Hereditary Hemorrhagic Telangiectasia, Pulmonary Arterial Hypertension
Conditions
Keywords
Hereditary Hemorrhagic Telangiectasia, HHT, BMPRII, ALK1, Bone morphogenetic protein receptor type II
Brief summary
This is a Phase 1/2, randomized, double-blind, placebo-controlled, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of subcutaneously administered DIAG723 in adult patients with hereditary hemorrhagic telangiectasia (HHT). The study consists of three parts: Part A (dose escalation): Single ascending subcutaneous doses of DIAG723 are evaluated in sequential cohorts to assess safety, tolerability, and pharmacokinetics. Part B (dose expansion): Multiple doses of DIAG723 administered over 13 weeks are evaluated in patients with HHT to assess safety and preliminary efficacy. Part C (dose expansion): Multiple doses of DIAG723 administered over 13 weeks are evaluated in patients with HHT and concomitant pulmonary arterial hypertension to assess safety and exploratory clinical effects in this population. Participants will be randomized within each study part to receive DIAG723 or placebo. The study includes dose escalation in Part A and dose expansion in Parts B and C.
Detailed description
This is a Phase 1/2, randomized, double-blind, placebo-controlled, first-in-human, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary clinical activity of DIAG723, a bispecific agonist monoclonal antibody targeting activin receptor-like kinase 1 (ALK-1) and bone morphogenetic protein receptor type II (BMPRII), in adult patients with hereditary hemorrhagic telangiectasia (HHT). The study is conducted in three sequential parts (Parts A, B, and C), each evaluating different dosing strategies and patient populations. Part A (Single Ascending DoseDose in HHT): Part A is a dose-escalation phase evaluating ascending single-dose levels of DIAG723 administered subcutaneously in sequential cohorts. Within each cohort, participants are randomized to receive DIAG723 or placebo. Dose escalation proceeds in a stepwise manner following review of safety, tolerability, and pharmacokinetic data. Sentinel dosing is implemented to allow for early safety assessment prior to dosing additional participants. Participants are monitored in an inpatient setting following dosing, with continued outpatient follow-up through the end of the assessment period. Part B (Multiple-Dose Expansion in HHT): Part B evaluates the safety, tolerability, pharmacokinetics, and preliminary clinical activity of DIAG723 administered as a multiple-dose regimen in patients with HHT symptoms. Participants are randomized to receive DIAG723 or placebo and receive repeated subcutaneous administrations over a planned treatment period of approximately 13 weeks. Dose levels and regimens evaluated in Part B are informed by available safety, pharmacokinetic, and pharmacodynamic data from Part A. An independent data monitoring process is used to support dose selection and cohort progression. Part C (Multiple-Dose Expansion in HHT with Pulmonary Arterial Hypertension): Part C evaluates the safety, tolerability, pharmacokinetics, and clinical effects of DIAG723 in a population of patients with HHT and concomitant pulmonary arterial hypertension. Participants are randomized to receive DIAG723 or placebo and receive the same general multiple-dose treatment approach as in Part B. Dose selection for Part C is informed by cumulative data from Part A and Part B, with additional assessments conducted to characterize effects in this specific patient population. Across all study parts, participants are randomized using an interactive response system, and study treatment is administered under double-blind conditions. A Safety Review Committee and an independent Data Safety Monitoring Board provide ongoing review of safety data and support dose-escalation and progression decisions throughout the study. Dose escalation and cohort progression are guided by predefined safety criteria and overall risk-benefit assessment. All doses are administered by subcutaneous injection, and participants undergo safety monitoring, pharmacokinetic sampling, and clinical assessments at scheduled study visits. The study includes both inpatient and outpatient components depending on the study part and stage of participation. This study is designed to characterize the safety profile and pharmacokinetic properties of DIAG723 and to support selection of appropriate doses and regimens for further clinical development in HHT.
Interventions
BIOLOGICALDIAG723
Bispecific agonist monoclonal antibody targeting ALK-1 and BMPRII, administered subcutaneously as: Single ascending dose in Part A; Multiple doses (7 doses over 13 weeks) in Parts B and C
OTHERPlacebo
Sterile normal saline (0.9% NaCl) administered subcutaneously in volumes matched to DIAG723 to maintain study blinding.
Sponsors
Diagonal Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Sponsor team unblinded during Part A for safety evaluation
Intervention model description
This is a 3-part sequential study (Parts A, B, and C) with separate randomization within each part
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients ≥18 years with a clinical or genetic diagnosis of HHT * Adequate hepatic and renal function * Part B: Epistaxis and anemia or transfusion/iron history * Part C: HHT with documented pre-capillary pulmonary arterial hypertension
Exclusion criteria
* Active or recent systemic infection * Recent thromboembolic events * Use of anti-angiogenic drugs within 6 weeks * Pregnancy or lactation * Recent participation in another investigational study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (TEAEs) - Part A (Single Dose) | From first dose through Day 28 | Number and proportion of participants experiencing TEAEs following single-dose administration of DIAG723. |
| Incidence of Serious Adverse Events (SAEs) - Part A (Single Dose) | From first dose through Day 28 | Number and proportion of participants experiencing SAEs following single-dose administration of DIAG723. |
| Incidence of Dose-Limiting Toxicities (DLTs) - Part A (Single Dose) | From first dose through Day 28 | Number and proportion of participants experiencing DLTs during the dose-escalation period following single-dose administration. |
| Number of participants with abnormal laboratory tests results - Part A (Single Dose) | Baseline through Day 28 | Laboratory assessments include hematology (complete blood count), clinical chemistry (basic metabolic panel; liver function tests; renal function; electrolytes; thyroid-stimulating hormone, free T4, free T3; cortisol; luteinizing hormone; lipase; amylase), coagulation (prothrombin time/international normalized ratio, activated partial thromboplastin time), and urinalysis. |
| Number of participants with abnormal vital signs - Part A (Single Dose) | Baseline through Day 28 | Vital sign measurements include body temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation. |
| Change from Baseline in Electrocardiogram (ECG) Parameters - Part A (Single Dose) | Baseline through Day 28 | Change from baseline in ECG parameters, including QTc interval. |
| Incidence of Treatment-Emergent Adverse Events (TEAEs) - Part B (Multiple Dose) | From first dose through 28 days after final dose | Number and proportion of participants experiencing TEAEs following multiple-dose administration of DIAG723. |
| Incidence of Serious Adverse Events (SAEs) - Part B (Multiple Dose) | From first dose through 28 days after final dose | Number and proportion of participants experiencing SAEs following multiple-dose administration. |
| Incidence of Dose-Limiting Toxicities (DLTs) - Part B (Multiple Dose) | From first dose through 28 days after final dose | Number and proportion of participants experiencing DLTs during multiple-dose treatment. |
| Number of participants with abnormal laboratory tests results - Part B (Multiple Dose) | Baseline through Week 15 | Laboratory assessments include hematology (complete blood count), clinical chemistry (basic metabolic panel; liver function tests; renal function; electrolytes; thyroid-stimulating hormone, free T4, free T3; cortisol; luteinizing hormone; lipase; amylase), coagulation (prothrombin time/international normalized ratio, activated partial thromboplastin time), and urinalysis. |
| Number of participants with abnormal vital signs - Part B (Multiple Dose) | Baseline through Week 17 | Vital sign measurements include body temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation. |
| Change from Baseline in Electrocardiogram (ECG) Parameters - Part B (Multiple Dose) | Baseline through Week 17 | Change from baseline in ECG parameters, including QTc interval. |
| Incidence of Treatment-Emergent Adverse Events (TEAEs) - Part C (Multiple Dose, HHT with PAH) | From first dose through 28 days after final dose | Number and proportion of participants experiencing TEAEs following multiple-dose administration in participants with HHT and pulmonary arterial hypertension. |
| Incidence of Serious Adverse Events (SAEs) - Part C (Multiple Dose, HHT with PAH) | From first dose through 28 days after final dose | Number and proportion of participants experiencing SAEs in this population. |
| Incidence of Dose-Limiting Toxicities (DLTs) - Part C (Multiple Dose, HHT with PAH) | From first dose through 28 days after final dose | Number and proportion of participants experiencing DLTs during treatment. |
| Number of participants with abnormal laboratory tests results - Part C (Multiple Dose, HHT with PAH) | Baseline through Week 15 | Laboratory assessments include hematology (complete blood count), clinical chemistry (basic metabolic panel; liver function tests; renal function; electrolytes; thyroid-stimulating hormone, free T4, free T3; cortisol; luteinizing hormone; lipase; amylase), coagulation (prothrombin time/international normalized ratio, activated partial thromboplastin time), and urinalysis. |
| Number of participants with abnormal vital signs - Part C (Multiple Dose, HHT with PAH) | Baseline through Week 17 | Vital sign measurements include body temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation. |
| Change from Baseline in Electrocardiogram (ECG) Parameters - Part C (Multiple Dose, HHT with PAH) | Baseline through Week 17 | Change from baseline in ECG parameters, including QTc interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve (AUC) of DIAG723 - Part A | Pre-dose through Day 28 | Plasma AUC following single-dose administration of DIAG723. |
| Maximum Observed Plasma Concentration (Cmax) of DIAG723 - Part A | Pre-dose through Day 28 | Maximum observed plasma concentration following single-dose administration. |
| Time to Maximum Plasma Concentration (Tmax) of DIAG723 - Part A | Pre-dose through Day 28 | Time to reach maximum plasma concentration following single-dose administration. |
| Area Under the Plasma Concentration-Time Curve (AUC) of DIAG723 - Part B (Multiple Dose) | Pre-dose through 28 days after final dose | Plasma AUC following repeated dosing of DIAG723. |
| Maximum Observed Plasma Concentration (Cmax) of DIAG723 - Part B (Multiple Dose) | Pre-dose through 28 days after final dose | Maximum observed plasma concentration following multiple-dose administration. |
| Time to Maximum Plasma Concentration (Tmax) of DIAG723 - Part B (Multiple Dose) | Pre-dose through 28 days after final dose | Time to reach maximum plasma concentration following multiple-dose administration. |
| Incidence of Anti-Drug Antibodies (ADA) to DIAG723 - Part A (Single Dose) | From first dose through Day 28 | Number and proportion of participants with detectable anti-drug antibodies following single-dose administration. |
| Incidence of Anti-Drug Antibodies (ADA) to DIAG723 - Part B (Multiple Dose) | From first dose through 28 days after final dose | Number and proportion of participants with detectable anti-drug antibodies following multiple-dose administration. |
| Change from Baseline in Epistaxis Frequency - Part B (Multiple Dose) | Baseline through end of treatment (13 weeks) | Change from baseline in frequency of epistaxis events as recorded in a participant-reported electronic daily diary. |
| Change from Baseline in Epistaxis Flow Intensity, Duration, and Intensity-Adjusted Duration - Part B (Multiple Dose) | Baseline through end of treatment (13 weeks) | Change from baseline in epistaxis flow intensity, event duration, and intensity-adjusted duration as recorded in an electronic daily diary. |
| Change from Baseline in Hemoglobin - Part B (Multiple Dose) | Baseline through Week 15 | Change from baseline in hemoglobin concentration. |
| Change from Baseline in Hematocrit - Part B (Multiple Dose) | Baseline through Week 15 | Change from baseline in hematocrit. |
| Change in Mean Corpuscular Volume (MCV) Following Multi-dose Treatment With DIAG723 (Part B) | Baseline through Week 15 | Change from baseline in mean corpuscular volume (MCV, fL) during Part B following multi-dose treatment with DIAG723. |
| Change from Baseline in Red Blood Cell Count Following Multi-dose Treatment With DIAG723 | Baseline through Week 15 | — |
| Change from Baseline in White Blood Cell Count Following Multi-dose Treatment With DIAG723 (Part B) | Baseline through Week 15 | — |
| Change from Baseline in Platelet Count Following Multi-dose Treatment With DIAG723 (Part B) | Baseline through Week 15 | — |
| Change in Red Blood Cell (RBC) Units Transfused During Treatment With DIAG723 (Part B) | Baseline through Week 15 | Change from baseline in the number of RBC units transfused, comparing a pre-treatment baseline period to the on-treatment period during Part B. |
| Change in Elemental Iron Infused During Treatment With DIAG723 (Part B) | Baseline through Week 15 | Change from baseline in total milligrams of elemental iron administered via infusion, comparing a pre-treatment baseline period to the on-treatment period during Part B. |
| Change in Hematologic Support Score (HSS) Following Treatment With DIAG723 (Part B) | Baseline through Week 17 | The Hematologic Support Score ranges from 0 to 100, with higher scores indicating greater transfusion and iron supplementation burden and worse outcomes. |
| Change in Hematologic Impact Score (HIS) Following Treatment With DIAG723 (Part B) | Baseline through Week 17 | The Hematologic Impact Score ranges from 0 to 100, with higher scores indicating greater hematologic disease burden and worse outcomes. |
Countries
Australia, Canada, New Zealand
Contacts
CONTACTDiagonal Therapeutics
Outcome results
None listed