Medical Watch | THE US FDA: 15 new drugs rejected for approval from 2021 to date

This article is reproduced from the "Precision Drugs" WeChat public account.

The FDA holds the "life and death power" of drug listing in the US market, which not only affects the progress of new drugs of large pharmaceutical companies, but also determines the life and death of Biotech, and also affects the hearts of domestic pharmaceutical companies. We selected 15 drugs that were rejected by the FDA this year to see why the rejection was done.

On March 1, 2021, Athenex announced that the FDA had issued a Complete Response Letter (CRL) for the company's metastatic breast cancer therapy, oral paclitaxel + Encequidar, rejecting the listing of the therapy. According to the announcement, the main reason for the rejection was the FDA's concern that oral paclitaxel may increase the safety risk of neutropenia-related sequelae compared to intravenous paclitaxel.

On March 22, 2021, Odonate Therapeutics announced the termination of the development of a novel oral taxane compound, tesetaxel. Based on FDA feedback at the pre-NDA conference, Odonate said, tesetaxel's clinical data is unlikely to support FDA approval for the product.

On March 26, 2021, the FDA Advisory Committee opposed the approval of Pfizer/Eli Lilly's osteoarthritis pain drug NGF antibody Tanezumab. "The proposed REMS is not sufficient to mitigate the risk of RPUA, nor can it ensure that the benefits of tanezumab outweigh the risks of RPUA," the FDA said in the review document. "Tanezumab is a monoclonal antibody used in clinical trials and is part of a non-opioid analgesic nerve growth factor (NGF) inhibitor. By inhibiting NGF, tanezumab may help stop pain signals produced by muscles, skin, and organs from reaching the spinal cord and brain.

On April 5, 2021, the FDA rejected Anadi's application to expand the treatment of its drug Nuplazid to hallucinations caused by dementia. The U.S. FDA said in its CRL that Acadia's Phase 2 Clinical Alzheimer's Psychiatric Study-019 used to support sNDA was not adequately and well controlled, and nuplazid lacked statistical significance in some dementia subgroups, claiming that not enough patients with dementia subtypes showed efficacy and did not raise safety concerns.

On June 18, 2021, the FDA rejected Orphazyme's rare disease drug arimoclomol. Orphazyme was approved in a single Phase 2/3 trial that included 50 patients with nasopharyngeal cancer, a rare neurological disease. This study showed that arimoclomol improved the severity of the disease compared to placebo. Before approval, the FDA wants more information about its efficacy and benefits-risks. Orphazyme said in a statement disclosing setbacks that the FDA has requested more evidence of the validity and interpretation of its primary endpoints, as well as additional data to support the risk assessment of interests.

On July 6, 2021, Provention Bio announced that the FDA declined to approve the company's biological product licensing application (BLA) for anti-CD3 monoclonal antibody tplizumab to delay clinical type 1 diabetes (T1D) in high-risk individuals. The main reason is that in a single-dose, low-dose pharmacokinetic/pharmacological (PK/PD) bridged study conducted in healthy volunteers, the proposed product was compared with the product previously used in clinical trials and failed to show comparability.

On July 23, 2021, Incyte announced that the FDA declined to approve the company's biologics licensing application for its PD-1 product, retifanlimab. Retifanlimab is an intravenous PD-1 inhibitor that has been declared as an indication for adults with locally advanced or metastatic squamous cell carcinoma for disease progression or intolerance to platinum chemotherapy. In July 2019, Zaiding Pharmaceutical signed an agreement with Incyte to obtain the exclusive authorization of retiredfanlimab in Greater China. Based on its June 24, 2021 recommendation from its Advisory Committee on Oncology Drugs (ODAC), the FDA determined that more data is needed to demonstrate the clinical efficacy of retifanlimab in patients with advanced or metastatic SCAC.

On July 30, 2021, the FDA rejected Ardelyx's chronic kidney disease (CKD) drug candidate tenapanor. With Aardelyx laying off a third of its workforce. According to Ardelyx, the FDA agreed that "the data submitted provides substantial evidence that Tenapanor is effective in reducing serum phosphorus in patients on CKD dialysis," but said the therapeutic effect was "small and of unclear clinical significance."

On August 11, 2021, based on the recommendations of its Advisory Board, fda rejected roxastat's listing application for safety reasons. Roxastat was jointly developed by FibroGen and AstraZeneca for the treatment of anemia caused by chronic kidney disease. The FDA asked FibroGen and AstraZeneca to do another safety clinical trial before reconsidering the review of roxastat. During the FDA's review, there was no doubt about the effectiveness of roxadustat, but concerns about its safety: mainly related to the risk of severe thromboembolic events.

On October 15, 2021, the FDA rejected The Marketing Application for Revance BotulinumtoxinA. According to the contents of the announcement, the FDA determined that It was not possible to approve DaxibotulinumtoxinA in its current state and noted that defects were found during on-site inspections of Revance's production facilities. Revance plans to communicate with the FDA as soon as possible and hold a meeting to address these deficiencies.

On October 18, 2021, Omeros announced that its application for the listing of its MASP-2 antibody drug was rejected by the FDA, and the stock price fell nearly 30% on the same day. The FDA's refusal of approval is due to the fact that current data are difficult to assess the efficacy of Narsoplimab in the treatment of HSCT-TMA and require different data necessary from Omeros to support approval.

On October 22, 2021, the FDA dissuaded Agenus, who announced that it had voluntarily withdrawn its marketing application for the PD-1 antibody Balstilimab. Balstilimab has an ORR of 20%, and the FDA deems it inappropriate to review its accelerated approval and recommends that Agenus withdraw the BLA, which has already been approved by the K drug, which has been approved one step ahead, and the two have similar efficacy. On June 22, 2020, Beida Pharmaceutical introduced the PD-1 antibody Balstilimab and CTLA-4 antibody Zalifrelimab from Agenus with an advance payment of US$15 million + US$20 million equity investment.

On October 25, 2021, the FDA rejected the application for the new drug of MyCombi, Eyenoiva's mydriatic product, because the product was reclassified as a pharmaceutical device combination product. MydCombi is a potential First-in-class topicaamide and phenylephrine micro-ophthalmic formulation for mydriasis.

On November 29, 2021, Fennec PharmaceuticalsInc said the FDA would again reject its application for the marketing of PEDMARK, a drug used to prevent hearing loss caused by chemotherapy in children, causing its stock price to plunge 50% at the close of the day. The company said the FDA found defects after inspecting the drug's manufacturing facilities, but did not provide further details.

On December 1, 2021, the FDA rejected Wanchun Pharmaceutical's application for the listing of punabulin. Plinabulin is a diketopiperazine tubulin inhibitor synthesized on the basis of the structure of Phenylahistin, a natural product isolated from Aspergillus a marine, and studied the structure-activity relationship. The FDA's CRL shows that the results of a single registry trial (Phase III) are not sufficient to demonstrate benefits and a second good controlled trial is needed to meet the substantive evidence requirements to support CIN indications. On August 26, Hengrui Pharmaceutical announced that it intends to sign a strategic cooperation agreement with Dalian Wanchun, a subsidiary of Wanchun Pharmaceutical. Hengrui Pharmaceutical will make an equity investment of 100 million yuan in Dalian Wanchun and pay a down payment and milestone payment of not more than 1.3 billion yuan in total.

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