FDA Rejects 6 New Drug Applications from January to April 2025

According to incomplete statistics, from January to April 2025, the FDA rejected 6 drug applications. The "Dual Ai Therapy" and the dry eye drug Reproxalap have faced FDA rejection before. The reasons for the rejections include two drugs being rejected due to CMC issues, two drugs due to clinical data issues, and one drug due to third-party problems.

Atara: Ebvallo

On January 16, 2025, Atara Biotherapeutics announced that the FDA rejected its Biologics License Application (BLA) for its cell therapy Ebvallo (Tabelecleucel). The application was for a single therapy treatment for adult and pediatric patients aged 2 years and above with Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disorder (PTLD) who had previously received at least one therapy, including anti-CD20 regimens. 

According to the press release, the FDA's rejection was solely related to third-party manufacturer inspection results. The CRL did not mention any issues with the manufacturing process, clinical efficacy, or safety data in the BLA, and the FDA did not require any new clinical studies to support Ebvallo's approval.

Tab-cel is an allogeneic, "off-the-shelf" EBV-specific T cell immunotherapy that targets and eliminates EBV-infected cells. In addition to treating EBV-positive post-transplant lymphoproliferative disorder, it is in early development for other EBV-related blood cancers and solid tumors.

As a result, Atara's stock dropped by 40%. However, Atara is still seeking collaboration with the FDA, Pierre Fabre Laboratories, and third-party manufacturers to achieve approval for Ebvallo in the U.S. Atara's CEO, Dr. Cokey Nguyen, expressed confidence that Ebvallo will eventually be approved, with a possible resubmission leading to approval within six months. The European Union granted marketing authorization for EBVALLO in December 2022.

Hengrui Medicine: "Dual Ai" Therapy

On March 21, 2025, Hengrui Medicine announced that it had received the FDA's complete response letter for the Biologics License Application (BLA) for the combination therapy of carrelizumab and apatinib mesylate for first-line treatment of unresectable or metastatic hepatocellular carcinoma (HCC). In the response letter, the FDA stated that further responses regarding the related manufacturing site inspection are required, but did not specify the exact reason. According to Korean company HLB, the rejection is still related to carrelizumab’s production and quality control (CMC) issues. This is not the first time the "Dual Ai" combination has been rejected due to CMC issues.

In May 2024, Hengrui received the first complete response letter, in which the FDA stated that due to defects in manufacturing site inspections and travel restrictions in some countries, the necessary biological research monitoring program (BIMO) clinical inspection could not be completed within the required review time. 

In October of the same year, Hengrui stated that it had resubmitted the application for carrelizumab and apatinib mesylate in first-line liver cancer treatment, which was accepted by the FDA. In January 2025, the FDA again inspected the relevant production site, and confirmed that the issues found in the CRL from the previous year had been rectified, with only three new improvement requirements. The company responded promptly within the specifie time and has maintained close communication with the FDA. It will take measures and resubmit the application as soon as the specific reasons are confirmed to seek approval.

Milestone: Etripamil Nasal Spray

On March 28, 2025, the FDA rejected the approval of Milestone Pharmaceuticals' Cardamyst (etripamil) nasal spray for the treatment of paroxysmal supraventricular tachycardia (PSVT), causing the company’s stock to drop by more than 60% after the news was released. Milestone pointed out that the CRL mainly focused on CMC issues and did not involve clinical studies.

In the CRL, the FDA requested that additional information on nitrosamine impurities be submitted based on new guidelines after the NDA submission and that an on-site inspection be conducted for equipment changes during the NDA review to ensure cGMP compliance. Milestone expressed disappointment with the CRL and stated that its team will evaluate the feedback and plan to hold an A-type meeting with the FDA to discuss the CRL. 

Etripamil Nasal Spray (brand name CARDAMYST?) is a new calcium channel blocker nasal spray developed by Milestone Pharmaceuticals for the treatment of PSVT.

Aldeyra: Reproxalap

On April 3, 2025, the FDA rejected Aldeyra Therapeutics' New Drug Application (NDA) for its investigational dry eye disease drug Reproxalap. Aldeyra plans to meet with the FDA in the coming weeks to discuss the specifics of the CRL and subsequent requirements. 

The FDA explicitly stated that additional clinical data is needed to support the drug's efficacy and required Aldeyra to conduct at least one more well-controlled clinical trial to ensure the drug's efficacy in improving dry eye disease-related ocular symptoms. The FDA also raised concerns about methodological issues, including baseline score differences between treatment arms, and their impact on the interpretation of results.

Reproxalap is an RASP inhibitor that reduces inflammation in the eyes and decreases tear secretion during eye or systemic inflammation. Many dry eye disease patients have high RASP levels. 

In November 2023, the FDA had already issued a CRL for Reproxalap, stating that it failed to demonstrate efficacy in treating dry eye disease and requiring another well-controlled trial to prove its effectiveness.

Regeneron: EYLEA HD

On April 18, 2025, the FDA sent a complete response letter (CRL) to Regeneron rejecting its supplemental Biologics License Application (sBLA) for extending the dosing interval of EYLEA HD? (aflibercept 8mg injection) from a maximum of 16 weeks to 24 weeks. The FDA disagreed with Regeneron’s proposal for an extended dosing interval but did not provide further explanations. Regeneron stated that the agency did not indicate any safety or efficacy issues. Regeneron is evaluating the FDA's decision and will determine the next steps at an appropriate time.

EYLEA HD was approved for dosing intervals of 8 to 16 weeks for wet age-related macular degeneration (wAMD) and diabetic macular edema (DME) patients, and 8 to 12 weeks for diabetic retinopathy (DR) patients, after a loading phase of monthly injections. 

The day before the rejection of the extended dosing interval, the FDA accepted Regeneron's sBLA for EYLEA HD for the treatment of retinal vein occlusion (RVO)-related macular edema, granting priority review. The goal approval date for the RVO indication is set for August 19, 2025.

Telix: Pixclara

On April 28, 2025, the FDA issued a complete response letter (CRL) to Telix Pharmaceuticals regarding its investigational glioma imaging agent TLX-101-CDx (18F-floretyrosine or 18F-FET, Pixclara), indicating that additional confirmatory clinical evidence is required. 

Telix stated that several approaches could address the CRL issues, including reanalyzing existing (unpublished) data or conducting additional clinical trials. 

Pixclara is a PET imaging agent used for characterizing progressive or recurrent gliomas in adult and pediatric patients due to treatment-related changes. FET PET has been included in international clinical practice guidelines for glioma imaging, but currently, the U.S. does not have an FDA-approved targeted amino acid PET agent for brain cancer imaging in both adults and children. Given Pixclara's potential to address an unmet medical need, it has been designated as an orphan drug and granted fast track designation by the FDA.