Assembling the evidence…
BACKGROUND: Hereditary angioedema (HAE) is a rare disorder caused by kallikrein-kinin system dysregulation. Donidalorsen is a prekallikrein-directed antisense oligonucleotide that can rebalance this system by reducing prekallikrein production and is indicated for prophylaxis to prevent HAE attacks in patients 12 years of age and older. OBJECTIVE: To report results from a 4-year, phase 2, open-label extension study of donidalorsen (NCT04307381). METHODS: The study on-treatment period included fixed (weeks 0-12) and flexible (weeks 16-208) treatment periods. Patients received donidalorsen 80 mg subcutaneously every 4 weeks (Q4W) in the fixed treatment period and could receive 80 mg every 8 weeks (Q8W) in the flexible treatment period if attack free for greater than or equal to 12 weeks or 100 mg Q4W if disease was not adequately controlled. End points are summarized through the end of the study (week 208). RESULTS: Of 17 patients with HAE-C1INH-type 1 or HAE-C1INH-type 2, 13 (76%) completed 4 years of treatment (median exposure: 3.99 years). Eight patients changed to donidalorsen Q8W; 5 stayed on Q8W to study completion. One patient received 100 mg Q4W. Mean monthly HAE attack rates decreased by 97% overall from baseline to the on-treatment period, with 97% (Q4W) and 83% (Q8W) decreases to the flexible treatment period. The median longest attack-free interval was 990 days. No serious treatment-emergent adverse events (TEAEs) occurred. One patient (6%) (100 mg Q4W) discontinued due to a TEAE (injection-site discoloration). Seven patients (41%) reported treatment-related TEAEs; the only treatment-related TEAEs reported in more than 1 patient were injection-site reactions. CONCLUSION: In this 4-year study, donidalorsen led to sustained reductions in monthly HAE attack rate with an acceptable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04307381 (https://www. CLINICALTRIALS: gov/study/NCT04307381).
In this 4-year study, donidalorsen led to sustained reductions in monthly HAE attack rate with an acceptable safety profile.
causal wording exceeds what a selected, uncontrolled descriptive extension can independently identify
Mean monthly HAE attack rates decreased by 97% overall from baseline to the on-treatment period, with 97% (Q4W) and 83% (Q8W) decreases to the flexible treatment period.
descriptive within-patient reductions are consistent, but the uncontrolled rollover design limits attribution
No serious treatment-emergent adverse events (TEAEs) occurred.
directly reported for the 17-person HAE-C1INH type 1 or 2 cohort, though rare events remain imprecisely estimated
10 of 12 patients (83%) with data at both baseline and week 156 achieved the MCID in AE-QoL total score.
paired quality-of-life data exceed the stated MCID, but missing observations and no comparator limit inference
Derived from the full evaluation — not a separate score.
Strengths
Median exposure was 3.99 years, 13 of 17 participants completed treatment, and the analysis reports attack rates, safety, quality of life, and pharmacodynamics over extended follow-up.
↳ Abstract; Results, pp. 701–703
The Methods specify fixed and flexible periods, switching criteria, analysis populations, endpoints, and baseline definitions, while Figure 1 and Tables 1–2 document disposition and safety.
↳ Methods, pp. 700–701; Figure 1; Tables 1–2
The Discussion identifies small overall and subgroup samples, absent pediatric participation, no placebo group, and no inferential testing, linking these constraints to subgroup and generalisability limits.
↳ Discussion, Limitations, p. 704
Limitations
Enrollment required completion of the parent trial with acceptable safety and tolerability, and the extension had no concurrent placebo group. This limits attribution of baseline-to-treatment changes and introduces survivor selection.
↳ Methods, Patients and Statistical Analysis, p. 700; Discussion, Limitations, p. 704
The main cohort contained 17 participants, 94% were White, no pediatric patients were included, and only five participants remained on Q8W dosing through completion.
↳ Table 1; Results, p. 701; Discussion, Limitations, p. 704
The Abstract says donidalorsen “led to” sustained reductions and the Discussion says it “drove” them, although the analyses were descriptive and uncontrolled.
↳ Abstract, Conclusion; Discussion, opening paragraph, p. 703
The four-year duration, detailed dosing timeline, disposition accounting, safety table, and longitudinal attack-rate reporting support a quality score in the competently executed range. The contribution is bounded because a two-year interim analysis had already reported a similar 96% reduction, making this primarily a durability extension. The principal methodological constraint is the selected, uncontrolled rollover design, which supports descriptive persistence but not independent causal attribution. Specific limitations are clearly stated, yet the Abstract and Discussion use stronger causal and treatment-endorsement language than the design warrants.
Nabu’s assessment, alongside the field’s view.
Are you an author of this paper?
Sound3.7
Confidence mediumThe final analysis adds two years beyond the prior interim report and supplies four-year safety, durability, and flexible-dosing observations. The advance remains incremental because the principal attack-rate result closely matches the previously reported two-year finding.
“Here, we report the final 4-year data for the phase 2 OLE”
The report defines eligibility, dosing transitions, endpoints, populations, baseline, and descriptive analyses, with disposition and safety outcomes presented in reconstructable detail. Lack of a concurrent comparator and selective rollover eligibility constrain inference but are explicitly acknowledged.
“Descriptive statistics were used to summarize all outcomes.”
The article follows a conventional rationale-to-methods-to-results structure and reports numerical findings with clear timepoints and denominators. The causal verbs “led to” and “drove” are stronger than an uncontrolled descriptive extension can independently support.
“donidalorsen led to sustained reductions”
The paper places the extension alongside the parent phase 2 trial, phase 3 OASIS-HAE trial, prior two-year analysis, and OASISplus follow-up. Its limitations are specific and linked to subgroup size, pediatric coverage, absence of placebo, and lack of inferential testing, although the concluding treatment endorsement remains assertive.
“there was no placebo group included and no inferential statistical testing was performed”
Caveats4 of 4 checks
Participant counts, disposition, attack-rate reductions, exposure, and safety totals reconcile across the Abstract, Results, Figure 1, and Tables 1–2. The uncontrolled design affects interpretation but does not create an internal inconsistency.
Ethics approval, informed consent, registration, funding, data-sharing conditions, and conflicts are declared. Manufacturer sponsorship, employee authorship, equity interests, and sponsor-funded editorial support warrant a disclosed-conduct watch-out.
Flags: 4 declared / 5 total
24 of 25 checkable references verified
26 references in manuscript 1 are books, websites or datasets — counted, but not index-checkable
No retraction notice found in Retraction Watch.
Sources: Retraction Watch ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
Donidalorsen is FDA-approved, and the study supplies four-year protocol-based follow-up relevant to current prescribing and adverse-reaction expectations. It remains short of real-world comparative implementation evidence.
“additional data on Q8W dosing will also be gathered from real-world clinical practice”
AI-generated, human-governed. Something look off? Contact us to request a review.