Familiar targets with a twist

Pharmaceutical assets newly into human trials include several hitting targets with which the industry is more than familiar – think CD19, Claudin18.2, KRAS G12C and B7-H3. However, some try to differentiate themselves from the herd, while others show true novelty in their choice of target antigen.

The last group includes an inhibitor from Ajax Therapeutics that specifically hits type II of the JAK2 tyrosine kinase, and an approach aimed at activating RNA in development by China’s Ractigen Therapeutics. OncoC4’s anti-Siglec10 MAb ONC-841 is also novel, being the industry’s only project with such a mechanism, though its first-in-human study reveals something of a knockback from the FDA.

A first-in-human study of ONC-841 was first listed on the clinicaltrials.gov registry in January, and was unusual in seeking to enrol healthy volunteers and including a placebo cohort. However, that was withdrawn after FDA reviewers said phase 1 should be carried out in cancer subjects, and a trial in solid tumours is now to begin in June.

OncoC4 gained prominence last year after licensing the anti-CTLA-4 MAb gotistobart for $200m to BioNTech. This analysis looks at new entries on clinicaltrials.gov over the past two weeks.

Next-gen JAK

Novel approaches to JAK2 inhibition include Incyte’s JAK2 V617F inhibitor INCB160058. Now Ajax is going into a post-Jakafi phase 1 trial with AJ1-11095, which specifically hits type II of the protein; this approach is intended to overcome G993A, a resistance mutation acquired in response to treatment with typical JAK1/2 inhibitors like Jakafi.

Meanwhile, RAG-01 is Ractigen’s first oncology project to enter human trials. The company is trying to develop short duplex RNA (small activating RNA or saRNA) to upregulate transcription of an endogenous gene, leading to restoration of endogenous protein function; in this way RAG-01 attempts to upregulate the tumour suppressor gene p21.

Among more familiar targets, Innovent is taking IBI3001, an ADC with activity at B7-H3, into a solid tumour trial, while BridgeBio’s TheRas subsidiary is advancing the KRAS G12C inhibitor BBO-8520 in the familiar setting of KRAS G12C-mutated NSCLC, where Amgen’s Lumakras and Bristol Myers Squibb’s Krazati are already approved.

ADCs against B7-H3 include Macrogenics’ vobramitamab duocarmazine and Daiichi Sankyo’s Merck & Co-partnered ifinatamab deruxtecan, though Innovent’s IBI3001 additionally hits EGFR. AbbVie recently discontinued two ADCs that separately target B7-H3 and EGFR.

And while KRAS G12C is a hugely crowded space BridgeBio reckons it’s differentiated by virtue of BBO-8520 being what it describes as a dual inhibitor, modifying both GTP (active) and GDP (inactive) forms of KRAS G12C. That said, Revolution’s pan-KRAS approach, which targets the active form, will loom large over all in this field if it comes to fruition.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 26 Mar and 9 Apr 2024.