some problems from receiving two biologic treatments while Exdensur is still in the body.
“Given depemokimab’s small effect size and lack of robustness in tipping point analyses, the benefit-risk relationship for the 6-month duration of action setting is unfavorable,” the FDA concluded.
Although the FDA declined to approve Exdensur in CRSwNP, the agency approved the long-acting IL-5 agent as an additional maintenance therapy for severe asthma with an eosinophilic phenotype. The drug is approved in the EU for both indications.
“We remain confident in the benefits that Exdenshul provides for patients with CRSwNP and are continuing discussions with the FDA,” a GSK spokesperson told Fierce Pharma.
GSK’s U.S. focus is on severe asthma and chronic obstructive pulmonary disease (COPD), which affects approximately 2 million Americans, more than half of whom are uncontrolled with current treatments, the spokesperson added.
Exdensur is a key element of GSK’s plans to achieve annual sales of more than £40bn 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.
