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Halting Threat of Kidney Failure by Hemolytic Uremic Syndrome and Other Thrombotic Microangiopathies

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 2012 Kidney Week of the American Society of Nephrology (ASN)

San Diego, California / October 30-November 4, 2012

San Diego - Two-year results with a targeted monoclonal antibody (MAb) against the complement protein C5 demonstrated that the kidney damage caused by atypical hemolytic uremic syndrome (aHUS) and shiga-toxin producing Escherichia coli HUS (STEC-HUS) can be largely aborted. While acute protection from progressive kidney dysfunction from this approach to complement inhibition has been demonstrated previously, new data presented during Kidney Week indicated that the protection persists indefinitely for those who remain on therapy. The sustained benefit also extends to other affected organs, including the central nervous system. In Germany, the urgent introduction of the novel MAb, which was an experimental agent at the time, was instrumental in reversing the morbidity and mortality associated with an outbreak of STEC-HUS, providing a vivid illustration of the clinical value of the treatment target.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Hemolytic uremic syndrome (HUS) is characterized by endothelial damage in arterioles and capillaries, leading to thrombotic microangiopathy (TMA). Activation of the complement pathway underlies both the non-infectious atypical HUS (aHUS) and infectious shiga-toxin producing Escherichia coli (STEC-HUS) forms. A series of studies with eculizumab, a monoclonal antibody targeted against the C5 protein, confirmed that halting complement activation aborts the disease process. A series of independent studies presented at Kidney Week demonstrated profound protection against end-stage renal disease (ESRD) and other forms of life-threatening organ damage.

Continuous Improvement in Renal Function

In a prospective trial conducted in aHUS, that now has 2 years of follow-up, 80% of patients on dialysis were able to regain kidney function with “significant and sustained, time-dependent improvement in renal function,” according to Dr. Christoph Licht, Hospital for Sick Children, Toronto, Ontario. Relative to the limited benefits of plasma exchange and plasma infusion (PE/PI), the efficacy of eculizumab was characterized as a “breakthrough” by Dr. Licht, who noted that control of aHUS is achieved regardless of genetic mutations involved in the etiology.

In new 2-year results presented by Dr. Licht, the study population consisted of patients who had been managed with PE/PI for up to 12 years before being enrolled. Nineteen of the 20 patients who participated in the initial 26-week trial have now been followed out to a median of 114 weeks, all remain TMA event-free, defined as no increase in platelet count >25% from baseline, no PE/PI and no new dialysis. Since initiating eculizumab, there has been continuous improvement in renal function. Nearly half of the patients achieved an increase in the estimated glomerular filtration rate (eGFR) of at least 15 mL/min/1.73 m2.

In a second study presented during Kidney Week, 13 patients enrolled within 10 months of the diagnosis of aHUS have now been followed for a median of 100 weeks. According to the investigator who presented these results, Prof. Christophe Legendre, Hôpital Necker, Paris, France, there have been significant gains in several clinical parameters since the initial 26-week assessment. For example, the proportion that had at least a one stage improvement in the severity of chronic kidney disease (CKD) climbed from 59% at week 26 to 71% at the most recent follow-up.

Against the historical experience that would predict ESRD in most or all patients and a mortality rate near 30%, “there have been no patient deaths in 2 years and we have continued to see an upward slope over time in the proportion of patients achieving key renal end points,” Dr. Legendre reported.

The previously reported 26-week results for both studies revealed a very rapid onset of action. There was a steep improvement in renal function and all patients were able to discontinue PE/PI. Of those already on dialysis at the initiation of eculizumab, about half had sufficient improvement in renal function to come off this therapy. Consistent with the steady improvement in renal function observed over time, no patient previously on dialysis had to return to this treatment over the long-term follow-up. However, as might be predicted from TMA-induced organ damage, earlier introduction of eculizumab was associated with greater relative improvement in renal function, making early diagnosis and treatment important.

The safety and tolerability of eculizumab is considered encouraging. In the prospective trials, most adverse events were non-specific, mild to moderate in severity and self-limited. There was one case of meningitis after eculizumab discontinuation. The most common side effects were diarrhea, reported by 35% of patients in one study and 30% in the other, upper respiratory infection, reported by 29% and 40%, respectively, and headache, reported by 41% and 20%, respectively. The long-term follow-up has not identified any new or unexpected drug-related adverse events.

aHUS Control Regardless of Genetic Mutations

Although aHUS is often but not always a familial disease, neither study employed genetic mutations as either an inclusion or an exclusion criterion. Both investigators reported that those with or without genetic markers for aHUS had comparable benefit from eculizumab.

A third study that evaluated data from these 2 trials and a third retrospective analysis with 17 pediatric patients reconfirmed this principle with larger numbers. In this analysis, the comparable benefits in those with or without identifiable complement genetic abnormalities were observed across a variety of end points, including TMA events and improvement in renal function. “Clinically, this result supports treatment with eculizumab in aHUS without a genetic test,” reported Prof. Tim Goodship, Professor of Renal Medicine, University of Newcastle upon Tyne, UK. This importance of blocking complement activation independent of etiology may be true of other forms of HUS, based on a favourable open-label trial of eculizumab in STEC-HUS.

Results of a Compassionate Access Program in STEC-HUS

The study of eculizumab, which was an experimental agent at the time, was designed and implemented on an urgent basis in an effort to stem the high rate of anticipated complications, including ESRD and death, anticipated from a STEC-HUS outbreak in Germany. The outbreak, which eventually involved 855 cases, began in April 2011.

“Initially, we treated patients with plasma exchange, but a high proportion proceeded to ESRD and dialysis as well as seizures and other neurologic symptoms,” explained Dr. Rolf A.K. Stahl, University Hospital Hamburg-Eppendorf, Germany. Prompted by early data, including a letter in the New England Journal of Medicine, suggesting eculizumab was effective in deactivating complement, the major driver of STEC-HUS pathology, a clinical trial within a compassionate access program was formed. Dr. Stahl explained that the critical situation dictated a simple single-arm study in order to minimize the delay to enrolment. The protocol selected for the trial was eculizumab 900 mg administered intravenously on days 0, 7, 14 and 21 followed by 1200 mg on days 28, 42 and 56. Of the 216 patients enrolled at 23 sites in Germany, 198 were available for final evaluation.

After 8 weeks of therapy, 94% of the patients initiated on eculizumab had a major response to therapy, including a clinically important improvement in affected organs. While 72% of those at the start of therapy were on dialysis, only 4% remained on dialysis at week 28. Similarly, while 84% of patients had neurologic involvement at baseline, including seizures or coma, 91% had achieved modified Rankin Scale (mRS) normalization by week 28. No patient required plasma exchange within 4 weeks of initiating eculizumab, and no patient receiving eculizumab died even though there had been several deaths on PE/PI before the trial was initiated.

“The rapid and sustained reversal of organ damage with eculizumab supports the vital role of uncontrolled complement activation in this disease,” according to Dr. Stahl, who presented these results during Kidney Week. He reported that most adverse events were mild to moderate in severity, and none were serious. Citing these findings and preliminary results from an ongoing post-hoc, case-control analysis, Dr. Stahl was already willing to identify eculizumab as a far more effective means to prevent the potentially devastating consequences of STEC-HUS than PE/PI and best supportive care.

Summary

An effective C5 monoclonal antibody, eculizumab has demonstrated that the most serious complications of aHUS and STEC-HUS can be modified or aborted entirely by complement deactivation. Early treatment improves likelihood of benefit relative to delayed treatment, and two-year follow-up from clinical studies indicates that the clinical improvement achieved within weeks of starting therapy is sustained indefinitely. The efficacy of the C5 complement antibody has been independent of the etiology of complement activation, including genetic mutations, in these diseases

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