D2.437 - Long-Term Analysis of the Phase 2 Open-Label Extension of Donidalorsen in Patients With Hereditary Angioedema

Hereditary angioedema (HAE) is a rare disease characterised by recurrent, potentially life-threatening swelling. We report an interim analysis of the phase 2 open-label extension study (NCT04307381) of patients with HAE treated with donidalorsen, an investigational antisense oligonucleotide that reduces plasma prekallikrein.

This study included an on-treatment period of fixed (Weeks 0–12; donidalorsen 80 mg every 4 weeks [Q4W]) and flexible (Weeks 16–208; donidalorsen 80 mg Q4W or every 8 weeks [Q8W] or 100 mg Q4W) dosing. Patients attack-free for ≥12 weeks could switch to 80 mg Q8W during the flexible dosing period. Endpoints summarise the on-treatment or flexible periods up to Week 196 (data cutoff) compared with the phase 2 study baseline (NCT04030598).

Thirteen (76%) patients have remained in the study for ≥3 years. Among all patients who entered the study, 15/17 (88%) patients experienced treatment-emergent adverse events (TEAEs) at the time of the data cut, with 12 (71%) experiencing only mild/moderate TEAEs; most study drug–related TEAEs were injection-site reactions. Overall (all dosing groups combined) mean monthly HAE attack rate during the on-treatment period decreased by 96% from baseline (97%, 80 mg Q4W; 83%, Q8W during the flexible treatment period) up to Week 196. In patients with available data at the prespecified Week 156 time point (n=12), the mean Angioedema-Quality of Life (AE-QoL) total score decreased in the Q4W and Q8W groups by 21 points and 22 points, respectively. Of these 12 patients, 10 (83%; 5 each in Q4W and Q8W groups) reported a clinically meaningful (≥6-point) improvement in AE-QoL total score at Week 156. Among this subgroup of patients with a clinically meaningful improvement in AE-QoL, the mean reduction from baseline in AE-QoL total score was 30 points (Q4W) and 22 points (Q8W) at Week 156. In all 13 patients who had available data at Week 156, trough plasma prekallikrein concentrations were reduced from baseline by 58% and 42% in the Q4W (n=8) and Q8W (n=5) groups, respectively.

At the Week 196 data cutoff, donidalorsen was well-tolerated, and reported adverse events were consistent with previous follow-ups of the phase 2 study, with injection-site reactions being the most common treatment-related events. Donidalorsen led to sustained reductions in HAE attacks and plasma prekallikrein concentrations, and most patients reported a clinically meaningful improvement in QoL.