Son of Darzalex hits the skids

The bar was always high for Genmab’s Darzalex follow-on erzotabart, and the project has failed to clear it: Genmab’s partner Johnson & Johnson said it wasn’t going to opt in to the asset, leading the Danish group to scrap development.

Investors who sent Genmab’s stock down 8% on Monday must be wondering how the company will fill a Darzalex-shaped hole when that drug’s US patent expires in 2029. Genmab cited the AbbVie-partnered Epkinly, the ProfoundBio-originated anti-FRα ADC rinatabart sesutecan, and the anti-PD-L1 x 4-1BB acasunlimab as its portfolio highlights. But there are big questions over the last asset, which BioNTech handed back last summer.

And Genmab has a long way to go to replace Darzalex, which sold $11.7bn in 2024, and on which the company collects royalties. The group estimates over $3bn in peak sales for Epkinly, over $2bn for rina-S and $1bn for acasunlimab.

The latest development could put pressure on Genmab to do deals, and during a conference call on Monday the group’s chief executive officer, Jan van de Winkel, noted that it was looking for phase 3 or phase 3-ready assets, with oncology still a key focus – although he also mentioned immunology as another potential area.

Not differentiated?

Darzalex and erzotabart (also known as Hexabody-CD38) both target CD38, but the newcomer was said to be more potent. Genmab and J&J are already partners on Darzalex, and the companies’ deal stipulated possible opt-in by J&J, based on head-to-head data from the phase 1/2 3014-01 trial in relapsed or refractory multiple myeloma.

J&J has long been clear that, to exercise this option, it needed to see something truly differentiated. In the event the study showed erzotabart looking slightly better than Darzalex, and clearly that wasn’t enough.

Not enough: erzotabart vs Darzalex in r/r multiple myeloma

Note: *all deaths deemed unrelated to therapy. Source: company presentation.

Meanwhile, secondary efficacy endpoints including duration of response, progression-free survival and overall survival were immature, Genmab said.

Toxicity might also have played a part: grade 3 or higher adverse events were more common with erzotabart, as were dose interruptions and discontinuations – echoing concerns around early data presented at ASH 2023. During the conference call Genmab execs suggested that one reason for the imbalance could be that erzotabart was given intravenously, and Darzalex subcutaneously.

Several analysts asked whether there was any negative readthrough to other hexabody projects, which make up around 10% of Genmab’s pipeline – something the company dismissed. In fact, execs said the results gave it higher confidence in its hexabody technology.

They added that J&J’s decision was also influenced by the changing landscape in multiple myeloma, a disease that’s becoming increasingly crowded.

Genmab was clear that there’s no chance for a resurrection of erzotabart, for example with another partner, not least because the group’s contract with J&J stipulates that the asset can’t be developed in areas in which Darzalex is on the market or in late-stage development.

In any case, without J&J it would have made no sense for Genmab to continue developing erzotabart alone, as it would be taking on its much bigger partner for Darzalex, and also cannibalising its own royalties. But its need to fill the shoes of Darzalex has become even more pressing.