A Randomized, Placebo-Controlled, Multicenter Proof-of-Concept (POC) Study to Assess the Safety and Efficacy of the Novel Allosteric AKT Inhibitor, VAD044, in Adults with Hereditary Hemorrhagic Telangiectasia (HHT)

Introduction: HHT is the second most common inherited bleeding disorder (1 in 5000 people) yet still lacks approved therapies. HHT results in severe recurrent epistaxis, chronic gastrointestinal bleeding, and visceral vascular complications that cause major clinical and psychosocial morbidity and reduce life expectancy. In HHT, mutations in endoglin or ALK1 cause overactivation of the serine/threonine kinase, AKT, driving telangiectasia formation and visceral organ arteriovenous malformation. VAD044 is an oral, once-daily allosteric selective inhibitor of AKT1/2 in development as a potential disease-modifying therapy for HHT. We report primary results from a POC study (NCT05406362) of VAD044 in adults with HHT.

Methods: This randomized, placebo-controlled study was conducted in the US and EU and evaluated the safety and efficacy of 2 oral doses of VAD044 in adults with moderate to severe HHT. Inclusion criteria included >20 episodes and >80 minutes duration of epistaxis per month (28 days), an Epistaxis Severity Score (ESS; range: 0–10) >4, and requirement for IV iron/RBC transfusion in the 6 months before enrollment. Patients were randomized 1:1:1 to VAD044 30 mg, VAD044 40 mg, or placebo orally once daily for 12 weeks with an 8-week follow-up period. The primary objective was to assess safety and tolerability of once-daily VAD044; the primary endpoint was adverse event (AE) frequency and severity. Secondary objectives included the impact of VAD044 on epistaxis endpoints. Exploratory endpoints included number of epistaxis-free days, Patient Global Impression of Change, and hemoglobin. Patients recorded epistaxis events daily using an HHT eDiary app. Meaningful change thresholds to assess clinically meaningful effects were determined using an anchor-based analysis.

Results: Seventy-five patients (mean [range] age: 56 [18–73] years; 57% female) were randomized and received VAD044 30 mg (n=24), 40 mg (n=25), or placebo (n=26). Six patients (30 mg n=4; 40 mg n=1; placebo n=1) discontinued treatment due to an AE. Grade 1 (30 mg 83% of patients; 40 mg 75%; placebo 65%) and 2 (30 mg 46%; 40 mg 54%; placebo 31%) AEs were the most common. Grade 3 AEs occurred in 17%, 13%, and 15% of patients in the 30-mg, 40-mg, and placebo groups, respectively. All serious AEs (30 mg 13%; 40 mg 4%; placebo 12%) were assessed as unrelated to study drug. Off-target AE profiles were similar between groups. AEs occurring in >10% of patients were mild, manageable, reversible, and dose-related on-target effects of AKT inhibition and included rash (30 mg 25%; 40 mg 46%; placebo 8%), hyperglycemia (40 mg 12%), and diarrhea (30 mg 12%; 40 mg 8%; placebo 4%). Most rashes resolved with topical corticosteroids without withholding study drug.

Mean (SD) epistaxis frequency, duration, and intensity of flow decreased by 33% (32), 43% (42), and 17% (25) in the 40-mg group versus 17% (38), 17% (53), and 7% (25) in the placebo group (sensitivity analyses, n=66). Epistaxis-free days increased by 5 days/month in the 40-mg group versus 2.7 days/month in the placebo group. The effects of VAD044 30 mg on epistaxis were either similar to 40 mg or dose-proportional. Meaningful change thresholds were reached for epistaxis frequency, duration, and epistaxis-free days for the 40 mg group but not placebo. The Patient Global Impression of Changes category of “much better” at week 12 was reported by 60%, 35%, and 17% of patients in the 40-mg, 30-mg, and placebo groups, respectively. At week 12, the median difference in hemoglobin between the 40-mg group and placebo was +1.1 g/dL in those with moderate/severe baseline anemia. By the end of treatment, visible regressions of telangiectasia were observed in some patients in the 40-mg group, suggesting a long-term potential for vascular remodeling.

Conclusions: These data show that the safety and tolerability of oral, once-daily VAD044 for 12 weeks were similar to placebo except for drug class effects, which were mostly mild and resolved while on study drug. Relative to placebo, VAD044 40 mg elicited substantial and clinically meaningful improvements in epistaxis parameters and other disease activity measures, and a major, dose-dependent improvement in Patient Global Impression of Change. These results support continued development of VAD044—the first-ever novel therapy being developed specifically for HHT—to address the major unmet need for patients with HHT. An open-label extension trial is ongoing.