The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 20 June 2012 CINRYZE 500 units, 2100 IU, powder and solvent for solution for injection B/2 bottles (CIP code: 218 563-0) Applicant: VIROPHARMA SAS C1-esterase inhibitor, human ATC code: B02AB03 (C1 inhibitor) List I Medicine for hospital prescription only, included in the list of medicines for delivery to outpatients. Date of Marketing Authorisation (centralised): 15/06/2011 Reason for request: Inclusion on the list of medicines approved for hospitals use. Medical, Economic and Public Health Assessment Division. 1/9
1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient C1-esterase inhibitor, human 1.2. Indication Treatment and pre-procedure prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). Routine prevention of angioedema attacks in adults and adolescents with severe and recurrent attacks of hereditary angioedema (HAE), who are intolerant to or insufficiently protected by oral prevention treatments, or patients who are inadequately managed with repeated acute treatment. 1.3. Dosage CINRYZE therapy should be initiated under supervision of a physician experienced in the care of patients with hereditary angioedema (HAE). Dosage Adults: Treatment of angioedema attacks 1000 Units of CINRYZE at the first sign of onset of an acute attack. A second dose of 1000 Units may be administered if the patient has not responded adequately after 60 minutes. For patients experiencing severe attacks particularly laryngeal attacks or if initiation of treatment is delayed, the second dose may be given sooner than 60 minutes. Routine prevention of angioedema attacks: 1000 Units of CINRYZE every 3 or 4 days is the recommended starting dose for routine prevention against angioedema attacks; the dosing interval may need to be adjusted according to individual response. The continued need for regular prophylaxis with CINRYZE should be reviewed on a regular basis. Pre-procedure prevention of angioedema attacks: 1000 Units of CINRYZE within 24 hours before a medical, dental, or surgical procedure. Paediatric population: For treatment, routine prevention and pre-procedure prevention in adolescents the dose is the same as for adults. The safety and efficacy of CINRYZE in children before adolescence has not yet been established. [ ] Elderly: No special investigations have been performed. For treatment, routine prevention and pre-procedure prevention in elderly patients, 65 years of age or older, the dose is the same as for adults. Patients with renal or hepatic impairment: No special investigations have been performed. For treatment, routine prevention and pre-procedure prevention in patients with renal or hepatic impairment, the dose is the same as for adults. Method of administration: For intravenous use. 2/9
2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2005) B: Blood and blood-forming organs B02: Antihaemorrhagics B02A: Antifibrinolytics B02AB: Proteinase inhibitors B02AB03: C1-inhibitor 2.2. Medicines in the same therapeutic category These are the other C1 esterase inhibitors indicated in the treatment of acute attacks of angioedema in adults with hereditary angioedema (HAE) caused by C1 esterase inhibitor deficiency: - BERINERT (human C1 esterase inhibitor); 9/07/2009, substantial actual benefit, IAB III, - RUCONEST (recombinant C1 esterase inhibitor); 9/03/2011, substantial actual benefit, IAB V compared to BERINERT and FIRAZYR. These proprietary medicinal products are not indicated in the prevention of attacks. The proprietary medicinal products BERINERT and CINRYZE contain the same active ingredient (human C1 esterase inhibitor) but have a different manufacturing process and different indications. 2.3. Medicines with a similar therapeutic aim Medicines used in attacks of hereditary angioedema : - EXACYL (tranexamic acid): off-label use, - FIRAZYR (icatibant); 29/10/2008, substantial actual benefit, IAB IV in the management. Medicine indicated in the basic treatment of hereditary angioneurotic oedema : - DANATROL 200 mg (danazol); RI 07/01/2009 substantial actual benefit 3/9
3. ANALYSIS OF AVAILABLE DATA 3.1. Efficacy The efficacy and tolerance of CINRYZE were evaluated in four phase III clinical studies. - two studies into the treatment of the attack: randomised, double-blind CHANGE trial Part A, whose aim was to compare the efficacy of CINRYZE with that of placebo in terms of the time taken for the symptoms of angioedema attacks to improve, non-comparative CHANGE 2 trial, whose aim was to evaluate the percentage of attacks treated with CINRYZE. - two studies into prophylactic treatment: randomized, double-blind CHANGE trial Part B, whose aim was to compare the efficacy of CINRYZE with that of placebo in terms of the number of angioedema attacks during each treatment sequence, non-comparative CHANGE 3 trial, whose aim was to evaluate the frequency of attacks under CINRYZE. 3.1.1. Treatment of acute attacks CHANGE A study Methodology: Randomized, double-blind, comparative, phase III study comparing CINRYZE versus placebo in 68 hereditary angioedema (HAE) patients. Inclusion criteria: Patients over the age of 6 years with documented HAE (diminished C4 levels and C1 inhibitor level) and experiencing a moderate to severe attack: - having lasted less than 4 hours, - affecting the abdomen, urogenital tract, or face. Because of the comparison with placebo, the severe forms (laryngeal oedema) were not included in the double-blind study. Treatment: - CINRYZE 1000 U, infusion, n = 35, - Placebo, n = 33. Primary endpoint: The median time between the initial symptoms of the HAE attack and the start of definite relief 1 for the patient after a single dose of treatment. Definite relief was defined by three consecutive responses of the type symptom absent now, but present before or symptom present, but better RESULTS: On inclusion, the patients characteristics were comparable. After one injection, a significant decrease in the median time to symptom relief was observed with CINRYZE compared to placebo: 2 hours [0.8 NA] with CINRYZE versus more than 4 hours [2.0 NA] with placebo, HR 2.407 [1.171; 4.948], p = 0.017. 1 Defined by a 5-point scale: 1. Absent now and before; 2. Absent now but present before; 3. Present, symptoms new; 4. Present, symptoms worse or the same; 5. Present, symptoms better 4/9
CHANGE 2 study Aim: To evaluate the efficacy and tolerance of repeatedly using CINRYZE in the treatment of HAE attacks. Methodology: Non-comparative, phase III study in 113 hereditary angioedema (HAE) patients: 101 patients were treated for an acute attack and 12 were given short-term preventive treatment before a minor surgical intervention. The CINRYZE treatment was proposed to patients as part of a surgical operation (whether emergency or scheduled) or dental work. Inclusion criteria: Patients over the age of 6 years with HAE and a history of more than two attacks per month, all areas combined. Primary endpoint: Median time between the initial symptoms of the HAE attack and the beginning of definite relief for the patient after a single dose of treatment. RESULTS: see Table 1 During the follow-up period (3 months), 15/101 patients with HAE were treated for more than 10 attacks and 4 for more than 20 attacks. In all, 609 attacks were observed during the follow-up phase. Table 1: Number of patients experiencing relief for each attack Number of attacks Number of patients still followed up Number of patients obtaining relief Response rate [95% CI] 1 101 80 0.79 [0.70; 0.87] 2 77 64 0.83 [0.73; 0.91] 3 58 52 0.90 [0.79; 0.96] 4 50 43 0.86 [0.73; 0.94] 5 38 32 0.84 [0.69; 0.94] 6 29 23 0.79 [0.60; 0.92] 7 23 21 0.91 [0.72; 0.99] 8 20 19 0.95 [0.75; 1.00] 9 18 16 0.89 [0.65; 0.99] 10 15 12 0.80 [0.52; 0.96] 15 9 88 0.89 [0.52; 1.00] 20 4 4 1.00 [0.54; 1.00]..55 2 2 1.00 [0.16; 1.00] These data suggest that the efficacy of CINRYZE is maintained until the fifteenth attack, but the numbers of patients under follow-up are small; besides, the number of patients followedup is too small (< 4) to permit a conclusion to be reached. 3.1.2. Prophylactic treatment CHANGE B study Methodology: Randomized, double-blind, crossover (2 periods of 12 weeks), phase III study comparing CINRYZE versus placebo in 22 hereditary angioedema (HAE) patients. The patients included in this study had previously taken part in the CHANGE A study described earlier. Inclusion criteria: Patients over the age of 6 years with documented HAE (diminished C4 levels and C1 inhibitor level) and experiencing more than two attacks per month. Treatment: - CINRYZE 1000 U, infusion, n = 11, - Placebo, n = 11. After 12 weeks, the treatments were switched for a second 12-week period. 5/9
Primary endpoint: Total number of HAE attacks during each treatment period. RESULTS: see Table 2 On inclusion, the patients characteristics were comparable. Table 2: Total number of attacks per group CINRYZE/Placebo n = 12 Number of attacks - Mean (SD) 6.1 (5.43) - Median [95% CI] 6 [0; 17] p < 0.001 Placebo/CINRYZE n = 12 12.7 (4.8) 13,5 [6; 22] During the two follow-up periods, 22 HAE attacks were observed (11 during each period). The number of attacks decreased significantly with CINRYZE compared to placebo: 6.1 (± 5.43) attacks versus 12.7 (± 4.8) attacks, p < 0.001. CHANGE 3 study Methodology: Non-comparative, phase III study conducted in 146 hereditary angioedema (HAE) patients. The patients were followed up for a mean duration of 243 days. Inclusion criteria: Patients aged over one year, coming from either the CHANGE A or B study, with a history of at least one HAE attack per month or with a history of laryngeal attacks. Treatment: CINRYZE 1000 U, infusion, n = 146. Primary endpoint: Mean frequency of HAE attacks during the follow-up. RESULTS: see Table 3 Table 3: Number of attacks per month Number of attacks/month On inclusion - Mean (SD) - Median [95% CI] At the end of follow-up - Mean (SD) - Median [95% CI] CINRYZE 4.7 (5.18) 3 [0.08; 28] 0.5 (0.754) 0.21 [0; 4.56] During the follow-up, the mean number of attacks fell from 4.7 per month (5.18) on inclusion to 0.5 (0.754) per month with CINRYZE (descriptive before-and-after study). 3.2. Adverse effects In the CHANGE A study, 6 patients (8.5%) presented adverse events (2 in the CINRYZE group and 4 in the placebo group), including dizziness (1 vs. 0) and anxiety (1 vs. 0). In the CHANGE 2 study, 46/113 patients (40.7%) presented adverse events. The most common adverse events (> 3%) were: sinusitis (6 patients), nasopharyngitis (5), HAE (4), and streptococcal pharyngitis (4). In the CHANGE B study, 9/24 patients (37.5%) presented adverse events. The most common adverse events (> 10%) were: upper respiratory tract infections (3 patients) and rash (3 patients). In the CHANGE 3 study, 39/146 patients (26.7%) presented adverse events. The most common adverse events (> 3%) were: headache (8 patients), nausea (6). 6/9
3.3. Conclusion CINRYZE was evaluated in hereditary angioedema patients over the age of 6 years, both as a treatment for attacks (lasting at least 4 hours, without laryngeal oedema) in two studies (the randomised, double-blind CHANGE A study, and the non-comparative CHANGE 2 study) and also as a prophylaxis in two studies (the randomised, double-blind CHANGE B study and the non-comparative CHANGE 3 study, as long term prophylaxis. Treatment of attacks: In the randomised, double-blind CHANGE A study, after an injection the median time to symptom relief was reduced with CINRYZE in comparison to placebo: 2 hours [0.8 NA] versus over 4 hours [2.0 NA] with placebo, HR 2.407 [1.171; 4.948], p = 0.017. In the non-comparative CHANGE 2 study, it was suggested that CINRYZE could maintain its efficacy up to the fifteenth attack, but patient numbers were too small to be able to make any conclusive judgement. Prevention of attacks: In the CHANGE B study (patients having first taken part in the CHANGE A study), during the two 12-week treatment periods the number of HAE attacks decreased with CINRYZE in comparison to placebo: 6.1 (± 5.43) attacks versus 12.7 (± 4.8) attacks, p < 0.001. In a non-comparative study performed in 146 patients coming from the CHANGE A or B studies, followed up over a mean period of 6 months (CHANGE 3), the mean monthly number of attacks fell from 4.7 (5.18) on inclusion to 0.5 (0.754). In view of the methodology used in this study (descriptive before-and-after study), these results should be interpreted with caution. No study versus an active comparator, including icatibant (FIRAZYR), C1-esterase inhibitors (BERINERT) or (RUCONEST) or danazol (DANATROL) is available. The adverse events most commonly observed during these studies were: dizziness, headache, anxiety, upper respiratory tract infections, rash, and nausea. 7/9
4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Hereditary angioedema (HAE) is characterised by transient and recurrent attacks of subcutaneous and/or submucosal oedema in variable locations (skin, digestive tract, pharynx, etc.). HAE is a rare and disabling genetic disorder which can be life-threatening when located in the larynx. This proprietary medicinal product is intended as a symptomatic therapy. This product is a first-line treatment of attacks and a second-line treatment for the prevention of HAE attacks. Alternative medicinal products exist, in particular for the treatment of attacks BERINERT, RUCONEST and FIRAZYR and for their prevention DANATROL. The efficacy/adverse effects ratio for this medicinal product is high. Public health benefit: The public health burden of patients who have acute attacks of hereditary angioedema (HAE) (with a deficiency in the C1-esterase inhibitor) is small because of their limited numbers. Improvement in the management of this disease is a public health need that is an established priority (Rare Diseases Plan 2010-2014). According to the results of clinical trials (of treatment and prevention), the proprietary medicinal product CINRYZE is not expected to have an impact on the morbidity, mortality and quality of life of these patients in population terms. CINRYZE is not able to offer any additional response to the identified need. Consequently, in the light of current knowledge, the proprietary medicinal product CINRYZE is not expected to offer any public health benefit in this indication (either for treatment or prevention). The actual benefit of these proprietary medicinal products remains substantial in the Marketing Authorisation indications. 4.2. Improvement in actual benefit (IAB) In the management strategy for HAE, CINRYZE does not offer any improvement in the Actual Benefit (IAB V) compared to the other treatments already available. 4.3. Therapeutic use 2, 3 HAE is characterized by episodes of subcutaneous and/or submucosal oedema that are transient (48-72 hours) and recurrent. The disease can manifest itself at any age but is most common during childhood and adolescence. The oedema may affect the digestive tract and produce a pseudo-occlusive syndrome responsible for severe pain which is sometimes associated with ascites and hypovolaemia. Involvement of the larynx can be life-threatening. HAE type I and II are due to different alterations to the C1-esterase inhibitor (C1-INH) gene: deletion or poor transcription for type I and mutation for type II. The diagnosis of HAE type I 2 Dr L. Bouillet Angio-œdème héréditaire Orphanet, February 2008 3 EPAR FIRAZYR 24/04/2008 8/9
and II is based on measuring the C4 concentration and on a C1-INH assay. Oedema is triggered by increased permeability of the blood vessels due to the release of excess bradykinin because of the C1-INH inhibitor deficiency. Current treatment relies on basic treatment to prevent attacks, suppressing identifiable triggering factors (foods, drugs such as ACE inhibitors, etc.), and short-term treatment of attacks. Corticosteroids are ineffective. - the basic treatment is an androgen (danazol), - the treatment of moderate attacks is based on tranexamic acid (EXACYL, off-label); the treatment of severe (laryngeal) episodes is based on the intravenous administration of C1-INH concentrate (BERINERT or RUCONEST) or on the subcutaneous administration of icatibant (FIRAZYR). CINRYZE, which is administered intravenously, has demonstrated its efficacy in terms of the median time until the alleviation of the symptoms of attacks of HAE. It represents an alternative to other treatments for HAE attacks available for intravenous use (BERINERT and RUCONEST) or subcutaneous use (FIRAZYR). CINRYZE has also shown its efficacy in terms of reducing the number of attacks in the context of preventive treatment. It may be offered to patients who are intolerant to or insufficiently protected by radical treatments (DANATROL). 4.4. Target population The target population for CINRYZE corresponds to patients suffering from acute hereditary angioedema (HAE) attacks and C1-esterase inhibitor deficiency. It can be estimated from the following data: - according to the French reference centre for nonhistaminic angioedema, 4 1000 patients had hereditary angioedema in 2007, - of these patients, 85% had a C1-esterase deficiency. Given the very limited nature of the epidemiological data available on the forms treated with CINRYZE, its target population cannot be established with any certainty. Nevertheless, the aforementioned data and expert opinions allow the number of patients with attacks of hereditary angioedema and a C1-esterase deficiency to be estimated at about 650 patients. 4.5. Transparency Committee recommendations The transparency Committee recommends inclusion on the list of medicines approved for hospitals use and various public services in the indication in the Marketing Authorisation. 4 CREAK Les angio-oedèmes non histaminiques, L. Bouillet, 1/07/2007 9/9