DUBLIN – The contest to develop new therapeutics targeting transforming growth factor beta 1 (TGF-beta1) signaling in cancer intensified this week, as both Abbvie Inc. and Scholar Rock Holding Corp. disclosed clinical trial starts for their respective drug candidates. In the case of Abbvie, of North Chicago, the move triggered a $30 million milestone payment to its partner, Argenx SE, of Breda, the Netherlands.

Abbvie is taking forward a first-in-class Argenx antibody, ARGX-115 – now called ABBV-151 – which targets TGF-beta1 signaling indirectly, by inhibiting glycoprotein A repetitions predominant (Garp), a cell-surface protein involved in TGF-beta1 activation. Cambridge, Mass.-based Scholar Rock is taking a more direct route with SRK-181, an antibody that binds the latent, inactive form of TGF-beta1 and prevents its activation. Both programs are intended to boost patient responses to immune checkpoint inhibitors by preventing TGF-beta1-mediated activation of immunosuppressive regulatory T cells (Treg cells).

Abbvie is embarking on an extensive phase I study, which will recruit 184 participants. It will study ABBV-151 as a monotherapy and in combination with its in-house PD-1 inhibitor, ABBV-181, which is undergoing numerous phase I trials across a range of indications. The ABBV-151 trial (NCT03821935), which includes dose-escalation and dose-expansion phases, will recruit patients with metastatic or locally advanced solid tumors.

Scholar Rock is some ways behind, but it nominated a clinical candidate this week, SRK-181, which it aims to move into a phase I trial in patients with solid tumors around mid-2020.

Both are, of course, some ways behind Merck KGaA, of Darmstadt, Germany, and London-based Glaxosmithkline plc, who last month entered a pact, worth up to €3.7 billion (US$4.2 billion), including €300 million up front, to co-develop Merck's fusion protein, M-7824 (bintrafusp alfa). (See BioWorld, Feb. 6, 2019.)

M-7824, which entered the clinic in 2015, is designed both to sequester TGF-beta within the tumor microenvironment and to block the immunosuppressive activity of PD-L1. It comprises the extracellular domain of human TGF-beta receptor II linked to an antibody fragment derived from Merck's marketed anti-PD-L1 antibody, Bavencio (avelumab).

The drug is undergoing numerous phase II studies – some of them potentially registrational – in a range of cancer indications, including non-small-cell lung cancer, small-cell lung cancer, human papillomavirus-associated malignancies and other solid tumor indications.

Also in the clinic is Austin, Texas-based Formation Biologics Inc. (Forbius), which is developing AVID-200, a dual TGF-beta1 and TGF-beta3 trap. It is currently recruiting 36 patients with advanced or solid tumors into a phase I study; a phase I study in systemic sclerosis is also underway.

Interest in TGF-beta as a drug target is undergoing a renaissance, driven largely by the need to boost responses to checkpoint inhibitors. The TGF-beta pathway has been the focus of numerous drug development efforts over several decades, but its complex biology proved difficult to crack. Early development efforts were plagued by cardiotoxicities, as the first wave of small-molecule and antibody drugs were unable to distinguish between the various isoforms, which play distinct physiological roles. According to Forbius, TGF-beta1 and TGF-beta3 are both associated with disease, while TGF-beta2 is involved in cardiac function and hematopoiesis. But excessive TGF-beta2 can also have pathological consequences in certain settings.

Isarna Therapeutics GmbH, of Munich, which is developing isoform-specific antisense inhibitors of TGF-beta for ophthalmic and fibrotic disease, has completed a phase I study of ISTH-0036, which targets TGF-beta2 expression in glaucoma.

Shares in Argenx (Brussels:ARGX) gained €3, or about 2.7 percent, during trading Thursday, to close at €114.80.