Highlight
– In a 12‑week, randomized, double‑blind trial (N=75), oral engasertib at 30 mg and 40 mg daily reduced epistaxis frequency and duration versus placebo in patients with hereditary hemorrhagic telangiectasia (HHT).
– Safety was broadly similar to placebo aside from a higher rate of reversible mild–moderate rash and some hyperglycemia with the 40 mg dose; serious adverse events were not increased.
– Changes were modest and variable; longer, larger trials with clinical endpoints (transfusion need, hemoglobin, quality of life) are required to define therapeutic role.
Background and disease burden
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by mucocutaneous telangiectasias and arteriovenous malformations. Recurrent epistaxis is the most common and often most troublesome manifestation, causing chronic blood loss, iron deficiency anemia, frequent clinic visits, and substantial reduction in health‑related quality of life. Current management is multimodal and largely symptomatic: nasal humidification and topical therapy, endoscopic vessel coagulation or laser, antifibrinolytics (e.g., tranexamic acid), and off‑label systemic anti‑angiogenic therapy (notably bevacizumab) for selected patients. There remains no globally licensed pharmacologic therapy specifically for bleeding in HHT, and high unmet need persists, particularly for patients with recurrent, transfusion‑dependent epistaxis or those who are poor candidates for repeated local procedures.
Study design
This proof‑of‑concept, multicenter, randomized, double‑blind, placebo‑controlled trial (ClinicalTrials.gov NCT05406362) evaluated oral engasertib, an allosteric, selective AKT inhibitor, administered once daily for 12 weeks. Seventy‑five adult patients with HHT were randomized 1:1:1 to receive engasertib 30 mg, engasertib 40 mg, or placebo. The trial prioritized safety as the primary outcome (frequency and severity of adverse events). Key secondary outcomes were measures of epistaxis, specifically frequency and duration over the 12‑week treatment period. An open‑label extension was planned to evaluate longer‑term safety and efficacy.
Key results
Population and exposure: Of the 75 randomized patients, 24 were allocated to engasertib 30 mg, 25 to engasertib 40 mg, and 26 to placebo. All randomized participants who received at least one dose were included in the safety analysis.
Safety
The overall safety profile of engasertib was similar to that of placebo with the notable exceptions of mild‑to‑moderate rash and, at the higher dose, hyperglycemia. Rash occurred in 21% of patients in the 30 mg group, 42% in the 40 mg group, and 8% in the placebo group; most rashes were grade 1–2 and resolved with continued therapy or after brief interruption. Mild‑to‑moderate hyperglycemia occurred in 12% of patients in the 40 mg group and was not reported in the 30 mg or placebo arms. Importantly, the incidence of serious adverse events (SAEs) was similar across active and placebo groups, and no new safety signals emerged in the 12‑week period.
Efficacy — epistaxis frequency and duration
From baseline to week 12, the mean (±SD) percentage decreases in epistaxis frequency were:
- 30 mg engasertib: 26.5% ± 26.5%
- 40 mg engasertib: 27.8% ± 35.1%
- Placebo: 18.0% ± 36.0%
Mean (±SD) percentage decreases in epistaxis duration were:
- 30 mg engasertib: 29.9% ± 53.2%
- 40 mg engasertib: 41.4% ± 41.0%
- Placebo: 23.8% ± 53.4%
These data show reductions in both frequency and duration of nosebleeds in engasertib‑treated patients compared with baseline, with numerically greater reductions than placebo. The trial report did not present formal p values for all pairwise comparisons in the summary text provided here nor confidence intervals around the between‑group differences in the excerpt available; variability was substantial as indicated by large standard deviations.
Dose effect
There was not a clear, consistent dose–response relationship between 30 mg and 40 mg in the short term: both doses produced similar mean reductions in frequency, with a suggestion of greater reduction in duration at 40 mg. However, the higher dose was associated with more frequent rash and isolated hyperglycemia, supporting careful dose selection in future studies.
Expert commentary and interpretation
Biologic plausibility: The AKT pathway is central to endothelial cell signaling and angiogenesis. Inhibiting AKT signaling could plausibly modulate aberrant angiogenic activity underlying telangiectasia fragility in HHT, thereby reducing spontaneous mucosal bleeding. Engasertib is an allosteric AKT inhibitor designed to selectively modulate this pathway; the observed clinical signal for reduced epistaxis is congruent with the proposed mechanism.
Clinical significance and limitations: This trial establishes preliminary proof of concept that targeting AKT can alter bleeding patterns in HHT. However, the magnitude of benefit was modest and highly variable across patients, and a substantial placebo response was observed (mean 18% reduction in frequency). The trial was short (12 weeks) and powered primarily for safety rather than definitive efficacy. Key clinical outcomes — transfusion requirement, hemoglobin concentration, iron indices, patient‑reported quality of life, and need for local procedures — were not detailed in the summary and will be important in subsequent larger trials. The subjective nature of epistaxis diaries and the natural waxing‑waning course of bleeding in HHT introduce noise; future trials should incorporate objective hematologic outcomes and standardized epistaxis severity scoring tools, as well as longer follow‑up to assess durability and late safety signals.
Comparative context: Current systemic approaches for severe HHT‑related bleeding include anti‑VEGF strategies (e.g., bevacizumab), which have shown clinical benefit in select patients but are limited by intravenous administration, cost, and class‑specific risks. An oral, targeted AKT inhibitor could offer a convenient alternative or adjunct if efficacy and safety are confirmed in larger studies. Patient selection (for example, by genotype — ENG, ACVRL1, SMAD4 — or severity) may refine benefit‑to‑risk profiles.
Implications for practice and research
At present, engasertib should be regarded as investigational for HHT‑related bleeding. The trial’s results justify continued development but do not yet support routine clinical use outside carefully monitored studies. Priorities for future trials include:
- Randomized studies powered for clinically meaningful endpoints such as change in hemoglobin, transfusion avoidance, and validated quality‑of‑life measures over longer follow‑up (6–12 months or longer).
- Stratification or prespecified analyses by HHT genotype and baseline bleeding severity to identify subgroups most likely to respond.
- Careful monitoring for metabolic effects (hyperglycemia) and cutaneous toxicity, with dose optimization to maximize efficacy while minimizing adverse events.
- Comparative trials versus established off‑label systemic options or combination strategies with local therapies.
Conclusions
The randomized proof‑of‑concept study of engasertib in HHT demonstrates a favorable short‑term safety profile aside from reversible rash and dose‑associated hyperglycemia and provides preliminary evidence of reduced epistaxis frequency and duration relative to baseline and numerically versus placebo. The effects are modest and variable, and placebo response was notable. These findings support continued clinical development, prioritizing larger and longer trials with clinically meaningful endpoints to clarify the therapeutic role of AKT inhibition in HHT.
Funding and clinicaltrials.gov
This trial was funded by Vaderis Therapeutics. ClinicalTrials.gov identifier: NCT05406362. The published report is: Al‑Samkari H, Hessels J, Riera‑Mestre A, et al. 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.
References
1. Al‑Samkari H, Hessels J, Riera‑Mestre A, et al. 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.
2. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev. 2010 Nov;24(6):203‑19. doi:10.1016/j.blre.2010.07.001.
Thumbnail image prompt (AI‑friendly)
A middle‑aged patient in an ENT clinic, seated and holding a tissue to their nose, a clinician beside them reviewing a tablet that displays nasal endoscopy photos and a simple bleeding frequency chart; warm clinical lighting, neutral background, realistic style, focus on empathy and clinical data overlay, high resolution.