Diagonal Launches with $128 Million to Pioneer Agonist Antibodies to Tackle Rare Diseases

Rare Daily Staff

Diagonal Therapeutics, which is pioneering a new approach to discovering and developing agonist antibodies, launched with $128 million in a series A financing.

BVF Partners and Atlas Venture co-led the financing, with participation from Lightspeed Venture Partners, RA Capital Management, Frazier Life Sciences, Viking Global Investors, Velosity Capital, and Checkpoint Capital.

Diagonal was co-founded by CEO Alex Lugovskoy and Atlas, and previously seeded by Atlas, Lightspeed Venture Partners, and Velosity Capital. The financing will support further advancement of the company’s proprietary DIAGONAL platform and pipeline of novel therapeutics to value-creating milestones, including its lead program for the treatment of hereditary hemorrhagic telangiectasia (HHT), a rare, severely debilitating bleeding disorder with limited therapeutic options, through clinical proof-of-concept. Diagonal’s agonist antibody activates a receptor complex in the TGF-β superfamily genetically impaired in HHT patients. In preclinical models of HHT, Diagonal’s agonist antibodies prevent and reverse the formation of pathological vascular malformations.

HHT is a monogenic, orphan disease for which there are currently no approved therapies. In HHT, mutations in the TGF-β receptor superfamily complex create two types of abnormal blood vessels – telangiectasias and arteriovenous malformations (AVMs) – that are fragile and susceptible to rupture and bleeding. These bleeding events lead to chronic anemia, necessitating frequent iron infusions or red blood cell transfusions. AVMs, if left untreated, may result in lung and brain hemorrhage, stroke, heart failure, and death. Diagonal’s agonist antibody candidates reactivate dormant signaling, addressing the root cause of the disease.

“We are fundamentally changing how agonist antibody therapies are developed. The DIAGONAL platform allows us to overcome technical limitations that hindered agonist antibody discovery in the past, and we have demonstrated that we can efficiently advance novel drug candidates for diseases where patients have limited or no treatment options,” said Lugovskoy. “Our approach enables us to treat a wide range of disorders where signaling pathways have been disrupted with agonist antibodies that have superior potency and selectivity, tunable and sustained pharmacology, excellent developability, and low immunogenicity.”

Unlike most approved antibodies, which inhibit a cellular function, agonist antibodies activate a signaling cascade by binding two receptors and bringing them together in a highly specific conformation that enables their activation. Given the many potential binding sites between each receptor and an antibody, nearly infinite binding configurations exist, of which only a small subset will result in the desired agonistic activity. Historically, this has made identifying or rationally designing agonist antibodies difficult.

The DIAGONAL platform solves this challenge, combining proprietary computational and experimental techniques that enable Diagonal scientists to sift through billions of combinations at unprecedented speeds and with high fidelity. Using the platform, Diagonal has discovered antibody candidates against four complex targets, providing a new path to treating severe diseases, including HHT and pulmonary arterial hypertension, an orphan disease that results in high blood pressure that affects the arteries in the lungs and the right side of the heart.

Photo: Alex Lugovskoy, CEO of Diagonal