Telangiectasis

Diagonal’s lead programme is being developed for the treatment of hereditary haemorrhagic telangiectasia. Credit: dimid_86 / Shutterstock.com. Biotechnology company Diagonal Therapeutics has announced its launch, raising $128m through a Series A financing round for its new approach to discovering and developing agonist antibodies. BVF Partners and Atlas Venture jointly led the financing round with participation from Checkpoint Capital, Frazier Life Sciences, Lightspeed Venture Partners, RA Capital Management, Velosity Capital and Viking Global Investors. The company plans a new approach to develop antibodies to address the underlying causes of severely debilitating disease. The funds will be utilised to advance its Diagonal platform and the development of a pipeline of new therapeutics. The platform merges computational and experimental approaches to detect rare agonist antibodies that can re-activate deficient signalling pathways. See Also: Obsidian raises $160.5m to advance TIL cell therapy programme Harnessing pharmacovigilance to turn reactive investigation into active discovery Diagonal will also use the funds to progress its lead programme for hereditary haemorrhagic telangiectasia (HHT) through clinical proof-of-concept. The asset activates a receptor complex in the TGF-β superfamily that is genetically impaired in HHT. In preclinical models, agonist antibodies of Diagonal demonstrated the ability to hinder and reverse the formation of pathological vascular malformations associated with HHT. The company also discovered antibody candidates against four complex targets, which could pave the way for new treatments for severe diseases such as pulmonary arterial hypertension. Diagonal Therapeutics co-founder Alex Lugovskoy stated: “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. “Our approach enables us to treat a wide range of disorders where signalling pathways have been disrupted with agonist antibodies that have superior potency and selectivity, tunable and sustained pharmacology, excellent developability and low immunogenicity.”

Diagonal Therapeutics is building a pipeline of antibody agonists rather than receptor blockers. Diagonal Therapeutics is taking shape, launching with $128 million and backed by the likes of BVF Partners, Atlas Venture and RA Capital to develop a pipeline of antibody agonists.  The company will use this significant financial firepower to accelerate development of its pipeline of four assets. Two of these candidates are more advanced, including a lead asset targeting the inherited bleeding disorder hereditary hemorrhagic telangiectasia (HHT) and a runner-up designed to treat pulmonary arterial hypertension (PAH).  Unlike conventional antibody development, Diagonal is working on candidates that activate broken signaling pathways rather than inhibit them. The HHT asset, for example, reignites a receptor in the TGF-β superfamily, with preclinical models showing that the agonist antibodies “prevent and reverse the formation of pathological vascular malformations,” the company said in a release. The $128 million will pay for at least a proof-of-concept study for the HHT program, the company noted in its announcement, though a full cash runway was not specified.  Diagonal is led by CEO Alex Lugovskoy, Ph.D., an entrepreneur-in-residence at Atlas who’s had previous C-suite stints at Dragonfly Therapeutics and Morphic Therapeutic. Diagonal's platform is the byproduct of computational and scientific advancements made in the last five to 10 years, Lugovskoy told Fierce Biotech. “I think more and more people will start using those types of approaches to all kinds of antibody engineering techniques, which is a blend of experimental and computational,” the CEO said in an interview. Diagonal’s stated PAH ambitions come days after Merck & Co.’s much-hyped Winrevair (sotatercept) received FDA approval for the condition, resetting the competitive landscape. Lugovskoy conceded that unlike HHT, which lacks treatment options, Winrevair is a “significant advance” for PAH patients. But he said that because the drug acts as an activin receptor ligand trap rather than a fix for genetic mutations, the worst case scenario for Diagonal is that its own candidate—if approved—is synergistic on the marketplace.  “I do not see us directly competing with sotatercept because what we are doing is promoting missing signaling, whereas [Merck is] inhibiting excessive activin signaling,” Lugovskoy said. Diagonal has a good sense of Winrevair's capabilities, with Acceleron's former vice president of biology, Patrick Andre, Ph.D., now Diagonal's chief scientific officer. Merck got hold of Winrevair when it acquired Acceleron for $11.5 billion in 2021.  Equipped with new cash, Lugovskoy expects Diagonal will grow its head count in the single digits, with most of the new jobs centered on building clinical capabilities. 

Rather than shutting down signalling pathways, Diagonal Therapeutics is developing antibodies to hit cellular “on” switches to treat rare, genetically linked diseases. The biotech raised a $128-million series A, co-led by BVF Partners and Atlas Venture, to take its lead candidate through proof-of-concept studies. While most approved antibody therapies inhibit a cellular function, often to treat cancer, Diagonal is developing agonists that activate a signalling cascade, thus reactivating biological pathways to treat the underlying cause of certain diseases. “The biopharmaceutical industry has a robust, growing toolkit of approaches to inhibit disease-associated pathways. However, we still lack systematic pharmacologic approaches to activate biological pathways to treat diseases caused by deficient signalling,” said Michael Gladstone, partner at Atlas and chair of Diagonal’s board. “Diagonal’s platform addresses this unmet need by rapidly identifying antibodies that activate key pathways.” According to the company, developing antibody agonists has been historically bottlenecked due to the complexity of identifying or designing such treatments. With more than 10 billion possible binding configurations, and only a small subset that result in the desired therapeutic activity, it’s difficult and time-consuming to home in on the right combinations.By combining computational and experimental technologies, Diagonal said its platform enables “scientists to sift through billions of combinations at unprecedented speeds and with high fidelity.”The company’s lead agonist activates a receptor complex in the TGF-β superfamily that is genetically impaired in patients with hereditary hemorrhagic telangiectasia (HHT). Wednesday’s round – which saw participation from Lightspeed Venture Partners, RA Capital Management, Frazier Life Sciences, Viking Global Investors, Velosity Capital, and Checkpoint Capital – will take the antibody through clinical proof-of-concept studies.Diagonal’s second candidate is in preclinical development for pulmonary arterial hypertension (PAH). While the specific target is undisclosed, Diagonal said the agonist antibody corrects imbalanced signalling in the antiproliferative and hyperproliferative pathways to restore vascular wall homeostasis. Last month, the FDA approved the first disease-modifying treatment for PAH: Merck & Co.’s  activin signalling inhibitor Winrevair (sotatercept-csrk).