AbbVie sees a world according to GARP

AbbVie’s oncology portfolio is one of few to feature a GARP inhibitor, an antibody called livmoniplimab, and the group has unveiled major plans for this asset: last week’s fourth-quarter update revealed that phase 3 studies would be under way soon.

This might come as a surprise. AbbVie got rights to livmoniplimab under a 2016 licensing deal with Argenx, and the then preclinical asset took another three years just to enter phase 1. Phase 2 only began last September, and while AbbVie claims to have seen incredibly encouraging results, all investors have been shown is a rather mediocre livmoniplimab dataset at the 2022 SITC conference, plus an update at ASCO-GU this year.

That 163-patient phase 1 cohort concerned livmoniplimab monotherapy as well as a combination with budigalimab, AbbVie’s in-house anti-PD-1 MAb. In 23 subjects given monotherapy there wasn’t a single response reported, while combo cohorts yielded an ORR of just 12%, SITC 2022 heard. 

In the combo expansion cohort the best results came in liver cancer, where a 33% response rate was cited, but this was put on hold owing to adverse events before AbbVie discontinued this study arm. Against this backdrop last September’s start of the phase 2 Livigno-1 trial, testing livmoniplimab plus budigalimab in PD-(L)1-relapsed liver cancer, might have come as a surprise.

Phase 3 next

Equally surprising will have been the disclosure that pivotal trials would now get under way, still without AbbVie having presented any clinical data beyond the phase 1 results to back its enthusiasm for livmoniplimab.

New clinicaltrials.gov listings reveal that the phase 2/3 budigalimab combo Livigno-2 study in liver cancer is to begin this month. Meanwhile, a combo with budigalimab plus chemo is to be tested versus Keytruda plus chemo in first-line non-squamous NSCLC, in the Livigno-4 trial starting in April.

A third advanced study, in urothelial bladder cancer, will also start soon, AbbVie told investors on Friday. That was likely driven by the ASCO-GU update this year, where an update on a bladder cancer expansion cohort showed an 18% confirmed ORR, again in a budigalimab combo.

Perhaps one reason for AbbVie’s interest in livmoniplimab is the asset's relatively unusual pharmacology. As a MAb that inhibits GARP livmoniplimab is one of just five projects with this mechanism to have entered clinical testing, OncologyPipeline reveals, and clinical support for the others is similarly scant.

GARP, standing for glycoprotein A repetitions predominant, works as a docking receptor for latent TGF-β1, and is said to be expressed on T regulatory cells. Its blockade aims to reduce Tregs’ immunosuppressive action by localised TGF-β1 inhibition, and the mechanism should be of interest to other companies working on TGF-β signalling.

When AbbVie signed the deal with Argenx livmoniplimab was known under the lab codes ARGX-115/ABBV-151. The modest $40m up-front fee, plus $20m near-term milestone payment, probably reflected the preclinical status of this project, though the milestone amount of $625m seems relatively undemanding too, even by 2016 standards.

With such modest beginnings it’s surprising how much prominence livmoniplimab now has in AbbVie’s oncology pipeline. The company has previously boasted of deepening responses over time and prolonged durability with the livmoniplimab/budigalimab combo, and presumably these have driven its phase 3 push. Perhaps data backing such activity will be revealed soon.

The GARP pipeline

Source: OncologyPipeline.