Ravulizumab: Is it the Ultimate Treatment for Atypical Uremic Syndrome?

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.

Recent Studies

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.

Author’s Conclusion

Ravulizumab is better than eculizumab, at least in terms of patient compliance and frequency of administration.

References:

  1. https://ghr.nlm.nih.gov/condition/atypical-hemolytic-uremic-syndrome#statistics (Accessed on December 07th, 2019).
  2. https://www.medscape.com/viewarticle/920120 (Accessed on December 07th, 2019).
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761108s001lbl.pdf (Accessed on December 07th, 2019).
  4. 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 JainRohit 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.

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Dulaglutide in Type 2 Diabetes: Do GLP-1 agonists delay progression of diabetic nephropathy?

By Connor Emdin
June 27, 2018

Forty percent of patients with type 2 diabetes go on to develop chronic kidney disease (CKD).1 These patients are at markedly elevated risk of death from cardiovascular disease.2 They also suffer from reduced quality of life, particularly when CKD progresses to end-stage renal disease and dialysis.3 Despite the substantial morbidity and mortality associated with diabetic kidney disease, therapies are limited. In the National Kidney Foundation Clinical Practice Guidelines for Diabetes and CKD from 2012, only angiotensin converting-enzyme-inhibitors (ACE-inhibitors) and angiotensin-receptor blockers were recommended for protection of renal function in patients with CKD and diabetes with albuminuria.4 Continue reading “Dulaglutide in Type 2 Diabetes: Do GLP-1 agonists delay progression of diabetic nephropathy?”

Assessing the Risks in Live Kidney Donation

By Martina McGrath, MD
February 13, 2018

Kidney transplantation is a life-saving procedure and is associated with at least a doubling in life expectancy of transplant recipients.1 Live-donor kidneys provide better kidney function and longer transplant survival than those from deceased donors. However, live donation is not entirely without risk, Continue reading “Assessing the Risks in Live Kidney Donation”

Sodium Restriction in Patients with Reduced GFR: Blood Pressure Benefits

By Martina McGrath, MD
October 18, 2017

The typical US diet is comprised of 3.4g of sodium per day on average, whereas current recommendations suggest that sodium intake should be limited to <2g/day for the general population1 and possibly lower for those with hypertension or cardiovascular disease.2 Continue reading “Sodium Restriction in Patients with Reduced GFR: Blood Pressure Benefits”

Vancomycin as a Rare Cause of Drug-Induced Cytopenias

By Martina M. McGrath, MD
May 30, 2017

Vancomycin is a glycopeptide antibiotic, with activity against gram positive organisms, including MRSA. It is widely prescribed for hospital-acquired infections, device-related infections, and treatment of resistant organisms. While side effects such as red man syndrome, ototoxicity, and nephrotoxicity are well recognized, immune thrombocytopenia is a less common, but potentially severe, complication of vancomycin therapy. Indeed, because many affected patients are critically ill or treated with other potential culprit agents such as heparin, vancomycin-induced platelet destruction can go unrecognized. Continue reading “Vancomycin as a Rare Cause of Drug-Induced Cytopenias”

Hep C Positive Kidneys into Hep C Negative Patients: Pushing the Boundaries of Transplantation

[Photo by Bill Branson, NIH Medical Arts, National Institutes of Health. Pictured are Robert Colbert, M.D., Ph.D., Amy Petrik, Ph.D., and Grace Kwon, Ph.D. ]

By Martina M. McGrath, MD
May 4, 2017

Currently, over 97,000 patients are awaiting kidney transplant.1 Hepatitis C (HCV) infection is prevalent in the community, and it has been reported that >3000 kidneys from HCV+ donors were offered between 2005 and 2014.2 Prior to the current era of direct-acting antiviral agents (DAAV), patients with HCV who underwent renal transplantation had poorer outcomes, and antiviral treatment with interferon was associated with increased risk of rejection. Likely related to these risks, it has been reported that over 500 kidneys from HCV+ donors are discarded annually.2 However, DAAVs have transformed the management of HCV infection. Greater than 90 percent cure rates have been reported with many of these medications, which are generally well-tolerated. With the availability of safe and effective antiviral therapy for HCV, the question has arisen, could these kidneys now be safely used in HCV-negative recipients? Continue reading “Hep C Positive Kidneys into Hep C Negative Patients: Pushing the Boundaries of Transplantation”

The Link Between Proton Pump Inhibitors and Kidney Disease

By Lea Borgi, MD
April 27, 2017

Proton pump inhibitors (PPI) are among the most prescribed medication in the United States1, with an increasing proportion of US adults reporting using prescription PPI (3.9% in 1999 to 7.8% in 2012) according to the National Health and Nutrition Examination Survey (NHANES).2 However, overall PPI use is most likely underestimated, given their widespread over-the-counter availability. Continue reading “The Link Between Proton Pump Inhibitors and Kidney Disease”

Metformin: Meta-Analysis of Benefits in Comorbid Patients

Broadening access: Meta-analysis suggests benefits of metformin therapy in patients with comorbid kidney or heart disease.

By Martina M. McGrath, MD
February 9, 2017

Metformin is a safe, effective and well-tolerated agent, which is recommended as the first line oral hypoglycemic in treatment of newly diagnosed Type II diabetes. Its central role is underpinned by research showing reductions in long-term cardiovascular mortality in patients treated with metformin, as compared to sulphonylureas or placebo. Continue reading “Metformin: Meta-Analysis of Benefits in Comorbid Patients”

Kidney Transplants from Deceased Donors: How Old is Too Old?

Are older deceased donors an underused resource?

By Martina M. McGrath, MD
December, 29, 2016

Since publication of Robert Wolfe’s landmark paper in 19991 demonstrating a doubling of life expectancy post-renal transplantation compared with remaining on dialysis, demand for renal transplants has continuously grown. Over 99,000 individuals are currently awaiting renal transplantation in the US.2 Kidneys from deceased donors previously termed ‘extended criteria donors’ (ECD), provide good outcomes with acceptable duration of function for selected, older recipients or those not expected to survive on long-term dialysis. ECD kidneys come from donors over 60 years old or from those aged 50-59 years old with coexisting medical conditions such as hypertension, cerebrovascular disease, or creatinine >1.5mg/dL. Despite good short-term outcomes, the rates of discard for these kidneys remain high. For those in the transplant community, these kidneys may be a precious resource that is being wasted. So the question remains—when it comes to deceased donation, how old is too old? Continue reading “Kidney Transplants from Deceased Donors: How Old is Too Old?”

Pushing the envelope across HLA boundaries: HLA-incompatible renal transplants

By Martina M. McGrath, MD
July 6, 2016

The deceased-donor renal transplant waiting list continues to expand inexorably, and currently, up to 15% of wait-listed patients are awaiting their second or subsequent kidneys. With this changing demographic, the challenge of transplanting patients with increasing levels of HLA sensitization becomes ever more prevalent. Continue reading “Pushing the envelope across HLA boundaries: HLA-incompatible renal transplants”