According to incomplete statistics, in the past year of 2023, 31 new drugs were rejected by the FDA for approval, involving tumors, heart diseases, respiratory system diseases, skin diseases, and so on.The reasons for rejection are overwhelmingly focused on doubts about the product's efficacy and safety, including issues such as questionable clinical benefits and limited clinical data.In addition to clinical issues, CMC (Chemistry, Manufacturing, and Controls) issues have also begun to emerge as another significant factor for FDA rejection of approvals. In this article, the editor has compiled a list of new drugs rejected by the FDA in 2023.May help the industry understand the FDA's review standards.

On January 19, 2023, Eli Lilly announced that the company had received a complete response letter from the FDA regarding its accelerated approval application for donanemab, its new Alzheimer's disease drug. The reason for the FDA's non-approval wasThe number of patients who received at least 12 months of drug treatment in the clinical trials on which the NDA submission was based is limited.FDA specifically requested that Eli Lilly provide data on at least 100 patients who have received continuous treatment with donanemab for at least 12 months.The FDA did not mention any other deficiencies in the complete response letter.

Eli Lilly explained at the press conference: "Although the trial included more than 100 patients treated with donanemab, many patients were able to stop dosing as early as 6 months into the treatment due to the rapid reduction of plaques, resulting in fewer than 100 patients receiving donanemab for 12 months."

On July 3, biopharmaceutical company Amneal Pharmaceuticals (NYSE: AMRX) stated that the FDA refused to approve the company's New Drug Application (NDA) for IPX203, intended to treat Parkinson's disease. The Complete Response Letter (CRL) indicated the reason as:Insufficient safety data for the drug, unable to help patients control symptoms long-term. Not related to the efficacy or production issues of IPX203.Moreover, the FDA stated that although the company has determined the safety of the ingredient levodopa based on research,But it cannot adequately determine the safety of another component, carbidopa.The FDA has requested more information.The submission of this NDA is based on the results of the RISE-PD Phase 3 clinical trial.

On July 29, Citius Pharmaceuticals, Inc. announced that it had received a Complete Response Letter (CRL) from the FDA regarding the Biologics License Application (BLA) for LYMPHIR™ (for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma). Citius Pharmaceuticals, Inc. stated,FDA Requests Additional Enhanced Product Testing and Increased Control Measures.The safety and efficacy clinical data package or proposed prescribing information submitted together with the BLA is not problematic.

On August 4, Mesoblast announced that it had received a Complete Response Letter (CRL) from the FDA regarding the marketing application for Remestemcel-L in the treatment of pediatric steroid-refractory acute graft-versus-host disease (SR-GVHD).FDA Requests More Data to Support Approval for Market Launch.Mesoblast to Conduct Controlled Trial in High-Risk Adult Patients with Higher MortalityFDA hopes the company will submit more data to support the approval of the BLA and wants it to address the chemistry, manufacturing, and controls (CMC) issues of remestemcel-L before initiating new clinical trials.。

On August 7, Sage Therapeutics announced its Q2 earnings and disclosed that the FDA had rejected the marketing application for Zuranolone, developed in collaboration with Biogen, for the treatment of Major Depressive Disorder (MDD).FDA Issues Complete Response Letter (CRL) for NDA of Zuranolone in Treatment of MDD. The CRL indicates that, in the company's new drug application for MDD,No substantial efficacy evidence has been provided to support the approval of zuranolone for the treatment of MDD.If they want to seek approval for MDD, Sage/Biogen will need to conduct at least one additional study on the drug. Sage and Biogen are reviewing the feedback and assessing the next steps.

On August 9, Galera Therapeutics announced receipt of a Complete Response Letter (CRL) from the FDA regarding the New Drug Application (NDA) for Avasopasem manganese (Avasopasem, GC4419) intended to treat severe oral mucositis (SOM) induced by radiotherapy in head and neck cancer (HNC) patients receiving standard care.The FDA stated in the CRL,Data from the Phase III ROMAN study and the Phase IIb GT-201 study are insufficient to demonstrate the efficacy and safety of Avasopasem in reducing severe oral mucositis in patients with head and neck cancer.The FDA believes that additional clinical trial results need to be resubmitted.

August 30,OutlookOutlook Therapeutics Announces Receipt of FDA Complete Response Letter (CRL) for ONS-5010 (Bevacizumab) for the Treatment of Wet Age-Related Macular Degeneration (wAMD)The FDA stated in the CRL that while the pivotal Phase III NORSE TWO study of ONS-5010 met the primary endpoints for efficacy and safety,However, due to some CMC (Chemistry, Manufacturing, and Controls) issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence, its market approval cannot be granted within the current review period.The marketing application of ONS-5010 is primarily based on three Phase III clinical trials (NORSE ONE, NORSETWO and NORSE THREE) positive results.

9June 6,AstraZenecaProclamationClothFDA Rejects Supplemental Application for Ultomiris, a Long-Acting C5 Complement Inhibitor, Seeking Approval for Use in Adult Patients with Anti-Aquaporin-4 (AQP4) Antibody-Positive (Ab+) Neuromyelitis Optica Spectrum Disorder (NMOSD)FDA Issues Complete Response Letter (CRL) for Ultomiris Supplemental Biologics License Application), the CRL did not raise any concerns regarding the efficacy and safety data of Ultomiris.Only Request to Modify the Ultomiris Risk Evaluation and Mitigation Strategy (REMS)`, and for the patient`Conduct a background investigation on the meningococcal vaccine接种状况, or require the prophylactic use of antibiotics before treatment.AstraZeneca will leverage its rareAlexion closely collaborates with the FDA to determine the best way to adjust the REMS program. Ultomiris for the new indication NMOSD is one step closer to being launched in the United States.

On October 2, the U.S. FDA rejected Eli Lilly's Biologics License Application (BLA) for lebrikizumab to treat moderate to severe atopic dermatitis (eczema).The reason is that a problem was found at a third-party manufacturer.The complete response letter (CRL) from U.S. regulators did not mention any concerns regarding the clinical data, safety, or labeling of lebrikizumab, raising hopes that the delay may not be prolonged — assuming the issues with the CMO can be resolved or production is transferred to a new partner.Eli LillyThe company stated that no other drugs were affected by the CRL."Continue to work closely with third-party manufacturers and the FDA to address feedback and enable patient access to lebrikizumab."

On October 9, Alnylam announced that it had received a Complete Response Letter (CRL) from the FDA regarding the supplemental New Drug Application (sNDA) for the RNAi therapy Patisiran (brand name: Onpattro). According to the content of the CRL,FDA Considers Alnylam's Existing Clinical Data Insufficient to Support Patisiran for the Treatment of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in its Marketing Application.In view of this result, Alnylam will no longer seek to expand the indications for Patisiran in the United States, but will instead focus on the Phase III study of another RNAi therapy for ATTR-CM — vutrisiran.

On October 12, 2023, Alvotech announced that the U.S. Food and Drug Administration (FDA) had refused to approve its Biologics License Application (BLA) for AVT04 (ustekinumab). The company proposed AVT04 as a biosimilar candidate to Johnson & Johnson's Stelara (ustekinumab). This marks the fourth rejection by regulatory authorities since last year.The regulatory agency noted in its Complete Response Letter (CRL) that,"Deficiencies" Found at Alvotech's Manufacturing Facility in Reykjavik, Iceland, The FDA identified these deficiencies during the on-site inspection in March 2023.Besides, the FDA did not point out any other issues in the BLA for AVT04.The company plans to resubmit the BLA in the near future.。This will trigger another six-month review cycle and a new Biosimilar User Fee Amendments (BsUFA) goal action date.

On October 20, Regeneron and Sanofi announced that they had received a Complete Response Letter (CRL) from the U.S. FDA regarding the supplemental Biologics License Application (sBLA) for Dupixent (dupilumab) in the treatment of Chronic Spontaneous Urticaria (CSU). The CRL indicated,Additional efficacy data is required to support approval.Regeneron stated that an ongoing clinical trial (Study C) will continue to recruit patients.Expected to obtain results by the end of 2024, will provide additional efficacy data.

On November 27, Aldeyra Therapeutics announced that it had received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding the New Drug Application (NDA) for reproxalap, a candidate drug for the treatment of dry eye disease. Although no safety or manufacturing issues were identified with reproxalap, the FDA noted in the letter,This NDA has not demonstrated efficacy in treating ocular symptoms related to dry eye disease.At least one more adequate and well-controlled study should be conducted to demonstrate a positive effect on ocular symptoms of dry eye disease. Depending on the remaining time in the NDA review cycle, the FDA may not be able to approve the NDA by the Prescription Drug User Fee Act (PDUFA) goal date of November 23, 2023, or around that date, and may require Aldeyra to conduct additional clinical trials and submit the results of these trials before reconsidering the application.

December 18,Checkpoint Checkpoint Therapeutics Announces FDA Rejection of BLA for Cosibelimab in Metastatic or Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC) Due to Manufacturing IssuesFDA Issues Complete Response Letter (CRL) for Cosibelimab BLA。CRL only pointed out in terms of the company'sIssues Identified During Multi-Sponsor Inspections Conducted by Third-Party Contract Manufacturing Organizations, as a resubmitted batchZhun ShenPlease clarify the issue that needs to be resolved.CRL expressed no concerns regarding the approvability of cosibelimab’s clinical data package, safety, or labeling.

On December 20, MSD announced that the FDA had issued a Complete Response Letter (CRL) for the New Drug Application (NDA) of its non-narcotic, orally administered selective P2X3 receptor antagonist gefapixant for the treatment of adult refractory chronic cough (RCC) or unexplained chronic cough (UCC). The FDA stated,MSD's application lacks sufficient evidence to prove that gefapixant is effective in treating RCC and UCC.CRL is unrelated to the safety of gefapixant. MSD stated that it is reviewing the feedback from the FDA to determine the next steps. 8. Aldeyra: Reproxalap for the treatment of dry eye disease.

On December 23, 2023, Zealand Pharma announced that the U.S. Food and Drug Administration (FDA)After discovering issues at the third-party production base, rejected Zealand's glucagon analog dasiglucagon for the treatment of congenital hyperinsulinism (CHI).CRL did not comment on the clinical data package or safety of dasiglucagon.Raise any concerns about sexuality.Zealand Pharma plans to resubmit the first part of the NDA in the first half of 2024, provided that the re-inspection of the relevant sites is successful. The company also hopes to conduct a supplementary analysis of the continuous blood glucose monitoring dataset regarding the use of dasiglucagon for more than three weeks, as required by the FDA in Part II of its NDA at CHI.

January 2023On February 26, Amgen announced that the FDA had completed its review of the supplemental new drug application for Lumakras (sotorasib) and refused to grant full approval for the use of Lumakras in treating patients with KRAS G12C-mutated non-small cell lung cancer who have received at least one prior systemic therapy.FDA Requires Amgen to Conduct Additional Confirmatory Studies, and no later than February 2028.

Summary

The United States has always been a superpower market for innovative drugs, and obtaining FDA approval often equates to receiving a global pass. However, in recent years, the FDA has become increasingly stringent in its approval process for innovative drugs, setting high standards and requirements that have kept multiple new drugs out of the market. Beyond impacting the commercialization process of these products, rejection of marketing applications can be fatal for small pharmaceutical companies heavily reliant on a single product. Many companies have suffered significant stock market hits after announcing receipt of a Complete Response Letter (CRL).

Reference: Announcements from various companies

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