BeiGene takes a new approach to a hot target

As more companies pile into crowded mechanisms like KRAS, a few groups are doing something different, ApexOnco’s latest look at first-in-human initiations reveals. This includes BeiGene, which is taking a co-stimulatory approach to GPC3 targeting, and Bristol Myers Squibb, which has quickly moved a GSPT1 degrader bought from Orum into the clinic.

Meanwhile, Miltenyi is targeting NPM1-mutant AML with its T-cell receptor project, a move that could pit it against menin inhibitors, the most advanced of which come from Syndax and Kura. And Regeneron is persevering with cytokines despite various failures in this field.

GPC3 me

GPC3 (glypican-3) emerged as a hot new target last week when the ASCO abstract drop revealed promising data with AbelZeta’s Car-T project C-CAR031 in heavily pretreated liver cancer.

The next day, a listing for a BeiGene GPC3-targeting MAb BGB-B2033 appeared on clinicaltrials.gov. However, this approach isn’t a slam dunk, with Takeda previously falling short with its own Car-T contender, TAK-102.

BeiGene’s attempt works differently, being a GPC3 x 4-1BB bispecific antibody. More broadly, big question marks remain around the merits of activating the 4-1BB co-stimulatory pathway, with other players exiting this arena and disappointing ASCO abstract data last week with Genmab and BioNTech’s anti-PD-L1 x 4-1BB MAb acasunlimab.

While several players are developing T-cell engagers that hit GPC3, according to OncologyPipeline the only other group with a GPC3 x 4-1BB is Boston Pharmaceuticals, whose Pieris-originated BOS-342 is in phase 1/2 in Australia.

More and less crowded

Still, BeiGene has followed the crowd with its anti-B7-H3 ADC, BGB-C354, which will soon move into the clinic, along with Innolake’s similarly acting ILB-3101.

This target fell under the spotlight last year when Merck & Co paid $1.5bn up front for Daiichi’s ifinatamab deruxtecan, followed by GSK swooping for Hansoh’s HS-20093. A search of OncologyPipeline reveals 13 clinical-stage B7-H3-targeting ADCs, despite AbbVie recently discontinuing its contender.

Another ever-popular target is KRAS, and here Quanta is about to begin human trials of its G12D-selective inhibitor – that group already has a supposedly “G12D preferring” pan-KRAS project, another relatively recent clinical entrant.

Much less crowded is GSPT1, and after a couple of false starts Bristol Myers Squibb’s focus is now on a CD33-targeting GSPT1 degrader acquired from Orum Therapeutics last year, now known as BMS-986497.

Bristol’s most advanced rival here is Monte Rosa Therapeutics, whose GSPT1 molecular glue degrader MRT-2359 had interim phase 1 dose-escalation data in solid tumours last year: among 15 evaluable patients there were two partial responses, with one unconfirmed, and there were dose-limiting toxicities at the highest dose tested, 2mg. 

Orum also has a HER2-targeting GSPT1 degrader, ORM-5029.

Menin rival

Meanwhile, privately held Miltenyi Biomedicine is taking a more novel approach with its autologous T-cell receptor project targeting dNPM1. The company is aiming at relapsed or refractory NPM1-mutant AML – a disease subtype being pursued by Syndax and Kura with their menin inhibitors, revumenib and ziftomenib respectively.

Currently, revumenib looks slightly ahead here, with pivotal data in NPM1m AML expected in the fourth quarter; Kura will have results with ziftomenib in early 2025. While there are a handful of other menin inhibitors in development, there are no other clinical-stage projects acting directly on NPM1, according to OncologyPipeline.

Cytokine perseverance 

Cytokine-based approaches were once big, but have fallen out of favour after disappointments from the likes of Nektar’s bempegaldesleukin. 

However, some groups are still active here, and it is notable that Regeneron is pressing ahead with a project described as a PD-1-targeted, receptor-masked IL-2. The company will hope that this more targeted approach could dial down the toxicity linked with recombinant human IL-2, Proleukin; however, various other methods designed to improve specificity have also fallen short.

Other anti-PD-1/IL-2 fusion proteins in development include Innovent’s IBI363, in phase 2, Roche’s RO7284755, in phase 1, and Novatim’s KY-0118, which is due to yield phase 1 dose-escalation data at this year’s ASCO; the abstract details no responses among 21 solid tumour patients.

Recently disclosed first-in-human studies*

Notes: projects newly listed on the clinicaltrials.gov database between 14 and 24 May 2024; **possibly an anti-PTK7 ADC, according to exclusion criteria on Chinese trials registry.