Despite the setbacks, interest in TGF-β remains

After TGF-β emerged as a hot target in the quest to improve on the efficacy of PD-(L)1 blockade numerous companies bought into the story, but the field just saw the setback of one of its most advanced projects, the anti-TGF-β MAb nisevokitug, which Novartis will shortly hand back to Xoma.

This follows the high-profile failure of Merck KGaA/GSK’s bintrafusp alfa, an anti-PD-L1/TGF-β fusion protein the companies had pitted head to head against Keytruda in lung cancer. There have been other setbacks in this field, too, but these do not appear to have deterred numerous groups from investigating how best to make use of TGF-β.

A good example is Scholar Rock, which is developing the rival anti-TGF-β1 MAb SRK-181, and zeroing in on patients with specific biomarkers, namely cytotoxic (CD8+) T-cell tumour infiltration, phosphorylation of Smad2, and the presence of myeloid-derived suppressor cells.

Biomarkers?

Notably, trials of nisevokitug had not apparently been enriched for biomarkers. Novartis announced last month that it had discontinued a pancreatic ductal adenocarcinoma study, but said a phase 2 colorectal cancer trial was ongoing; now the Swiss group has pulled the plug entirely, Xoma revealed in a US SEC filing.

Back in 2019 GSK paid Merck KGaA €300m up front for rights to biintrafusp, but two years later that deal was scrapped. Though that project remains in a few trials, its active development is effectively over.

It is important to recognise the possible drawbacks of bintrafusp. TGF-β is seen as a key driver of resistance by stopping immune system cell tumour infiltration, and so its blockade has potential in combination with anti-PD-(L)1 MAbs. But it relies on dosing flexibility – something that was impossible with a fusion protein like bintrafusp.

Another group that has placed a bet on TGF-β is Bristol Myers Squibb, which in 2020 bought the private company Forbius for an undisclosed amount. Forbius boasted a portfolio of selective and potent inhibitors of TGF-beta 1 and 3, and the lead of these, BMS-986416, remains in clinical trials.

Selected clinical-stage projects with activity on TGFβ

Source: OncologyPipeline.

Among other setbacks, Sanofi’s anti-TGF-β MAb SAR439459 was discontinued some time ago, while Pfizer’s TGFβR1 inhibitor PF-06952229 has had its sole study on clinicaltrials.gov marked terminated owing to “strategic considerations”.

In late 2018 Gilead signed an immuno-oncology collaboration with Agenus worth $120m up front, whose lead asset was AGEN1423/GS-1423, an anti-CD73-TGFβ-Trap bifunctional MAb. This was later given the INN dalutrafusp alfa, but no longer appears in the pipeline, its clinical trial having been terminated for what looks like lack of activity.

It is also worth mentioning small-molecule agents, specifically inhibitors of TGFβR1. Bristol and Lilly both dabbled here, with BMS-986260 and the once highly touted galunisertib respectively, but neither remains in active clinical development. Lilly is apparently continuing with the galunisertib follow-on LY3200882 in phase 1, though its Keytruda combo trial was withdrawn before enrolling any patients.

Medpacto’s small molecule vactosertib remains in phase 2, and with the exit of nisevokitug is now one of the industry’s most advanced TGFβ assets.