Nuvalent’s next battleground is HER2

The targeted oncology biotech Nuvalent has much to prove to justify its $4.6bn market cap, though it’s already impressed with projects against ALK and ROS1. Its next battleground is the highly competitive space of HER2, though here Nuvalent is sticking to its core competency in small molecules rather than pursuing the much more crowded ADC approach.

Nuvalent’s HER2 inhibitor NVL-330 last month entered its first-in-human Heroex-1 study, whose design can now be scrutinised, having recently been entered on the clinicaltrials.gov registry. Other recent entrants to human trials include a CDK4/6 degrader from BioTheryX, and T-cell engagers from Context Therapeutics and Zymeworks.

In the more familiar anti-HER2 ADC space Shanghai Institute Of Biological Products has just started a phase 1 study of SIBP-A17, though like other ADCs this simply uses the wild-type HER2 protein as a marker of cancer cells to which the conjugate can be anchored.

For its part, Nuvalent’s NVL-330 is designed to bind specifically to mutated HER2, which the group reckons drives some lung cancers. The small molecule is said to be brain penetrant, and to avoid wild-type HER2. Its Heroex-1 trial is enrolling patients whose NSCLC tumours have documented HER2 mutations, including exon 20 insertion and HER2 amplification.

Degrader focus

Like HER2, targeting CDK4/6 is an established strategy, but the private US biotech BioTheryX is applying to it its own focus on degraders, via the molecule coded BTX-9341.

Its phase 1 study targets ER-positive, HER2-negative breast cancer, an established space for CDK4/6 inhibitors like Pfizer’s Ibrance and Novartis’s Kisqali. BTX-9341 appears to be the only degrader of CDK4/6 in development, according to OncologyPipeline, and BioTheryX says it has better in vivo efficacy than CDK4/6 inhibitors, and is able to overcome key resistance mechanisms.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 22 and 29 Jul 2024.

Meanwhile, one of the first companies to target Claudin6 was BioNTech, with the Car-T therapy BNT211. BioNTech now also has an mRNA-encoded anti-Claudin6 CD3-based T-cell engager BNT142 in development, while clinical-stage anti-Claudin6 T-cell engager MAbs include Xencor’s XmAb541; these will now be joined by Context’s CTIM-76, which started a phase 1 trial in Claudin6-positive tumours last month.

Context announced the clearance of CTIM-76’s IND in May, and this is its first clinical-stage project. It will soon have a second, however, in the anti-mesothelin T-cell engager CT-95, which the company acquired for just $4m last month from Link Immunotherapeutics.

Link had been developing this as LNK101, and had obtained IND clearance for it, but then moved to sell off assets. CD3-based anti-mesothelin T-cell engagement is also the target of another project newly into phase 1, namely Zymeworks’ ZW171, on whose IND the US regulator signed off in June. 

And another private biotech, the Germany-based Eisbach Bio, is now a clinical-stage company, after starting phase 1 of its lead asset, the ALC1 inhibitor EIS-12656, in cancers with homologous recombination deficient mutations. Eisbach says its focus is on synthetic lethality, and OncologyPipeline reveals no other industry projects targeting ALC1.