≥ 16 years of age.
Molecular diagnosis of HHT by genetic testing or clinical diagnosis of definite HHT by the Curaçao criteria, defined as spontaneous and recurrent epistaxis, and at least 2 of the following:
Multiple telangiectasias at characteristic sites (ie, lips, oral cavity, fingers, outer ear, nose)
Visceral AVMs or telangiectasias
A first-degree relative with HHT according to these criteria OR a gene sequencing diagnosis of HHT based on local testing
Moderate to severe HHT as defined by all of the following:
ESS ≥ 4 measured over the preceding 3 months prior to screening
28-day frequency of ≥ 20 episodes plus a total 28-day duration ≥ 80 minutes (cumulative) as assessed during the 28-day observation period prior to randomization
Anemic at screening (hemoglobin < 13 mg/dL in males or < 12 mg/dL in females at screening) and/or has required IV hematologic support of at least 1 red-cell unit equivalent (RUE) (1 RUE = 1 unit of packed red cells or 250 mg elemental iron) in the 6 months prior to screening
Agrees to not undergo cautery of nasal telangiectasias (except as required in emergent circumstances) or take any other systemic therapies for bleeding in HHT other than the study treatment while participating in the study, with the exception of oral tranexamic acid or epsilonaminocaproic acid (maintained at a stable dose and regimen from the time of informed consent through the end of the double-blind period). Examples of other systemic therapies for HHT that are not permitted include, but are not limited to, bevacizumab, thalidomide, pomalidomide, pazopanib, somatostatin derivatives, selective estrogen response modifiers, tacrolimus, sirolimus, and other investigational therapies for bleeding in HHT, but does not include doxycycline.
Adequate bone marrow reserve or organ function as demonstrated by all of the following laboratory values:
Platelet count > 80 × 109/L
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (≥ 1500/mm3 ) or ≥ 1.0 × 109/L (≥ 1000/mm3 ) in participants with known Duffy null-associated neutrophil count as diagnosed by the treating investigator
Serum creatinine ≤ 1.5 × the upper limit of normal (ULN) and/or estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 calculated by Chronic Kidney Disease Epidemiology Collaboration formula
Total serum bilirubin ≤ 1.5 × ULN (or ≤ 3 × ULN with direct bilirubin ≤ 1.5 × ULN in the presence of Gilbert’s syndrome) and alanine aminotransferase and aspartate aminotransferase ≤ 3 × ULN
Women of childbearing potential (WOCP) must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. A female will be considered to be of childbearing potential following menarche unless they have undergone permanent sterilization (ie, hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or are postmenopausal. Postmenopausal is defined as at least 12 months without menses with no other medical reasons (eg, chemical menopause due to anticancer treatment).
For WOCP, agreement must be provided to use a medically approved, highly effective contraceptive method from the time of screening throughout the study and for 6 months after administration of the last dose of ATV-1601.
All fertile male participants must agree to condom use throughout the study and for 4 months following the last dose of study treatment.
Willing and able to comply with reasonable sun protection measures, including avoidance of direct sunlight and UV light exposure (except when using proper UV skin protection) during treatment with ATV-1601 and for 4 weeks after the last dose of ATV-1601.
Ability to complete all study required procedures and assessments
Completion of a daily electronic epistaxis diary for a minimum of 28 days within 33 days prior to Day 1. Participants who have not met inclusion criterion #3, and who miss up to 3 days of epistaxis diary completion, must complete up to an additional 3 days for a total of 28 days. Participants who miss more than 3 days (> 11%) of epistaxis daily e-diary completion, unrelated to technological difficulties with the app, will be a screen failure and must repeat all screening assessments.
Ability to understand and sign informed consent.
Clinically significant abnormalities of glucose metabolism as defined by any of the following:
Diagnosis of diabetes mellitus type 1 or uncontrolled type 2 diabetes
Fasting plasma glucose > 100 mg/dL (5.6 mmol/L) (fasting is defined as no caloric intake for at least 8 hours)
Glycosylated hemoglobin > 6.0%
Requirement of insulin for routine diabetic management and/or requirement for more than 2 oral hypoglycemic medications for routine diabetic management
Any of the following cardiac criteria:
Mean resting corrected QT interval (Fridericia formula) for heart rate (QTcF) > 450 msec for males and > 470 msec for females obtained from 3 consecutive electrocardiograms (ECGs); participants with falsely prolonged QT due to incomplete or complete right bundle branch block will be eligible with QTc ≤ 450 msec (males) and ≤ 470 msec (females) after applying the Bogossian modification (Bogossian 2000)
Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block, Type II second-degree heart block, PR interval > 250 msec). Participants with adequately controlled atrial fibrillation are eligible.
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure with reduced ejection fraction or severe diastolic dysfunction, potential for torsades de pointes, congenital long QT syndrome, or required use during study participation of concomitant medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard premedication (eg, diphenhydramine, ondansetron). The use of other concomitant medications that present a low risk of QT/QTc prolongation are permitted.
Any of the following procedures or conditions in the 6 months prior to screening: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, uncontrolled congestive heart failure with New York Heart Association Classification Class ≥ II, cerebrovascular accident or transient ischemic attack (except in the setting of pulmonary AVMs that have since been successfully embolized or surgically removed), or symptomatic bradycardia
Cardiac ejection fraction ≤ 40% (as measured by echocardiogram [ECHO], TTCE, or multigated acquisition scan if an ECHO cannot be performed or is inconclusive).
Any surgical or known medical condition which might significantly alter the absorption of the study drug (eg, prior major GI tract surgery).
Known significant untreated pulmonary AVMs accessible to treatment on computed tomography scan. A significant untreated lesion is defined as one for which embolization or treatment is currently recommended without equivocation but has yet to be treated.
Known actively bleeding GI ulcers not associated with GI vascular lesions within 12 months prior to inclusion in study.
Known significant untreated cerebral AVM, cerebral arteriovenous fistulae, or cerebral cavernous malformations detected on magnetic resonance imaging. A significant untreated lesion is defined as one for which embolization or treatment is currently recommended without equivocation but has yet to be treated.
Participants who require full-dose therapeutic anticoagulation (eg, vitamin K antagonists, heparin, dabigatran, rivaroxaban, apixaban) or high-dose antiplatelet therapy. Low-dose antiplatelet therapy (eg, acetylsalicylic acid at doses of ≤ 100 mg daily) is permitted.
History of clinically significant venous thromboembolic disease, including pulmonary embolism, splanchnic venous thrombosis, cerebral venous sinus thrombosis, or untreated proximal deep vein thrombosis, within 3 months prior to screening.
Prior disease-directed therapy prior to screening defined as treatment with:
Thalidomide, pomalidomide, or other immunomodulatory imide drugs within 4 weeks
Bevacizumab (systemic) within 6 weeks
Pazopanib within 6 weeks
Octreotide or oral estrogens within 4 weeks
AKT inhibitor at any time
Any other investigational drug within 4 weeks or 5 half-lives of the agent (whichever is shorter)
Any major surgery or local ablative procedures for nasal telangiectasias within 6 weeks prior to screening or during the screening period prior to randomization. Nasal packing and topical application of therapies to the nose are not considered procedures and are allowed.
Active or chronic corneal, choroidal, or retinal disorders requiring ongoing therapy, or any clinically significant disease that prevents adequate monitoring of drug-induced keratopathy.
Unstable illness that would impact a candidate’s ability to participate in the study within 28 days prior to randomization
Requires necessary treatment with a proton pump inhibitor, histamine-2 receptor antagonists (H2 blockers), or concomitant medication that is a strong inhibitor or strong inducer of cytochrome P450 (CYP)1A2 or CYP3A4/5 enzymes or an inhibitor of breast cancer resistance protein (BCRP) and/or strong inhibitor of P-glycoprotein (P-gp) enzymes/transporters, sensitive CYP3A substrates with narrow therapeutic index, or sensitive substrates of multidrug and toxin extrusion transporter (MATE)1.
History of hypersensitivity to active or inactive excipients of ATV-1601, (microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium, magnesium stearate, gelatin of animal origin), or drugs with a similar chemical structure or class to ATV-1601.
Use of herbal preparations or natural substances including but not limited to marijuana (tetrahydrocannabinol pills or edibles), St. John’s wort, grapefruit juice, pomegranate juice, starfruit, or orange marmalade (made with Seville oranges) from the start of the screening period and during study participation.
Pregnant or breastfeeding