Merck and Sanofi sound the alarm for ILT inhibition

ILT inhibition has attracted the likes of Pfizer, but two big names no longer in this game are Merck & Co and Sanofi. Merck told ApexOnco that it has deprioritised MK-4830, an anti-ILT4 antibody it had been developing with Agenus, just as the French group returned rights to BND-22, an anti-ILT2 MAb, to its originator Biond Biologics. 

Merck’s move came after a “routine evaluation” of its pipeline, the spokesperson said, while Biond also pointed to Sanofi’s R&D prioritisation, adding that the phase 1 portion of an ongoing phase 1/2 trial of BND-22 had posted “encouraging results”. However, an ESMO 2024 presentation suggests otherwise and there must now be doubts about this mechanism, particularly after lacklustre early data with another contender, NGM’s NGM707.

For now, MK-4830 is still listed on Agenus’s website as being Merck-partnered; the group will report fourth-quarter earnings on 11 March, so perhaps the status of the collaboration will become clearer then. The groups began working together in 2014.

In hindsight the writing has been on the wall for MK-4830 for some time: in its third-quarter SEC filing Agenus disclosed that development of the project was being limited to a phase 2 neoadjuvant ovarian cancer study testing MK-4830 plus Keytruda and chemotherapy, with or without Avastin.

Biond belief

As for BND-22, the dose-escalation portion of the phase 1/2 study revealed a 3% ORR with monotherapy (1/31 responses); 4% with a Keytruda combo (1/23 responses); and 9% with an Erbitux combo (2/22 responses). Serious adverse events were seen in 29% of patients across the cohorts, and there were two deaths in the monotherapy arm, one from cancer and one from urosepsis, although these weren’t deemed related to BND-22.

Enrolment is now ongoing into the phase 2 dose-optimisation and expansion portion of the trial, which will evaluate BND-22 monotherapy in cholangiocarcinoma, and an Erbitux combo in NSCLC and colorectal cancer.

These results came after an ORR of 13% in the phase 1/2 trial of NGM Biopharmaceuticals' NGM707, presented at last year’s AACR meeting. This looks particularly unimpressive given that NGM707 was combined with Keytruda, though four of the five responders had been previously treated with checkpoint inhibitors.

NGM707 acts slightly differently, being an ILT2/ILT4-targeting bispecific.

Pfizer entry

This is the same dual mechanism that Pfizer has plumped for with PF-07826390, which it took into the clinic last summer. Agenus, meanwhile, also has a shot at ILT2, with its antibody AGEN1571.

ILT2 and ILT4, also known as LILRB1 and LILRB2, are expressed on myeloid cells in the tumour microenvironment, and are implicated in suppressing the body’s antitumour immune response. It’s hoped that hitting these targets could help overcome PD-(L)1 resistance.

However, Sanofi and Merck are clearly no longer convinced.

Clinical-stage projects with activity against ILT2 and/or ILT4

Note: *includes one pathologic complete response; **Roche-sponsored umbrella trial. Source: OncologyPipeline.