Tilos Therapeutics Inc. CEO Barbara Fox told BioWorld that the relationship with Merck & Co. Inc. "went pretty deep pretty fast," culminating in the pharma giant's decision to take over her firm for as much as $773 million. "We never intended to do this," she said. "We always assumed we were going to raise a series A, take these [candidates] forward independently, get some clinical proof of concept and look for partnerships later."

Tentative contacts, though, had begun with would-be partners and "we've been talking to investors up until last week because you never know what's going to happen," Fox said. The synergy between Kenilworth, N.J.-based Merck and Tilos, of Cambridge, Mass., quickly became obvious. "People are looking at the clinical data that are emerging from a number of different sources, from patients on checkpoint inhibitors and other therapies, and finding that transforming growth factor (TGF)-beta is a signal that keeps cropping up as a major driver of resistance," she said.

Merck brings aboard from Tilos a portfolio of antibody prospects that target TGF-beta. Specifically, Tilos deploys candidates that bind to latency-associated peptide (LAP). TGF-beta is secreted as a complex with LAP, which forms a cage around TGF-beta and keeps the cytokine inactive until it's used. Anti-LAP antibodies block the release of TGF-beta from the TGF-beta-LAP complex, which means the technology should knock down TGF-beta activity. The extracellular matrix (ECEM) is believed to store most of the latent TGF-beta in the body, and Tilos' anti-LAP antibodies not only deplete immunosuppressive cells but can inhibit TGF-beta release from inhibitory cells while leaving LAP-TGF-beta in the ECM untouched. Such an approach is meant to inhibit pathological and immunoregulatory processes without disturbing normal tissue homeostasis processes mediated by TGF-beta.

The buyout gives Merck all of Tilos' outstanding shares and includes an up-front payment as well as more if undisclosed milestones are reached, though Fox said she could not provide more detail.

Founders put together Tilos in 2016 based on research by Galina Gabriely and Howard Weiner at the Brigham and Women's Hospital. Weiner's work in autoimmune disease sent him in the direction of LAP and its expression on clinically relevant suppressive cell populations, and the Weiner lab developed antibodies specific for LAP, which showed a strong effect in animal models. Findings published in Science Immunology in 2017 found that an anti-LAP monoclonal antibody pushed back tumor growth in mouse models of melanoma, glioblastoma and colorectal carcinoma. Anti-LAP effects included decreasing LAP-positive CD4 T cells and blocking the release of TGF-beta. Other efforts published two years earlier in Nature Communications identified and characterized LAP-expressing gamma-delta cells.

Tilos, which takes its name from an island in the Aegean Sea and contains an acronym for tumor-infiltrating lymphocytes, was established by Boehringer Ingelheim Venture Fund and Partners Innovation Fund, with added funding provided by Shangpharma Innovation Fund. About $10 million has been brought into Tilos, which employs fewer than 10 people and will become a wholly owned subsidiary of Merck. Fox will step down from her full-time role and serve as a consultant, she said, though others – including Chief Scientific Officer Jessie English – will stay on.

Scholar Rock, GARP bids comparable

Drug developers are exploring many ways to hit TGF-beta, from antibodies at Basel, Switzerland-based Novartis AG and Sanofi SA, of Paris, to small molecules at Indianapolis-based Eli Lilly and Co. and Pfizer Inc., of New York. "The overall approach that we've taken is supported by other things in the field as is always the case, but we have a unique handle on the biology of what's been happening, based on decades of work in our founder's lab," Fox said. She called the Tilos effort "similar although distinguishable" from Scholar Rock Holding Corp., of Cambridge, Mass., which last December struck a deal in fibrosis with Foster City, Calif.-based Gilead Sciences Inc. The pact included $80 million up front – $50 million in cash and $30 million in Scholar Rock common shares – along with a one-time milestone payment of $25 million when certain preclinical studies are completed. More could come later, with $1.425 billion in potential payments across three programs in the form of research, development, regulatory and commercialization milestones. Scholar Rock also is eligible for high single-digit to low double-digit tiered royalties on product sales. Gilead took exclusive options to license global rights to candidates emerging from three TGF-beta programs, including inhibitors said to target activation of latent TGF-beta1 with high specificity, inhibitors that selectively target activation of latent TGF-beta1 localized to the ECM and a third, undisclosed, TGF-beta1 discovery program. (See BioWorld, Dec. 20, 2018.)

Another firm with projects underway in the realm is North Chicago-based Abbvie Inc., which has a deal with Argenx SE, of Breda, the Netherlands. Abbvie is taking forward a first-in-class Argenx antibody, ARGX-115 – more recently dubbed ABBV-151 – to target TGF-beta1 signaling indirectly by inhibiting glycoprotein A repetitions predominant (GARP), a cell-surface protein involved in TGF-beta1 activation. Also, Merck KGaA, of Darmstadt, Germany, and London-based Glaxosmithkline plc, in February signed an agreement worth up to €3.7 billion (then US$4.2 billion), including €300 million up front, to co-develop Merck's fusion protein, M-7824 (bintrafusp alfa). The compound, 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's made up of 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). (See BioWorld, Feb. 6, 2019, and March 15, 2019.)

Fox said Scholar Rock's research is "really the closest" to Tilos', though different nomenclature is used to describe the program and the level of selectivity in various environments may differ. As for Abbvie's GARP push, one could "certainly look at them as comparable," she said. "We think we're better."