Real-World Effectiveness of Ravulizumab Among Adults with Atypical Hemolytic Uremic Syndrome (aHUS) Who Switched to Ravulizumab within 3 Months of Eculizumab Treatment: A Physician Panel-Based Chart Review Study (aHUS IMPACT)

Introduction: Atypical hemolytic uremic syndrome (aHUS), a form of thrombotic microangiopathy (TMA), is a progressive rare disease caused by complement dysregulation that, if untreated, can lead to severe organ damage and death. Ravulizumab, a next-generation terminal complement C5 inhibitor (C5i), was designed via the targeted modification of eculizumab and has been shown to achieve immediate, complete and sustained terminal complement inhibition with an extended dosing interval compared with eculizumab. Ravulizumab is approved for aHUS based on registrational clinical studies. Real-world evidence has further supported ravulizumab effectiveness in patients already stable on eculizumab. However, evidence of ravulizumab effectiveness following short-term eculizumab treatment (≤ 3 months) is limited.

Methods: This was a retrospective, longitudinal, physician panel-based chart review of adults with aHUS in the USA who switched from eculizumab to ravulizumab between November 1, 2019 and September 30, 2022 and within 3 months of eculizumab initiation. Physicians with medical and laboratory records for ≥ 1 patient(s) with aHUS randomly selected ≤ 5 patients with aHUS who had ≥ 6 months of medical records after ravulizumab initiation (index date), unless the patient died within 6 months of ravulizumab initiation. Laboratory parameters (platelet count, lactate dehydrogenase [LDH] levels and serum creatinine levels) were collected at index date or at the point closest to the index date within the prior 6 months, and at 1, 3, 6 and 12 months after the index date. Laboratory parameters were summarized using descriptive statistics; values pre- and post-index date were compared by linear regressions with generalized estimating equations. Complete TMA response was defined as having platelet count normalization (≥ 150 × 10⁹/L), LDH normalization (≤ 246 U/L) and ≥ 25% reduction in serum creatinine levels compared with the last measure before eculizumab treatment, and was determined based on laboratory data or physician-reported complete TMA response.

Results: Overall, 36 patients with aHUS (enrolled by 25 physicians) were included in the analysis; 23 (63.9%) were male, 25 (69.4%) were White, 6 (16.7%) were Asian and 5 (13.9%) were Black or African American. In addition, 33 (91.7%) were non-Hispanic. Mean (standard deviation [SD]) patient age at index date was 44.3 (16.0) years. Mean (SD) time from diagnosis to eculizumab initiation was 1.0 (2.5) month(s), and from eculizumab initiation to ravulizumab initiation was 1.4 (0.9) months. Genetic tests were performed in 18 patients (50.0%), of whom 8 (44.4%) had ≥ 1 genetic variant. Overall, 2 patients (5.6%) had a kidney transplant prior to eculizumab treatment, and 3 patients (8.3%) received acute (n = 1) or chronic (n = 2) dialysis during the 12 months before and ≤ 2 weeks after the index date. On or before the index date, median (interquartile range [IQR]) platelet count was 98.5 × 10⁹/L (65.0, 130.0) and LDH level was 322.0 U/L (230.0, 362.0). After the index date, median (IQR) platelet count increased to 156.0 × 10⁹/L (135.0, 196.0) at Month 1 and to 199.0 × 10⁹/L (158.0, 250.0) at Month 12; LDH level decreased to 217.0 U/L (181.0, 266.0) at Month 1 and to 162.0 U/L (110.0, 217.0) at Month 12. Compared with the pre-index date, mean (95% confidence interval) serum creatinine levels significantly decreased by 25.0% (11.5%, 36.4%; p < 0.001) at Month 1 and by 44.0% (31.2%, 54.4%; p < 0.001) at Month 12. Complete TMA response was achieved in 26 patients (72.2%) within 18 months of eculizumab initiation and early switch to ravulizumab.

Conclusion: This study provides real-world evidence that switching to ravulizumab after short-term eculizumab treatment can result in further hematologic and renal improvement in patients with aHUS, as demonstrated by both an early response and continued improvement through 1 year after ravulizumab initiation.

Study/writing support funder: Alexion, AstraZeneca Rare Disease.