An interim assessment of bleeding events in a prospective natural history study of hereditary hemorrhagic telangiectasia patients using a validated bleeding scale and a novel daily reporting instrument

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is an inherited bleeding disorder characterized by recurrent hemorrhagic events in multiple vascular beds. To date, there are no approved therapies for patients with HHT, which remains the largest unaddressed bleeding disorder worldwide. More than 90% of HHT cases are caused by loss-of-function mutations in endoglin (HHT1) or ALK1 (HHT2). Nearly all patients have recurrent epistaxis due to nasal telangiectasias, and approximately 1/3 of patients have recurrent GI bleeding caused by arteriovenous malformations (AVMs) in the GI tract. Natural history studies of rare-disease populations like HHT provide important insights into how patients experience various aspects of disease progression in the absence of available therapies. Data generated in these observational studies support development of novel therapies by identifying optimal stages of disease for intervention, novel aspects how patients feel and function for endpoint development, and the extent of variability in the population around symptom severity, regional standards of supportive care, and health-related quality of life (HRQoL). Methods A prospective natural history study of patients with HHT with an Epistaxis Severity Score (ESS) at enrollment of ≥ 4 was jointly initiated by Diagonal Therapeutics, Inc. (Boston, MA) and Cure HHT (Monkton, MD) to evaluate various aspects of HHT disease progression, including epistaxis, need for hematologic support, and HRQoL. A novel patient-reported outcome instrument was implemented – the During My Day Diary – that captured daily reported frequency, duration, and severity of epistaxis events. ESS assessments were performed for each enrolled subject at initiation and monthly thereafter. Interval data were extracted from the ongoing study. Interim data are summarized descriptively. Results Interim data are from all enrolled patients meeting eligibility criteria between initiation of recruitment in January 2025 and the end of June 2025. Overall, 94 adult patients with HHT were screened, and 91 enrolled. At baseline, the study population had a mean age of 48.6 years (SD 14.9 years), 76% were female, 93% Caucasian, 9.3% Hispanic or Latino, and 7% African American or Other. Mean and median ESS at screening were 5.3 (SD 1.5) and 5.5, respectively. In addition to epistaxis, 41% of the patients reported having lung AVMs, 12% hepatic AVMs, and 7% brain AVMs. Based on ESS reporting, 22.7% of the population had mild epistaxis (ESS ≤ 4), 68.0% were considered moderate (4 < ESS ≤ 7), and 9.3% severe (ESS > 7). For epistaxis frequency, 60% of patients reported at least daily epistaxis with 39% reporting several epistaxis events per day. Typical nosebleed duration in 60% of the population was 6-15 minutes (37%) or 16-30 minutes (23%). Epistaxis intensity was reported as typically pouring or gushing in 41% of patients. At baseline, 47% of the population reported being anemic in the last 3 months. Daily recording of epistaxis frequency, duration, and intensity in the During My Day Diary was initiated by all patients at enrollment. After 1 month of recording, mean frequency of diary nosebleed events was 25/month and mean duration was 18 minutes/event. Using a visual analog scale in the diary, typical epistaxis intensity at 1 month was reported as pouring or gushing in 5.6% with dripping-quickly or steady-stream intensity occurring in 33.7% of patients. Daily-diary reporting of frequency, severity, and intensity of epistaxis events at 3 months did not differ significantly from the 1-month timepoint. HRQoL assessments and other events of interest, such as nocturnal bleeding events and menstrual bleeding, will be reported in the final analysis. Conclusions Here we report preliminary results of an ongoing natural history study of HHT patients with moderate-to-severe bleeding. Baseline ESS results and daily-diary reporting at 1 and 3 months were generally consistent, describing a population significantly impacted by daily bleeding events described by many patients during ESS assessment as frequently gushing or pouring. In contrast, diary-reported bleeding intensity was markedly lower than that reported by ESS which required recall of intensity over a 1–3-month period. Final analysis will report patient bleeding events, QoL and impact of HHT on daily living to support interventional clinical trial and pivotal endpoint design to test novel therapies in the moderate-to-severe HHT population.