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

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The United States Food and Drug Administration (FDA) had a very full schedule for this week, but almost everything on it fell under a Priority Review pad. They have all 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 intended action date dated 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) following at least one prior systemic therapy. It was considered as part of a Priority Review process. On May 28, the FDA approved the drug for this indication based on the overall response rate (ORR) and duration of response (DoR). Continued approval is subject to verification and evidence of clinical benefit in confirmatory studies.

The application was based on the results of the Phase II CodeBreaK 100 trial. Sotorasib is a KRASG12C inhibitor and is being evaluated in 10 combinations at clinical sites around the world. NSCLC accounts for 80% to 85% of all lung cancers and 66% of patients have advanced or metastatic disease at 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 intended action date of August 17 for their two additional Biologics License Application (sBLA) for Padcev (enfortumab vedotin-ejfv) for locally advanced or metastatic urothelial cancer. Applications received Priority Review and were assessed under Project Orbis, which allows for simultaneous 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 mainstream approval. The second sBLA was based on cohort 2 of the pivotal study EV-201 and was intended to expand the current indication to include patients with locally advanced or metastatic urothelial cancer previously treated with a PD-1 or PD-L1 checkpoint inhibitor and are not eligible for cisplatin, a platinum-based chemotherapy.

On July 9, the FDA promised Padcev regular approval in the US as well as for this new indication.

“Padcev allows physicians to treat advanced urothelial cancer for the first time after treatment with platinum-containing therapy and immunotherapy using an FDA-approved therapy that has demonstrated an overall survival advantage over 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 intended action date of Aug. 18 for his BLA for Viceneum for high-risk, BCG-irresponsible non-muscle-invasive bladder cancer. It was evaluated under a Priority Review process. The drug is a locally administered fusion protein consisting of a recombinant fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens on the surface of cancer cells to deliver a protein payload, Pseudomonas Exotocin AA.

On August 13, the companies have received a Complete Response Letter (CRL) from the FDA to the BLA. The FDA declined to approve the application as it stands and made recommendations regarding more clinical and statistical data and analysis, as well as chemistry, manufacturing, and controls (CMC) issues related to 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 committed to our mission to save and improve patients’ lives by providing patients with new treatment options, and we plan to work closely with the FDA to understand the next steps.”

Vosoritide from BioMarin for achondroplasia

BioMarin Pharmaceuticals had a intended action date of Aug. 20 for his 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 initially did not specify filing issues with the NDA, but reiterated an objection raised at the Pediatric Advisory Committee (PAC) and Endocrinological and Metabolic Drugs Advisory Committee (EMDAC) 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 results of the one-year Phase III study and the data from the Phase II program with a follow-up of up to five years were “very convincing.”

The company later provided that the FDA with the two-year data from the Phase III extension study to complement the NDA. The FDA subsequently pushed back the PDUFA target action date three months to November 20, 2021, as it was a major change in filing.

On 25 June, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) offered a positive marketing advice for vosoritide for achondroplasia in two-year-old children until the growth plates have closed.

At the company 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 aged two and up, our commercial team is eagerly preparing for possible European approval and launch later this summer. If approved, Voxzogo will be the first pharmacological treatment option for children with achondroplasia. Following possible approval in Europe later this summer, we hope to have a positive outcome in the United States ahead of our November 20 PDUFA target action date. Following potential worldwide approvals from Voxzogo for achondroplasia, we have a great opportunity to capture the interest of families seeking treatment for their children.”

Axsome’s AXS-05 for Major Depressive Disorder

Axsome Therapeutics has a intended action date dated Aug. 22 for his NDA for AXS-05 for Major Depressive Disorder (MDD). It is also subject to a Priority Review process. 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 been given the Breakthrough Therapy designation for MDD, as well as agitation in Alzheimer’s disease.

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

On August 9 at the company second quarter financial report, Herriot Tabuteau, Chief Executive Officer of Axsome, said: “As part of the ongoing review of our NDA for AXS-05, the FDA recently informed us that they have identified deficiencies that currently stand in the way of discussions about labeling . We are trying to understand the nature of these shortcomings with the aim of addressing them, but this development could lead to a delay in the possible approval of ASX-05. We’ll keep you posted when we know more.”

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