Highlight
– In a multicenter, double-blind, placebo-controlled proof-of-concept trial (NCT05406362), oral engasertib (30 mg or 40 mg daily), an allosteric selective AKT inhibitor, was evaluated for safety and effects on epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT).
– Engasertib produced modest mean reductions in epistaxis frequency (26.5% with 30 mg; 27.8% with 40 mg) and duration (29.9% with 30 mg; 41.4% with 40 mg) over 12 weeks versus 18.0% and 23.8% reductions with placebo, respectively; variability was large and formal statistical comparisons were not reported in the summary.
– Safety over 12 weeks was broadly similar to placebo except for a higher incidence of mild-to-moderate rash (dose-related) and hyperglycemia (seen with 40 mg); serious adverse events were similar across groups and most drug-associated events were reversible.
Background: Disease burden and unmet need
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by mucocutaneous telangiectasia and arteriovenous malformations in visceral organs. Recurrent epistaxis is the most common and often the most impactful manifestation, causing chronic blood loss, iron-deficiency anemia, frequent transfusions in severe cases, and a substantial reduction in quality of life. Despite various local and systemic interventions (nasal humidification, topical therapies, endoscopic laser ablation, antifibrinolytics, and systemic anti-angiogenic agents), there are no universally licensed therapies for HHT-related bleeding in many jurisdictions, and treatment choices are frequently individualized and limited by toxicity.
Study design and methods
This trial was a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept study designed principally to evaluate safety and to provide preliminary efficacy signal data. Patients with HHT and clinically significant epistaxis were randomized 1:1:1 to receive engasertib 30 mg once daily, engasertib 40 mg once daily, or placebo for 12 weeks. Key primary outcomes were safety-focused (frequency and severity of adverse events). Key secondary outcomes included epistaxis frequency and duration measured from baseline to week 12. An open-label extension was planned and is ongoing.
A total of 75 patients were randomized: 24 to engasertib 30 mg, 25 to engasertib 40 mg, and 26 to placebo. Analyses reported were among patients who received at least one dose of the trial regimen.
Key results
Safety
- The most common treatment-associated adverse events attributed to on-target AKT inhibition were rash and hyperglycemia.
- Mild-to-moderate rash occurred in 21% of patients in the 30-mg group (5/24), 42% in the 40-mg group (10/25), and 8% in the placebo group (2/26). Most rashes resolved and did not necessitate permanent discontinuation.
- Mild-to-moderate hyperglycemia was observed in 12% of patients in the 40-mg engasertib group (3/25) and in none of the patients in the 30-mg or placebo groups; hyperglycemia was described as reversible.
- The incidence of serious adverse events was similar between the engasertib groups and placebo over the 12-week blinded period.
Efficacy — epistaxis frequency and duration
- From baseline to week 12, mean (±SD) relative reductions in epistaxis frequency were: 26.5% ± 26.5% with 30 mg engasertib; 27.8% ± 35.1% with 40 mg engasertib; and 18.0% ± 36.0% with placebo.
- Mean (±SD) relative reductions in epistaxis duration were: 29.9% ± 53.2% with 30 mg engasertib; 41.4% ± 41.0% with 40 mg engasertib; and 23.8% ± 53.4% with placebo.
- Absolute reduction magnitudes and variability were substantial; standard deviations indicate wide interpatient heterogeneity. The summary report does not present p-values, confidence intervals for these changes, or prespecified responder analyses in the excerpt provided.
Interpretation of numerical results
The data show numerically greater mean reductions in both frequency and duration of epistaxis with engasertib compared with placebo, with the 40-mg dose achieving larger reductions in duration than the 30-mg dose. However, the differences versus placebo are modest and given the large standard deviations and overlap with placebo, the clinical significance at the individual-patient level is uncertain from these aggregate means alone. The short duration (12 weeks) also limits assessment of durability of benefit for this chronic condition.
Mechanistic rationale and biological plausibility
HHT results predominantly from mutations in genes encoding components of the transforming growth factor–β (TGF-β)/bone morphogenetic protein signaling pathway (including ENG and ACVRL1), which lead to dysregulated angiogenesis and fragile telangiectatic vessels. The PI3K-AKT pathway is an important regulator of endothelial cell survival, proliferation, and angiogenesis. Engasertib is an allosteric, selective AKT inhibitor that targets intracellular signaling implicated in abnormal angiogenic responses. The observed on-target adverse events (rash and hyperglycemia) are consistent with AKT pathway inhibition and provide biological plausibility for both effects and potential efficacy in reducing abnormal bleeding driven by pathological vascular remodeling.
Expert commentary and critical appraisal
Strengths of the trial include randomized, double-blind placebo-controlled design, multicenter enrollment, and prespecified safety focus appropriate for a first-in-disease proof-of-concept study. The trial provides valuable early human data on a novel mechanism (AKT inhibition) in HHT.
Important limitations must temper interpretation:
- Sample size was small (n=75), intended for safety and signal detection rather than definitive efficacy.
- Duration of blinded treatment was short (12 weeks), limiting conclusions about long-term efficacy, sustainability of response, and late adverse events.
- Reported outcomes are summarized as mean percent changes with large standard deviations; the provided summary does not include statistical testing, confidence intervals, or responder-level analyses (for example, proportion achieving a clinically meaningful reduction in epistaxis or improvement in hemoglobin or transfusion requirements).
- Patient characteristics such as genotype (ENG vs ACVRL1 vs others), baseline severity, prior treatments, iron status, or concurrent therapies were not detailed in the summary and could modify treatment effect, limiting generalizability.
- Placebo response was substantial, underscoring the importance of randomized designs for epistaxis trials and the need for objective, standardized bleeding assessments (daily diaries, validated Epistaxis Severity Score, hemoglobin, transfusion rates, quality-of-life instruments) in future studies.
Clinical interpretation
Engasertib appears to have an acceptable short-term safety profile for many patients with HHT, with dose-dependent mild-to-moderate rash and higher rates of hyperglycemia at 40 mg that were reversible. Efficacy signals — modest reductions in epistaxis frequency and duration — support continued clinical development but are not definitive. Whether these percentage reductions translate into meaningful improvements in hemoglobin, transfusion needs, or patient-reported quality of life remains to be established.
Implications for practice and future research
For practicing clinicians, engasertib should not yet change standard management of HHT outside clinical trials. The data justify progression to larger, adequately powered randomized trials that incorporate the following design elements:
- Longer blinded treatment periods (6–12 months or longer) to assess durability and longer-term safety.
- Clinically meaningful primary endpoints such as change in Epistaxis Severity Score, transfusion requirement, hemoglobin concentration, or proportion of patients with predefined clinically important bleeding reductions.
- Predefined responder analyses and presentation of confidence intervals and p-values to quantify uncertainty.
- Stratification or prespecified subgroup analyses by genotype, baseline bleeding severity, and prior systemic antiangiogenic therapy.
- Exploration of optimal dosing balancing efficacy and metabolic adverse effects (hyperglycemia) and standard mitigation strategies (monitoring glucose, dermatologic management).
Conclusion
This proof-of-concept randomized trial of engasertib in HHT demonstrates a tolerable short-term safety profile with dose-related rash and expected metabolic effects, and shows modest, variable reductions in epistaxis frequency and duration compared with placebo over 12 weeks. These findings support further clinical development but are insufficient to establish clinical usefulness. Larger, longer, and more thoroughly powered trials that evaluate robust clinical endpoints (hemoglobin, transfusion needs, validated bleeding and quality-of-life measures) and report inferential statistics are required to determine whether AKT inhibition will become a therapeutic option for HHT-related bleeding.
Funding and trial registration
Funded by Vaderis Therapeutics. ClinicalTrials.gov number: NCT05406362.
References
Al-Samkari H, Hessels J, Riera-Mestre A, Dupuis-Girod S, Van Zele T, Gómez Del Olmo V, Hodges PG, Torres-Iglesias R, Bertè R, Saint-Mezard P, Lazar H, Benedict N, Barker D, Bernasconi C, Picard D, Buscarini E, Mager HJ. Engasertib versus Placebo for Bleeding in Hereditary Hemorrhagic Telangiectasia. N Engl J Med. 2025 Nov 27;393(21):2131-2141. doi: 10.1056/NEJMoa2504411. PMID: 41297007.
