BACKGROUND: Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥12 years, demonstrated efficacy and acceptable safety in the phase 3, placebo-controlled OASIS-HAE trial (NCT05139810). Here, we report 1-year results from the corresponding open-label extension (OLE) cohort of the OASISplus study (NCT05392114).
METHODS: OASISplus included patients who rolled over from OASIS-HAE. Patients who received donidalorsen 80 mg or placebo subcutaneously every 4 weeks (Q4W) in OASIS-HAE received donidalorsen Q4W in OASISplus. Patients who received donidalorsen 80 mg or placebo every 8 weeks (Q8W) in OASIS-HAE received donidalorsen Q8W or Q4W, if not attack-free in the final 8 weeks of OASIS-HAE. The primary endpoint was safety (ie, incidence of treatment-emergent adverse events [TEAEs]). Secondary endpoints included the monthly rate of HAE attacks and Angioedema Quality of Life (AE-QoL).
RESULTS: The OLE cohort included 83 patients (Q4W, n=69 [83%]; Q8W, n=14 [17%]). Of these, 75 (90.4%) completed Year 1, and 6 patients receiving donidalorsen Q8W in OASIS-HAE switched to the Q4W dosing group in the OLE. Median donidalorsen exposure was 392.3 days. From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W), and patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points). Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported.
CONCLUSION: Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.
From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W)
large descriptive reductions in an uncontrolled rollover cohort without a concurrent comparator
Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.
consistent one-year outcomes, though the open-label design limits independent efficacy attribution
patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points)
validated scores exceeded the clinical threshold, but the uncontrolled comparison limits attribution
Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported.
directly documented adverse-event counts and classifications in the full treated cohort
Derived from the full evaluation — not a separate score.
Strengths
Table 2 reports adverse-event incidence, seriousness, severity, treatment relationship, and discontinuations, while the Safety section provides narratives for serious events and laboratory abnormalities.
↳ Results, Safety; Table 2
The study extends follow-up beyond the parent trial and reports attack rates, quality of life, disease control, treatment satisfaction, and median exposure through Year 1.
↳ Results, Efficacy; Results, QoL, Disease Control, and Treatment Satisfaction
The Discussion identifies selection bias, racial homogeneity, the small Q8W subgroup, and the absence of a placebo comparator, including their implications for inference and generalisability.
↳ Discussion, Limitations
Limitations
All Year-1 analyses are descriptive within an open-label rollover cohort, so the extension cannot independently separate treatment effects from selection, carryover, or temporal influences.
↳ Materials and Methods, Statistical Analysis; Discussion, Limitations
Only 14 participants received Q8W dosing, and eligibility for that schedule favored patients without recent breakthrough attacks, limiting regimen-specific conclusions.
↳ Results, Patients; Table 1; Discussion, paragraph 2 and Limitations
The cohort was 91.6% White and included only seven adolescents, restricting confidence across racial, ethnic, and age subgroups.
↳ Table 1; Discussion, Limitations
The one-year extension adds clinically relevant durability and safety observations to an established phase 3 program, but the advance remains incremental relative to the parent trial and earlier long-term extension evidence. Methods specify dosing transitions, endpoint definitions, descriptive analyses, and safety classification, with outcomes documented across Tables 1–2 and Figures 2–4. The principal interpretive constraint is the uncontrolled rollover design, which supports descriptive persistence while limiting independent causal efficacy inference, particularly in the 14-person Q8W group. Contextualization and limitation handling are substantive, although occasional terms such as “demonstrated” and “led to” are stronger than the extension design alone warrants.
Nabu’s assessment, alongside the field’s view.
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Sound3.6
Confidence mediumThe study adds one-year safety, attack-rate, and quality-of-life observations beyond the 24-week parent trial. The contribution is clinically useful but incremental given the prior phase 3 and long-term phase 2 evidence.
“Here, we report results from a prespecified interim analysis at 1 year in the OLE study.”
The prospective extension defines dosing transitions, endpoints, analysis sets, exposure, and adverse-event grading in detail. Its uncontrolled rollover structure, selection risk, and small Q8W cohort limit efficacy and regimen-specific inference despite competent execution.
“the lack of a placebo group comparator…prevents inferential statistics and may limit interpretation of the results.”
The article follows a traceable methods-to-results structure and distinguishes descriptive analysis from formal inference. Some headline phrasing uses a stronger efficacy register than the uncontrolled extension independently supports, although the Conclusions and Limitations add appropriate qualification.
“Donidalorsen demonstrated sustained reductions in HAE attack rate”
The Discussion relates the findings to the parent phase 3 trial, phase 2 extension evidence, and available prophylactic options. It identifies demographic, subgroup, selection, and comparator limitations and generally carries them into the interpretation.
“OLE studies have a risk of selection bias”
Caveats4 of 4 checks
Participant disposition, exposure, efficacy denominators, and adverse-event totals reconcile across the abstract, Results, and Tables 1–2. The descriptive analysis matches the stated uncontrolled open-label design.
Ethics approval and trial registration are declared, and the Data Availability Statement specifies conditions for access through Vivli. No conflict-of-interest disclosure statement appears in the supplied full text.
Flags: 3 declared / 5 total
22 of 22 checkable references verified
28 references in manuscript 6 are books, websites or datasets — counted, but not index-checkable
References not verified automatically are resolved manually within 24 hours.
No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
Donidalorsen is already approved, placing the evidence near clinical deployment rather than at an exploratory stage. The report adds longer-term trial follow-up but not comparative implementation evidence.
“these long-term results…add to the evidence supporting the efficacy and safety”
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Well-supportedRiedl, Tachdjian, Lumry, et al. · 2024 · Clinical medicine
Donidalorsen at a dose of 80 mg administered subcutaneously every 4 or 8 weeks significantly reduced the hereditary angioedema attack rate
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Tentative