Efficacy and Safety of Concomitant Use of Ravulizumab and IST in Patients with Paroxysmal Nocturnal Hemoglobinuria up to 52 Weeks
Authors: Schrezenmeier Hubert , Lee Jong Wook , Hill Anita , Ptushkin Vadim V , Pessoa Viviani , Notaro Rosario , Wang Jimmy , Ogawa Masayo , Okamoto Shinichiro , Wong Lily LL , Peffault De Latour Regis , Kulasekararaj Austin 
Published: February 2021

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disease characterized by uncontrolled complement activation on the surface of PNH blood cells, which can lead to hemolytic anemia. Aplastic anemia is a closely related rare bone marrow disorder and commonly treated with immunosuppressive therapy (IST), such as cyclosporine and anti-thymocyte globulin. Previous research has shown that IST is effective when used concomitantly with eculizumab, regardless of the sequence of treatment initiation with IST or eculizumab. However, there are little available data in patients with PNH who may require concomitant ravulizumab and IST.
Aims: To evaluate the efficacy and safety of concomitant ravulizumab and IST use in patients with PNH who received ravulizumab up to 52 weeks and those who switched to ravulizumab following the 26 weeks of treatment with eculizumab during the primary evaluation period, and to assess the transfusion requirements in these patients.
Methods: Patient data from Study 301 (Lee JW, et al. Blood. 2019;133[6]:530-539; NCT02946463) were stratified by concomitant IST use during the primary evaluation period and extension period of this phase 3, multicenter, randomized, active-controlled, open-label, multicenter study. The study consisted of a 26-week primary evaluation period in which patients ≥18 years old with a documented diagnosis of PNH received either ravulizumab or eculizumab, followed by an extension period of up to 5 years, during which all patients received ravulizumab. Efficacy data were collected at the end of the primary evaluation period (through week 26) and through week 52 of the extension period. Data from week 52 were then compared with week 26 data to assess for maintenance of treatment response. Maintenance of treatment response is defined as patients who achieved the primary and secondary efficacy endpoints at both 26 weeks and 52 weeks. Safety variables were also assessed. Descriptive statistics are provided; no tests for differences between treatment groups were performed.
Results: There were 246 patients receiving either ravulizumab or eculizumab in the 26-week primary evaluation period of Study 301, and 243 of these patients then received ravulizumab during the extension period. Of these patients, 28 received concomitant IST and 215 did not. Efficacy data are described in Table 1. For lactate dehydrogenase (LDH) normalization (LDH levels &lt; 1x upper limit of normal; ULN), 50.0% of patients on IST maintained the treatment response from week 26 to week 52 vs 75.5% of patients without IST. Patients on IST had a numerically lower mean change in LDH levels compared with patients without IST at week 26, compared with baseline (Table 2). A total of 75.0% of patients taking IST maintained transfusion avoidance through 52 weeks compared with 89.9% of patients without IST, which may also be caused by an underlying coexisting condition such as bone marrow disease in patients who required IST. A similar proportion of patients on IST and without IST maintained stabilized hemoglobin levels through week 52 (avoidance of &gt;2 g/dL decrease in hemoglobin levels from baseline in the absence of transfusion): 88.9% and 87.6%, respectively. Furthermore, a higher proportion of patients who were treated with IST also required transfusions: 53.3-61.5% of patients on IST vs 21.1-38.7% of patients without IST through week 26 and week 52. Similarly, patients treated with IST received, on average, more transfusions than patients without IST (Table 3). Safety results were similar between the IST and non-IST patient subgroups (Table 4).
Conclusions: Despite a limited number of patients with available data for evaluating the effects of IST, concomitant use of ravulizumab and IST was effective and well tolerated in patients with PNH. Furthermore, patients treated with ravulizumab for the whole 52-week treatment period and did not receive concomitant IST had numerically fewer pRBC/whole blood transfusions compared with patients treated with IST.

Disclosures
Schrezenmeier: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Ptushkin:Alexion Pharmaceuticals Inc.: Honoraria. Notaro:Alexion Pharmaceuticals Inc.: Honoraria, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Okamoto:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Peffault De Latour:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees.