FDA Action Alert: Amgen, Seagen/Astellas, Enzon/Sesen, BioMarin and Axsome

FDA_Sarah Silbiger/Getty Images

Sarah Silbiger/Getty Images

The U.S. Food and Drug Administration (FDA) had a very packed calendar for this week, but almost everything on it was under a Priority Review pathway. All have either been approved, rejected or pushed back to a later date. Read on for more information.

Amgen’s Lumakras for Non-Small Cell Lung Cancer

Amgen had a target action date of August 16, 2021, for its New Drug Application (NDA) for Lumakras (sotorasib) for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCL) after at least one previous systemic therapy. It was being considered under a Priority Review pathway. On May 28, the FDA approved the drug for this indication based on its overall response rate (ORR) and duration of response (DoR). Continued approval will be dependent upon verification and proof of clinical benefit in confirmatory trials.

The application was based on results from the Phase II CodeBreaK 100 trial. Sotorasib is a KRASG12C inhibitor and is being evaluated in 10 combinations with clinical sites around the world. NSCLC makes up 80% to 85% of all lung cancers, and 66% of patients have advanced or metastatic disease at the initial diagnosis. KRAS G12C is one of the most common driver mutations in NSCLC.

Seagen and Astellas’ Padcev for Urothelial Cancer

Seagen and Astellas Pharma had a target action date of August 17 for their two supplemental Biologics License Application (sBLA) for Padcev (enfortumab vedotin-ejfv) for locally advanced or metastatic urothelial cancer. The applications were granted Priority Review and were evaluated under Project Orbis, which allows for concurrent submissions in participating countries. The first sBLA was built on the Phase III EV-301 trial, which hopes to shift the drug’s accelerated approval to regular approval. The second sBLA was based on the pivotal trial EV-201’s cohort 2, and was for an expansion of the current indication to include locally advanced or metastatic urothelial cancer patients who have been previously treated with a PD-1 or PD-L1 checkpoint inhibitor and are ineligible for cisplatin, a platinum-based chemotherapy.

On July 9, the FDA granted Padcev regular approval in the U.S. as well as for this new indication.

“With Padcev, for the first time, physicians can treat advanced urothelial cancer following treatment with a platinum-containing therapy and immunotherapy using an FDA-approved therapy that has demonstrated an overall survival benefit compared with chemotherapy,” said Andrew Krivoshik, senior vice president and Oncology Therapeutic Areas Head, Astellas.

Enzon and Sesen Bio’s Viceneum for Non-Muscle Invasive Bladder Cancer

Enzon Pharmaceuticals and Sesen Bio had a target action date of August 18 for its BLA for Viceneum for high-risk, BCG-unresponsible non-muscle invasive bladder cancer. It was being evaluated under a Priority Review pathway. The drug is a locally administered fusion protein made up of a recombinant fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens on the surface of cancer cells in order to deliver a protein payload, Pseudomonas Exotocin AA.

On August 13, the companies received a Complete Response Letter (CRL) from the FDA for the BLA. The FDA indicated it can’t approve the application in its current form and offered recommendations related to more clinical and statistical data and analyses as well as Chemistry, Manufacturing and Controls (CMC) issues associated with a recent pre-approval inspection and product quality.

“We are deeply disappointed by this unexpected result, and it is an unfortunate day for patients suffering from BCG-unresponsive NMIBC,” said Thomas Cannell, president and chief executive officer of Sesen. “We remain dedicated to our mission to save and improve the lives of patients by bringing new treatment options to patients, and we intend to work closely with the FDA to understand next steps.”

BioMarin’s Vosoritide for Achondroplasia

BioMarin Pharmaceuticals had a target action date of August 20 for its NDA for vosoritide for children with achondroplasia, the most common form of disproportionate short stature in humans. The drug is a once daily injection analog of C-type Natriuretic Peptide (CNP).

When the NDA was accepted, the FDA did not initially specify any filing issues with the NDA, but repeated an objection raised during the Pediatric Advisory Committee (PAC) and Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) that was held on May 11, 2018. Those advisory committees recommended two-year controlled studies in different age groups. However, BioMarin indicated at the time that it believed the outcomes from the one-year Phase III trial and data from the Phase II program with up to five years of follow-up were “highly persuasive.”

The company later provided the FDA with the two-year data from the Phase III extension study to supplement the NDA. The FDA then pushed the PDUFA target action date back three months to November 20, 2021, due to it being a major change to the submission.

On June 25, the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) offered a positive recommendation for marketing authorization for vosoritide for achondroplasia in children two years until growth plates are closed.

At the company’s second-quarter financial report on July 28, Jacques Bienaime, chairman and chief executive officer of BioMarin, said, “With the positive CHMP opinion for Voxzogo [vosoritide] for children, two years of age and older, our commercial team is eagerly preparing for potential European approval and launch later this summer. If approved, Voxzogo will be the first pharmacological treatment option for children with achondroplasia. Following potential approval in Europe later this summer, we hope to have a positive outcome in the United States pending our November 20 PDUFA target action date. Upon potential global approvals of Voxzogo for achondroplasia, we have a tremendous opportunity to address the interest from families seeking treatment for their children.”

Axsome’s AXS-05 for Major Depressive Disorder

Axsome Therapeutics has a target action date of August 22 for its NDA for AXS-05 for major depressive disorder (MDD). It is also under a Priority Review pathway. AXS-05 (dextromethorphan-bupropion) is a novel, oral, NMDA receptor antagonist with multimodal activity. It is also being developed for other CNS disorders. The drug has also received Breakthrough Therapy Designation for MDD, as well as for Alzheimer’s disease agitation.

The NDA is based on data from two trials of the drug in patients with a confirmed diagnosis of moderate to severe MDD. They GEMINI and ASCEND trials demonstrated statistically significant improvements in depressive symptoms compared to placebo and active controls.

On August 9, at the company’s second-quarter financial report, Herriot Tabuteau, Axsome’s chief executive officer, stated, “As part of the ongoing review of our NDA for AXS-05, the FDA recently notified us that they have identified deficiencies that preclude labeling discussions at this time. We are attempting to learn the nature of these deficiencies with the goal of addressing them, however, this development may lead to a delay in the potential approval of ASX-05. We will keep you informed as we learn more.”

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