Diagonal Therapeutics announced it will present groundbreaking preclinical data at the 30th European Hematology Association (EHA) Congress demonstrating the disease-modifying potential of its clustering antibody approach for hereditary hemorrhagic telangiectasia (HHT). The biotechnology company's lead program, DIAG723, showed remarkable efficacy in multiple preclinical models of the rare bleeding disorder.
Breakthrough Results in Disease Models
The preclinical data reveal that Diagonal's bispecific clustering antibodies targeting ALK1 and BMPRII receptors successfully restored cell signaling disrupted in HHT. In relevant disease models, the antibodies preferentially bound to vascular endothelium, clustering key receptors and activating ALK1-mediated signaling pathways.
Most notably, administration of DIAG723 prevented and reversed arteriovenous malformation (AVM) pathology across multiple mouse models, including BMP9/10-deficient mice, fully ENG-deficient mice, and mice with haploinsufficient ALK1 mutations. The treatment demonstrated dramatic survival benefits, improving survival rates from 25% to 100% during the study period.
"With a thorough understanding of the biology underpinning HHT and our proprietary platform, we have designed highly specific antibodies capable of restoring ALK1-mediated cell signaling lost due to disease-causing mutations to key receptors," said Patrick Andre, Ph.D., Chief Scientific Officer of Diagonal.
Clinical Validation and Patient Impact
The therapeutic effects extended beyond survival improvements. DIAG723 administration prevented the formation of HHT-associated anemia and heart enlargement in mouse models. Importantly, the effects were confirmed in HHT patient-derived endothelial cells, demonstrating normalization of homeostatic ALK1 signaling.
Philippe Marambaud, Ph.D., Professor at the Institute of Molecular Medicine, Feinstein Institutes for Medical Research and Diagonal HHT collaborator, emphasized the clinical significance: "As someone who has extensively studied several mechanistic approaches for this serious disease, I am highly encouraged by the data supporting Diagonal's bispecific antibody-mediated receptor clustering approach."
Addressing Critical Unmet Need
HHT affects more than 150,000 people in the U.S. and EU, with no currently approved therapies available. The disease results from loss-of-function point mutations in members of the TGF-β receptor superfamily complex, creating abnormal blood vessels 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. Internal arteriovenous malformations pose severe risks, potentially causing lung and brain hemorrhage, stroke, heart failure, and death if left untreated.
Regulatory Recognition and Development Path
DIAG723 has received orphan drug designation from both the US FDA and the European Medicines Agency (EMA) for HHT treatment, recognizing the significant unmet medical need and the drug's potential therapeutic benefit.
The bispecific antibody is designed to address both HHT and pulmonary arterial hypertension (PAH), conditions where dysregulated ALK1 signaling drives pathological vascular changes. In PAH preclinical models, DIAG723 prevented disease development, cardiac remodeling, and improved hemodynamics while restoring normal signaling in patient-derived pulmonary microvascular endothelial cells.
EHA Congress Presentation
The company will present its findings in a poster session titled "ALK1-BMPRII receptor agonism treats vascular pathology in hereditary hemorrhagic telangiectasia models" on Saturday, June 14, from 18:30-19:30 CEST at the EHA Congress in Milan, Italy. The presentation will subsequently be available on Diagonal's website.
Marambaud noted the broader implications: "With its demonstrated ability to prevent and reverse arteriovenous malformations and normalize cell signaling in multiple translational HHT models, Diagonal's approach has the potential to significantly impact the lives of individuals living with HHT."
