The FDA has given a thumbs-down to Daiichi Sankyo’s HER3 antibody-drug conjugate patritumab deruxtecan.
The Wednesday rejection deals a blow to the Japanese pharma’s plans for a near-term expansion of its ADC portfolio beyond its wildly successful and HER2-altering medicine Enhertu. It also throws a roadblock in front of Daiichi’s partner Merck, which had signed on to jointly develop and commercialize patritumab deruxtecan for about $1.5 billion upfront last October as part of a three-ADC pact.
The duo said the rejection was not due to any safety or efficacy concerns.
“The CRL results from findings pertaining to an inspection of a third-party manufacturing facility,” the companies said in a statement.
“We will work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible,” Ken Takeshita, global head of R&D at Daiichi Sankyo, said in a statement. “We remain confident in the ability to develop this medicine to its full potential.”
It wasn’t immediately clear if the rejection would have ramifications on other HER3 ADCs. Multiple other drugmakers have joined the HER3 race, notably in the past year, to follow Daiichi and Merck.
BioNTech partnered with MediLink Therapeutics on a HER3 ADC, which ran into safety concerns and a partial clinical hold this month. Endeavor BioMedicines also licensed an asset, as did Bristol Myers Squibb with an $800 million upfront deal for SystImmune’s Phase 1 candidate.
Daiichi and Merck were seeking a third-line nod for the drug in adults with locally advanced or metastatic EGFR-mutated non-small cell lung cancer based on the 255-patient Phase 2 HERTHENA-Lung01 study, which showed an overall response rate of 29.8%.
There was one death due to treatment-related interstitial lung disease, or ILD, in the trial. Thrombocytopenia, neutropenia, anemia, leukopenia and fatigue were the most common side effects.
Patients with this form of NSCLC have “very limited options,” Merck Research Laboratories chief medical officer Eliav Barr told Endpoints News in a recent interview.
Barr added that 15% of NSCLC patients in the US and Europe, and about 40% of patients in Asia, have the EGFR mutant form of the cancer, and a “great majority” of those patients express the HER3 receptor. That “becomes more enriched as the tumors become more resistant after long-term therapy with EGFR mutation inhibitors,” he said.
The FDA assigned the drug priority review last December, just two months after Daiichi and Merck disclosed their sprawling partnership. A confirmatory trial of the medicine is fully enrolled and is set to read out “over the course of the next few months,” Barr said.
The drug is in multiple additional trials, including a Phase 3 comparing it to chemotherapy in patients who have previously taken AstraZeneca’s Tagrisso, as well as a Phase 1 combining it with Tagrisso. It’s also been through a Phase 1/2 in patients with certain forms of breast cancer.
A crimp to Daiichi’s portfolio and Merck’s first ADC approval
Almost every major pharma has forged an ADC deal in recent years. The “fancy chemotherapy,” which has been around for decades, now has more refined chemistry, better linker technology and mostly safer profiles.
With the category becoming more crowded, Daiichi sought to further solidify its standing in the field. It’s had quite a bit of success with its AstraZeneca-allied Enhertu, which generated $2.5 billion in sales in 2023. The drug has transformed the treatment landscape for HER2 breast cancers and opened the door to ADC’s golden age. Daiichi has a suite of other ADCs in all phases of development, as well as other oncology candidates, specialty medicines and vaccines in the works.
For Merck, the rejection means it can’t yet enter the commercial-stage ADC club, which includes Pfizer, GSK, Takeda, Roche, AstraZeneca and AbbVie, among a few others. Most of those companies entered the ADC category by way of licensing deals or acquisitions, including Pfizer’s $43 billion acquisition of Seagen and AbbVie’s $10.1 billion ImmunoGen buyout.
In the past few years, Merck has been building up its ADC pipeline. It’s inked two large pacts with Sichuan Kelun-Biotech and acquired VelosBio and Abceutics. It also has an in-house pipeline of ADCs. There was also a Seagen partnership that collapsed.
Merck recently secured a key approval for its pulmonary arterial hypertension drug Winrevair and pneumococcal vaccine Capvaxive. Combined, Winrevair and the Daiichi-partnered ADC were expected to reel in $2.4 billion in revenue by 2028, Mizuho Securities analyst Mara Goldstein wrote in a January note. That’s the year the drugmaker’s megablockbuster, the world’s top-selling medicine Keytruda, begins to fall off the patent cliff.