Opinion 23 April 2014

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE Opinion 23 April 2014 MIMPARA 30 mg, film-coated tablet B/14 (CIP: ) B/28 (CIP: ) B/30 (CIP: ) B/84 (CIP: ) MIMPARA 60 mg, film-coated tablet B/14 (CIP: ) B/28 (CIP: ) B/30 (CIP: ) B/84 (CIP: ) MIMPARA 90 mg, film-coated tablet B/14 (CIP: ) B/28 (CIP: ) B/30 (CIP: ) B/84 (CIP: ) Applicant: AMGEN S.A.S INN ATC Code (2011) Reason for the review List concerned Indications concerned cinacalcet (as hydrochloride) H05BX01 (other anti parathyroid agents) Renewal of inclusion National Health Insurance (French Social Security Code L ) "Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate. Treatment of hypercalcaemia in patients with: parathyroid carcinoma primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated. " HAS - Medical, Economic and Public Health Assessment Division 1/20

2 Actual Benefit Maintenance of the substantial actual benefit in the Marketing Authorisation indications. HAS - Medical, Economic and Public Health Assessment Division 2/20

3 01 ADMINISTRATIVE AND REGULATORY INFORMATION Marketing Authorisation (centralised procedure) Prescribing and dispensing conditions ATC Classification 22 October 2004; 19 June 2008: extension of indication in the treatment of hypercalcaemia in patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated Describe any specificities (conditional Marketing Authorisations, under exceptional circumstances, RMP or other specific monitoring etc.) List I 2011; H : Systemic hormonal preparations, excl. sex hormones and insulins H05 : Calcium homeostasis H05B : Anti-parathyroid agents HB05BX : Other anti-parathyroid agents HB05BX01 : cinacalcet 02 BACKGROUND Review of the proprietary medicinal products included on the list of medicines refundable by National Health Insurance for a 5 year period by order of 18 May 2006 (Official Gazette of 1 June 2006). Summary of previous opinions: Opinion of 7 September 2005: Inclusion on the National Health Insurance and Hospital Use lists in the following indications: "Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate (see section 5.1 of the SPC). Treatment of hypercalcaemia in patients with parathyroid carcinoma. " Actual Benefit: substantial in both indications. Improvement in Actual Benefit: - in secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy, MIMPARA provides a moderate improvement in actual benefit (IAB level III) in patients who have failed currently available conventional treatments and with PTH > 600 pg/ml. Although MIMPARA cannot be compared with currently available hyperparathyroid treatments, it provides an IAB which is the more plausible in that the patients are at clinical risk (increase of mortality), therefore with a PTH > 600 pg/ml. 1 1 Block G. et al. Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis. J Am Soc Nephrol 15: , HAS - Medical, Economic and Public Health Assessment Division 3/20

4 The patients most likely to benefit from MIMPARA are those with a temporary or permanent contraindication to parathyroidectomy or who are awaiting kidney transplant and who meet the previously cited conditions. - in the treatment of hypercalcaemia in patients with parathyroid carcinoma, MIMPARA provides a substantial improvement in actual benefit (IAB level II) in terms of efficacy in the therapeutic strategy of hypercalcaemia treatment in patients with parathyroid carcinoma in the event of failure of or contraindication to parathyroidectomy. Request for a post-approval study: The Transparency Committee requested the establishment of a follow-up study of patients with end-stage renal disease on maintenance dialysis therapy treated with MIMPARA so as to become familiar with the conditions of use of this proprietary medicinal product and describe the clinical outcome for these patients (particularly in terms of the occurrence of bone disease and cardiovascular risk). For this study, a description of the following in particular was required: - the population treated with MIMPARA: profile of treated patients (age, severity of disorder, levels of PTH, serum calcium and serum phosphate), previous treatments and treatments in progress (drug, surgical), kidney transplant considered. - MIMPARA s methods of use (dosages, treatment duration, concomitant treatments, role in the therapeutic strategy, etc.), - biological patient outcomes (PTH, bone alkaline phosphatase, phosphocalcic product, serum calcium, serum phosphate), - patient outcomes in terms of morbidity and mortality: occurrence of bone diseases (radiological and adynamic osteopathy), cardiovascular risk (and particularly changes in the coronary artery calcium score (spiral CT)) and the adverse effects of this treatment. The duration of the study, which is justified, should be sufficient to be able to answer questions raised. Opinion of 4 February 2009: Inclusion on the list of medicines refundable by National Health Insurance and approved for hospital use in the extension of the indication: "in the treatment of hypercalcaemia in patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated." AB: substantial IAB: moderate (level III) HAS - Medical, Economic and Public Health Assessment Division 4/20

5 03 THERAPEUTIC INDICATIONS "Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate. Treatment of hypercalcaemia in patients with: parathyroid carcinoma primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated. ". 04 DOSAGE See SPC. 05 CLINICALLY RELEVANT COMPARATORS 05.1 Medicinal products Indication for secondary hyperparathyroidism in patients on dialysis There is no clinically relevant comparator in this indication. Indication for hypercalcaemia in patients with parathyroid carcinoma In this indication, the comparators are the following bisphosphonates: NAME (INN) Company OSTEPAM (pamidronic acid) NORDIC PHARMA DISODIUM PAMIDRONATE (pamidronic acid) HOSPIRA, MYLAN, RATIOPHARM ZOMETA (zoledronic acid) NOVARTIS EUROPHARM LTD and generic drugs from MYLAN, FRESENIUS, KABI, HOSPIRA, MEDAC, SANDOZ BONDRONAT 6 mg 2 mg (ibandronic acid) ROCHE CLASTOBAN 300mg/5 ml 800 mg (clodronic acid) BAYER SANTE LYTOS (clodronic acid) RIEMSER PHARMA GMBH PAMINJECT (pamidronic acid) EG LABO Laboratoires EuroGenerics *TC = pharmacotherapeutic category TC* Yes/No NO Indication Treatment of severe hypercalcaemia of malignant origin Hypercalcaemia of malignant origin Treatment of tumour-induced hypercalcaemia (TIH) in adult patients Treatment of tumour-induced hypercalcaemia with or without metastases Initial treatment of severe hypercalcaemia of malignant origin Treatment of malignant hypercalcaemia as an alternative to the injectable form Treatment of malignant hypercalcaemia as an alternative to the injectable form Date of opinion Actual Benefit 18/06/2003 Substantial 15/03/2006 (Ratiopharm) Substantial 06/11/2013 Substantial 21/07/ /07/2005 Insufficient Substantial 21/07/2010 Substantial 21/07/2010 Substantial Hypercalcaemia of malignant origin 06/07/2005 Substantial HAS - Medical, Economic and Public Health Assessment Division 5/20

6 The calcitonin-based proprietary medicinal products indicated in hypercalcaemia of malignant origin are back-up drugs in the initial treatment of severe forms. They are not considered as relevant comparators. Indication for hypercalcaemia in patients with primary hyperparathyroidism There is no clinically relevant comparator in this indication (vitamin D is recommended only if compensating for a deficiency and bisphophonates in the case of bone disease 2 ) Other health technologies Parathyroid carcinoma: Surgery 2 Cazalda-Nocaudie M, Chanson P, Conte-Devoux B et al. Prise en charge de l hyperparathyroïdie primaire asymptomatique, consensus d expert de la SFE-2005-WW.endocrino.net HAS - Medical, Economic and Public Health Assessment Division 6/20

7 06 ANALYSIS OF NEW AVAILABLE DATA The company submitted three randomised studies (EVOLVE, ADVANCE and OPTIMA) and an observational study following the request from the Transparency Committee relating to the treatment of secondary hyperparathyroidism in patients with kidney disease on dialysis. Two meta-analyses of randomised trials studying the effect of cinacalcet in patients on dialysis were identified. 3,4 Only the second was taken into account as the first did not include the EVOLVE study. The company did not submit any new data relating to the treatment of hypercalcaemia secondary to parathyroid carcinoma or primary hyperparathyroidism Randomised studies Efficacy The company provided new clinical efficacy data: a randomised, double-blind, placebo-controlled study (EVOLVE) and two randomised, open-label studies (ADVANCE and OPTIMA). EVOLVE study Method Objective: To evaluate the efficacy of cinacalcet in terms of the reduction of cardiovascular mortality and morbidity in patients with kidney disease on dialysis. Study design: Randomised, controlled, double-blind, placebo-controlled trial (1:1). Randomisation was stratified on the existence of diabetes and the country. Primary efficacy endpoint: The primary efficacy endpoint was the time to death from any cause or to the first non-fatal cardiovascular accident (myocardial infarction, hospitalisation for unstable angina pectoris, heart failure, peripheral vascular accident). Secondary endpoints: Time to: - death from any cause, - death with a cardiovascular cause, - myocardial infarction, fatal or non-fatal, - hospitalisation for unstable angina pectoris, fatal or non-fatal - episode of heart failure, fatal or non-fatal - peripheral vascular accident, fatal or non-fatal - cerebral vascular accident, fatal or non-fatal - fracture - parathyroidectomy Inclusion criteria: - patients aged 18 years or over 3 Zhang Q et al. Effects and safety of calcimimetics in end stage renal disease patients with secondary hyperparathyroidism: a meta-analysis. PLoS One.: 2012: 7 (10) 4 Palmer S et al. Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med. 2013; 10 (4) HAS - Medical, Economic and Public Health Assessment Division 7/20

8 - on haemodialysis 3 times a week for at least 3 months before inclusion - ipth 300 pg/ml, serum calcium 8.4 mg/dl, Ca x P 45 mg 2 /dl 2 Non-inclusion criteria: - health not stabilised according to the investigator - parathyroidectomy during the 12 weeks preceding inclusion or planned in the following 6 months - serious concurrent disease (reducing life expectancy) - cinacalcet treatment in the 3 months prior to the study - hospitalisation in the 12 weeks before inclusion for myocardial infarction, unstable angina pectoris, heart failure, unplanned dialysis, peripheral vascular disease, cerebral vascular accident - seizure in the 12 weeks before randomisation - transplant planned Treatment investigated Duration: - Phase of increase in dose: 20 weeks, with one visit every 2 weeks - Follow-up phase: up to 4 years with one visit every 8 weeks during which time an adjustment to the dose was made if required. Doses: - The possible doses of cinacalcet or placebo were 30, 60, 90, 120, or 180 mg/d. - The daily starting dose was 30 mg/d once. It was increased if the PTH level measured during the previous visit was > 300 pg/ml. It was not increased if the serum calcium level was < 8.0 mg/dl, if the subject presented symptoms of hypocalcaemia, if he/she had reached the highest dose or if he/she presented with an adverse effect preventing an increase in the dose. - The dose was reduced if the PTH level was < 150 pg/ml during the two consecutive visits without any possibility of reducing the dose of vitamin D, in the event of an adverse event requiring a reduction in the dose, if the serum calcium level was < 7.5 mg/dl or if the subject presented symptoms of hypocalcaemia. If a subject receiving the lowest dose presented criteria for a reduction in the dose, the treatment was suspended. It was re-started if the PTH level was 300 pg/ml, with a serum calcium level 7.5 mg/dl and in the absence of any signs of hypocalcaemia or any adverse event making restarting treatment impossible. Associated treatments authorised in the cinacalcet group and in the placebo group: Treatments for secondary hyperparathyroidism and mineral metabolism disorders such as vitamin D or phosphorus binders following the decision of the investigator. Statistical method Overall, 3800 patients were required. The study had to be conducted until the occurrence of 1882 events entering into the composition of the primary endpoint. Kaplan-Meier survival curves were established for the primary efficacy endpoint analysis and compared using the Log-rank test stratified on the existence of diabetes at baseline and the country. Three intermediate analyses were scheduled after the occurrence of 20%, 50% and 75% of the planned number of events making up the primary efficacy endpoint. The multiplicity of the tests was taken into account in the analysis. The secondary endpoints were only to be analysed if the analysis of the primary efficacy endpoint showed any significant difference. An intention-to-treat analysis was carried out. Results A total of 3883 patients were included, of whom 1948 in the cinacalcet group and 1935 in the placebo group. Their main characteristics at baseline are shown in Table 1: HAS - Medical, Economic and Public Health Assessment Division 8/20

9 Table 1: main characteristics of the patients at baseline Cinacalcet (n = 1948) Placebo (n = 1935) Women n (%) Men n (%) 809 (41.5) 1139 (58.5) 769 (39.7) 1166 (60.3) Mean age (years) ± standard deviation 54.8 ± ± 14.2 Previous history of diabetes n (%) 654 (33.6) 648 (33.5) Previous history of parathyroidectomy n (%) 91 (4.7) 87 (4.5) Mean duration of dialysis (months) ± standard 63.5 ± ± 62.2 deviation Previous history of liver transplant n (%) 257 (13.2) 242 (12.5) The mean duration (extent) of treatment was ( ) months in the cinacalet group and ( ) months in the placebo group. Primary efficacy endpoint: The result of the Log-rank test adjusted for the presence of diabetes at baseline and the country did not demonstrate any significant difference for the comparison of the survival curves: p=0.112; According to the Cox model stratified on the presence of diabetes at baseline and the country, the hazard ratio was 0.93 [95% CI: 0.85; 1.02]. Overall, 938 events (48.2% of patients) occurred in the group treated with cinacalcet and 952 (49.2%) in the group receiving the placebo. The annual event rate was 14.0% [95% CI: 13.2; 14.9] in the treated group and 14.8% [95% CI: 13.9; 15.7] in the placebo group. 5, 6, 7 ADVANCE study Method Objective: To compare the effect of cinacalcet combined with a low dose of vitamin D with that of an adjusted dose of vitamin D alone in terms of the progression of vascular calcifications in subjects with chronic kidney disease on dialysis. However, it should be noted that the 2010 KDIGO [Kidney Disease Improving Global Outcomes] guidelines 8 state that a patient who has vascular calcifications should be considered as being at risk of cardiovascular disease. There is no evidence to suggest that the decrease of arterial calcifications can reduce mortality. Study design: Randomised (1:1), controlled, open-label study in two parallel groups. Primary efficacy endpoint: Percentage of the change to the CAC score 9 measured using the Agatston method 10 (based on the surface, density and number of calcified lesions in the coronary arteries) and using the volumetric method, between baseline and Week 52. Measurement of calcifications using the volumetric method was not planned in the initial protocol. 5 Clinical study report. 6 Floege J, Raggi P, Block G A, Urena Torre sp, Csiky B, Naso A et al. Study design and subject baseline characteristics in the ADVANCE study: effects of cinacalcet on vascular calcification in haemodialysis patients. Nephrol dial.transplant. 2010; 25: Raggi P, Chertow G, Urena Torres P, Csiki B, Naso A, Nossuli K et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrik Dial. Transplant 2011; 20: Jean C et Chazot C. L essentiel des nouvelles recommandations des kidney disease: improving global outcome (KDIGO) pour les désodres du métabolisme minéral osseux à l usage du clinicien francophone. Néphrologie et thérapeutique 2010; 6: Coronary Artery Calcium score. 10 Agatston AS, Janowitz WR, Hildner F, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15 : HAS - Medical, Economic and Public Health Assessment Division 9/20

10 Inclusion criteria: - adults on dialysis for at least 3 months - concentration of intact plasma PTH (ipth) > 300 pg/ml or bio intact PTH (bipth) > 160 pg/ml - coronary artery calcium score (CAC) measured using the Agatston method 30 - serum calcium level 8.4 mg/dl Non-inclusion criteria: - prior treatment with cinacalcet - treatment with a phosphate binder which does not contain any calcium, such as sevelamer, lanthanum carbonate, aluminium salts within 30 days before inclusion, - treatment with bisphosphonates, start of treatment or change of dose of a cholesterol lowing agent within 30 days before inclusion, - atrial fibrillation, history of CABG or placement of a stent, cardiac or aortic valve, heart transplant, aortic aneurysm, presence of a pacemaker, - parathyroidectomy dating back less than 3 months or scheduled within 6 months Treatments: Duration: - dose adjustment phase: 20 weeks - follow-up phase: 32 weeks Cinacalcet + vitamin D group: - The starting dose of cinacalcet, 30 mg/d, was increased to 60, 90, 120 or 180 mg/day at 4- week intervals if the ipth was > 300 pg/ml or the bipth > 160 pg/ml or serum calcium 8.0 mg/dl and in the absence of adverse effects. The dose could be decreased if necessary. - Vitamin D: either calcitriol 0.5 µg, alfacalcidol 1 µg, doxercalciferol 1 µg or paricalcitol 2 µg administered IV with each dialysis or oral calcitriol 0.25 µg 1 day/2 or oral alphacalcidol 0.25 µg/day. Subjects receiving lower doses of vitamin D or not receiving them at baseline continued in the same manner. Control group: Vitamin D at the dose prescribed before inclusion, then adjusted if necessary. Statistical method: The calculated number of subjects required to demonstrate a difference of 15% between treatments for the CAC score using the Agatston method, with a power of 80%, an α risk of 5% and a standard deviation of 35%, was 165 per group. The primary efficacy endpoint was analysed using the generalised Cochran-Mantel-Haenszel test, stratified in three classes according to the CAC score at baseline ( 30 to 399, 400 to 999, 1000). No change in the significance threshold is mentioned following the addition of an analysis of the primary efficacy endpoint measured using the second method. Analysis of the results: The efficacy analysis was not carried using the intention-to-treat method. It related to the patients who had a measurement for the CAC score at baseline and at the end of the study, had completed the treatment and had not had any unauthorised medicines for over 2 weeks, i.e. 115 patients in the cinacalcet group and 120 in the control group. HAS - Medical, Economic and Public Health Assessment Division 10/20

11 Results A total of 180 patients were included and 140 patients completed the study in each treatment group. The main characteristics of patients at baseline are shown in Table 2: Table 2: characteristics of the patients at baseline Cinacalcet Control n= (47) 95 (53) n=180 Women n (%) 68 (38) Men n (%) 112 (62) Mean age (years) 61.2 ± ± 12.8 Overall CAC score (median, Q1-Q3) (220.7; ) (202.1; ) The results for the primary efficacy endpoint analysis are given in Table 3: Table 3: percentage of change to the overall CAC score between baseline and Week 52 Overall CAC score (median, Q1-Q3) Agatston method Volumetric method * generalised Cochran-Mantel-Haenszel test Cinacalcet n= (-1.1; 63.1) 22.3 (1.7; 51.6) Control n= (7.6; 81.1) 30.1 (10.3; 178.0) p* ns , 12 OPTIMA study This randomised (2:1), open-label study aimed to compare the efficacy of a treatment including cinacalcet (daily dose: 30, 60, 90, 120, or 180 mg) with that of a conventional treatment (vitamin D and phosphate binder) in the treatment of secondary hyperparathyroidism in patients on dialysis. The primary efficacy endpoint was the proportion of subjects with a mean ipth 300 pg/ml during the efficacy evaluation period (7-week period preceded by a 16-week dose optimisation phase). The ipth concentration was measured every 2 weeks. A total of 368 patients were included in the cinacalcet group and 154 in the group receiving conventional treatment; 76% (n=150) of patients in the cinacalcet group and 82% of patients in the control group completed the efficacy evaluation period. Seventy-one percent of patients included in the cinacalcet group had a mean ipth 300 pg/ml during the efficacy evaluation phase versus 22% in the control group (p < 0.001) Safety/adverse effects EVOLVE study All subjects who received at least one dose of cinacalcet were included in the analysis. In the group treated with cinacalcet, 93.2% of patients presented with adverse events and 90.9% in the placebo group. As the total duration of follow-up was different in the two groups (around 264 additional patient-years in the cinacalcet group), incidences of adverse events were expressed per 100 patient-years: - the most common adverse events in the cinacalcet group and the placebo group were nausea (18.3 versus 9.1% patient-years), vomiting (15.4 versus 8.0%) and diarrhoea (12.0 versus 11.5%), - incidence of hypocalcaemia was 6.0% in the cinacalcet group and in the placebo group, 11 Clinical study report. 12 Messa P, Macàrio F et al. The OPTIMA study: assessing a new cinacalcet (SENSIPAR/MIMPARA) treatment algorithm for secondary hyperparathyroidism. Clin J Am Soc Nephrol 2008; 3: HAS - Medical, Economic and Public Health Assessment Division 11/20

12 - incidence of adverse events possibly attributable to the treatment was 35.3% in the cinacalcet group and 11.3% in the placebo group. The most common were nausea (10.6 versus 2.9%) and vomiting (7.1 versus 1.2%). Overall, 69% of subjects in the cinacalcet group and 70.3% in the placebo group presented with a serious adverse event. The most common were infections (3.1 versus 3.0% patient-years) and pneumonia (3.0 versus 4.9% patient-years). The proportion of deaths in the cinacalcet group was 34.7% and in the placebo group 35.8%. The most common causes of death were infections (1.6 versus 1.3% patient-years), cardiac arrests (1.3 versus 1.3% patient-years), myocardial infarction (1.2 versus 1.2% patient-years). The treatment was discontinued in 21.6% of patients in the cinacalcet group and 19% in the placebo group because of the occurrence of adverse events. The most common events which caused a treatment discontinuation were nausea (1.8 versus 0.4% patient-years), vomiting (1.5 versus 0.2% patient-years) and hyperparathyroidism (0.3 versus 1.1% patient-years). The incidence of hypocalcaemia which caused a treatment discontinuation was 0.3% patient-years in the cinacalcet group and < 0.1 in the placebo group. The incidence of adverse events individualised in the risk management plan for MIMPARA is shown in Table 1. Table 1: incidence of adverse events individualised in the risk management plan Cinacalcet (% patient-years) Identified risks: - hypocalcaemia - seizures/epilepsy - hypotension - worsening heart failure - hypersensitivity (rash, angioedema, urticaria) Potential risks - myocardial ischaemia - ventricular arrhythmia - fracture - acute pancreatitis - hepatic disorders - nervous system disorders Randomised, open-label studies (ADVANCE, OPTIMA) Placebo (% patient-years) In these studies, patients presented with at least one adverse event in 80 to 87% of cases on cinacalcet treatment and in 59 to 87% of cases in the control groups. The most common adverse events in patients on treatment with cinacalcet and in the control groups were nausea (32 i.e. 18% versus 8 i.e. 3%), vomiting (24 i.e. 13% vs 12 i.e. 7%), diarrhoea (17 i.e. 13% vs 14 i.e. 7%). Serious events were reported for 23 to 49% of patients in the cinacalcet groups and 17 to 46% of patients in the control groups. The drop-outs from the trial due to adverse events affected 4 to 6% of patients in the cinacalcet groups and 1 to 2% in the control groups. Deaths affected the same proportion (3 to 7%) of patients in the cinacalcet and control groups; they were not considered as attributable to treatment except in one case treated with cinacalcet for which any relation to the treatment could not be excluded by the investigator. The adverse events attributed to the treatment affected 29 to 39% of patients treated with cinacalcet and 0 to 4% of patients included in the control groups HAS - Medical, Economic and Public Health Assessment Division 12/20

13 Other data related to safety Changes to the SPC: Since 2005, changes to the SPC were carried out in the following sections: Special warnings and precautions for use: - There have been reports of isolated, idiosyncratic cases of hypotension and/or worsening heart failure in patients with impaired cardiac function. For these patients the causal link with cinacalcet was not able to be completely excluded and may be due to the decreases in serum calcium. - Cinacalcet is not indicated for CKD patients not on dialysis. Investigational studies have shown that CKD patients not on dialysis treated with cinacalcet have an increased risk for hypocalcaemia (serum calcium levels < 8.4 mg/dl [2.1 mmol/l]) compared with cinacalcet treated CKD patients on dialysis. This may be due to lower baseline calcium levels and/or the presence of residual kidney function. - Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with cinacalcet (see section 4.8). Caution is advised in patients with risk factors for QT prolongation such as patients with a history of congenital long QT syndrome or patients receiving medicinal products known to cause QT prolongation. Undesirable effects: The following undesirable effects have been identified during post marketing use of MIMPARA. Their frequencies cannot be estimated from available data: - isolated, idiosyncratic cases of hypotension and/or worsening heart failure in patients with impaired cardiac function. - allergic reactions, including angioedema and urticaria. - QT prolongation and ventricular arrhythmia secondary to hypocalcaemia. Letter to prescribers, March 2013: In agreement with the EMA and ANSM [National Medicines and Health Products Safety Agency], AMGEN sent a letter to the prescribers in March 2013 informing them of the suspension of paediatric trials with MIMPARA because of the death of a patient with severe hypocalcaemia. The company issues a reminder of the need for regular monitoring of serum calcium levels in patients so as to prevent the occurrence of hypocalcaemia Post-approval study In its opinion of 07 September 2005, the Transparency Committee requested the establishment of a follow-up study of patients with end-stage renal disease on maintenance dialysis therapy treated with MIMPARA so as to become familiar with the conditions of use of this proprietary medicinal product and describe the clinical patient outcomes (particularly in terms of the occurrence of bone disease and cardiovascular risk). HAS - Medical, Economic and Public Health Assessment Division 13/20

14 For this study, a description of the following in particular was required: - the population treated with MIMPARA: profile of treated patients (age, severity of disorder, levels of PTH, serum calcium and serum phosphate), previous treatments and treatments in progress (drug, surgical), kidney transplant considered, - MIMPARA s conditions of use (dosages, treatment duration, concomitant treatments, role in the therapeutic strategy, etc.), - biological patient outcomes (PTH, bone alkaline phosphatase, phosphocalcic product, serum calcium, serum phosphate), - patient outcomes in terms of morbidity and mortality: occurrence of bone diseases (radiological and adynamic osteopathy), cardiovascular risk (and particularly changes in the coronary artery calcium score (spiral CT) and the adverse effects of this treatment. After a new request at the end of 2006, the company proposed that they respond to the Committee's request by providing the results of two existing observational studies (CinObs and ECHO) and two European trials (EVOLVE and ADVANCE). Partial results of these studies have been provided in support of the application for renewal of inclusion of MIMPARA in At the Committee's request, the complete reports were obtained in February 2012 and January Study design proposed: The retrospective observational CinObs study was carried out in 203 patients reimbursed in the ATU [temporary authorisation for use] system, treated between April 2004 and January 2005, with a data collection 6 months after the first administration of MIMPARA: this study was not included (problem of representativeness of patients included and interpretation of results due to frequent missing data). The European observational study ECHO was carried out between for 187 sites (250 expected), including 44 in France, with the aim of evaluating the use of MIMPARA in 3000 patients on haemodialysis or peritoneal dialysis. Two sections were implemented: the first retrospective section dating back 6 months before the start of treatment with MIMPARA, and a prospective section with, overall, one year of treatment. The patients presented with CKD requiring dialysis. The main objective was to measure the attainment of the National Kidney Foundation Outcome Quality Initiative (K/DOQI)'s objectives by country after use of MIMPARA. The main criteria were the proportion of patients who had achieved the K/DOQI targets for the PTH (parathyroid hormone) and for the calcium phosphorus product (Ca x P), 12 months after being put on MIMPARA. From a study design point of view, the Committee had underlined, during the protocol validation, that this study could provide interesting results on the biological outcomes for patients treated with MIMPARA, but that it would not be possible to satisfactorily record associated treatments and the management strategy, as well as patient outcomes in terms of cardiovascular morbidity and mortality. To document this risk, the company implemented the two clinical trials EVOLVE and ADVANCE. Main results of the ECHO (Evaluation of the Clinical Use of MIMPARA in Haemodialysis and Peritoneal Dialysis Patients, an Observational Study) study A total of 865 patients were included, 1607 (86.2%) of whom completed the study: 1647 (88.3%) were treated for 6 months and 1408 (75.5%) were treated for 12 months with MIMPARA. Moreover, 254 patients (13.6%) dropped out of the study: death (n=100; 5.4%), change in the location of treatment (n=55; 2.9%), withdrawal of consent (n=3; 0.2%) and other reasons (n=90; 4.8%). At 12 months, 453 patients (24.3%) discontinued MIMPARA: because of excessive PTH suppression (n=67; 3.6%), nausea and vomiting (n=49; 2.6%), hypocalcaemia (n=11; 0.6%), other adverse effects of MIMPARA (n=19; 1.0%), parathyroidectomy (n=0; 1.1%), kidney transplant (n=97; 5.2%), non-compliance (n=26; 1.4%), weak response (n=8; 0.4%) and other reasons (n=128; 6.9%). Twelve months after starting treatment with MIMPARA, 18.7% of patients in the total cohort had achieved the K/DOQI targets for the PTH (parathyroid hormone) and for the calcium-phosphorus HAS - Medical, Economic and Public Health Assessment Division 14/20

15 product (Ca x P). The results are quite disparate according to country (without any statistical test being carried out): from 6.4% for patients included in Great Britain Ireland to 22.7% for French patients, the mean for the countries of the EEC being 20.7%. The proportion of patients who presented with a reduction of at least 30% of the PTH at 12 months was 66% for the total cohort and 68.6% for the French patients. The percentage of patients combining the two criteria (attainment of the K/DOQI target or with a reduction of at least 30% of the PTH at 12 months) is 68.2% for the total cohort and 69.6% for the French patients. The proportion of patients who were hospitalised was 25.9% 6 months before start of treatment with MIMPARA (first period) and 26.9% 12 months after (second period). The most common (> 1%) reasons for hospitalisation were the following: infections (6%), peripheral vascular disease (2.2%), cardiac ischaemic disease (2%), infarction (1.1%) and fractures (1%). The frequency of admission to intensive care was 2.1% for 6 months before MIMPARA was started (1st period) and 3% between 6 and 12 months after (2nd period). The frequency of symptomatic fractures was 1.7% during the 1st period and 1.9% during the second period. Finally, the parathyroidectomy rate was 8.4% during the first period and 1.6% during the second period. Other treatments were frequently combined: alfacalcidol (40% co prescription throughout the follow-up), and calcitriol (18%). The most used phosphate binders were calcium or sevelamer in 81.5% to 90.8% of patients at different measurement times. Paricalcitol was the most rarely co-prescribed but its frequency of use increased throughout the follow-up: in 2.7% of patients during the first period, 3.7% at the start of treatment, 5.6% at 6 months and 6.5% at 12 months after the start of treatment. Non-serious adverse effects affected 211 patients (11.3%), most often nausea (85 patients, 4.6%) and vomiting (57 patients, 3.1%). All other events were found in less than 1% of patients. Hypocalcaemia was reported in 11 patients (0.6%) without it leading to hospitalisation. The serious adverse events affected 6 patients (0.3%). The serious adverse events were a gastrointestinal ulcer (2 patients), 1 case of hypercalcaemia with muscle weakness and paraesthesia, 1 case of seizures with pulmonary disease and associated neuralgia, 1 case of angina pectoris and 1 case of hypocalcaemia. Conclusion: The results presented provide no evidence to directly support the representativeness of centres and patients included in this study. However, in terms of biological parameters, the population of the ECHO study seems similar to that of the trials presented during initial registration of MIMPARA. The efficacy results in clinical practice (biological criteria) seem similar to those of the trials. It must be emphasized, however, that these findings are the result of all treatments carried out, not only the action of MIMPARA. However, this study, as expected due to the methodological choices made, provided little evidence on the impact of MIMPARA on morbidity and mortality, particularly in terms of cardiovascular risk Meta-analysis The PALMER 4 meta-analysis studied the effect of cinacalcet in patients on dialysis. A total of 14 randomised trials versus placebo or group not treated with cinacalcet and relating to patients on haemodialysis was included in the analyses, carried out randomly. In most of the analyses, the weight of the EVOLVE study was predominant. HAS - Medical, Economic and Public Health Assessment Division 15/20

16 The main results were: No significant change in the risk of all-cause mortality (14 studies): RR = 0.97 [95% CI: 0.89; 1.05]. Reduced risk: - of parathyroidectomy (5 studies): RR=0.49 [95% CI: 0.40; 1.59], - of hypercalcaemia (limit: 2.55 or 2.63 mmol/l according to the studies; 4 studies): RR=0.23 [95% CI: 0.05; 0.97]; Increased risk: - of hypocalcaemia (limit between 1.88 and 2.10 mmol/l according to the studies; 12 studies): RR=7.38 [95% CI: 5.43; 10.03], - of nausea (12 studies): RR=2.05 [95% CI: 1.54; 2.75], - of vomiting (9 studies): RR=1.95 [95% CI: 1.74; 2.18] Summary & discussion The company submitted three randomised studies: a double-blind, placebo-controlled study (EVOLVE) for which all the patients included were able to receive conventional treatment if necessary and two open-label studies versus vitamin D (ADVANCE) for one, and versus conventional treatment for the other (OPTIMA). In the EVOLVE study (3883 patients included) there was no difference between the groups in terms of the primary efficacy endpoint: time to death from any cause or to first non-fatal cardiovascular accident (myocardial infarction, hospitalisation for unstable angina pectoris, heart failure, peripheral vascular accident). In the ADVANCE study there was no difference between groups in terms of the coronary artery calcium score (CAC) measured using the Agatston method. The analysis concluded that there was a significant difference between groups in terms of the coronary artery calcium score measured using the volumetric method: this endpoint was not considered in the initial protocol or in the statistical analysis plan. In the OPTIMA study, there was a higher proportion of patients with a mean ipth 300 pg/ml in the cinacalcet group than in the group receiving conventional treatment (71% versus 22%, p<0.001). The results of the post-approval study in terms of the efficacy of MIMPARA in clinical practice in terms of biological criteria are similar to those of the trials. It must be emphasized, however, that these findings are the result of all treatments carried out, not only the action of MIMPARA. However, this study provided little evidence on the impact of MIMPARA on morbidity and mortality, particularly in terms of cardiovascular risk. A meta-analysis of randomised studies versus placebo or no treatment with cinacalcet concluded that there was no effect on all cause mortality, a reduced risk of parathyroidectomy and hypercalcaemia, an increased risk of hypocalcaemia, nausea and vomiting. The most common adverse events during the two studies were nausea, vomiting and diarrhoea. The possibility of hypotension and/or worsening heart failure in patients with impaired cardiac function may be due to hypocalcaemia, the non-indication in patients not on dialysis because of a risk of hypocalcaemia and the possibility of allergic reactions including angioedema and urticaria were added to the SPC Prescription data According to IMS data (moving annual total autumn 2013), 12,514 prescriptions have been issued for MIMPARA 30 mg and 3145 prescriptions for MIMPARA 60 mg. The small number of prescriptions is insufficient to allow a qualitative analysis of the data. HAS - Medical, Economic and Public Health Assessment Division 16/20

17 06.6 Therapeutic use Scientific data obtained regarding secondary hyperparathyroidism (HPT) in patients with end-stage renal disease on maintenance dialysis therapy (ESRD), hypercalcaemia in patients with parathyroid carcinoma, hypercalcaemia in patients with primary hyperparathyroidism, for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated and their treatment methods were also considered. 8,13 Since the last assessments by the Committee on 7 September 2005 and 4 February 2009, the role of MIMPARA in the therapeutic strategy has remained unchanged. 13 Goldsmith DJA. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease Mineral and Bone Disorder (CKD MBD) Guidelines: a European Renal Best Practice (ERBP) commentary statement. Nephrol Dial Transplant Advance Access published September 9, 2010, doi: 10:1093/ndt/gfq513. HAS - Medical, Economic and Public Health Assessment Division 17/20

18 07 TRANSPARENCY COMMITTEE CONCLUSIONS In view of all the above information, and following the debate and vote, the Committee s opinion is as follows: 07.1 Actual benefit Treatment of secondary hyperparathyroidism in patients with kidney disease on dialysis Secondary hyperparathyroidism in patients on dialysis is a serious condition which can be life-threatening, either immediately or as a result of complications. MIMPARA is intended as curative or preventive therapy. The efficacy/adverse effects ratio for MIMPARA in this indication is high. There are treatment alternatives. MIMPARA is a second-line medicinal product after failure of other treatments. Public health benefit: Despite its severity, hyperparathyroidism secondary to end-stage renal disease in patients on maintenance dialysis therapy does not carry much weight in terms of public health because of the restricted number of patients affected. As a result, the management of this clinical situation is not a public health need. Given the data available, in particular those of the EVOLVE study, MIMPARA does not have any impact on the morbidity and mortality and quality of life of patients treated. Given its methods of use (ECHO study), MIMPARA does not have any impact on the organisation of care. Consequently, the new data confirm that MIMPARA does not have any impact on public health in this indication. Consequently, the Committee considers that the actual benefit of MIMPARA remains substantial in patients with kidney disease on dialysis. Reduction of hypercalcaemia in patients with parathyroid carcinoma Hypercalcaemia in patients with parathyroid carcinoma is a serious condition which can be life-threatening, either immediately or as a result of complications. MIMPARA is intended as symptomatic treatment. The efficacy/adverse effects ratio for MIMPARA in this indication is high. There are treatment alternatives (bisphosphonates, calcitonin) MIMPARA is a second-line medicinal product in the event of failure or contraindication to surgery. Public health benefit: Despite its severity, hypercalcaemia secondary to parathyroid carcinoma does not carry much weight in terms of public health because of the restricted number of patients affected. As a result, the management of this clinical situation is not a public health need. In the absence of any new data, the impact of MIMPARA on morbidity and mortality, the quality of life of patients treated and its impact on the organisation of care are not quantifiable. Consequently, the new data confirm that MIMPARA does not have any impact on public health in this indication. Consequently, the Committee considers that the actual benefit of MIMPARA remains substantial in the treatment of hypercalcaemia in patients with parathyroid carcinoma. HAS - Medical, Economic and Public Health Assessment Division 18/20

19 Treatment of hypercalcaemia in patients with primary hyperparathyroidism Primary hyperparathyroidism is responsible for serious complications, such as calcium stones, fibrocystic osteitis, calcium pyrophosphate dihydrate, osteoporosis, asthenia, depression, digestive disorders. MIMPARA is intended as curative or symptomatic therapy. The efficacy/adverse effects ratio is high. There are treatment alternatives. Mimpara is a second-line therapy in the event of failure or contraindication to surgery. Public health benefit: Despite its severity, hypercalcaemia secondary to hyperparathyroidism does not carry much weight in terms of public health because of the restricted number of patients affected. As a result, the management of this clinical situation is not a public health need. In the absence of any new data, the impact of MIMPARA on morbidity and mortality, the quality of life of patients treated and its impact on the organisation of care are not quantifiable. Consequently, the new data confirm that MIMPARA does not have any impact on public health in this indication. Consequently, the Committee considers that the actual benefit of MIMPARA remains substantial in the treatment of hypercalcaemia in patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated Transparency Committee recommendations The Committee recommends continued inclusion on the list of medicines refundable by National Health Insurance in the indications in the Marketing Authorisation. Proposed reimbursement rate: 65% Packaging Appropriate for the prescribing conditions as regards the indication, dosage and treatment duration. HAS - Medical, Economic and Public Health Assessment Division 19/20

20 Appendix 1 Comparison of the SPCs MIMPARA (cinacalcet) Serum calcium: Old SPC (29 November 2011) New SPC (15 January 2013) 4.4 Special warnings and precautions for use Serum calcium: MIMPARA treatment should not be initiated in patients with a serum calcium (corrected for albumin) below the lower limit of the normal range. Since cinacalcet lowers serum calcium, patients should be monitored carefully for the occurrence of hypocalcaemia (see section 4.2). In CKD patients receiving dialysis who were administered MIMPARA, 4% of serum calcium values were less than 7.5 mg/dl (1.875 mmol/l). In the event of hypocalcaemia, calcium-containing phosphate binders, vitamin D sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium. If hypocalcaemia persists, the dose of MIMPARA should be reduced or the treatment suspended. Symptoms of hypocalcaemia may be paraesthesia, myalgia, cramping, tetany and seizures. ( ) Post-marketing experience The following undesirable effects have been identified during post marketing use of MIMPARA. Their frequencies cannot be estimated from available data: Post-marketing safety data show isolated, idiosyncratic cases of hypotension and/or worsening heart failure in patients with impaired cardiac function. Allergic reactions, including angioedema and urticaria. MIMPARA treatment should not be initiated in patients with a serum calcium (corrected for albumin) below the lower limit of the normal range. Symptoms of hypocalcaemia may be paraesthesia, myalgia, cramping, tetany and seizures. Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with cinacalcet (see section 4.8). Caution is advised in patients with risk factors for QT prolongation such as patients with known congenital long QT syndrome or patients receiving medicinal products known to cause QT prolongation. Since cinacalcet lowers serum calcium, patients should be monitored carefully for the occurrence of hypocalcaemia (see section 4.2). In CKD patients receiving dialysis who were administered MIMPARA, 4% of serum calcium values were less than 7.5 mg/dl (1.875 mmol/l). In the event of hypocalcaemia, calcium-containing phosphate binders, vitamin D sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium. If hypocalcaemia persists, the dose of MIMPARA should be reduced or the treatment suspended. Symptoms of hypocalcaemia may be paraesthesia, myalgia, cramping, tetany and seizures. ( ) 4.8 Undesirable effects Post-marketing experience The following undesirable effects have been identified during post marketing use of MIMPARA. Their frequencies cannot be estimated from available data: Post-marketing safety data show isolated, idiosyncratic cases of hypotension and/or worsening heart failure in patients with impaired cardiac function. Allergic reactions, including angioedema and urticaria. QT prolongation and ventricular arrhythmia secondary to hypocalcaemia (see section 4.4). HAS - Medical, Economic and Public Health Assessment Division 20/20