Subjects are ≥18 years of age at the Screening Visit.
Subjects are willing and able to understand and comply with the requirements of the study, per Investigator’s judgement, including completion of the HHT eDiary using a smartphone.
Subjects 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:
Multiple telangiectases at characteristic sites: lips, oral cavity, fingers, or nose
Visceral lesions: gastrointestinal telangiectasia and/or pulmonary, hepatic, cerebral, or spinal AVMs; or
A first degree relative with HHT according to these criteria.
Subjects must have an ESS >4 at screening, and, in the judgement of the Investigator, subjects 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.
Subjects have anemia (hemoglobin levels <13 g/dL in men and <12 g/dL in women) 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.
Subjects with prediabetes should be clinically stable, and those with known diabetes must have their disease adequately controlled, as defined by a glycosylated hemoglobin (HbA1c) ≤8.0%.
Female subjects of childbearing potential fulfilling the following criteria:
A negative serum pregnancy test result at the Screening Visit and negative urine pregnancy test at Day 1 (prior to the first dose of study drug) and must not be pregnant, lactating, or planning a pregnancy from the Screening Visit to 30 days after the last dose of study drug.
Either sexually inactive (abstinent) for 90 days prior to the first dose of study drug or are using 1 of the highly effective birth control methods (ie, <1% failure rate when used consistently and correctly) and agree to abstain from egg donation until 60 days after the last dose of study drug.
Female subjects of non-childbearing potential will be included if they meet the criteria outlined at the Screening Visit, based on the central laboratory’s ranges.
Male subjects who are fertile with female partners of childbearing potential must use highly effective methods of birth control during their participation in the study, , and agree to abstain from sperm donation until 30 days after the last dose of study drug. A man is considered fertile unless permanently sterile by bilateral orchiectomy.
The subject has given written informed consent prior to any study-related procedures that are not part of normal medical care.
History or current diagnosis of clinically significant ECG abnormalities such as:
Concomitant clinically relevant cardiac findings (eg, sustained ventricular tachycardia and clinically significant second- or third-degree atrioventricular block without a pacemaker)
History of familial long QT syndrome or known family history of torsades de pointes
Resting QTcF ≥450 msec (male) or ≥460 msec (female); subjects with falsely prolonged QT due to incomplete or complete right bundle branch block are eligible if heart ratecorrected QT meets these thresholds after applying the Bogossian modification
Concomitant use of agents known to prolong the QT interval and known to cause torsades des pointes
Uncontrolled hypertension as per Investigator’s judgement. If blood pressure is uncontrolled at the Screening Visit, initiation or adjustment of antihypertensive medication(s) is permitted during the Qualifying Period. The dose should be stable prior to randomization.
Active, uncontrolled infection with human immunodeficiency virus, hepatitis B, or hepatitis C infection.
Any other severe, progressive, or uncontrolled acute or chronic medical or psychiatric condition, or clinical laboratory abnormalities that may increase the risk associated with study participation/treatment or may interfere with interpretation of study results, and, in the Investigator’s opinion, would make the subject inappropriate for entry in this study.
History of any malignancy within the past 5 years prior to the start of the Screening Period, except subjects with complete removal of non-melanoma skin cancer.
History of significant or uncontrolled skin disorders per Investigator’s judgement.
Presence of ANY of the following laboratory abnormalities:
Platelets ≤75 × 109 /L
Absolute neutrophil count ≤1.5 × 109 /L or ≤1.0 × 109 /L in subjects with Duffy null-associated neutrophil count (DANC), as diagnosed by the treating investigator
Substantive chronic renal disease (estimated glomerular filtration rate ≤45 mL/min/1.73 m2 calculated using the Modification of Diet in Renal Disease equation)
Substantive abnormal hepatic function meeting 1 or more of the following criteria:
Total bilirubin ≥2 × upper limit of normal (except in subjects with Gilbert’s syndrome)
Aspartate transaminase/alanine aminotransferase ≥5 × the upper limit of normal. iii) Alkaline phosphatase ≥5 × the upper limit of normal
Local ablative (eg, cauterization) or surgical procedures on nasal telangiectases <6 weeks before the Screening Visit.
Any surgical or medical condition which might significantly alter the absorption of the study drug (eg, major gastrointestinal tract surgery such as gastrectomy, significant gastroenterostomy, bowel resection, or short bowel syndrome).
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.
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.
Participating in another interventional clinical trial at the time of screening or within 4 weeks prior to screening or within 5 half-lives of the investigational medicinal product (IMP) being administered in the previous trial (whichever is longer) prior to the expected date of the first dosing or participated in an engasertib clinical trial at any time.
A history of uncontrolled alcohol use disorder or substance use disorder within the 12 months prior to the Screening Period (based on the opinion of the Investigator). Subjects taking prescription drugs will be allowed.
A history of hypersensitivity or allergies to engasertib (including the formulation excipients: microcrystalline cellulose). Skin testing may be performed according to local standard practice to confirm hypersensitivity.
Use of excluded medication or treatment listed in the protocol that cannot be discontinued.
Subject is a study site employee, an immediate family member of a study site employee, is in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling), or who may have consented under duress.