The morning after ProfoundBio

Seven months after shelling out $1.8bn for the ADC specialist ProfoundBio, Genmab has quietly revealed the R&D cuts it's now making to help balance the books. The biggest retreat is from taking Tivdak into head and neck cancer, and also gone are three of Genmab's phase 1 projects.

While not related to the ProfoundBio move, a delay to erzotabart, a potential follow-on to Darzalex, was also revealed: readout from a vital phase 1/2 trial, previously expected this year, has now slipped into 2025. The refocused Danish group says it now has three key priorities: the marketed lymphoma drug Epkinly, acasunlimab and ProfoundBio's lead asset, rinatabart sesutecan.

Rina-S, an anti-FRα ADC, was the main reason Genmab bought ProfoundBio, so this prioritisation is hardly a surprise. Acasunlimab is more of a head-scratcher, given its mechanism – as an anti-PD-L1 MAb that's co-stimulated with 4-1BB it represents a strategy that's not delivered, and Genmab recently lost BioNTech as a partner for it; a phase 3 NSCLC study of acasunlimab gets under way this month.

Son of Darzalex

Erzotabart is seen by analysts as an important Genmab project, with possible opt-in by Johnson & Johnson seen as a key catalyst for the company. Like Darzalex it targets CD38, but is said to be more potent.

While erzotabart generated positive uncontrolled data at last year's ASH this came with a 50% discontinuation rate due to adverse events. A decision from J&J on opting in had been expected this year, the trigger being results of a phase 1/2 trial of erzotabart versus Darzalex, but this is now not expected until the first quarter of 2025, Genmab said on its third-quarter earnings call.

As for Tivdak, the anti-tissue factor ADC approved for cervical cancer, in February Genmab said it planned to "engage actively" with health authorities regarding the next steps in head and neck cancer, and listed the beginning of phase 3 in this indication among its "2024 priorities".

However, this plan has now been trashed, with Genmab citing "strategic prioritisation" as the reason for not, after all, starting this phase 3 study. Its enthusiasm had been driven by data from the phase 2 InnovaTV 207 trial, revealed at ASCO to have yielded a 33% ORR among 40 second-line head and neck cancer patients, but this has now been deemed insufficiently positive.

Not meeting the bar

Also insufficiently positive are three of Genmab's clinical-stage projects, GEN1047 (targeting B7-H4), GEN3017 (CD30) and GEN1056/BNT322, which have now been discontinued.

Remarkably, all three were marked "ongoing" in Genmab's interim report on 6 November, and it was only at the end of a question-and-answer session in the company's earnings call that its chief executive, Jan van de Winkel, revealed that their development had stopped, stating: "These programmes simply didn't meet the high bar for a truly differentiated therapeutic candidate."

B7-H4 has seen buy-in from GSK and Pfizer, but positive data have been hard to come by, as AstraZeneca discovered with puxitatug samrotecan, and presumably Genmab decided that GEN1047 wasn't good enough either. However, NextCure recently went all-in on its anti-B7-H4 ADC LNCB74, claiming differentiation and abandoning its previous lead, the Lair-2 fusion protein NC410.

CD30 is the target of Pfizer's blockbuster Adcetris, while the target of GEN1056 hadn't been disclosed, but that molecule is part of a 2015 tie-up with BioNTech.

"We have now really reprioritised our pipeline," van de Winkel told analysts, also floating the possibility of taking the ProfoundBio-originated PRO1286 into clinical trials shortly. This ADC hits EGFR and cMet, and there had been some speculation that Genmab couldn't develop it since it shares its targets with the J&J-partnered Rybrevant; this now seems not to be an issue.

Three other MAbs from the BioNTech deal remain in play, though at least one might be under threat: Genmab said it was collecting data on tecaginlimab, a 4-1BB co-stimulated anti-CD40 MAb, and would decide on its next steps later this month.

What's in and what's out? Genmab's oncology pipeline

Source: Genmab Q3 2024 earnings call & OncologyPipeline.