In a drug discovery profession spanning greater than 20 years, Alex Lugovskoy has seen lots of antibodies come and go. The overwhelming majority of them work by inhibiting a mobile perform. Lugovskoy, now the CEO of startup Diagonal Therapeutics, stated he lengthy hoped somebody would provide you with a option to develop antibodies that activate their targets. With every passing yr, nobody did. So he took up the problem himself.
Diagonal makes use of computational and experimental methods to grasp what occurs when an antibody binds to a receptor and which binding combos will yield the specified impact. After creating its platform for the previous two years, the startup this previous week pulled again the curtain on its strategy. Diagonal additionally revealed $128 million in financing to help a pipeline that features a lead program for a uncommon bleeding dysfunction that has no FDA-approved therapies.
Cambridge, Massachusetts-based Diagonal is just not reinventing the wheel in the case of antibodies. The corporate’s medicine leverage the biopharmaceutical business’s greater than 40 years of expertise designing and manufacturing antibodies, Lugovskoy stated. However he added that one key distinction is that whereas Mom Nature can level the way in which to inhibit a goal, it’s much less clear have interaction a receptor to create a desired signaling impact. Every Diagonal antibody binds to 2 targets, bringing them collectively in a selected method. The numerous methods for an antibody to bind to varied websites on receptors quantities to billions of potential combos.
“Filtering by means of all these combos was not attainable with out our tech, that’s what we carry to the desk,” Lugovskoy stated.
Alex Lugovskoy, photograph by Diagonal Therapeutics
Early in his profession, Lugovskoy labored in drug discovery at Biogen. His expertise additionally consists of senior roles at Merrimack Prescription drugs, Morphic Therapeutic, and Dragonfly Therapeutics. After leaving Dragonfly in 2021, Lugovskoy stated his ideas returned to the query of why antibody analysis was so centered on inhibitors relatively than agonists. However in contrast to the beginning of his profession, extra highly effective applied sciences are actually out there that may be utilized to agonist antibody R&D. He took the concept to Michael Gladstone, a associate at Atlas Enterprise. In 2022, they co-founded Diagonal, whose title is a portmanteau of the phrases “digital,” “agonist,” “antibody,” and “ligand.” The startup acquired seed financing from Atlas, Lightspeed Enterprise Companions, and Velosity Capital.
Diagonal spent its first yr testing its expertise to see what it might do. The analysis ultimately turned to hereditary hemorrhagic telangiectasia (HHT), a dysfunction attributable to genetic mutations that result in malformations in blood vessels that may rupture. HHT is commonly first observed when sufferers develop frequent nosebleeds, however the situation additionally poses dangers to the gastrointestinal tract and artery-vein connections in inside organs, significantly the lungs, liver, and mind.
Whereas Diagonal’s drug candidate doesn’t repair the mutations on the root of HHT, it might handle the signaling issues that result in irregular blood vessels. The mutated genes that trigger HHT encode proteins within the TGF-beta signaling pathway. Diagonal designed an antibody that reactivates receptors on this pathway. Lugovskoy stated preclinical analysis confirmed Diagonal’s drug prevented and reversed the formation of pathological vascular malformations attribute of HHT.
A second Diagonal program is in improvement for pulmonary arterial hypertension (PAH), a uncommon type of hypertension affecting the arteries main from the guts to the lungs. The illness develops because the arteries slim, making the guts work more durable and in addition inflicting respiration issue. Not like HHT, there are medicine for PAH. Vasodilators, medicine that widen blood vessels, have been a typical PAH remedy for years. Not too long ago accepted Winrevair, a fusion protein from Merck, takes a unique strategy, trapping proteins related to driving the proliferation of cells that construct up and make blood vessels narrower. Diagonal goals to carry yet one more strategy to PAH with agonist antibody supposed to appropriate the signaling imbalance that’s tipped towards cell proliferation.
Lugovskoy stated Diagonal’s expertise can yield a working prototype of an agonist antibody in eight months or much less, which is about the identical time wanted to develop an inhibitor antibody. As for security, Lugovskoy stated opposed results haven’t been a difficulty thus far, which he attributes to what these medicine are doing. Moderately than creating a brand new signaling cascade, Diagonal is making an attempt to revive signaling that ought to be there however was misplaced to illness.
The Diagonal expertise is indication agnostic and has produced agonist antibodies for 4 targets. In addition to the HHT and PAH packages, the pipeline consists of an antibody that prompts IL-18 receptor signaling to spark anti-tumor results. The fourth goal stays undisclosed. Going ahead, Diagonal’s focus is uncommon cardiovascular ailments pushed by a genetic lack of perform, Lugovskoy stated. Now that Diagonal has exited stealth mode, the corporate is on the lookout for biopharma companions focused on making use of the expertise to therapeutic areas outdoors of the startup’s core cardiovascular focus.
Diagonal’s Collection A financing was co-led by BVF Companions and Atlas. It consists of the participation of Lightspeed, RA Capital Administration, Frazier Life Sciences, Viking International Buyers, Velosity, and Checkpoint Capital. Many of the new capital will help the HHT program, which is funded all through scientific proof of idea, Lugovskoy stated. He supplied no timelines for that aim. The PAH program received’t get as far with out extra funding.
“It will get us to IND,” Lugovskoy stated, referring to an investigational new drug utility. “However not a lot farther than that. As of proper now, we’re making selections on the premise of emergent knowledge on a regular basis.”
Picture: Juan Gartner, Getty Pictures
