BeiGene tries where others failed

The recent tribulations of Sanofi in targeting CEACAM5 and of Amgen in hitting PRMT5 haven’t discouraged BeiGene, which has just moved two pipeline assets with these mechanisms, BG-C477 and BGB-58067 respectively, into human studies, listings new to the clinicaltrials.gov registry reveal.

Other first-in-human initiations include a molecule against integrin αvβ8, from Corbus, following Vincerx’s disappointment with a separate integrin mechanism in April, and a BTK degrader from Ubix hoping to rival projects from BeiGene and Nurix with this approach. BeiGene has been especially active in pushing preclinical assets into the clinic, and it now also has a new trispecific antibody entrant.

That last asset is BG-T187, a MAb combining EGFR blockade with activity at two distinct cMet epitopes, a step up from Johnson & Johnson’s approved anti-EGFR x cMet MAb Rybrevant. Merus also has an anti-EGFR x cMet MAb, petosemtamab, while anti-cMet ADCs are in development at AbbVie, Regeneron (with a biparatopic MAb davutamig) and others.

Questions

Other assets BeiGene has recently taken into phase 1 include the pan-KRAS inhibitor BGB-53038, but its latest entrants will raise some questions.

BG-C477, an ADC against CEACAM5, is a case in point, given that the leading example of this mechanism, Sanofi’s tusamitamab ravtansine, was discontinued after failing the phase 3 Carmen-LC03 trial in second-line non-squamous NSCLC. The French company has switched to another similarly acting project, SGN-CEACAM5C, which has yet to generate human data.

A post-mortem of Carmen-LC03 at the recent ESMO meeting suggested that the trial would have had a better chance of succeeding had a higher level of CEACAM5 expression been mandated, but the entry for the phase 1 solid tumour study of BG-C477 makes no mention of required levels of this antigen.

Meanwhile, the PRMT5 inhibitor BGB-58067 faces the precedent of Amgen’s AMG 193, which despite scoring a last-minute presidential session spot at ESMO has continued to post broadly disappointing data. In taking BGB-58067 into phase 1 BeiGene is joining Tango Therapeutics, Bristol Myers Squibb and AstraZeneca with this synthetic lethality approach.

Recently disclosed first-in-human studies*

Note: *selected projects newly listed on the clinicaltrials.gov database between 19 and 23 Sep 2024.

While another of BeiGene’s clinical efforts, the BTK degrader BGB-16673, is in a battle against Nurix’s NX-5948 – both impressed at EHA this year – this approach now has a new clinical competitor in Ubix Therapeutics’ UBX-303061. Ubix, a private South Korean biotech, specialises in protein degradation, with a pipeline that also includes AR, BCR-ABL and LCK degraders.

Finally, Corbus is following its lead project against Nectin-4 with CRB-601, a MAb targeting integrin αvβ8 that additionally blocks the activation of TGFβ. Work on integrins had a setback when at AACR Vincerx stock crashed after VIP236, that company’s small-molecule drug conjugate targeting the separate integrin αvβ3, yielded zero responses among 15 patients. 

There are two other clinical-stage αvβ8 players, according to OncologyPipeline: Pfizer's PF-06940434 and Pliant's PLN-101095. A key feature of Corbus's trial is that patients must express αvβ8; in the VIP236 study Vincerx declined to set a similar stipulation regarding αvβ3.