The world needs Garp, according to Abbvie

In the search for immuno-oncology mechanisms that can improve on PD-(L)1 blockade Abbvie is putting a major effort behind Garp. Yesterday the group pledged to take its Argenx-derived anti-Garp MAb ABBV-151 into further trials, citing this as one reason why its R&D bill would increase from $6.5bn last year to $6.8bn in 2023.

According to comments on yesterday’s financials call, Abbvie has seen “incredibly encouraging data” with ABBV-151. Investors, however, have witnessed something else entirely: decidedly mediocre phase 1 results presented at last November’s SITC meeting, and a development programme that has so far proceeded at a snail’s pace.

For a start the Abbvie/Argenx deal was struck back in 2016, and it then took another three years before ABBV-151 entered phase 1. It was only last year that meaningful efficacy data emerged, and already in August Abbvie was boasting of "deepening responses over time and prolonged durability" with its Garp/PD-1 combo, saying it would move this into phase 2.

Six months on, and today ABBV-151 remains in phase 1. Yesterday Abbvie told analysts: "If that programme continues to advance the way we see it now we will want to expand our phase 2 and then phase 3 trials significantly across the road to the broad range of solid tumours."

Why?

So what has Abbvie seen to be so upbeat? It surely cannot be the 163-patient SITC dataset, which detailed ABBV-151 monotherapy results as well as those from patients given ABBV-151 plus budigalimab, Abbvie’s in-house anti-PD-1.

There was not a single remission in 23 subjects given ABBV-151, while across combo cohorts the ORR was 10%. In the combo expansion cohort the best results came in liver cancer (ORR 33%), but treatment of these patients was put on hold owing to adverse events. Abbvie then scrapped this study arm, citing liver cancer’s changing treatment landscape.

At least relative scarcity is one thing Garp inhibition has going for it. According to Evaluate Pharma only two other anti-Garp MAbs are in the clinic – Daiichi Sankyo’s DS-1055 and Shanghai Henlius’s HLX60 – and there are no human data yet to estimate their potential.

Safety is a live issue not only because of the liver cancer experience detailed at SITC, but also because Garp works by inhibiting expression of the cytokine TGF-β1, a mechanism that itself has been associated with cardiovascular toxicities.

However, Abbvie stresses that this has been seen when attempting to inhibit TGF-β1 directly, which results in an indiscriminate effect. Garp, on the other hand, is a docking receptor for TGF-β1, and is said to be expressed predominantly on activated T regulatory, or Treg, cells.

Thus blocking Garp is thought to result in an effect on TGF-β1 that is localised to Tregs, which are depleted as a result, and which are therefore unable to exert their immunosuppressive action.

This is all very well in theory, but some evidence in practice is also needed to back the kind of confidence Abbvie has shown. Look no further than Tigit for an example of the perils of launching a massive pivotal programme in the absence of monotherapy activity and without first obtaining convincing clinical backing.

Investors must hope that Abbvie has seen much more about ABBV-151 than they have.