Setback For Athenex, Hanmi As CRL Requests New Trial
Another US Delay For Korean Firm's Assets
Executive Summary
Hanmi partner Athenex has had a US complete response letter for its oral paclitaxel plus encequidar product for the treatment of metastatic breast cancer, amid concerns of safety risks associated with an increase in neutropenia-related sequelae. While the decision marks another setback for Hanmi in the US, Athenex is aiming to resolve the issues.
The US Food and Drug Administration's (FDA) issuance of a complete response letter (CRL) on Athenex, Inc.’s new drug application for its oral paclitaxel plus encequidar product for metastatic breast cancer is disappointing, not only for the US firm but also its licensor, South Korea's Hanmi Pharmaceutical Co., Ltd., which will see an approval delay for another of its product candidates.
In the CRL decision, the FDA indicated its concern of a safety risk to patients in terms of an increase in neutropenia-related sequelae on the oral paclitaxel arm compared with the intravenous paclitaxel arm. The agency also expressed uncertainty over the results of the primary endpoint of objective response rate (ORR) at week 19, as conducted by blinded independent central review (BICR).
The FDA stated that the BICR reconciliation and re-read process may have introduced unmeasured bias and influence on the BICR, and recommended that Athenex conduct a new Phase III trial in patients with metastatic breast cancer representative of the population in the US.
It determined that additional, predefined risk mitigation strategies to improve toxicity, which may involve dose optimization and/or exclusion of patients deemed to be at higher risk of toxicity, are required to support a potential approval of the NDA.
“The NDA filing was a long shot given the lack of US sites and poor safety/tolerability profile, and this update affirms those problems," Informa’s Biomedtracker said in an analyst comment. "Significantly, this release also raises the issue that the positive response data were potentially biased.”
Another US Delay For Hanmi
In October last year, the FDA deferred action on the US biologics license application for Spectrum Pharmaceuticals Inc.'s neutropenia drug Rolontis (eflapegrastim), also licensed from Hanmi, due to pandemic-related difficulties inspecting Hanmi’s manufacturing plant. While no CRL was issued, the action date was put back by around four months. (Also see "Inspection Delay Puts Back Hanmi/Spectrum’s Rolontis" - Scrip, 28 Oct, 2020.)
Hanmi had expected to receive US marketing authorization this year under its licensing out deals for both Rolontis and oral paclitaxel/encequidar, which was under priority review for the metastatic breast cancer indication. Encequidar (formerly known as HM30181A) is a P-glycoprotein inhibitor and oral absorption enhancer that forms the basis of Hanmi’s proprietary Orascovery technology, in this case applied to paclitaxel.
Given that many anticancer drugs are substrates of P-glycoprotein, when orally administered they will be pumped back into the gastrointestinal tract. Encequidar enables oral absorption by localizing P-glycoprotein inhibitory activity in the GI tract, thereby improving absorption.
Poziotinib, an EGFR/HER2 inhibitor developed by the Korean firm and also licensed to Spectrum, successfully concluded clinical trials last year in non-small cell lung cancer and is now set for a US filing this year.
Athenex 'Disappointed' But Committed
Athenex said it plans to request a meeting with the FDA to discuss the CRL, engage in a dialogue on the design and scope of a trial to address the requirements, and to align on the next steps required.
“Our clinical and regulatory teams are disappointed by the complete response letter,” said Rudolf Kwan, the Buffalo, NY-based firm's chief medical officer. “We plan to work with the agency to resolve the issues raised in the CRL and to obtain approval.”
CEO Johnson Lau added, “We remain committed to the breast cancer community and will explore the best path forward to obtain regulatory approval. In the interim, we will identify and undertake the appropriate internal organizational adjustments accordingly.”
Founded in 2003, oncology specialist Athenex is organized around three platforms, Oncology Innovation, Commercial and Global Supply Chain. The company’s current clinical pipeline is derived from four different platform technologies - the Orascovery technology licensed in from Hanmi in 2011, Src kinase inhibition, T-cell receptor-engineered T-cells, and arginine deprivation therapy.
Earlier Efficacy/Safety Results
Following the CRL, Biomedtracker has lowered the likelihood of approval for oral paclitaxel/encequidar by 8%, to 4% below the average for a Phase III asset. It noted that invalidation of the response rate data is highly significant and drove this reduction, as the results were the primary basis for the regulatory submission.
At the San Antonio Breast Cancer Symposium 2019, Athenex had presented updated data showing a statistically significant improvement in response rates and a trend in progression-free survival and overall survival results favoring oral paclitaxel.
The intention-to-treat (ITT) group demonstrated an overall response rate of 35.8%, compared to 23.4% for intravenous paclitaxel (p=0.011), and rates of 40.4% for oral paclitaxel in the modified ITT group (baseline scans and at least 75% of first-cycle dosing), compared to 25.6% for intravenous paclitaxel (p=0.005). Further, upon subgroup analysis, only triple-negative breast cancer patients and those with unknown biomarker status derived a statistically significant improvement.
“We previously noted Oraxol’s questionable safety profile as a cause for concern despite the positive response data seen,” said Biomedtracker.
Compared to intravenous paclitaxel, Oraxol had higher rates of Grade 3 neutropenia (14.8% vs 6.9%), urinary tract infection (2.4% vs 0%), and anemia (2.3% vs 0%); neutropenia-related sequalae are mentioned by the FDA as an additional reason for the new CRL. One Grade 5 anemia event also occurred in a patient receiving Oraxol. Additionally, Oraxol had increased rates of grade 3 diarrhea (4.9% vs 1.5%), nausea (3.8% vs 0.2%), vomiting (4.9% vs 0.7%) and abdominal pain (2.3 vs 1.5%), gastrointestinal toxicities that necessitated prophylaxis which was not part of the initial study protocol.