NextCure joins the B7-H4 brigade

B7-H4 has so far largely disappointed, but NextCure has a lot riding on this target with its lead project, LNCB74, just going into the clinic, according to the latest listings on clinicaltrials.gov. The company last year abandoned its previous lead, a Lair-2 fusion protein, so will have to hope that its shift pays off.

Other new entrants include Olema’s OP-3136, the third KAT6 inhibitor to be tested in humans, and Eilean’s menin inhibitor balamenib.

B7-H4

NextCure’s LigaChem-partnered LNCB74 is a B7-H4-targeting ADC; the company had also been developing a naked antibody against the same target, but deprioritised this in late 2023.

There are currently nine clinical-stage assets against B7-H4, six of these ADCs, according to OncologyPipeline. However, development here has been tricky, and it’s looking increasingly likely that therapy will be limited to patients with high B7-H4 expression.

NextCure’s phase 1 trial, in various solid tumours, doesn’t appear to require B7-H4 expression for enrolment, but will correlate expression with response and progression-free survival, according to its clinicaltrials.gov entry. In any case, the primary endpoints are safety and tolerability, and defining a recommended phase 2 dose.

Even if it does succeed, NextCure could end up competing against the likes of GSK, Pfizer and AstraZeneca, although there are questions about the therapeutic window for Astra’s project, puxitatug samrotecan.

At the last count NextCure had cash until the second half of 2026.

KAT6

Although Olema unveiled its KAT6 inhibitor OP-3136 in September 2023, the project has only just gone into phase 1 in late-line solid tumours; specifically breast, castrate-resistant prostate, and non-small cell lung cancers. Initial data are due in 2026, according to the company’s recent JP Morgan healthcare conference presentation.

Pfizer has set the bar with PF-07248144, which recently produced a 37% ORR in combination with Faslodex, in relapsed ER-positive, HER2-negative breast cancer. Pfizer has already disclosed plans to begin phase 3.

Still, toxicity will be closely watched, with neutropenia looking potentially problematic. Another competitor here is Menarini, whose MEN2312 recently started phase 1.

Menin, Claudin18.2 & KIF18A

Menin inhibition is more crowded, but that hasn’t stopped other contenders joining the fray, including the private US group Eilean Therapeutics, with balamenib.

Balamenib’s phase 1, being carried out in Australia and the US, began in April 2024, according to its clinicaltrials.gov listing – but was only recently posted on the site. Eilean reckons it can sidestep the QTc prolongation that’s been seen with Syndax’s Revuforj, which became the first FDA-approved menin inhibitor in November, for KMT2A-rearranged relapsed/refractory acute leukaemia.

However, more advanced assets have also avoided QTc prolongation, including Kura’s ziftomenib, which is set to yield pivotal data soon in second-line NPM1-mutant AML. Other menin hopefuls include Johnson & Johnson and Sumitomo, whose enzomenib recently impressed at ASH.

Even more popular is Claudin18.2, where Shenzhen Celconta hopes to make its mark with the Car-T XKDCT225. But standing out here looks like a tough task: there are 21 Car-Ts against this target in the clinic, according to OncologyPipeline. And most of them, like XKDCT225, are being studied in China.

Meanwhile, GeneScience’s GenSci122, also being studied solely in China, is joining only a handful of other KIF18A inhibitors. Volastra is a big proponent of this synthetic lethality approach, with two shots in the clinic, while China’s Genhouse Bio also has an early-stage project, GH2616.

Recently disclosed first-in-human studies*

Notes: *projects newly listed on the clinicaltrials.gov database between 14 and 20 Jan 2025.