A Trial to Assess the Efficacy and Safety of Engasertib in Participants With Moderate to Severe Hereditary Hemorrhagic Telangiectasia (HHT)

• Engasertib (Drug), also known as VAD044: Engasertib will be administered as oral capsules.
• Placebo (Drug): Placebo will be administered as oral capsules.

Primary outcomes

• Total Number of Epistaxis Events Through Week 28 [Day 1 through Week 28]

Secondary outcomes

• Absolute Change from Baseline in Total Duration of Epistaxis at Week 28 [Baseline and Week 28]
• Absolute Change from Baseline in Epistaxis Severity Score (ESS) at Week 28 [Baseline and Week 28]
• Absolute Change from Baseline in the Nasal Outcome Score for Epistaxis in HHT (NOSE HHT) Score at Week 28 [Baseline and Week 28]
• Absolute Change in Red Blood Cell (RBC) Unit Equivalents (RUEs) Received at Week 28 [Baseline and Week 28]
• Patient Global Impression of Change (PGIC) Nosebleeds Sub-score at Week 28 [Week 28]
• HHT-specific Quality of Life (HHT-QoL) Score at Week 28 [Week 28]
• Absolute Change from Baseline in the Intensity-adjusted Duration of Epistaxis per Month at Week 28 [Baseline and Week 28]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Participants are ≥18 years of age at the Screening Visit.
2. Participants have a definite diagnosis of HHT by the Curaçao criteria, defined as spontaneous and recurrent epistaxis and having at least 2 of the following criteria:

   1. Multiple telangiectases at characteristic sites: lips, oral cavity, fingers, or nose;
   2. Visceral lesions: gastrointestinal telangiectasia and/or pulmonary, hepatic, cerebral, or spinal arteriovenous malformations (AVMs); or
   3. A first degree relative with HHT according to these criteria.
3. Participants must have an ESS >4 at screening, and, in the judgement of the Investigator, participants are expected to have regular epistaxis that typically lasts for several minutes. This criterion is assessed at screening only and does not require reconfirmation prior to randomization on Day 1.
4. Participants have anemia OR in the prior 6 months have received a parenteral infusion of at least 250 mg of iron OR in the prior 6 months have received a red cell or whole blood transfusion.

Exclusion Criteria:

1. History or current diagnosis of clinically significant electrocardiogram (ECG) abnormalities.
2. History of significant or uncontrolled skin disorders per Investigator's judgement.
3. Local ablative (eg, cauterization) or surgical procedures on nasal telangiectases <6 weeks before the Screening Visit.
4. Use of drugs with anti-angiogenic properties, including, but not limited to, bevacizumab, pazopanib, thalidomide, lenalidomide, pomalidomide, tacrolimus, sirolimus, or selective estrogen response modulators (tamoxifen, raloxifene, or bazedoxifene) < 6 weeks before the Screening Visit.
5. Use of oral tranexamic or epsilon-aminocaproic acid unless they are on a stable dose for at least 4 weeks before the Screening Visit, which will need to be continued during the entire duration of the double-blind Treatment Period.

NIH grants: 2025