If there was uncertainty about the validity of targeting TGF-β in immuno-oncology then last month’s €300m ($343m) deal between Merck KGaA and Glaxosmithkline helped dispel it. Targeting this cytokine, it is thought, could help treat patients who are unresponsive to, or relapse after, checkpoint blockade alone.
Now the young biotech Scholar Rock, previously known to have researched TGF-β inhibition, has selected SRK-181 as a lead molecule to take into a phase I solid tumour study next year. This puts it among a group of small companies, including Formation Biologics, Isarna and Venn Therapeutics, that are also putting their faith in this mechanism.
The involvement of big pharma could either be seen as a significant obstacle, or as an endorsement for biotechs seeking partnerships with big players that have yet to get a foothold here. The Glaxo deal, to license M7824 from Merck KGaA, will have done nothing to temper expectations of what deals could be worth.
Broadening the response
As is typical nowadays the rationale with TGF-β inhibition is that clinical response to checkpoint blockade needs to be broadened, and Scholar reckons TGF-β signalling is responsible for patients developing resistance to anti-PD-(L)1 drugs.
Cancer cells frequently express TGF-β, and one school of thought is that this cytokine affects the balance of the tumour microenvironment by inducing regulatory T cells and inhibiting effector T cells.
Scholar will presumably want to combine SRK-181 with a checkpoint blocker. This would mirror the approaches taken by Lilly with galusinertib, Sanofi with SAR439459, Novartis with NIS793 and the South Korean biotech Medpacto with vactosertib.
A similar thinking lies behind M7824 (bintrafusp alfa), the subject of the Merck KGaA/Glaxo tie-up, which captures both elements of a combinatorial approach in a single molecule; the asset is a bispecific fusion protein targeting TGF-β and PD-L1, and in a bold move it is already in a head-to-head first-line lung cancer trial against Merck & Co’s Keytruda.
|Selected oncology assets targeting TGF-β|
|M7824 (bintrafusp alfa)||Merck KGaA/ Glaxosmithkline||Anti-PD-L1/TGF-β fusion protein||NCT03631706||Head to head vs Keytruda|
|Galunisertib||Lilly||TGF-β R1 kinase inhibitor||NCT02423343 & NCT02734160||Combos with anti-PD-1 (Opdivo & Imfinzi)|
|SAR439459||Sanofi||Anti-TGF-β MAb||NCT03192345||Combo with anti-PD-1 (Libtayo)|
|NIS793||Novartis/Xoma||Anti-TGF-β Mab||NCT02947165||Combo with anti-PD-1 (PDR001)|
|Vactosertib||Medpacto||TGF-β inhibitor||NCT03724851 & NCT03732274||Combos with anti-PD-1 (Keytruda & Imfinzi)|
|AVID200||Formation Biologics||TGF-β inhibitor||NCT03834662|
|ARGX-115/ABBV-151*||Argenx/Abbvie||TGF-β-inactivating MAb||NCT03821935||Combo with anti-PD-1 (ABBV-181)|
|Trabedersen||Isarna Therapeutics||TGF-β2 antisense||NCT00844064|
|VTX-002||Venn Therapeutics||Anti-TGF-β MAb||NA|
|ACE-1332||Acceleron Pharma||TGF-β ligand trap||NA||Likely discontinued|
|SRK-181||Scholar Rock||TGF-β1 inhibitor||NA|
|TGF Beta Inhibitors||Rigel||TGF-β kinase inhibitor||NA||Bristol-Myers Squibb terminated deal in 2018|
|Source: EvaluatePharma & clinicaltrials.gov. *ARGX-115 and ABBV-151 are assumed to be the same.|
Another sign of how some companies are using TGF-β targeting to broaden response to checkpoint blockade is that some studies specifically test this approach in subjects who have already failed anti-PD-(L)1 treatment. This is the approach taken in Sanofi’s first-in-human trial of SAR439459 combined with Libtayo.
This is also the case in some cohorts of Abbvie's study of ABBV-181, an anti-PD-1, combined with ABBV-151. The mechanism of the latter has not been disclosed, but it is thought to be the TGF-β-inactivating MAb previously known as ARGX-115, and licensed from Argenx three years ago.
Pfizer and Isarna, meanwhile, are taking a different tack. Their respective early studies of PF-06952229 and trabedersen test these TGF-β-inhibiting assets as monotherapies in subjects whose cancers express high TGF-β signatures or are known to overproduce TGF-β.
In 2015 Bristol-Myers Squibb paid Rigel $30m in a discovery deal focusing on TGF-β kinase inhibitors, but scrapped this tie-up last year. That decision, said to have been due to the lack of a therapeutic window, has been the most significant recent setback to this quietly growing field of research.