Diagonal Therapeutics doses first patient in HHT antibody trial
Diagonal Therapeutics has dosed the first patient in DIAMOND, a Phase 1/2 multicentre, randomised, double-blind, placebo-controlled trial evaluating DIAG723 in adults with hereditary haemorrhagic telangiectasia (HHT). The milestone marks the debut of the company's clustering antibody platform in the clinic and the first prospective attempt to address the root genetic driver of a disease that currently has no approved therapies.
HHT is a rare inherited vascular disorder in which loss-of-function mutations impair normal development of blood vessels, producing fragile vasculature prone to recurrent bleeding, chronic anaemia, and arteriovenous malformations (AVMs) in organs including the lungs, liver, and brain. Ruptured AVMs can cause life-threatening complications, and management has historically been limited to symptomatic control of bleeding and its sequelae.
The mechanism and the drug
DIAG723 is designed to restore ALK1 signalling by bridging receptors at the cell surface, effectively reactivating a pathway that HHT mutations suppress. The approach differs from the dominant mode of action in antibody therapeutics, which typically block overactive signals rather than amplify deficient ones. In preclinical HHT models, the compound is reported to have both prevented and reversed AVMs and improved anaemia parameters, findings the company characterises as indicative of disease modification rather than symptomatic relief.
John Lee, Chief Medical Officer of Diagonal, described the initiation of DIAMOND as "an important step toward understanding its potential for patients," noting that the programme is "designed to restore normal ALK1 signalling" rather than manage consequences.
DIAG723 holds orphan drug designation from both the US FDA and the European Medicines Agency for HHT. The compound is also being evaluated in pulmonary arterial hypertension (PAH), a second indication where ALK1 pathway dysregulation is implicated in vascular hyperproliferation. Part C of the DIAMOND trial specifically enrols HHT patients with co-existing PAH, creating an early-stage readout in that overlap population.
Trial design and competitive landscape
The DIAMOND trial (NCT07623525) plans to enrol up to 93 participants across three sequential parts. Part A is a Phase 1 single ascending dose cohort assessing safety, tolerability, pharmacokinetics, and target-engagement biomarkers. Part B, a 14-week multiple ascending dose phase, will gather preliminary efficacy data including epistaxis frequency, severity, and haematological parameters. Part C extends enrolment to HHT patients with co-existing PAH.
The HHT therapeutic landscape remains largely empty at the approved level, though the condition's genetic architecture and patient advocacy infrastructure have made it an increasingly attractive rare-disease target. Bevacizumab, a VEGF-targeting monoclonal antibody, is used off-label in some HHT patients for epistaxis management, and a small number of academic groups have explored anti-angiogenic approaches. DIAG723's agonist mechanism is mechanistically distinct from these approaches, and its dual read-across to PAH is commercially significant: PAH is a better-established rare-disease commercial market with several approved therapies and defined reimbursement pathways in both the US and Europe.
Diagonal's clustering antibody platform is intended to extend beyond HHT and PAH into haematological, cardiovascular, and renal indications, though no further clinical programmes have been disclosed. For the near term, investors and clinicians will focus on Part A safety and tolerability data from DIAMOND as the first signal of whether agonist antibody dosing in humans is well tolerated before any efficacy readout is meaningful.