Akeso builds on earlier success with bispecifics

China’s bispecific antibody specialist Akeso is taking two more such molecules into phase 1. The projects, AK132 and AK131, which respectively hit Claudin18.2 x CD47 and PD-1 x CD73, appear in the latest new listings on the clinicaltrials.gov registry.

Several other bispecifics appear among these first-in-human entrants, including the latest MAb to emerge from a long-standing alliance between Genmab and BioNTech. Meanwhile, Compass Therapeutics is combining PD-1 with PD-L1 blockade in CTX-8372, while Bristol Myers Squibb is bolstering its multiple myeloma effort with BMS-986453, which targets BCMA and GPRC5D.

BMS-986453 aims to combine the mechanism of Johnson & Johnson’s Talvey with that of Tecvayli, for instance, and Bristol’s GPRC5D-targeting Car-T project BMS-986453, impressed at the recent ASH conference. Compass’s PD-1 x PD-L1 MAb aims to eliminate PD-1 from effector cells rather than inhibiting PD-1/PD-L1 interaction, something the group hopes will prove more efficacious than monospecific binding.

Pressing ahead

The fact Akeso is pressing ahead with two more bispecifics looks like the company making the most of its first two successes: cadonilimab became the world’s first PD-1 x CTLA-4 bispecific to be approved, while ivonescimab, which targets PD-1 and VEGF, was licensed to Summit for $500m up front.

That said, AK132 and AK131, which are starting trials in unspecified solid tumours, are playing into extremely competitive markets. CD47 blockade has generated few successes so far, and there’s little evidence backing its combination with more familiar targets; notably, Pfizer recently canned the PD-1 x CD47 bispecific PF-07257876.

Another bispecific MAb newly into phase 1 is Genmab/BioNTech’s GEN1059, which hits Epcam and the co-stimulatory protein 4-1BB. The companies have had a discovery alliance since 2015 focusing on Genmab’s Duobody technology, and this was expanded last year.

An even more audacious approach is being tested by AstraZeneca, whose FPI-2068 targets EGFR and cMet, just like J&J’s Rybrevant, for instance, but additionally delivers alpha particles by virtue of an actinium-225 label. Astra isn’t a major force in radiopharmaceuticals, but in 2020 it tied up with Fusion Pharmaceuticals to work on alpha emitters; FPI-2068 is the result.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 27 Nov and 15 Dec 2023.

A separate recent deal saw Gilead acquire Xinthera, a private biotech developing three small-molecule PARP1 inhibitors. The first of these, now coded GS-0201, is now entering a phase 1 solid tumour trial with or without Trodelvy.

And various companies are looking at synthetic lethality mechanisms beyond PARP, with ATR and PRMT5 generating interest. Though toxicity hangs over the viability of the former approach – Bayer and Astra have experienced setbacks with elimusertib and ceralasertib respectively – Chia Tai Tianqing is moving its ATR contender TQB3015 into the clinic.

In addition to the novel projects above, two biosimilar versions of Merck & Co’s Keytruda, Sandoz’s GME751 and Qilu’s QL2107, will undergo comparator studies testing pharmacokinetics. Last month Biocad’s BCD-263, a biosimilar version of Bristol’s Opdivo, entered a similar pharmacokinetics trial, a strategy Amgen is separately pursuing with ANP 206. 

This story has been updated to correct the mechanism of AK131.