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Beyond Hemostasis: ALK1 Agonist Antibody Enters Human Trials for HHT for the First Time
DIAG723 aims to reactivate dysregulated angiogenic signaling, addressing recurrent nosebleeds, anemia, and arteriovenous malformations at the level of disease mechanism; however, dosing the first patient marks only the beginning of clinical validation, and its safety and efficacy in humans remain unknown.
For patients with hereditary hemorrhagic telangiectasia (HHT), the challenge is not merely occasional nosebleeds. Fragile, abnormal blood vessels may bleed over prolonged periods, causing chronic anemia and the need for blood transfusions; arteriovenous malformations in the lungs, liver, or brain may also lead to serious complications. Current care largely focuses on controlling bleeding and its consequences, and no treatment specifically for HHT has yet been approved.
Diagonal Therapeutics announced on July 16 that the first patient had been dosed in the Phase 1/2 DIAMOND trial of DIAG723. This is the drug’s first study in humans and the first step in moving the disease-modifying concept of “restoring ALK1 signaling” from animal models into clinical testing.
DIAG723 is a subcutaneously administered, clustering bispecific agonist antibody targeting ALK1 and BMPRII. Rather than blocking overactive signaling, it brings receptors on the cell surface closer together in an effort to reactivate the ALK1 pathway impaired by HHT-related genetic defects and return vascular development to a more normal state of regulation.
According to the ClinicalTrials.gov registry, DIAMOND is a randomized, double-blind, placebo-controlled first-in-human trial expected to enroll 93 adults. The study is divided into three parts: it will begin with single ascending doses, followed by an evaluation of multiple doses in patients with HHT; the third part will enroll patients who have both HHT and pulmonary arterial hypertension to explore whether this signaling-modulation strategy can address relevant measures of both vascular diseases.
The trial will initially focus on safety, tolerability, pharmacokinetics, and target-engagement biomarkers for the ALK1 pathway. The subsequent 14-week multiple-dose stage will then make preliminary assessments of nosebleed frequency and severity, hematologic measures, and other HHT-related changes. The patient organization Cure HHT said that the study is currently recruiting in Australia and New Zealand, with trial sites in additional countries expected to be added in the future.
The company said that DIAG723 prevented and reversed arteriovenous malformations and improved anemia in preclinical HHT models; it also showed signals including improved hemodynamics in models of pulmonary arterial hypertension. However, these results cannot yet predict responses in humans, and improvements in vascular structure in animal models may not translate into clinical benefits involving nosebleeds, transfusion needs, or organ complications.
The significance of dosing the first patient therefore lies primarily in testing whether an unusual antibody design can safely “switch on” impaired signaling, rather than proving that it can already alter the course of HHT. DIAMOND must next answer questions about dosage, long-term tolerability, and the magnitude of efficacy; until controlled data become available, DIAG723 remains an early-stage candidate therapy with a novel mechanism but clinical risks that have yet to be clarified.