Reports

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PRIORITY PRESS - 43rd Annual Meeting and Scientific Exhibition of the American Society of Nephrology – Renal Week 2010

Denver, Colorado / November 16-21, 2010

Although introduction of plasma therapy (plasmapheresis) has helped reduce atypical hemolytic uremic syndrome (aHUS) mortality, it still leads to end-stage renal disease (ESRD) or death in 60% of patients within 1 year of diagnosis. Currently, patients with aHUS who do not respond to plasma therapy or other conventional approaches have no additional options other than kidney transplantation and chronic hemodialysis. A clinical study of patients, with persistent thrombotic microangiopathy and resistant to plasma therapy, provided evidence that the complement inhibitor eculizumab has potential as a therapy for aHUS.

The study involved 17 adults and adolescents treated with eculizumab for 26 weeks in a single-arm trial. Median age was 28 years, 12 patients were female, 12 had complement-inhibitor mutations and 7 had received donor kidneys, reported Prof. Christophe M. Legendre, Hôpital Necker, Paris, France.

Each patient received eculizumab 900 mg once a week for 4 weeks and then 1200 mg every 2 weeks. Additional therapy included Neisseria vaccine and a 14-day course of prophylactic antibiotics.

The primary end point was the change from baseline in platelet count. Principal secondary end points included freedom from thrombotic microangiopathy events, defined as stable platelet count, no plasma therapy and no new dialysis; no thrombotic microangiopathy intervention; time to first thrombotic microangiopathy intervention; and the proportion of patients who had =1 stage improvement in chronic kidney disease (CKD) stage.

Immediate and Sustained Improvement

After 26 weeks of treatment, platelet count in the 17 patients had increased by an average of 96 x 109/L, which proved to be highly significant (P<0.0001). “The patients had immediate and sustained increases in platelets,” Prof. Legendre told delegates. “We observed that 13 of 17 patients achieved platelet normalization.” The results also showed significant improvement in the secondary end points, including a thrombotic microangiopathy-free status in 15 of 17 patients. Additionally, all 17 patients had stable or increased platelet counts, no need for new plasma therapy and no new dialysis for a minimum of 12 weeks.

At baseline, the patients had an average thrombotic microangiopathy event rate of 0.51/patient/day. At 26 weeks, the rate had decreased to 0 (P<0.0001).

Prof. Legendre reported that 11 patients had improvement in estimated glomerular filtration rate (eGFR) that constituted at least a 1-stage improvement in CKD and 4 others had improvement that fell short of the 1-stage criterion, resulting in an overall improvement rate of 88%. Importantly, 5 of 7 patients on dialysis at baseline discontinued dialysis by 26 weeks. “Patients had continued improvement in renal function with sustained eculizumab therapy,” stated Prof. Legendre. “Platelet counts rose and remained stable at the higher levels, and serum creatinine began to decline almost immediately and continued to decline until the end of follow-up.” The cohort also had significant improvement in quality of life (P<0.0001) as assessed by the EuroQol 5D survey instrument. Clinically meaningful improvement occurred in 15 of the 17 patients.

Investigators performed several exploratory analyses which yielded additional positive findings. Three-fourths of the patients achieved a complete heme response, defined as a normal lactate dehydrogenase (LDH) and normal platelet count. Two-thirds of patients achieved a complete thrombotic microangiopathy response, defined as a complete heme response plus at least a 25% decrease in serum creatinine. The eGFR improved by at least 15 mL/min/1.73 m2 in 9 of 17 patients, and two-thirds of patients had improvement in hemoglobin values by at least 20 g/dL (200 g/L).

The agent was well tolerated and the most common adverse events were anemia, diarrhea, headache, nausea and vomiting (24 to 41%), which were mild or moderate in severity in most cases. “These interim results indicate that eculizumab achieves early and sustained improvement in platelet levels, rapidly stops thrombotic microangiopathy and restores renal function without the need for plasma therapy in patients with aHUS,” Prof. Legendre concluded.

Patients on Chronic Plasma Therapy

A second report focused on a group of patients on chronic plasma therapy for aHUS. The 20 patients all required plasma exchange at least once every 2 weeks but no more than 3 times per week. The patients had stable platelet counts, LDH level at or above the upper limit of normal (ULN) and serum creatinine level =ULN for age (which was at least 12 years).

The patients had a median age of 28 and mutation testing showed 10 patients had 1 mutation, 4 had multiple mutations and 6 had no mutations. Two patients required dialysis and 8 had undergone kidney transplantation, Dr. Christoph Licht, Hospital for Sick Children, Toronto, Ontario, reported here at the ASN in a poster presentation.

The eculizumab protocol adhered to the same parameters as the study reported by Prof. Legendre. Patients received meningococcal vaccine 14 days prior to starting eculizumab.The primary end point was thrombotic microangiopathy event-free status, defined as at least 12 consecutive weeks without a decrease in platelet count =25% from baseline plus no plasma therapy plus no new dialysis. Secondary end points included the change in thrombotic microangiopathy event rate, change in platelet count from baseline, quality of life and renal function.

Of 15 evaluable patients, 13 (87%) fulfilled the criteria for event-free status at 26 weeks. Additionally, no patient required a thrombotic microangiopathy-related intervention, and the intervention rate decreased from 0.16/patient/day at baseline to 0 (P<0.0001).

“Eculizumab stabilized or increased renal function,” observed Dr. Licht. “At baseline, more than half of patients had an eGFR <30, and the median value was 27, despite plasma therapy. After 26 weeks of treatment with eculizumab, the median eGFR had increased to 31.” “Eculizumab was well tolerated by all patients, and all patients remain alive,” he added. Adverse events occurred infrequently and were mild or moderate in severity. The most common adverse events were diarrhea (4 patients), headache (3), nausea and hypertension (2 each).

Case Study

A case study published as an abstract by Dr. Christian Hanna, State University of New York, Upstate Medical Center, Syracuse, and colleagues illustrated the use of eculizumab in an infant. A 10-month-old girl was hospitalized with severe relapsing aHUS. Plasma infusion therapy led to improved status during the first 2 months of treatment but the infant subsequently became resistant to therapy.

The patient’s condition deteriorated rapidly, necessitating hemodialysis and a switch from plasma infusion to plasma exchange. Upon initiating treatment with eculizumab, the infant had rapid improvement in clinical and serologic parameters. After 2 months of continuous treatment, the patient had a sustained response, including normalization of renal and hematologic parameters without the need for plasma therapy or dialysis.

Complete control of plasma-resistant aHUS was achieved over a few weeks and was sustained following initiation of chronic treatment with eculizumab, investigators reported. They concluded that eculizumab intervention appeared to be a more effective and a simpler treatment option for aHUS than plasma-based approaches, including affecting the reversal of renal failure.

Summary

Despite advances in therapy and clinical management, aHUS remains treatment-resistant in many cases, leading to ESRD or death in 60% of patients within 1 year of diagnosis. As a humanized monoclonal antibody that binds to complement protein C5 to inhibit complement activation, eculizumab has demonstrated therapeutic potential in preliminary clinical evaluation of patients with aHUS. Recent studies have shown a rapid and sustained improvement in platelet counts, prolonged periods free from intervention for thrombotic microangiopathy, discontinuation of dialysis and an improved quality of life.