By Rohit Jain, B. Pharmacy, MBA, PGDBM, LL.B, DCR
January 23, 2020
Atypical hemolytic uremic syndrome (aHUS) is a rare, serious, and progressive condition characterized by thrombocytopenia, hemolytic anemia, and renal failure. The condition occurs in both children and adults. In almost half of all the cases, the patient suffers from end-stage renal disease due to damage to tiny blood vessels in the kidney. Unlike typical hemolytic uremic syndrome (tHUS) which is related to Shiga-like toxin (E. coli), aHUS is associated with prolonged and uncontrolled activation of the complement system. Comparatively 10 times less common than tHUS, the incidence of aHUS is about 1 in 500,000 people in the United States1.
In October this year, USFDA had approved ravulizumab for the treatment of adults and pediatric patients one month of age and older with the atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). The approval is with the limitation that this drug should not be used in Shiga toxin E. coli related hemolytic uremic syndrome. The drug was also approved in 2018 by USFDA in the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). Ravulizumab, a long-acting C5 complement inhibitor, is approved for the first time in pediatric patients2.
Administration of ravulizumab is through intravenous injection and it is available as a single-dose vial containing 300 mg ravulizumab-cwvz at a concentration of 10 mg/mL. The drug prevents the generation of the terminal complement complex C5b9 by specifically binding to the complement protein C5 with high affinity.
The efficacy of ravulizumab was evaluated through two open-label, single-arm studies3. One study, ALXN1210-aHUS-311, enrolled adult patients and the other study, ALXN1210-aHUS-312, enrolled pediatric patients. Important inclusion criteria in both the studies were evidence of hemolysis such as elevated serum lactate dehydrogenase (LDH) and platelet count ≤150 x 109/L.
In the study involving adults, analysis of efficacy was done on 56 patients. Complete thrombotic microangiopathy response was observed in 54% of the patients during the initial evaluation period of 26 weeks. There was an increase in mean platelet count to 240.34 ×109/L at Day 8 from 118.52 × 109/L at baseline. The platelet count remains above 227 × 109/L in the initial evaluation period of 26 weeks. There was an increase in mean eGFR from 15.86 to 51.83 indicating an improvement in the renal function, and 76.8% of the patients experience normalization in LDH level indicating a reduction in hemolysis.
Fourteen patients were enrolled in the study on pediatric patients. In 71% of the patients, there was complete thrombotic microangiopathy (TMA) response. Improvement in renal function was noted as there was an increase in eGFR from 28.4 at baseline to 108.0 by 26 weeks. An increase in mean platelet count from 60.50 × 109 /L at baseline to 296.67 × 109/L at day 8 was observed. The platelet count remained above 296 × 109/L throughout the initial evaluation period. Reduced hemolysis was observed in 85.7% of patients as normalization of LDH was observed in these patients.
Eculizumab is the first and the only other drug approved by USFDA for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Although there is no head-to-head study available to compare the efficacy of eculizumab and ravulizumab in the treatment of aHUS, a comparison can be done based on their respective pharmacokinetic data and dose frequency.
Comparing Ravulizumab to Eculizumab
The terminal half-life of ravulizumab is approximately fourfold longer as compared to eculizumab. The elimination half-life of eculizumab is approximately 270 hours to 375 hours while ravulizumab has an elimination half-life of approximately 51 days indicating a longer duration of action. The immediate, complete, and sustained action of ravulizumab is due to 4-amino substitutions in the FC regions and complimentary-determining regions. The prolonged effect of ravulizumab as compared to eculizumab is also obvious from the dose frequency. While eculizumab is generally required to be administered every 2 weeks, the administration frequency of ravulizumab is 8 weeks.
A study comparing the safety and efficacy of ravulizumab and eculizumab in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) concluded that both ravulizumab and eculizumab were well tolerated. The same study concluded that switching of patients with PNH from eculizumab to ravulizumab may reduce the occurrence of breakthrough hemolysis, improved quality of life, reduced treatment burden, and increased retention of long-term therapy4.
Ravulizumab is better than eculizumab, at least in terms of patient compliance and frequency of administration.
- https://ghr.nlm.nih.gov/condition/atypical-hemolytic-uremic-syndrome#statistics (Accessed on December 07th, 2019).
- https://www.medscape.com/viewarticle/920120 (Accessed on December 07th, 2019).
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761108s001lbl.pdf (Accessed on December 07th, 2019).
- Austin G. Kulasekararaj, Anita Hill, Scott T. Rottinghaus et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7; 133(6): 540–549.
Rohit Jain is a medical writing expert, medico-marketing trainer, and patent specialist who has written various medical articles covering different therapeutic areas. He is a registered patent agent in India and is currently pursuing a Masters in Pharmacy. He has more than a decade of experience in the pharmaceutical industry and as an avid reader, his interests include reading about the latest research in the medical and pharmaceutical arenas.