A pioneering drug for the rare kidney disease atypical haemolytic uraemic syndrome prevented organ failure and significantly improved the outcome for patients, new UK research confirmed.
Atypical haemolytic uraemic syndrome (aHUS) is a genetic life-threatening condition caused by a defect in the immune system that leads to kidney failure. According to the National aHUS Service the condition has an incidence in the UK of 0.4-0.5 per million population, with an estimated 20 to 30 new patients being diagnosed with the condition each year.
The condition presents acutely with acute kidney injury and, not infrequently, multi-organ involvement. "Without treatment the prognosis for patients is poor, with 50% of patients developing renal failure or dying in the first year after presentation," alerted the Service.
"Historically, the majority of patients with complement-mediated atypical haemolytic uraemic syndrome (CaHUS) progressed to end stage kidney disease (ESKD)", underlined the authors of the new study, published in the journal Blood.
Previously, the researchers from Newcastle University had carried out single arm clinical trials of eculizumab (Soliris, Alexion Pharma UK), with short follow-up, that suggested efficacy of the drug.
Eculizumab costs £328,000 per year per adult patient and is given intravenously every 2 weeks. It was recommended for use on the NHS in England by the National Institute for Health and Clinical Excellence (NICE) in 2015.
For the new investigation — the "largest study of its kind" — the researchers carried out a randomised controlled clinical trial of eculizumab.
The control CaHUS cohort included 279 individuals with a median age of 22 years. The eculizumab treated cohort comprised 243 individuals — median age 23 years — of whom 192 had CaHUS and 51 had a subsequent diagnosis identified, which included glomerular disease, infection associated, and autoimmune disease.
Of the eculizumab treated CaHUS cohort 47% had an inherited or acquired complement abnormality, or both.
The authors described how in a "genotyped matched CaHUS cohort the 5-year cumulative estimate of ESKD free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab treated cohort".
"Eculizumab prevented 86% of patients going into kidney failure, which highlights the importance of the use of the medication," hailed the authors.
David Kavanagh, professor of complement therapeutics at Newcastle University, and study leader, commented that the study had confirmed the effectiveness of eculizumab in preventing kidney failure for those with aHUS. "It further strengthens the importance of patients receiving early treatment, as it's lifesaving and helps significantly improve quality of life without the need for dialysis or a kidney transplant," he said.
However, a proportion of the patients did not improve with the drug treatment, with 14% of patients still requiring long-term dialysis.
For some of those who did not benefit, a new genetic cause for aHUS was identified. The researchers found that "bi-allelic pathogenic mutations" in RNA processing genes, including EXOSC3, caused eculizumab non-responsive aHUS. This finding allowed the drug to be stopped to avoid the potential side-effects of ineffective treatment.
The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for those with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. There were no relapses recorded in 67.3 person-years off eculizumab in those with no rare genetic variants, the authors pointed out.
Eculizumab was restarted in six individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD, reported the authors.
Management of aHUS "Revolutionised"
The results of the new study were "fantastic", according to Professor James Palmer, national medical director for specialised services at NHS England, who believed the findings would "help save and improve" patients' lives and could "help enable doctors to identify those who are unlikely to benefit from the drug and could be spared the side effects".
Dr Aisling McMahon, executive director of research and policy at Kidney Research UK, commented that the study was a "really important example of how, with collaboration between several partners, laboratory research can lead to clinical benefits for patients".
First author Dr. Vicky Brocklebank, a clinical research fellow at Newcastle University, heralded the "pioneering" research that had allowed for genetically targeted treatments to improve patient outcomes and "revolutionise" the way aHUS was managed.
The study was funded by Kidney Research UK and the Medical Research Council.
Asked to comment for Medscape News UK, Fiona Loud, policy director for Kidney Care UK, praised the researchers for their "valuable" work and "excellent patient-centred care" in supporting people to live with aHUS.