Looking for an ivonescimab encore

If the management teams of several companies are suddenly scrambling to get their hands on a VEGF x PD-(L)1 bispecific you can hardly blame them; results at last weekend’s ESMO conference with Akeso’s ivonescimab confirmed this mechanism to be among the hottest in biotech.

In investors’ eyes the data backed the enthusiasm of Summit, which paid Akeso $500m for rights to ivonescimab. The licensing trick has been done twice more, by BioNTech and Instil Bio, both for considerably smaller up-front amounts. A search of OncologyPipeline reveals five other currently unpartnered clinical-stage anti-VEGF x PD-(L)1 MAbs, all in development at Chinese companies.

Perhaps the most prominent is Shanghai Junshi’s JS207. Junshi is the originator of toripalimab, the anti-PD-1 MAb that’s widely marketed in China and was last year approved in the US as Loqtorzi, after being licensed to Coherus. Junshi’s partnering pedigree also includes a short-lived China-focused toripalimab deal with AstraZeneca.

JS207 is known to have a similar mechanism to ivonescimab, targeting VEGF-A and PD-1, but its precise structure is undisclosed, and the molecule only recently entered phase 1.

Best modality

The jury is still out on the best modality for this approach, and BioNTech, which has rights to Biotheus’s BNT327, argues that that molecule’s action on VEGF-A and PD-L1 causes precise VEGF blockade by anchoring to tumour cells. BNT327 also impressed at ESMO, in triple-negative breast cancer, while ivonescimab added TNBC and colorectal to NSCLC as potential indications, all with the claim of reduced toxicity versus separate Avastin use. 

Meanwhile, Instil Bio argues that using a VEGF “trap” enables SYN-2510, an anti-VEGF x PD-L1 MAb it licensed from ImmuneOnco in August, to target multiple VEGF receptor ligands, not just VEGF-A. Though clinical data have so far failed to live up to the promise, Instil is up an extraordinary 370% since the ImmuneOnco deal was signed.

Two other VEGF x PD-1 bispecifics are in clinical trials, according to OncologyPipeline. These are SCBio’s SSGJ-707 and Sinocelltech’s SCTB14, but like JS207 neither has yet generated human data.

Meanwhile, on the VEGF x PD-L1 side of the fence Tasly Biopharmaceuticals is developing B1962, while the private group Hangzhou Sumgen Biotech is working on SG1408. The former was originated by the OBI Pharma subsidiary AP Biosciences, and Tasly’s 2019 licence concerns rights only in China, so those in western markets are likely still available.

Trispecifics

OncologyPipeline also reveals trispecifics, adding TGF-β or activity at CTLA-4 to VEGF x PD-(L)1. However, the former approach is beset with failures, while the latter might be expected to add significant toxicity.

But Instil's success will have been noted by more than one biotech mulling a pivot after a clinical disappointment. In Instil’s case the disappointment concerned TIL therapeutics, that company’s original focus, and investors’ positive reaction shows the ImmuneOnco licensing deal to have been a smart move – at least so far.

Coincidentally, another TIL player, Achilles Therapeutics, this week threw in the towel on TILs, and moved to refocus. While that refocus is said to involve alternative ways of targeting clonal neoantigens, for many others Instil’s blueprint will be hard to ignore.

Industry projects with activity at VEGF and PD-(L)1

Note: *fusion protein, as the rest are multispecific MAbs. Source: OncologyPipeline.