Eculizumab for paroxysmal nocturnal haemoglobinuria

Transcription

1 London New Drugs Group Page 1 APC/DTC Briefing Document Eculizumab for paroxysmal nocturnal haemoglobinuria Contents Background 2 Dose & administration 3 Clinical Evidence 4 Side effects 10 Precautions 11 Drug interactions 12 Special populations 12 Economic considerations 13 Place in therapy 13 Conclusions 14 References 15 Produced for the London New Drugs Group Contact: Katie Smith East Anglia Medicines Information Service Ipswich Hospital Heath Road Ipswich IP4 5PD Tel: Katie.smith@ipswichhospital.nhs.uk Further copies of this document are available from URL: Or Summary Eculizumab (Soliris) is the first drug in a new drug class terminal complement inhibitors. It is the first licensed product specifically for treatment of paroxysmal nocturnal haemoglobinuria (PNH). Evidence of clinical benefit is limited to patients with a history of transfusions. PNH is a rare, genetically acquired blood disorder characterised by chronic intravascular haemolysis, with acute exacerbations, classically manifesting as haemoglobinuria, most pronounced in the morning. PNH is clinically defined by the lack of the complement inhibitory protein CD59 on the surface of red blood cells. PNH has high morbidity and mortality. Current treatments are generally supportive and do not address the serious underlying condition. Eculizumab is a recombinant humanised monoclonal IgG antibody that binds to the human C5 complement protein. This action inhibits the cleavage of C5 which prevents the generation of the terminal complement complex and therefore blocks complement mediated cell lysis. Eculizumab is administered as an intravenous infusion over minutes. The first 5 doses are given once weekly and then maintenance doses are administered once a fortnight. Four clinical studies One phase II, 2 phase III and a common extension study, provide the evidence for the safety and efficacy of eculizumab in 195 PNH patients. The double blind, randomised, placebo-controlled, multicentre TRIUMPH study enrolled patients who had received at least 4 transfusions in the past 12 months. In comparison to placebo, eculizumab stabilised haemoglobin levels in 49% of patients, 51% of patients achieved independence from transfusions of packed red blood cells; there was a 73% reduction in overall transfusion requirements, a 44% reduction in those still requiring transfusions and all measures of quality of life were improved including a significant improvement in fatigue. The multicentre, open label, non-placebo controlled SHEPHERD study enrolled patients with thrombocytopenia and minimal transfusion requirements. The study showed that eculizumab was well tolerated and few adverse effects were probably or definitely related to the drug. Over 52 weeks, all patients had significantly reduced haemolysis (as shown by lactate dehydrogenase levels). 51% of patients became transfusion independent, intravascular haemolysis was significantly reduced and there was significant improvement in quality of life. An extension study assessing the number of thromboembolic events in patients following long term administration of eculizumab has shown that eculizumab results in a significant 7 fold reduction in the thromboembolism event rate from 7.37 events per 100 patient years pre-eculizumab treatment to 1.07 events per 100 patient years during eculizumab treatment. This is an NHS document not to be used for commercial and marketing purposes. Produced to inform local decision making using the best available evidence at the time of publication. The information in this document may be superseded in due course.

2 Page 2 Summary continued In a post-hoc analysis of the extension study, eculizumab treatment was associated with a significant increase in the likelihood of improvement and prevention of worsening of kidney function. The most commonly reported adverse effects are headache, nasopharyngitis, nausea, pyrexia, myalgia, fatigue and herpes simplex. Each occur in 5 or more out of 100 patients. Adverse effects were mostly mild to moderate in severity in clinical trials. Uncommon or rare events can not be estimated due to limited patient exposure (195 patients). Identified and potential risks from eculizumab use are general infections, especially meningococcal infections, haemolysis after drug discontinuation and haematologic abnormalities. The cost per standard maintenance dose of eculizumab 900mg every 14 days is 9,450. The cost per 28 days is 18,900 and per year is 245,700. Approximately a third of the PNH patient population would be likely to have evidence of haemolysis (~300) however only about 50% would require therapy with eculizumab (~150). These figures are estimates based on clinical experience and are considered to be high. The benefits of eculizumab include reduced morbidity, reduced mortality and improved quality of life. Background Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, genetically acquired blood disorder characterised by chronic intravascular haemolysis (destruction of red blood cells), with episodic acute exacerbations. Exacerbations may classically manifest as haemoglobinuria (free haemoglobin in the urine), producing dark urine in the morning. Signs and symptoms of PNH include anaemia, fatigue, dark red/brown urine, difficulty swallowing, abdominal pain, erectile dysfunction in men and thrombosis. PNH is clinically defined by the lack of the complement inhibitory protein CD59 on the surface of red blood cells. CD59 normally blocks the formation of the terminal complement complex on the surface of the red blood cell, which prevents haemolysis. (1-3) PNH has high morbidity and mortality. Clinical manifestations commonly seen are haemolytic anaemia, venous thrombosis and inadequate haematopoiesis (formation of red blood cells and platelets). Thromboembolism is the leading cause of mortality in about 45% of patients with PNH. Granulocytopenia and thrombocytopenia are also commonly seen. (2,3) The median age for diagnosis of PNH is mid 30s to mid 40s, although it can occur at any age. Patients have an approximately year median survival from the initial diagnosis. The estimated incidence of PNH is 13 cases per million (0.13 per 100,000), this equates to about 70 new cases per year in England and Wales. The prevalence is estimated as 1.59 per 100,000, therefore there are about 850 patients with PNH at any time in England and Wales. (1,3) Current treatments are generally supportive and do not address the serious underlying condition. Quality of life of PNH patients is impaired by the underlying condition and associated comorbidities anaemia, tiredness, difficulty in functioning, pain, shortness of breath and blood clots. Stem cell transplantation is a potentially curative option but is rarely used as it may not be possible to find a suitable donor, it may not be advisable due to the risks of the procedure or acceptable to the patient. (1, 3, 4, 6)

3 Page 3 Current management options include: Folic acid and iron to help the production of new red blood cells Blood transfusion for severe symptomatic anaemia Prophylactic anticoagulants e.g. warfarin, to prevent thrombosis Heparin to treat venous thrombosis Platelet transfusion for severe thrombocytopenia Corticosteroids, anabolic steroids and androgens to reduce haemolysis and stimulate bone marrow Erythropoeitin to stimulate production of new red blood cells. Eculizumab is a recombinant humanised monoclonal IgG antibody that binds to the human C5 complement protein. This action inhibits the cleavage of C5 which prevents the generation of the terminal complement complex and therefore blocks complement mediated cell lysis and activation. Eculizumab is the first drug in a new drug class called terminal complement inhibitors and is also the first licensed product specifically for the treatment of PNH. Eculizumab was designated as an orphan drug in both Europe and the USA in 2003 because PNH is a rare disease. (1,3,5) Eculizumab (Soliris) was licensed throughout the European Union in June 2007 for the treatment of patients with PNH. The licence specifies that evidence of clinical benefit in the treatment of patients with PNH is limited to patients with a history of transfusions. (6) It was also licensed in the USA in March (7) Management of PNH in the UK is undertaken at specialist centres. St James Hospital in Leeds is the largest centre and St Georges Hospital in London is another centre. PNH is currently not under the remit of the National Commissioning Group (NCG) however an application has been submitted, which if successful would mean treatment of PNH would be funded from April (8) Dose and administration Eculizumab should be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological disorders. (6) Eculizumab is supplied in vials containing 300mg in 30ml solution. Eculizumab should be prepared for administration as an IV infusion by a qualified healthcare professional using aseptic technique. (6) To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients must be vaccinated at least 2 weeks prior to receiving eculizumab and must be re-vaccinated according to current medical guidelines for vaccination use. (6) The dosing regimen consists of a 5- week initial phase followed by a maintenance phase: Initial phase: 600 mg of eculizumab via a minute intravenous infusion via gravity feed, a syringe-type pump or an infusion pump every week for the first 4 weeks, followed by 900 mg of eculizumab for the fifth week of the initial phase. Maintenance phase: 900 mg of eculizumab administered via a minute intravenous infusion (as above) every 14 ± 2 days. Eculizumab should only be administered via intravenous infusion, and not as an intravenous push or bolus injection. (6) Patients should be monitored for one hour following the infusion. If an adverse event occurs during the administration of eculizumab, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time may not exceed two hours. (6)

4 Page 4 Clinical Evidence Four clinical studies provide the evidence for the safety and efficacy of eculizumab in PNH patients. The studies have included 195 patients from 13 countries. There was one phase II study, two phase III trials and a common extension study. (3) There has been one randomised, double blind, placebo controlled trial. (8) The Transfusion Reduction Efficacy and Safety Clinical Investigation, a Randomised, Multicentre, Double Blind, Placebo Controlled, Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (TRIUMPH) study was published in A non-controlled, open label study (SHEPHERD) and an extension study for patients who participated in the TRIUMPH, SHEPHERD and phase II studies have not been fully published yet. (3) The TRIUMPH trial was a double blind, randomised, placebocontrolled, multicentre study conducted at 34 sites in the United States, Canada, Europe and Australia in adult patients with PNH who had received at least 4 transfusions during the previous 12 months. (9) The trial consisted of a 2 week screening period, an observation period of up to 3 months and a 26 week treatment period. 115 patients underwent screening and observation to determine whether a transfusion was required. Patients who did not require a transfusion did not enter the study. 87 patients (35 men and 52 women) who had a haemoglobin level of 9g per decilitre or less with symptoms or 7g per decilitre or less with or without symptoms received a qualifying transfusion and were randomly assigned in a 1:1 ratio to either eculizumab or placebo. Concomitant administration of a number of other drugs was allowed (erythropoietin, immunosuppressive drugs, corticosteroids, coumarins, low molecular weight heparins, iron supplements and folic acid) provided the doses used before and throughout the study stayed the same. All study participants were vaccinated against Neisseria meningitidis as people who have a genetic deficiency of terminal complement proteins have an increased risk of neisserial infections. Exclusion criteria included patients with a complement deficiency, an active bacterial infection or a history of meningococcal disease and those who had undergone bone marrow transplantation. Patients received the first infusions of placebo (n=44) or eculizumab (n=43) within 10 days after the administration of the transfusion. The dose of eculizumab administered was 600mg every week (±2 days) for 4 weeks, followed 1 week (±2 days) later by 900mg and then a maintenance dose of 900mg every 2 weeks (±2 days) through to week 26. The 2 primary end points were 1) the stabilisation of haemoglobin levels and 2) the number of units of packed red cells transfused during the 26 weeks in the absence of transfusions. The stabilisation of haemoglobin level was defined as the haemoglobin value that was maintained above the level at which the qualifying transfusion was administered. Prespecified secondary end points included transfusion independence, haemolysis (as measured by the lactate dehydrogenase (LDH) value for the area under the curve from baseline to 26 weeks) and changes in the level of fatigue (assessed from baseline to 26 weeks with the use of the Functional Assessment of Chronic Illness Therapy

5 Page 5 Fatigue (FACIT-Fatigue) instrument scores range from 0 to 52, higher scores indicate improvement in fatigue). Quality of life, assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30); changes in lactate dehydrogenase levels from baseline to study end and the presence of thrombosis were also assessed. The planned sample size of 75 patients provided the study with a statistical power of 82%, at an alpha level of 0.05 to detect an increase of 35 percentage points (i.e. a change from 20% to 55%) in the rate of the stabilisation of haemoglobin levels and a reduction in the median number of units of packed red cells transfused from 6 to 2 (±2). There were no significant differences in the baseline characteristics of the patients in the 2 groups. 85 patients completed the trial 2 patients in the eculizumab group did not complete the trial. Ten patients in the placebo group discontinued infusions due to a perceived lack of efficacy but remained in the study for monitoring. The data relating to the achievement of the primary endpoints are highlighted in table 1. At the end of the study, 21 out of 43 patients in the eculizumab group had levels of haemoglobin that remained above 7.7g/decilitre (a prespecified endpoint) in the absence of transfusions, whereas no patient in the placebo group had a stabilised haemoglobin level. On the basis of these results, the number of patients that would need to be treated with eculizumab for 26 weeks to stabilise haemoglobin levels for 1 to benefit, is 2. At the end of the 26 weeks, the median number of units of packed red cells transfused per patient was 0 in the eculizumab group and 10 in the placebo group. By the end of the trial, the total number of units of packed red cells that had been transfused was 131 in the eculizumab group vs. 482 in the placebo group. The corresponding figures for the 6 months prior to the study were 413 and 417 respectively. The median time to the first transfusion was significantly longer in patients treated with eculizumab vs. placebo (p<0.001). 51% of patients in the eculizumab group achieved independence from transfusions vs. 0% in the placebo group (p<0.001). Table 1 achievement of the primary end points in the TRIUMPH trial Primary endpoints Before treatment* During treatment P Eculizumab Placebo Eculizumab Placebo value 1) Stabilisation of hemoglobin levels N/A N/A 49% 0% < ) No. of units of packed red cells transfused per patient Median <0.001 Mean 9.6 ± ± ± ± 0.8 * transfusion data obtained during 12 months before treatment were normalised to a value equivalent to the value for a 6 month period

6 Page 6 Eculizumab showed an immediate and sustained decrease in lactate dehydrogenase levels from ± U/litre at baseline to ± 67.6 U/litre at 26 weeks. The lactate dehydrogenase level in the placebo group remained elevated throughout the 26 week study. The drop in lactate dehydrogenase is indicative of a reduction in intravascular haemolysis, which leads to an improvement in quality of life. Use of the FACIT-Fatigue instrument showed that patients on eculizumab exhibited an increase of 6.4 ± 1.2 points from baseline to week 26, which indicates improvement, while patients on placebo recorded a decrease of 4.0 ± 1.7 points. The total difference of 10.4 points was statistically significant (p<0.001). A change of 3 or more points represents a clinically important difference. All measures of quality of life were improved in patients taking eculizumab vs. placebo. Serious adverse events were reported in 4 patients in the eculizumab group and 9 in the placebo group, none of which were considered to be treatment related. The most common adverse effects in the eculizumab group were headache, nasopharyngitis, nausea and back pain and these all occurred more frequently in patients on eculizumab than placebo - headache (44% vs. 27%), nasopharyngitis (23% vs. 18%), back pain (19% vs. 9%) and nausea (16% vs. 11%), although statistically there was no difference in the incidence between groups. The study authors conclude that the data from the trial indicate that eculizumab is an effective treatment in patients with PNH. The Safety in Haemolytic PNH Patients Treated with Eculizumab: A Multi-centre Open-label Research Design (SHEPHERD) study has finished and has been published online. (3, 10-12) Following a screening phase, the SHEP- HERD study enrolled 97 PNH patients 18 years old at 33 international sites who had had at least 1 blood transfusion in the previous 24 months, to receive IV infusions of eculizumab for 52 weeks. Patients also had to have a PNH type III erythrocyte proportion of 10%, platelets 30,000ml and lactate dehydrogenase 1.5 times the upper limit of normal to be included in the study. Exclusion criteria included an absolute neutrophil count <500/µl, complement deficiencies, active bacterial infection, prior meningococcal disease or prior bone marrow transplant. All patients were vaccinated against Neisseria meningitidis at least 14 days prior to receiving the first dose of eculizumab. Eculizumab administration began with an induction period with patients receiving 600mg eculizumab once weekly for 4 doses followed by 1 dose of 900mg one week later. During the maintenance phase, patients received 900mg every 2 weeks for a total of 52 weeks. Each dose was administered by IV infusion over minutes. Throughout the study patients continued to receive transfusions of packed RBCs if medically indicated. The primary objective was to evaluate the safety of eculizumab in patients who had received at least 1 blood transfusion in the previous 24 months. This was assessed by adverse events reported, clinical laboratory and electrocardiogram data and vital signs. The primary efficacy endpoint was reduction in intravascular haemolysis measured

7 Page 7 by change in the LDH area under the concentration curve (AUC). Secondary endpoints were haemolysis as measured by LDH change from baseline and fatigue measured by the FACIT-Fatigue instrument. Quality of life was assessed on the EORTC QLQ- C30 scale. The patient population in the SHEP- HERD trial was 48 males and 49 females, with a median age of 41 years and a diagnosis of PNH for 4.9 years. The patients in the SHEPHERD study were more diverse than the TRIUMPH study as the inclusion criteria allowed patients with a minimal transfusion history and evidence of thrombocytopenia to participate. 96 patients completed the study. Most adverse effects (96.4%) in the study were of mild to moderate severity. 76.1% of adverse effects were not considered to be related to eculizumab. Two thrombotic events were reported during the study in patients with a history of thrombosis and both were considered to be unrelated to eculizumab. The most common adverse events seen in 10% of patients are listed in table 2. Adverse effects that were considered to be definitely related to eculizumab were dysgeusia and mild haematoma and were of mild intensity. The incidence of adverse effects during the second 26 weeks was either similar or lower compared to the first 26 weeks. The number of patients reporting headaches was significantly lower in the second 26 weeks (14.6% vs. 48.5%). 94% of headaches occurred within the first 48 hours of drug administration and were experienced in the first 2 weeks of the induction phase. The headaches responded to treatment with non-opioid analgesics and were mild to moderate in severity. The frequency of headaches with eculizumab during the second 26 weeks was lower than the placebo group in the TRIUMPH study. Vital signs, physical examination and ECG data did not reveal temporally associated adverse effects. No clinically significant laboratory abnormalities were seen. During the 52 weeks, 44 serious adverse events occurred, of which 7 were considered to be possibly related to eculizumab pyrexia (2), headache (1), abdominal distension (1), viral infection (1), anxiety (1) and renal impairment (1). No serious adverse effect was considered to be probably or definitely related to eculizumab. Eighty nine patients experienced at least 1 infection during the 52 week study. 98.9% of infections were reported as mild to moderate in intensity. 8.3% of infections were possibly related to eculizumab whereas 91.3% were considered as unrelated. The authors of the SHEPHERD study state that the proportion of patients experiencing 1 or more infections during the first 26 week (75.3%) and second 26 week (70.8%) treatment periods was similar to that of placebo treated patients during the 26 week TRIUMPH study (77.3%). Serum haemolytic activity can be completely inhibited by eculizumab at levels above 35 mcg/ml. Eighty nine patients maintained complete inhibition of serum haemolytic activity with 14 day dosing. Eight patients exhibited haemolysis during the last 1-2 days of the 14 day dosing interval, this was overcome by adjusting the dosing interval to 12 days. Intravascular haemolysis was significantly reduced as indicated by the levels of LDH which decreased substantially within 1 week of treatment initiation. Control of intravascular haemolysis also resulted in an improvement in anaemia. Transfusion requirements decreased

8 Page 8 from a median of 8 units of packed red blood cells per patient before treatment to 0 during treatment (p<0.001), 51% of patients became transfusion independent (p<0.001), haemoglobin levels increased from baseline and all patients experienced substantial reduction in intravascular haemolysis as demonstrated by reduced LDH levels. Fatigue significantly improved within 1 week of eculizumab treatment starting and this was maintained throughout the entire study. Significant improvement in quality of life as measured by the EORTC QLQ-C30 scale was also demonstrated. The results relative to the various study endpoints are shown in table 2. The conclusion from the SHEPHERD study is that eculizumab is safe and well tolerated. Use of eculizumab results in substantial reduction in haemolysis leading to improvements in anaemia, fatigue, quality of life and a reduced need for transfusions. The SHEPHERD study also shows that eculizumab is beneficial in PNH patients with thrombocytopenia and/or minimal infusion requirements. Virtually all patients who have participated in the TRIUMPH, SHEPHERD and phase II studies were entered into a phase III, open label, extension study of eculizumab in patients with transfusion-dependent, haemolytic PNH. (3, 13) The extension study is an ongoing study assessing the number of thromboembolic events in patients treated with eculizumab as these are the leading cause of morbidity/mortality in patients with PNH. To assess the effect of eculizumab, thromboembolic rates during eculizumab treatment have been compared to pre-eculizumab event rates in the same patients. 187 patients have been enrolled in the extension study and continue to receive the 900mg maintenance dose of eculizumab. The extension study shows that eculizumab treatment reduced thromboembolic events substantially in patients enrolled in each of the clinical studies see table 3. The reduction in the thromboembolic event rate during eculizumab treatment as compared to the same patients pre-treatment, was statistically significant (p<0.001). Analysis of data available in November 2006 showed that the reduction in risk of thromboembolism has been maintained. When compared to the rate of thromboembolism events in all enrolled Table 2 results of primary and secondary objectives from the SHEPHERD study Endpoint Safety of eculizumab Intravascular haemolysis LDH AUC & change from baseline Quality of life Result Most common adverse effects in >10% of patients after 52 weeks Headache: 53% Nasopharyngitis: 32% Upper respiratory tract infection: 30% Nausea: 21% Pyrexia: 20% Back pain:16% Dizziness: 14% Change in LDH AUC, p<0.001 Mean baseline LDH level: 2,201 ± 105 U/L Mean 52 week LDH level: 297 ± 21 U/L (p<0.001) Fatigue rapidly and significantly improved, p<0.001 Other measures of quality of life significantly improved, p<0.001

9 Page 9 Table 3 Thromboembolism (TE) events in patients with and without eculizumab Phase II pilot studies TRIUMPH SHEPHERD Extension (all studies) Placebo Eculizumab Pre-treatment Patients (n) TE events (n) Patient years (n) TE event rate (n/100 patient yrs) Eculizumab Patients (n) TE events (n) Patient years (n) TE event rate (n/100 patient yrs) patients before treatment, eculizumab results in a significant 7 fold reduction in the thromboembolism event rate overall from 7.37 events per 100 patient years pre-eculizumab treatment to 1.07 events per 100 patient years during eculizumab treatment (p<0.001). 103 of the 195 patients enrolled in the extension study were taking antithrombotic agents prior to enrolment and their therapy was continued during the study. In these patients the rate of thrombosis was per 100 patient years pre-treatment and 0.62 with eculizumab treatment (p<0.001). The authors of the extension study conclude that long term administration of eculizumab in a diverse population of PNH patients substantially reduces the risk of thrombosis. This is a significant finding as thrombosis has been demonstrated to cause the majority of deaths in PNH. If the risk of thrombosis can be reduced, it is reasonable to expect that life expectancy on PNH patients may be increased. A post-hoc analysis of the eculizumab trial database examined renal function pre and post-treatment. Renal damage is common in PNH and may be due to repetitive exposure of tissue to cell-free haemoglobin. At baseline, before treatment, 65% of the PNH patients were found to have some evidence of chronic kidney disease (stage 1-5 Chronic Kidney Disease (CKD) using national Kidney Foundation rating), 21% were found to be at pre-dialysis or at end stage renal disease (ESRD). (14) Eculizumab treatment over 18 months was associated with a significant increase in the likelihood of improved kidney function and decreased likelihood of worsened kidney function in all stages of CKD (p<0.001). Improvements occurred as early as 6 months of treatment. Patients with pre-dialysis CKD at baseline (stage level 3 or 4) or ESRD (stage level 5) were more likely to be stabilised during treatment with eculizumab, whilst patients with mild CKD at baseline (stage level 1 or 2) were more likely to improve during eculizumab treatment. Overall, during the course of 18 months of eculizumab treatment, 40/195 (21%) patients with initial CKD were no longer classified as having CKD.

10 Page 10 The authors concluded that long-term eculizumab treatment resulted in a significant improvement and prevention of worsening of CKD at all initial stages of renal disease. Side Effects The most commonly reported adverse effects are headache, nasopharyngitis, nausea, pyrexia, myalgia, fatigue and herpes simplex. Each have occurred in 5 or more out of 100 patients. (6) Adverse effects reported as occurring as very common ( 1/10) or common ( 5/100 and 10/100) in the TRI- UMPH and SHEPHERD studies are listed in table 4. Adverse effects were mostly mild to moderate in severity. Uncommon or rare events can not be estimated due to limited patient exposure (195 patients). (6) Based on the safety data collected to date, eculizumab does not appear to be associated with an increase in severity of adverse effects in treated patients and no cumulative, irreversible toxicities or treatment related deaths have been reported. (3) Due to the mechanism of action of eculizumab, the potential for carcinogenic activity needs to be monitored, particularly regarding haematological abnormalities. (3) Table 4 Very common and common adverse effects seen with eculizumab Adverse effect Very common (>1/10) Common (5/100 1/10) Infections & infestations Urinary tract infection Nasopharyngitis Respiratory tract infection Herpes simplex Upper respiratory tract Sinusitis infection Viral infection Gastroenteritis Psychiatric disorders - Insomnia Nervous system disorders Dizziness Headache - Respiratory, thoracic & - Epistaxis mediastinal disorders Pharyngolaryngeal pain Cough Gastrointestinal disorders Skin & subcutaneous tissue disorders Musculoskeletal & connective tissue disorders General disorders & administration site conditions Injury, poisoning & procedural complications Diarrhoea Nausea Vomiting Abdominal pain Upper abdominal pain Constipation - Rash Pruritis Back pain Myalgia Arthralgia Pain in extremity Muscle cramp Pyrexia Influenza-like illness Fatigue Contusion -

11 Page 11 The scientific discussion document on eculizumab produced by the European Medicines Agency states that there are some limitations regarding the size of the safety database and duration of treatment. As limited long term safety data are available and it is expected that a number of patients will require long term treatment, further experience will be obtained from post-marketing experience, as well as through a specific patient registry. (3) Precautions Due to its mechanism of action, the use of eculizumab increases the patient s susceptibility to meningococcal infection (Neisseria meningitidis). These patients might be at risk of disease by uncommon serogroups (particularly B, Y, W135 and X), although meningococcal disease due to any serogroup may occur. To reduce the risk of infection, all patients must be vaccinated at least 2 weeks prior to receiving eculizumab and must be re-vaccinated according to current medical guidelines for vaccination use. Tetravalent vaccines against serotypes A, C, Y and W135 are strongly recommended, preferably conjugated ones. Vaccination may not be sufficient to prevent meningococcal infection as there is no vaccine against serotype B. Consideration should be given to official guidance on the appropriate use of antibacterial agents. (6, 13) There have been 3 reported cases of meningococcal infection in eculizumab treated patients: two in vaccinated PNH patients and one in an unvaccinated patient with idiopathic membranous glomerulonephropathy. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with antibiotics if necessary. Patients should be informed of these signs and symptoms and steps taken to seek medical care immediately. (6) Due to its mechanism of action, eculizumab therapy should be administered with caution to patients with active systemic infections. The overall severity and frequency of infections in patients taking eculizumab in clinical studies was similar to placebo treated patients, although an increase in the number and severity of infections, particularly due to encapsulated bacteria, cannot be excluded. (6) Administration of eculizumab may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis), though immune system disorders within 48 hours of eculizumab administration did not differ from placebo treatment in PNH and non-pnh studies. In clinical trials, no PNH patients experienced an infusion reaction that required discontinuation of eculizumab. Administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered. (6) Infrequent, low titre antibody responses have been detected in patients treated with eculizumab across all PNH and non-pnh studies with a frequency (3.4%) similar to that of placebo (4.8%). No patients have developed neutralising antibodies following therapy with eculizumab, and there has been no observed correlation of antibody development to clinical response or adverse events. (6) The detection of antieculizumab antibodies is highly dependent on the specificity and sensitivity of technique used and the manufacturer of eculizumab has committed to developing a specific technique to be used in future trials. (3) PNH patients should be monitored for signs and symptoms of intravascular haemolysis, including serum lactate dehydrogenase (LDH) levels. PNH patients receiving eculizumab therapy should be similarly monitored for intravascular haemolysis by measuring LDH levels,

12 Page 12 and may require dose adjustment within the recommended 14±2 day dosing schedule during the maintenance phase (up to every 12 days). (6) Patients who discontinue treatment with eculizumab should be monitored for signs and symptoms of serious intravascular haemolysis. Serious haemolysis is identified by serum LDH levels greater than the pre-treatment level, along with any of the following: greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; a haemoglobin level of <5 g/dl or a decrease of >4 g/dl in one week or less; angina; change in mental status; a 50% increase in serum creatinine level or thrombosis. Any patient who discontinues eculizumab should be monitored for at least 8 weeks to detect serious haemolysis and other reactions. If serious haemolysis occurs after eculizumab discontinuation, one of the following procedures/treatments should be considered: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of eculizumab. In PNH clinical studies, 16 patients discontinued the eculizumab treatment regimen. Serious haemolysis was not observed. (6) The eculizumab product contains 5.00 mmol sodium per dose (1 vial). This should be taken into consideration by patients on a controlled sodium diet. (6) Drug interactions No drug-drug interaction studies have been performed. (6) This is highlighted as a limitation in the scientific discussion document on eculizumab produced by the European Medicines Agency, although it is recognised that interactions with antibodies are difficult to predict. (3) Special populations There is no experience of use of eculizumab in children. (6) Eculizumab may be administered to patients aged 65 years and over. There is no evidence to suggest that any special precautions are needed when older people are treated although experience in this patient population is still limited. (6) The safety and efficacy of eculizumab have not been studied in patients with renal or hepatic impairment. (6) The Summary of Product Characteristics for eculizumab states that there is no clinical data on pregnancies exposed to eculizumab available and animal reproduction studies have not been conducted with eculizumab. There were 3 pregnancies in the clinical trials. One woman elected to have a termination, and the other 2 patients stopped eculizumab at week 8 and 12 of gestation and both had normal, healthy babies. Human IgG are known to cross human placental barrier, and thus eculizumab may potentially cause terminal complement inhibition in the foetal circulation. Therefore, eculizumab should be given to a pregnant woman only if clearly needed. Women of childbearing potential have to use adequate contraception methods during treatment and up to 5 months after stopping treatment. (6, 8) It is not known whether eculizumab is secreted into human milk. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, lactation should be discontinued during treatment and up to 5 months after treatment. (6)

13 Page 13 Economic considerations The cost per standard maintenance dose of eculizumab 900mg every 14 days is 9,450. The cost per 28 days is 18,900 and per year is 245,700. (15) Additional costs will arise from the need for regular venous access, the administration of infusions and potential training of staff. (1) The cost of vaccination against Neisseria meningitidis also needs to be taken in to consideration. The manufacturers of eculizumab (Alexion Pharma UK) are planning to fund the delivery and administration of eculizumab via a third party homecare provider for PCTs and patients who wish to use the drug. This will allow patients to be treated in their own time at work or at home and reduce the burden to the NHS in terms of ordering, handling, storing, preparation and administration of the infusion. (15) By using eculizumab, savings may be realised by a reduction in complications from PNH resulting in fewer or no hospital admissions and reduced need for supportive therapy e.g. transfusions of packed red blood cells. (1) Place in therapy A review of eculizumab by the National Horizon Scanning Centre in December 2006 estimated that between 33% to 50% of patients with PNH in England and Wales may benefit from eculizumab. This estimate was based on the results of trials available at the time of publication. The benefits include reduced morbidity, reduced mortality and improved quality of life. (1) achieved transfusion independence in approximately 50% of patients. In these studies there was a 73% and 52% reduction in transfusion requirements across the whole study populations. (3, 9-12) A UK specialist in the management of PNH has suggested that approximately a third of the PNH patient population would be likely to have evidence of haemolysis (~300) and of these patients, only about 50% would require therapy with eculizumab (~150). These figures are estimates based on clinical experience and are considered to be high. (8) In the patient group that receive eculizumab, approximately 50% will become completely transfusion independent, 40% will have a marked reduction in transfusion requirements and less than 10% will see little change in the number of transfusions they require. Marked improvement in quality of life, disappearance of PNH symptoms (e.g. abdominal pain, dysphagia, severe lethargy, erectile dysfunction) and marked reduction in thrombotic risk all occur in almost all patients. Very few patients would stop therapy because of lack of efficacy. Identification of appropriate patients to start therapy is critical and should be done at a specialist centre. (8) Although the licence for eculizumab states that evidence of clinical benefit of eculizumab for patients with PNH is limited to those with a history of transfusions, as per the TRIUMPH study, the scientific discussion document on eculizumab produced by the European Medicines Agency acknowledges that because available treatments for PNH have a limited effect and do not affect the course of treatment, the risk of off label use and paediatric off label use is recognised and should be monitored through routine pharmacovigilance and a safety registry. (3) The TRIUMPH and SHEPHERD studies indicate that use of eculizumab

14 Page 14 To ensure safe and effective use of eculizumab, the European Medicines Agency has instructed the drug manufacturer to undertake risk minimisation activities Distribute the drug only after checking that the patient has received a meningococcal vaccine. Provide health care professionals with information on key safety concerns before the drug is distributed: headache, infusion reaction, Neisseria and general infection, risk of serious haemolysis following discontinuation and proposed management, pregnancy and the need for adequate contraception in women of child bearing potential, immunogenicity, renal and hepatic impairment. Implement a patient card system that will provide details of the signs and symptoms of infection as well as instruction for the patient to immediately seek medical care. The card will also provide information to health care professionals that the patient is receiving eculizumab treatment. (3) The manufacturer is going to establish a PNH Registry which will monitor the long term safety and efficacy of eculizumab as well as record the history and ongoing clinical prognosis of patients not treated with eculizumab. In November 2007, the Scottish Medicines Consortium decided that in the absence of a submission from the manufacturers, eculizumab was not recommended for use within NHS Scotland for treatment of PNH. (16) Conclusions from the clinical evidence The double blind, randomised, placebo-controlled, multicentre TRIUMPH study enrolled patients who had received at least 4 transfusions in the past 12 months. In comparison to placebo, eculizumab stabilised haemoglobin levels in approximately 50% of patients, 50% of patients achieved independence from transfusions of packed red blood cells; patients not experiencing transfusion independence saw a 44% decrease in transfusions and all measures of quality of life were improved including a significant improvement in fatigue. The multicentre, open label, non-placebo controlled SHEPHERD study enrolled patients with thrombocytopenia and minimal infusion requirements. The study showed that eculizumab was well tolerated and few adverse effects were probably or definitely related to the drug. 51% of patients became transfusion independent, intravascular haemolysis was significantly reduced in all patients and there was significant improvement in quality of life. An extension study assessing the number of thromboembolic events in patients following long term administration of eculizumab has shown that eculizumab results in a significant 7 fold reduction in the thromboembolism event rate from 7.37 events per 100 patient years pre-eculizumab treatment to 1.07 events per 100 patient years during eculizumab treatment. If patients respond to eculizumab, treatment would be given indefinitely, however, it is not possible to say currently how many years of life eculizumab adds for patients with PNH. (17)

15 Page 15 References 1. Horizon Scanning Technology Briefing. Eculizumab (Soliris) for paroxysmal nocturnal haemoglobinuria. National Horizon Scanning Centre, December pcpoh.bham.ac.uk/publichealth/horizon/pdf_files/2006reports/december06/ Eculizumab(Solaris).pdf 2. Porter RS (Editor). Merck Manual Online. Paroxysmal Nocturnal Hemoglobinuria (PNH). Last full review/revsion November Soliris European Public Assessment Report Scientific Discussion. European Medicines Agency, June soliris/soliris.htm 4. Luzzatto L & Gianfaldoni G. Recent advances in biological and clinical aspects of paroxysmal nocturnal hemoglobinuria. International Journal of Hematology 2006; 84: Soliris European Public Assessment Report Summary for the Public. European Medicines Agency, May H-791-en1.pdf 6. Summary of Product Characteristics Soliris. Alexion Europe SAS, text last revised 20 June Soliris Label and Approval History. US Food and Drug Administration. 16/03/ Dr P Hillmen. Consultant Haematologist, Department of Haematology, Leeds General Infirmary. Personal communication, January Hillmen P, Young NS et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine 2006; 355: Schrezenmeier H, Luzzatto L et al. Safety and efficacy of the terminal complement inhibitor eculizumab in patients with paroxysmal nocturnal hemoglobinuria: SHEP- HERD phase III clinical study results. Haematologica 2007; 92 (suppl 1): Young NS, Antonioli E et al. Safety and efficacy of the terminal complement inhibitor eculizumab in patients with paroxysmal nocturnal hemoglobinuria: interim SHEPHERD phase III clinical study. Blood 2006; 108 (11): abstract Brodsky RA, Young NS et al. Multicenter phase III study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Data provided by the manufacturers Alexion Pharma UK, December Hillmen P, Muus P et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110 (12): Hillmen P et al. High incidence of progression to Chronic Renal Insufficiency in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Poster Session; Board #897- III, [3678], ASH, December Information to support the evaluation of exceptional case funding requests for Soliris (eculizumab) in the treatment of patients with Paroxysmal Nocturnal Haemoglobinuria (PNH). Alexion Pharma UK, September Scottish Medicines Consortium. Eculizumab (Soliris) Statement of Advice. 9 November Non%20Submission%20FINAL%20Nov%202007%20for%20website.pdf 17. Anon. Eculizumab (Soliris) for paroxysmal nocturnal hemoglobinuria. The Medical Letter 2007; 49 (1270): The London New Drugs Group would like to thank Dr Peter Hillmen, Consultant Haematologist at Leeds General Infirmary for their comments and assistance in preparing this document.