Topical TOR-582 Treatment of Epistaxis in HHT

Inclusion criteria

• Age 18 years or older at the time of consent.
• Confirmed diagnosis of HHT, defined as meeting at least three of the four Curaçao criteria or preferably by genetic testing.
• Moderate nasal epistaxis represented by an Epistaxis Severity Score (ESS) between 3 and 8 at screening, average NOSE-HHT score of 1.01-2, with a self-reported history of at least four spontaneous nosebleeds per week and a cumulative weekly bleeding duration of at least 60 minutes.
• Stable nasal hygiene regimen and epistaxis-related medical management for at least 3 months prior to enrollment.
• Stable epistaxis pattern for at least 3 months prior to enrollment
• Adequate bone marrow function defined as:
• Platelet count ≥ 100 × 10⁹/L (≥ 100,000/mm3)
• WBC count ≥ 2.5 × 10⁹/L at screening (≥ 2,500/mm3)
• Hgb ≥ 6g/dL with no transfusion in the prior 2 months
• INR ≤ 1.4 and activated partial thromboplastin time (aPTT) within institutional normal limits.
• Willingness to avoid initiation of other investigational or targeted therapeutic agents for epistaxis (including antiangiogenic or mTOR-modulating therapies) from the time of enrollment through study completion.
• Female participants of childbearing potential must have a negative pregnancy test at screening and agree to use effective contraception during the study and for 28 days following the final dose.
• Ability to comply with study procedures and follow-up visits, and capacity to provide written informed consent.

Exclusion criteria

• Any medical contraindication to systemic sirolimus use.
• Prior use of any mTOR inhibitor within the past 3 months.
• Endoscopic evaluation of nasal cavity (HES-based)
• Site: No numerical site exclusion
• Pattern: AVM-type vascular pattern (HES pattern score = 2).
• Crusting: Moderate to severe nasal crusting (HES crusting score ≥ 2).
• Location: Telangiectasias isolated to the middle or posterior turbinates (HES location score ≥ 2).
• Perforation: Presence of a nasal septal perforation
• Surgical cautery or sclerotherapy within the past 3 months prior to enrollment
• Vascular embolization of nasal vasculature within the past 3 months prior to enrollment
• Clinically significant peripheral vascular disease or circulatory compromise.
• Current use of strong CYP3A4 modulators, including inhibitors (e.g., ketoconazole, clarithromycin) or inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's wort).
• Use of anti-angiogenic therapies within 30 days prior to screening (e.g., bevacizumab, pazopanib, thalidomide, lenalidomide).
• Use of illicit substances within the past 30 days, excluding marijuana.
• Use of anticoagulant, antiplatelet, or fibrinolytic medications within the past 30 days, except for low-dose aspirin (81 mg or less).
• Use of octreotide or systemic estrogen therapy within the past 30 days.
• Clinical laboratory evaluation:
• Renal dysfunction, defined as a serum creatinine level greater than 2.0 mg/dL.
• Hepatic impairment, indicated by total bilirubin above 2.0 mg/dL (or above 4.0 mg/dL in patients with a known diagnosis of Gilbert's syndrome) or liver transaminases exceeding three times the upper limit of normal.
• Known SMAD4 mutation with a history of significant gastrointestinal polyposis, unless colonoscopy within the past 18 months demonstrated either no polyps or ≤5 polyps judged to be clinically insignificant by a gastroenterologist.
• History of unprovoked venous thromboembolism, confirmed by imaging.
• Diagnosis of peripheral neuropathy as confirmed by neurologic evaluation.
• Documented hyperproliferative anemia (myelodysplastic syndrome, aplastic anemia, etc.). a. Current pregnancy or planned pregnancy within the next 6 months, or active breastfeeding.
• Concurrent participation in another interventional research study.
• Any condition, circumstance, language, or literacy limitation, that in the judgment of the investigator, would interfere with study participation or completion.