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Improving Outcomes in Disorders of Complement Activation

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 - 54th Annual Meeting of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2012

Atlanta - Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are chronic, life-threatening hematologic conditions that have limited therapeutic options. Both conditions arise from uncontrolled complement activation that predisposes patients to serious thrombotic complications. In particular, aHUS has a progressive, systemic impact associated with substantial extrarenal morbidity. Severe complement-mediated thrombotic microangiopathy (TMA) persists despite plasma exchange/infusion, dialysis or kidney transplantation. The condition affects both men and women, and children account for about half of the cases. In 2011, the C5 complement protein inhibitor eculizumab was approved in the US as the first aHUS-specific therapy, 2 years after it was approved in Canada for PNH. Prospective clinical trials showed that it prevented or reversed TMA-associated organ damage, and eliminated the need for plasma exchange/perfusion and dialysis by patients with aHUS.

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

Inherited or acquired defects in the complement system lead to atypical hemolytic uremic syndrome (aHUS), which then causes platelet activation, thrombosis, hemolysis and thrombotic microangiopathy (TMA), Dr. Christoph Licht, Hospital for Sick Children, Toronto, noted in a poster presentation. Conventional therapy for aHUS often fails to slow the progressive consequences of persistent platelet activation. It can progress rapidly to end-stage renal disease (ESRD) or death in more than a third of patients. The monoclonal antibody eculizumab targets the human C5 complement protein, inhibiting production of proinflammatory C5a and C5b-9.

Preliminary data from a phase II clinical trial showed that eculizumab inhibited TMA and prevented or reversed organ damage in 20 patients with longstanding aHUS and chronic kidney disease (CKD). After a median follow-up of 62 weeks, 85% of treated patients remained TMA event-free, and estimated glomerular filtration rate (eGFR) increased by 30% from baseline (P=0.002).

All patients received eculizumab for 26 weeks and 19 continued treatment during a long-term extension phase. After an 8-week observation period, patients discontinued plasma exchange/infusion before starting eculizumab. Dr. Licht reported data from a median follow-up duration of 2 years.

Median aHUS duration was 48 months before enrolling in the trial. Median eculizumab treatment duration was 114 weeks. Dr. Licht noted that 14 patients had mutations in genes encoding for complement proteins and 6 did not.

The intent-to-treat analysis performed at the end of the extended follow-up showed that all values had improved from the 26-week assessment. TMA event-free status was achieved in 19 of 20 (95%) patients with sustained inhibition of complement activation. Analysis of renal outcomes showed that 12 of 20 (60%) patients had ≥1-stage improvement in CKD stage, 11 of 20 (55%) had at least a 25% reduction in serum creatinine, GFR increased by ≥15 mL/min/1.73 m2 in 8 of 20 (40%) patients, and the cohort had a mean improvement in eGFR of 7.1 mL/min/1.73 m2.

Additionally, 12 of 15 evaluable patients had a ≥1-grade decrease in proteinuria, as compared with 8 of 16 after 26 weeks.

According to Dr. Licht, terminal complement activity reduction was demonstrated as early as 1 hour after the first infusion of eculizumab and sustained through the end of the study. “Clinically meaningful improvement was observed in health-related quality of life [HRQoL] with ongoing eculizumab therapy in aHUS patients,” he confirmed.

Patients achieved TMA event-free status regardless of their mutation status, as all 14 patients with mutations and 5 of 6 without mutations had event-free follow-up. With ongoing therapy, 18 of 20 patients achieved and maintained hematologic normalization, beginning with the 26-week follow-up evaluation. Hematologic normalization was defined as normal platelet and lactate dehydrogenase (LDH) on ≥2 consecutive measurements at least 4 weeks apart.

Progressive TMA Despite Plasma Exchange/Infusion

A companion phase II study examined the efficacy of eculizumab in a group of 17 patients with evidence of progressive TMA, defined as platelets <150 x 109/L despite ≥4 sessions of plasma exchange/infusion. As in the study reported by Dr. Licht, the first analysis occurred after 26 weeks of treatment. Subsequently, the patients entered a long-term extension study. At week 26, patients had achieved significant and sustained improvement in platelet count (73 x 109/L), TMA event-free in 15 of 17 patients, eGFR improvement averaging 31 mL/min/1.73 m2, discontinuation of dialysis by 4 of 5 patients, and clinically meaningful improvement in HRQoL.

Dr. Larry Greenbaum, Emory University, Atlanta, Georgia, presented results from an analysis performed after a median treatment duration of 100 weeks (vs. baseline). The mean platelet count change was 88 x 109/L (P<0.0001), and 15 (88%) patients had hematologic normalization. Additionally, 10 (59%) patients had an eGFR increase ≥15 mL/min/1.73 m2, 12 (71%) had a ≥1-stage improvement in CKD, and 13 (76%) had a ≥25% decrease in serum creatinine. Improvement occurred irrespective of mutation status, in 3 of 4 patients with no known complement mutations and 12 of 13 patients with known mutations.

“Ongoing treatment with eculizumab in patients with progressing TMA led to continued improvement in patient outcomes at 26 weeks, 1 year and 2 years,” reported Dr. Greenbaum. “We observed sustained inhibition of complement-mediated TMA, reduced need for plasma exchange/infusion and dialysis, and continuous improvement in renal function.”

“These 2-year efficacy and safety outcomes underscore the importance of early and onging eculizumab treatment in patients with aHUS and progressing TMA,” he added.

Genetics of aHUS Revisited

Although aHUS is considered a disease of genetic mutations, as many as 50% of patients have no identified complement mutations at diagnosis. These patients have a risk of mortality and ESRD similar to that of patients with mutations, making effective therapy for aHUS an important issue regardless of mutation status, according to Dr. Samhar I. Al-Akash, Driscoll Children’s Hospital, Corpus Christi, Texas.

To compare the effectiveness of eculizumab in aHUS patients ±complement mutations, Dr. Al-Akash and colleagues analyzed data from the 2 phase II clinical trials and a retrospective study of 17 pediatric patients with aHUS. Across the 3 studies, 24% to 41% of patients did not have complement mutations. Safety and efficacy of the C5 complement inhibitor did not differ significantly by mutation status, including TMA event-free status, platelet count, hematologic normalization, decline in serum creatinine or improvement in eGFR.

“Given that genetic testing often requires several months to complete, that uncontrolled complement activation places aHUS patients at risk of life-threatening systemic TMA events and organ damage, and that earlier intervention with eculizumab is associated with greater clinical improvement, the results of this analysis provide a rationale for initiating eculizumab as first-line therapy at the time of clinical diagnosis of aHUS, without the availability of genetic testing results,” Dr. Al-Akash and colleagues concluded.

Paroxysmal Nocturnal Hemoglobinuria: Improved Outcomes

As in aHUS, consequences of paroxysmal nocturnal hemoglobinuria (PNH) makes diagnosis and clinical intervention critical. Data from a large multinational clinical-practice cohort study showed that treatment with eculizumab was associated with a reduced risk of thromboembolism and death in patients with PNH. The analysis comprised 1047 patients, 536 of whom received eculizumab, as reported by Prof. Gérard Socie, Hôpital Saint-Louis, Paris, France.

A review of baseline characteristics showed that the cohort had a median age of 44.2, that women accounted for 51.3% of the study population, that the mean and median LDH values were 2.7 and 1.4 x upper limit of normal, respectively, and that 38% had received at least one red blood-cell (RBC) transfusion within the previous 6 months.

During a median follow-up of 22.5 months, 16 patients had a thromboembolic event and 51 patients died. Cardiovascular events and infection were the most common causes of death (21.6% and 25.5%, respectively). The eculizumab-treated patients had a thromboembolism rate of 0.41% at 1 year and 1.35% at 2 years. The rates were 1.70% and 2.61%, respectively, in those not treated with C5 complement inhibitor. Mortality was 2.31% at 1 year and 4.21% at 2 years for the eculizumab group vs. 4.40% and 7.01% for the control group.

Multivariate analysis showed that risk factors for thromboembolism were RBC transfusion in the 6 months before enrollment (HR 9.61), history of impaired liver function (HR 4.78), presence of dyspnea (HR 2.42) or headache
(HR 2.33) at enrollment. After controlling for those variables, treatment with eculizumab was associated with a significant protective effect (HR 0.23, P=0.0053).

Predictors of mortality were age ≥60 (HR 5.33), bone marrow transplantation during follow-up (HR 4.71), Karnofsky score <80 (HR 2.19), fatigue at enrollment (HR 1.86) and recent RBC transfusion (HR 1.75). In an adjusted model, treatment with eculizumab significantly reduced the risk of mortality (HR 0.41).

Summary

PNH and aHUS pose significant risks of mortality and morbidity, making accurate diagnosis and prompt intervention with effective therapy necessities for favourable outcomes. Conventional treatment consists of plasma exchange/infusion, dialysis and kidney transplantation. However, many patients remain at high risk of thromboembolic events and death because of persistent complement activation and associated platelet activation, even with treatment. The monoclonal antibody eculizumab directed against C5 complement protein has been shown to reduce the risk of thromboembolism and death in patients with PNH and improve TMA event-free status in patients with aHUS during follow-up for as long as 2 years. Continuous therapy with this agent has demonstrated similar efficacy in patients with and without complement mutations.

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