eculizumab, 300mg concentrate for solution for infusion (Soliris ) SMC No. (436/07) Alexion Pharma UK Ltd

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1 eculizumab, 300mg concentrate for solution for infusion (Soliris ) SMC No. (436/07) Alexion Pharma UK Ltd 8 October 2010 (Amended 11 July 2011) The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a full submission eculizumab (Soliris ) is not recommended for use within NHS Scotland. Indication under review: for the treatment of patients with paroxysmal nocturnal haemoglobinuria (PNH). Evidence of clinical benefit of eculizumab in the treatment of patients with PNH is limited to patients with a history of transfusions. In a controlled study in patients with transfusion-dependent PNH, eculizumab reduced the rate of haemolysis and improved anaemia compared to placebo. Uncontrolled data suggest that eculizumab reduces the incidence of thrombosis in patients with PNH. The manufacturer did not supply any health economic analysis and cost-effectiveness was not demonstrated in an independent economic analysis therefore eculizumab cannot be recommended for use within NHS Scotland. Overleaf is the detailed advice on this product. Chairman Scottish Medicines Consortium Published 08 November

2 Indication For the treatment of patients with paroxysmal nocturnal haemoglobinuria (PNH). Evidence of clinical benefit of eculizumab in the treatment of patients with PNH is limited to patients with a history of transfusions. Dosing Information The dosing regimen consists of a 5-week initial phase followed by a maintenance phase: initial phase: eculizumab 600mg by a 25 to 45 minute intravenous (iv) infusion every week for the first 4 weeks, followed by eculizumab 900mg for the fifth week of the initial phase. maintenance phase: eculizumab 900mg by a 25 to 45 minute iv infusion every 14 ( 2) days. Eculizumab should be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological disorders. All patients must be vaccinated to reduce the risk of meningococcal infection at least 2 weeks prior to receiving eculizumab and re-vaccinated according to current medical guidelines. Product availability date June The Committee for Orphan Medicinal Products granted a positive opinion for orphan designation of eculizumab for the treatment of PNH in October Summary of evidence on comparative efficacy Paroxysmal nocturnal haemoglobinuria (PNH) is a rare genetically acquired, blood disorder in which there is a deficiency of glycosyl phosphatidylinositol (GPI)-linked complement inhibitory protein C59 on the surface of blood cells. These proteins block the formation of the terminal complement complex on the surface of red blood cells preventing haemolysis. The resulting intravascular haemolysis causes haemolytic anaemia, thrombosis and deficient haematopoiesis. The median survival from initial diagnosis is 15 years. Eculizumab is a monoclonal antibody which acts as a terminal complement inhibitor restoring terminal complement regulation. tthe prevalence of PNH in the European Union is estimated at 13 cases per million. This is below the threshold (5 in 10,000) for orphan designation and so eculizumab was granted orphan drug status for the treatment of PNH by the European Medicines Agency (EMA). There is one 26-week, phase III, placebo-controlled, randomised study of eculizumab which investigated whether eculizumab stabilised haemoglobin levels and reduced transfusion requirements in 87 patients with PNH. Eligible patients were aged 18years with 10% PNH type III erythrocyte cells and platelet counts of 100,000/mm 3, lactate dehydrogenase (LDH) levels 1.5 times the upper limit of normal (ULN) and having received 4 transfusions in the previous 12 months. After a 2-week screening period, eligible patients entered a 13-week observation period, during which they were given a red blood cell (RBC) transfusion if they had a haemoglobin level 9g/dL with symptoms or 7g/dL with or without symptoms. This served as the haemoglobin setpoint for the individual patient for the rest of the study. 2

3 Patients were randomised in a ratio of 1:1 to receive eculizumab (licensed dose) or placebo for 26 weeks with stratification by the number of units of RBC transfused during the previous year. Patients could continue to receive stable doses of erythropoietin, immunosuppressive drugs, corticosteroids, coumarins, low-molecular-weight heparins, iron supplements and folic acid. All patients were vaccinated against Neisseria meningitidis. There were two primary endpoints: stabilisation of haemoglobin (defined as a haemoglobin value maintained above the setpoint in the absence of transfusions) and the number of units of RBC transfused. After 26 weeks of treatment, significantly more eculizumab-treated patients had stabilisation of haemoglobin compared to placebo-treated patients; 49% (21/43) versus zero (0/44). The median number of RBC units transfused was significantly reduced in the eculizumab group (0 [range 0 to 16]) versus placebo (10 [range 2 to 21]) after 26 weeks; corresponding 6-month, pre-study values were 9.0 and 8.5 respectively. Secondary endpoints included transfusion independence which was achieved by 51% (22/43) eculizumab- and zero (0/44) placebo-treated patients. Haemolysis, as measured by lactate dehydrogenase (LDH) area under the curve (AUC) from baseline, was significantly reduced by 86% in the eculizumab compared to the placebo group (58,587 versus 411,822 U/L x day). The mean LDH level decreased from a baseline of 2200 U/l to 327 U/l at week 26 in the eculizumab group and remained high in the placebo group (2258 U/l and 2419 U/l respectively). Changes in the functional assessment of chronic illness therapy fatigue (FACIT-fatigue) were also measured as a secondary endpoint and were significantly improved in the eculizumab group compared to placebo: difference of 10.4 points ( 4 points is considered minimally important). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 was an exploratory endpoint which assessed global health status, functioning scales (role, social, cognitive, physical and emotional), symptom scales (fatigue, pain and nausea and vomiting) and single-items measures (dyspnoea, loss of appetite, insomnia, financial difficulties, constipation and diarrhoea). Eculizumab was associated with significant improvements over placebo in all scales except the symptom scale on nausea and vomiting, and the single-items measures on financial difficulties, constipation and diarrhoea. Subsequent analysis of this study demonstrated that 29% of eculizumab-treated patients improved and 4.9% worsened in terms of renal function (p=0.005), while in the placebo group, 17% improved and 14% worsened (p=0.78). In a supportive, open-label, uncontrolled study, 97 patients with PNH and a lower baseline transfusion requirement ( one transfusion in the past 2 years), received eculizumab for 52 weeks. The primary efficacy outcome measure of haemolysis, assessed by LDH AUC, was significantly reduced after 52 weeks of eculizumab therapy, with a median change of -632,264 U/L x day. There were significant differences in secondary outcomes, including LDH changes from baseline and associated increases in the proportion of PNH type III RBC and haemoglobin levels. Transfusion requirements reduced to a median of 0 units per patient during the 52 week study period and 51% (49/97) patients did not require any transfusions. In an open-label extension study, including patients from the two studies described above plus one small pilot study, 187 patients were treated with eculizumab for 102 weeks. In this study, the rate of thrombosis per patient year was compared for the pre-eculizumab and the eculizumab treatment periods. The rate of thrombosis reduced from 7.37 events per 100 patient-years (124 total events) before eculizumab to 1.07 events per 100 patient-years (3 total events) during eculizumab treatment; representing a significant 85% relative reduction and an 3

4 absolute reduction of 6.3 thrombotic events per 100 patient-years. Following equalisation of the duration of exposure before and during treatment for each patient, the number of thrombotic events remained significantly reduced with eculizumab, 39 versus three. There was also a significant reduction in thrombotic events for those patients receiving concomitant antithrombotic drugs. Subsequent post-hoc analysis of data from the extension study has suggested that eculizumab improved renal function and reduced pulmonary hypertension. A preliminary post hoc analysis has suggested that treatment with eculizumab may beneficially affect survival. During 2-years of treatment with eculizumab, only two deaths were reported, 87% fewer than expected based on historical controls. Recent data for 79 eculizumab-treated PNH patients from a UK centre has supported this, finding no significant mortality difference when compared with the normal population (matched for age and sex). Summary of evidence on comparative safety There are no active comparative data for eculizumab, only comparisons with placebo. In the 26- week study, the most frequently reported adverse events in the eculizumab group were headache (44% versus 27% in placebo group), nasopharyngitis (23% versus 18% in placebo group), back pain (19% versus 9% in placebo group), nausea (16% versus 11% in placebo group) and fatigue (12% versus 2% in placebo group). There were no significant differences between the two groups in the incidence of any adverse event. After two weeks, the incidence of headache was similar in the two groups. Serious adverse events were reported in 13 patients (4 in the eciluzumab group and 9 in the placebo group) but none were considered to be related to treatment. One patient in the placebo group experienced a thrombosis. Detectable levels of antibodies were recorded at a single visit in one patient in each group. However levels were low and did not affect complement inhibition. Eculizumab, through its mechanism of action, increases patient s susceptibility to meningococcal infection (Neisseria meningitidis). It is therefore recommended that all patients are vaccinated against meningococcal infection at least 14 days before they begin eculizumab treatment and re-vaccinated according to current guidelines. During the clinical development, there were three cases of meningococcal infection, two in vaccinated PNH patients which were considered as probably related to eculizumab treatment. As a result of the risk, all patients are to receive a Patient Safety Information Card outlining the warning signs. Since eculizumab is a monoclonal antibody, it has the potential to result in infusion reactions or immunogenicity. However during clinical studies, no PNH patients developed infusion reactions that required discontinuation of eculizumab or neutralising antibodies. Infrequent, low titre antibody responses have been detected in eculizumab treated patients during clinical studies but, as described above, at a similar frequency as placebo. There is a possibility of serious rebound haemolysis on discontinuation and patients should be monitored for signs of serious haemolysis and other reactions for at least 8 weeks after discontinuation. These issues are being monitored as part of a risk management plan which includes a PNH global registry. 4

5 Summary of clinical effectiveness issues Eculizumab has been designated an orphan medicine for the treatment of PNH and, due to the rarity of the disease, patient numbers enrolled in studies are small. Eculizumab is the first medicine to be licensed for PNH and offers a therapeutic option beyond the current management with supportive care. Results from the controlled 26-week, study have shown improvements in haemolysis, anaemia, fatigue and quality of life. These results were confirmed by the supportive, open-label, 52-week study. The latter study enrolled patients with minimal transfusion requirements which may not be representative of the patients likely to be treated with eculizumab in clinical practice. Neither study assessed other PNH symptoms including thrombosis, one of the serious consequences of PNH and the leading cause of death in patients. Uncontrolled data from the 2-year extension study indicates that the rate of thrombosis is reduced with eculizumab when compared to the rate observed before treatment. Thrombotic events measured in this study included various types of venous and arterial thrombosis: 85% of events in the pre-treatment period were venous thrombosis (105/124) and the remainder arterial (19/124). The three events that occurred in patients during eculizumab treatment included two cases of deep vein thrombosis and one of pulmonary embolism. Subsequent analysis of data from the 2-year extension study suggests that eculizumab improved renal function and reduced pulmonary hypertension but these data are also uncontrolled. A preliminary post hoc analysis has suggested that treatment with eculizumab may beneficially affect survival which is confirmed by recent UK survival data. The company has indicated that they fund a home delivery and infusion service for eculizumab treated PNH patients. Summary of comparative health economic evidence Clinical and cost data were supplied by the manufacturer to support the assessment which was informed by an independent health economic review. The cost effectiveness of eculizumab was not demonstrated and therefore eculizumab cannot be recommended for use within NHS Scotland. Summary of patient and public involvement A Patient Interest Group Submission was received from the Scottish PNH Patient Group. Additional information: comparators There are no direct comparators. Standard treatment of PNH includes supportive care comprising blood transfusions for anaemia and thromboprophylaxis with warfarin or heparin. The only curative therapy is bone marrow transplant in suitable patients for whom a donor can be found. 5

6 Cost of relevant comparators Drug Dose Regimen Cost Per Year ( ) Eculizumab 900mg by iv infusion every 14 ( 2) days* 252,000 the dose detailed is the maintenance dose which in new patients is preceded by an initial phase dose of 600mg intravenous infusion every week for the first 4 weeks, followed by 900mg for the fifth week of the initial phase. In subsequent years the annual cost would be 245,700. Costs from evadis on 9 August 2010 and include an initial 5 week phase followed by the maintenance phase. Additional information: budget impact The manufacturer estimated a gross drug budget impact of 2.6m in year one rising to 4.1m in year five. There was no net drug budget impact as eculizumab is a new therapy and not replacing any existing treatment. The manufacturer suggested that there would be some cost offsets due to the reduced incidence of thrombosis and other sequelae. The manufacturer assumed that there were 84 patients with PNH in Scotland and that 35% of these would be eligible for treatment with eculizumab. The manufacturer estimated that uptake among eligible patients would be 35% in year one rising to 55% in year five. This resulted in an estimated 10 patients being treated with eculizumab in year one rising to 17 patients in year five. It should be noted that the manufacturer estimated that 8 patients are currently being treated with eculizumab in Scotland and the cost of treatment for these patients is included in the above budget impact estimates. 6

7 References The undernoted references were supplied with the submission. The references shaded in grey are additional to those supplied with the submission. Hillmen P, Young, NS, Schubert J et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355: Brodsky RA, Young NS, Antonioli E et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111: Hillmen P, Muus P, Duhrsen U et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110: Hillmen P, Elebute M, Kelly R et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal haemoglobinuria. Am J Hematol 2010; 85: Rother RP, Rollins SA, Mojcik CF et al. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal haemoglobinuria. Nature Biotechnology 2007;25: The European Medicines Agency (EMA). European Public Assessment Report for eculizumab (Soliris ), Hill A, Rother RP, Wang X et al. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2010; 149: Baglin TP, Keeling DM and Watson HG. Guidelines on oral anticoagulation (warfarin): third edition 2005 update. British Society for Haematology 2005; 132: This assessment is based on data submitted by the applicant company up to and including 17 September Drug prices are those available at the time the papers were issued to SMC for consideration. These have been confirmed from the evadis drug database. SMC is aware that for some hospital-only products national or local contracts may be in place for comparator products that can significantly reduce the acquisition cost to Health Boards. These contract prices are commercial in confidence and cannot be put in the public domain, including via the SMC Detailed Advice Document. Area Drug and Therapeutics Committees and NHS Boards are therefore asked to consider contract pricing when reviewing advice on medicines accepted by SMC. 7

8 Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. 8