A Trial of TER-1754 in Patients With Hereditary Hemorrhagic Telangiectasia

This is a first-in-human, Phase 1, multicenter trial that includes two parts:

* Phase 1a (dose escalation) will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of TER-1754 in patients with HHT and determine the maximum tolerated or administered dose.
* Phase 1b (proof of concept) will evaluate clinical activity and further characterize the safety profile of TER-1754 in patients with HHT. The Phase 1b treatment period is separated into a blinded treatment segment followed by an open-label extension (OLE) segment.

• TER-1754 (Drug): QD or BID, orally in 28-day cycles
• Placebo (Drug): Number of tablets will be confirmed post Phase 1a
• TER-1754 (Drug): Phase 1b dose to be determined post Phase 1a

Primary outcomes

• Phase 1a: Safety and Tolerability of TER-1754 [up to 48 weeks]: Incidence of adverse events characterized by type, seriousness, relationship to study treatment, and severity according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0
• Phase 1a: Maximum Tolerated Dose (MTD) and/or Maximum Administrated Dose (MAD) of TER-1754 [28 days]: Incidence dose-limiting toxicities (DLTs) characterized by type, seriousness, and severity according to NCI CTCAE v5.0 (dose escalation only).
• Phase 1b - Evaluate the Change from baseline in epistaxis and symptom-related clinical activity scores at Week 24 [48 weeks]: Assess change from baseline in epistaxis duration

Secondary outcomes

• Phase 1a and 1b: Evaluate TER-1754 Peak Plasma Concentration (Cmax) [up to 48 weeks]: Cmax of TER-1754 following single and multiple dosing.
• Phase 1a and 1b: Evaluate change from baseline in Daily Epistaxis (EQ) Questionnaire [up to 48 weeks]: Change from baseline in EQ Questionnaire based on patient self-reported epistaxis frequency, severity and duration, where: Epistaxis frequency: number of epistaxis events per week Epistaxis duration: total minutes of bleeding Epistaxis intensity - From mild to severe: Spotting, dripping, dripping quickly, steady stream, pouring, and gushing.
• Phase 1a and 1b: Evaluate HHT-specfic quality of life [Up to 48 weeks]: Change from baseline in HHT-specific QoL (HHT-QoL), where The total score ranges from 0 (no limitations) to 16 (severe limitations).
• Phase 1a and 1b: Evaluate TER-1754 Time to Peak Concentration (Tmax) [Up to 48 weeks]: Time at which maximum observed plasma concentration occurs.
• Phase 1a and 1b: Evaluate TER-1754 Area Under the Concentration-Time Curve (AUC0-last) [Up to 48 weeks]: Area under the plasma concentration-time curve from time zero to last measurable concentration (AUC0-last)
• Phase 1a and 1b: Evaluate TER-1754 AUC0-24 [Up to 48 weeks]: Area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24)
• Phase 1a and 1b: Evaluate TER-1754 AUC∞ [Up to 48 weeks]: Area under the plasma concentration versus time curve extrapolated to infinity (AUC∞) of TER-1754 following single and multiple dosing.
• Phase 1a and 1b: Evaluate TER-1754 Terminal Half-Life (t½) [Up to 48 weeks]: Terminal elimination half-life (t½) of TER-1754 calculated from the terminal slope of the plasma concentration versus time profile.
• Phase 1a and 1b: Evaluate TER-1754 Mean Residence Time (MRT) [Up to 48 weeks]: Mean residence time (MRT) of TER-1754.
• Phase 1a and 1b: Evaluate TER-1754 Accumulation Ratio at Steady State [Up to 48 weeks]: Accumulation ratio of TER-1754 at steady state, calculated as the ratio of exposure at steady state to exposure after the first dose.
• Phase 1a and 1b: Change from baseline in Nasal Obstruction Symptom Evaluation Score for HHT (NOSE HHT) [up to 48 weeks]: Change from baseline in the NOSE HHT score, a validated scale measuring nasal obstruction in HHT. The score ranges from 0 to 4, with higher scores indicating more severe symptoms.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Able to provide a signed and dated written informed consent prior to any study-specific procedures, sampling, or data collection.
* A clinical diagnosis of HHT as defined by the Curaçao criteria
* Baseline (1-month) ESS ≥ 4
* ECOG ≤ 2
* Anemia or parental iron infusion of at least 500 mg or transfusion of at least 2 units of RBCs within the preceding 24 weeks.
* Adequate bone marrow function
* Adequate renal function
* Adequate hepatic function

Exclusion Criteria:

* Prior nonresponse or loss of response to an agent that inhibits AKT1 and/or AKT2 as the primary mechanism of action.
* Diagnosis of DM requiring insulin treatment
* Known significant bleeding sources other than nasal, GI, or menstrual/ uterine
* Known underlying hypoproliferative anemia or clinically significant hemolytic anemia