Alex Lugovskoy has seen many antibodies come and go in his more than two-decade career in drug discovery. The vast majority of them work by inhibiting a cell function. Lugovskoy, now CEO of the startup Diagonal Therapeutics, said he had long hoped that someone would find a way to develop antibodies that activate their targets. With each passing year no one did it anymore. So he took on the challenge himself.
Diagonal uses computational and experimental techniques to understand what happens when an antibody binds to a receptor and which binding combinations produce the desired effect. After developing its platform over the past two years, the startup pulled back the curtain on its approach last week. Diagonal also announced $128 million in financing to support a pipeline that includes a lead program for a rare blood clotting disorder for which there are no FDA-approved therapies.
Cambridge, Massachusetts-based Diagonal isn’t reinventing the wheel when it comes to antibodies. The company’s drugs leverage the biopharmaceutical industry’s more than 40 years of experience in developing and producing antibodies, Lugovskoy said. However, he added that a key difference is that while Mother Nature may point the way to inhibiting a target, it is less clear how a receptor can be activated to produce a desired signaling effect. Each diagonal antibody binds to two targets and brings them together in a specific way. The many ways for an antibody to bind to different sites on receptors result in billions of possible combinations.
“Filtering all these combinations was not possible without our technology, that’s what we bring,” Lugovskoy said.
Alex Lugovskoy, photo by Diagonal Therapeutics
Early in his career, Lugovskoy worked in drug development at Biogen. His experience also includes senior positions at Merrimack Pharmaceuticals, Morphic Therapeutic and Dragonfly Therapeutics. After leaving Dragonfly in 2021, Lugovskoy said his thoughts returned to the question of why antibody research was so focused on inhibitors rather than agonists. But unlike at the beginning of his career, more powerful technologies are now available that can be used for research and development of agonist antibodies. He brought the idea to Michael Gladstone, a partner at Atlas Venture. In 2022, they founded Diagonal, whose name is a combination of the words “digital,” “agonist,” “antibody,” and “ligand.” The startup received seed funding from Atlas, Lightspeed Venture Partners and Velosity Capital.
Diagonal has spent the first year testing its technology to see what it can do. Research eventually turned to hereditary hemorrhagic telangiectasia (HHT), a condition caused by genetic mutations that lead to malformations in blood vessels that can rupture. HHT is often first noticed when patients develop frequent nosebleeds, but the condition also poses risks to the gastrointestinal tract and the artery-vein connections in internal organs, particularly the lungs, liver and brain.
While Diagonal’s drug candidate doesn’t address the mutations at the cause of HHT, it could address the signaling problems that lead to abnormal blood vessels. The mutated genes that cause HHT encode proteins in the TGF-beta signaling pathway. Diagonal has developed an antibody that reactivates receptors in this way. Lugovskoy said preclinical studies have shown that Diagonal’s drug prevents and reverses the development of pathological vascular malformations characteristic of HHT.
A second Diagonal program is in development for pulmonary arterial hypertension (PAH), a rare form of high blood pressure that affects the arteries leading from the heart to the lungs. The disease develops when the arteries narrow, causing the heart to work harder and also causing difficulty in breathing. In contrast to HHT, there are medications against PAH. Vasodilators, drugs that expand blood vessels, have been part of the standard treatment for PAH for years. Merck’s recently approved fusion protein Winrevair takes a different approach, capturing proteins that drive the proliferation of cells that build and constrict blood vessels. Diagonal’s goal is to develop another approach to treating PAH with agonist antibodies that aim to correct the signaling imbalance that leads to cell proliferation.
Lugovskoy said Diagonal’s technology can produce a working prototype of an agonist antibody in eight months or less, about the same time it takes to develop an inhibitor antibody. As for safety, Lugovskoy said side effects have not been a problem so far, which he attributes to the effectiveness of these drugs. Instead of creating a new signaling cascade, Diagonal attempts to restore the signaling that should be there but has been lost due to disease.
The Diagonal technology is indication-agnostic and has produced agonist antibodies for four targets. In addition to the HHT and PAH programs, the pipeline includes an antibody that activates IL-18 receptor signaling to elicit antitumor effects. The fourth target remains unknown. Going forward, Diagonal’s focus will be on rare cardiovascular diseases caused by genetic loss of function, Lugovskoy said. Now that Diagonal has moved out of stealth mode, the company is looking for biopharma partners interested in applying the technology to therapeutic areas outside of the startup’s core cardiovascular focus.
Diagonal’s Series A financing was co-led by BVF Partners and Atlas. It involves Lightspeed, RA Capital Management, Frazier Life Sciences, Viking Global Investors, Velosity and Checkpoint Capital. The majority of the new capital will support the HHT program, which is funded entirely by clinical evidence of effectiveness, Lugovskoy said. He gave no timeline for that goal. Without additional funding, the PAH program will not make it this far.
“That brings us to the IND,” Lugovskoy said, referring to an investigational application for a new drug. “But not much further than that. Currently, we are constantly making decisions based on new data.”
Image: Juan Gartner, Getty Images