FDA Update: Keytruda and Aduhelm News Leads the Week

Keytruda loses one indication but gains another, Biogen narrows use of Aduhelm, Padcev gets regular approval and expanded indication, Amgen submits application for asthma biologic, agency issues complete response letter for diabetes prevention therapy teplizumab, Novartis resubmits NDA for inclisiran.

Keytruda loses one indication and gains another. Merck has announced that it has received an expanded label for Keytruda (pembrolizumab) as monotherapy for the treatment of patients with locally advanced cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. This approval is based on data from the second interim analysis of the phase 2 KEYNOTE-629 trial, which was multicenter, multi-cohort, non-randomized, open-label trial.

Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.

Merck recently announced it will voluntarily withdraw the U.S. accelerated approval indication for Keytruda (pembrolizumab) for certain patients with gastric cancer or gastroesophageal junction adenocarcinoma whose tumors express PD-L1, who have seen their disease progress after at least two lines of therapy. The decision follows the April 29 hearing of the FDA Oncology Drugs Advisory Committee, where the panel recommended against continuing the indication. The decision does not affect other indications for Keytruda.

Acting FDA commissioner seeks review of Aduhelm approval. Janet Woodcock, M.D., acting commissioner of the FDA has requested an investigator by the Inspector General to review the process for the approval of Aduhelm.

She said she has confidence in the integrity of the staff and the review process.

“There continue to be concerns raised, however, regarding contacts between representatives from Biogen and FDA during the review process, including some that may have occurred outside of the formal correspondence process,” she said in a letter that was posted to Twitter on Friday afternoon. “To the extent that these concerns could undermine the public’s confidence in FDA’s decision, I believe it is critical that the events at issue be reviewed by an independent body such as the Office of the Inspector General to determine whether any interactions that occurred between Biogen and FDA review staff were inconsistent with FDA policies and procedures.”

She further mentioned on Twitter that it’s important for there to be transparency around the decision-making process. She said an independent assessment will help ensure confidence in the integrity of the FDA.

FDA approves updated label for controversial Alzheimer’s therapy. Biogen and Eisai have announced that the FDA has approved updated prescribing information for Aduhelm (aducanumab-avwa) to specify its use in patients with mild Alzheimer’s disease.

The Indications and Usage section of the label now says “Treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).”

Alfred Sandrock, Jr., M.D., Ph.D., head of research and development at Biogen, said in a statement, “Based on our ongoing conversations with prescribing physicians, FDA and patient advocates, we submitted this label update with the goal to further clarify the patient population that was studied across the three Aduhelm clinical trials that supported approval. We are committed to continue to listen to the community’s needs as clinical practice adapts to this important, first-in-class treatment option.”

The FDA had approved the therapy in June 2021, even though an advisory committee in November 2020 recommended against approval. FDA officials had said in a statement the therapy is first treatment directed at the underlying pathophysiology of Alzheimer’s disease, the presence of amyloid beta plaques in the brain.

Padcev gets full approval and new indication in urothelial cancer. Astellas Pharma and Seagen announced the FDA granted Padcev (enfortumab vedotin-ejfv) regular approval in the United States and approved a new indication for adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

In 2019, the FDA granted accelerated approval for Padcev for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery, or in a locally advanced or metastatic urothelial cancer setting. The conversion from accelerated approval to regular approval and the label expansion were based on two supplemental Biologics License Applications (sBLAs) reviewed under the Real-Time Oncology Review (RTOR) pilot program.

Bayer gets FDA nod for therapy that reduces heart and kidney complications. The FDA has approved Bayer Healthcare’ Kerendia (finerenone) tablets to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes.

Kerendia is a non-steroidal, selective mineralocorticoid receptor (MR) antagonist. By blocking MR overactivation, a key driver of chronic kidney disease progression, the therapy works on a pathway largely unaddressed by existing treatments.

The approval of Kerendia is based on the positive results of the pivotal phase III FIDELIO-DKD study, which was published in the New England Journal of Medicine in October 2020. The FDA had granted priority review designation in January 2021.

“There is a high unmet medical need for early intervention to prevent further end-organ damage and premature death by slowing patients’ rate of decline in kidney function as well as reducing cardiovascular risk,” Principal investigator George L. Bakris, M.D., department of medicine, American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine, said in a statement.

FDA issues complete response letter for teplizumab. Despite an advisory committee recommendation for approval, the FDA did not approve what would have been the first disease-modifying therapy for type 1 diabetes. The agency indicated that a single, low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in healthy volunteers to compare planned commercial product with drug product originating from drug substance manufactured for historic clinical trials had failed to show PK comparability.

Provention Bio expects relevant additional PK/PD data being, or to be, collected from a PK/PD substudy in patients receiving 12-days of therapy in the ongoing phase 3 PROTECT trial in newly diagnosed T1D patients later this quarter. These data will be analyzed by independent, unblinded third-parties to maintain the integrity of this placebo-controlled trial.

In the CRL, the FDA cited several additional considerations related to product quality, which company officials believe have either been addressed in amendments already submitted to the BLA or can be addressed in the short-term.

Amgen submits application for asthma biologic. The FDA has accepted Amgen’s Biologics License Application (BLA) and granted priority review for tezepelumab to treat patients with severe, uncontrolled asthma. Tezepelumab is being developed by Amgen in collaboration with AstraZeneca.

The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is during the first quarter of 2022.

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell–derived cytokine implicated in asthma.

The BLA was based on results from the PATHFINDER clinical trial program, including results from the pivotal NAVIGATOR phase 3 trial. Investigators in the NAVIGATOR study found that patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo. Results were published May 13, 2021, in the New England Journal of Medicine.

Novartis resubmits application for inclisiran. Novartis has resubmitted its New Drug Application for inclisiran to treat hyperlipidemia in adults who have elevated low-density lipoprotein cholesterol (LDL-C).

In December 2020, the FDA issued a Complete Response Letter for inclisiran because of issues related to a third-party manufacturing facility. In its resubmission, Novartis indicated that it is listing its own site in Schaftenau, Austria, as the manufacturing location for the finished product. Novartis indicated that the transfer of the manufacturing of inclisiran to Austria was planned and initiated in 2020, prior to the receipt of the CRL.

The FDA did not raise any concerns related to the efficacy or safety of inclisiran.