TRANSPARENCY COMMITTEE

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE Opinion 1 October 2014, 1 mg/ml, concentrate for solution for infusion B/1 (CIP: ) Applicant: BIOMARIN EUROPE Limited INN ATC code (2014) Reason for the request Elosulfase alfa A16AB12 Inclusion List concerned Hospital use (French Public Health Code L ) Indication concerned " is indicated for the treatment of mucopolysaccharidosis, type IVA (Morquio A Syndrome, MPS IVA) in patients of all ages" HAS - Medical, Economic and Public Health Assessment Division 1/23

2 Actual Benefit Improvement in Actual Benefit Therapeutic use Transparency Committee recommendations Substantial Considering the severity of the disease, the only available palliative treatment alternatives and the modest efficacy of elosulfase alfa on the walking distance, as demonstrated in the short term, the Committee considers that provides a moderate improvement in actual benefit (level III) to patients with Morquio A syndrome (mucopolysaccharidosis type IVA). is the only replacement therapy for Morquio A disease that has demonstrated its efficacy in terms of improvement of the 6-minute walk distance. It should be initiated as first-line treatment and as early as possible, subject to verification of its long-term efficacy. The Committee would like to have follow-up data on the efficacy of elosulfase alfa in the longer term for all patients with Morquio A syndrome treated in France. If the registry provided for in the risk management plan, provided in the context of the Marketing Authorisation, addresses this question, it will not be necessary to set up an ad hoc study. The Committee will re-assess on the basis of these data, within a maximum of 5 years. The Transparency Committee raises the issue of newborn screening for Morquio syndrome which, although very rare, probably requires early initiation of replacement therapy, which would be facilitated by the screening. HAS - Medical, Economic and Public Health Assessment Division 2/23

3 01 ADMINISTRATIVE AND REGULATORY INFORMATION Marketing Authorisation Prescribing and dispensing conditions 28 April 2014 (centralised procedure) Medicine for restricted medical prescription. Orphan medicinal product treatment should be supervised by a physician experienced in the management of patients with MPS IVA or other inherited metabolic diseases. Administration of should be carried out by an appropriately trained healthcare professional with the ability to manage medical emergencies. ATC Classification 2015 A A16 A16A A16AB12 Alimentary tract and metabolism Other alimentary tract and metabolism products Other alimentary tract and metabolism products elosulfase alfa 02 BACKGROUND This is an application for inclusion on the list of medicines approved for hospital use of the proprietary medicinal product, whose active substance is elosulfase alfa, a recombinant form of N-acetylgalactosamine-6-sulfatase (GALNS). Deficiency of this enzyme is the origin of Morquio A syndrome or mucopolysaccharidosis type IVA (MPS IVA). is the only proprietary medicinal product indicated in the treatment of mucopolysaccharidosis type IVA. is designated as an orphan medicinal product. 03 THERAPEUTIC INDICATION " is indicated for the treatment of mucopolysaccharidosis, type IVA (Morquio A Syndrome, MPS IVA) in patients of all ages". 04 DOSAGE " treatment should be supervised by a physician experienced in the management of patients with MPS IVA or other inherited metabolic diseases. Administration of should be carried out by an appropriately trained healthcare professional with the ability to manage medical emergencies. Dosage The recommended dose of elosulfase alfa is 2 mg/kg of body weight administered once a week. The total volume of the infusion should be delivered over approximately 4 hours. Because of the potential for hypersensitivity reactions with elosulfase alfa, patients should receive antihistamines with or without antipyretics 30 to 60 minutes prior to start of infusion (see Special warnings and precautions for use). HAS - Medical, Economic and Public Health Assessment Division 3/23

4 Special populations Elderly patients ( 65 years) The safety and efficacy of in patients older than 65 years has not been established, and no alternative dosage regimen can be recommended in these patients. It is not known whether elderly patients respond differently from younger patients. Paediatric population The posology in the paediatric population is the same as in adults Method of administration For intravenous infusion only. For instructions for dilution of the medicinal product prior to administration, see Special precautions for disposal and other handling. [ ]." 05 THERAPEUTIC NEED 1,2,3 Mucopolysaccharidosis (MPS) type IVA (Morquio A disease) is a rare genetic multi-systemic disease of autosomal recessive lysosomal overload due to a deficit of N-acetylgalactosamine-6- sulfatase (GALNS), an enzyme necessary for the breakdown of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The build-up of KS is responsible for a generalised bone dysplasia, cardiac valve (mitral and/or aortic) disorders, obstructive lung disease, corneal opacification with decreased visual acuity, and hearing disorders. Skeletal abnormalities include, in the severe form, kyphoscoliosis, chest deformities, genu valgum and a short final height associated with ligamentous laxity, and C1-C2 instability. They are responsible, in particular, for pain, spinal cord compression which can cause early cervical myopathy, and the restrictive part of respiratory failure. These complications are treated surgically; for 10% of patients, death occurs following these procedures. Unlike other MPS diseases, patients with Morquio A disease retain normal intelligence. There is significant heterogeneity in progression of the disease, ranging from a severe and rapidly progressive form in which symptoms begin before 1 year of age to a slowly progressive form that can begin after 20 years of age. Onset of clinical symptoms generally occurs around 2 to 3 years of age. Life expectancy is currently 30 years, or even 20 years in severe forms that affect approximately 70% of patients. In moderate forms, life expectancy is longer, and can reach over 60 years. The main causes of death are respiratory failure, which is of multi-factorial origin (obstructive lung disease, cervical myelopathy, chest deformations) and heart failure. Reduction in mobility and endurance is the main cause of reduced quality of life and independence of patients. Conventional treatment is symptomatic and limited to palliative procedures that do not impact disease progression or mortality. 1 Bouzidi H et al. La mucopolysaccharidose IV A (syndrome de Morquio A) : aspects cliniques biologiques et thérapeutiques. Ann Biol Clin 2007; 65: Lavery C et al. Mortality in patients with Morquio Syndrome A. JIMD Rep 2014 Apr Tomatsu S et al. Mucopolysaccharidosis Type IV A (Morquio A disease): clinical review and Current treatment: a special review. Current pharmaceutical biotechnology 2011; 12: HAS - Medical, Economic and Public Health Assessment Division 4/23

5 There was no replacement therapy for this disease. 06 CLINICALLY RELEVANT COMPARATORS is the only proprietary medicinal product indicated in the treatment of mucopolysaccharidosis type IVA (Morquio A syndrome, MPS IVA). Conclusion There is no clinically relevant comparator. 07 INTERNATIONAL INFORMATION ON THE MEDICINAL PRODUCT Marketing Authorisation Country YES (date)/ NO / assessment in Indication and special conditions progress USA Yes, on 14 February 2014 Canada Yes, on 7 July 2014 Switzerland Treatment of Morquio A disease Brazil Assessment in progress Australia Mexico REIMBURSEMENT Country Population YES/NO That of the Marketing Authorisation If not, why not or restricted USA Yes, since 14 February 2014 Treatment of Morquio A disease HAS - Medical, Economic and Public Health Assessment Division 5/23

6 08 ANALYSIS OF AVAILABLE DATA The company has submitted six clinical studies of efficacy and/or safety, including: - an efficacy study (MOR 004) - a follow-up efficacy and safety study of patients in the MOR 004 study (MOR 005) - a safety study (MOR 002) - three studies in progress: a follow-up study of the MOR 002 study (MOR 100), a medium- and long-term safety study in children under 5 years of age (MOR 008) and a study to evaluate the safety of at doses of 2 mg/kg/week and 4 mg/kg/week (MOR 007) Efficacy MOR 004 Study (efficacy study in adults and children) Method: Primary objective of the study Method Study population Inclusion criteria Non-inclusion criteria Treatment groups Course of the study MOR 004 Study To evaluate the efficacy of two dose regimens of compared with placebo on the evolution of endurance of subjects with mucopolysaccharidosis IVA between the start and end of a 24-week treatment. Randomised (1:1:1), double-blind, placebo-controlled study with three parallel groups. The randomisation was stratified based on the results of the 6MWT at inclusion ( 200 and > 200 metres) and on age groups (5-11, 12-18, and 19 years) - subjects 5 years of age, - subjects with Morquio A disease diagnosed based on clinical signs and reduced fibroblast or leukocyte GALNS enzyme activity or genetic testing, - average distance covered in 6MWT 30 and 325 metres - history of haematopoietic stem cell transplant, - prior treatment with, - known allergy to, - surgical procedure in the 3 months prior to inclusion or planned during the study (24 weeks following inclusion), - pregnant or breast-feeding during the study or planning to become pregnant during the study, - use of any investigational medical product or device in the 30 days prior to inclusion or before the planned end of the study, - concomitant pathology, especially symptomatic cervical spine instability, clinically significant spinal cord compression, or severe heart disease that could interfere with participation in the study or patient safety in the opinion of the investigator - Placebo - at a dose of 2 mg/kg/week - at a dose of 2 mg/kg/every 2 weeks Treatment was planned for 24 weeks. - pre-treatment with an antihistamine was administered 30 to 60 minutes before each infusion. Antipyretic treatment could be administered based on the decision of the investigator, - the study product was diluted so that administration lasted around 4 hours, with monitoring before, during and after infusion. HAS - Medical, Economic and Public Health Assessment Division 6/23

7 Associated treatments Pre-treatment with antihistamines was administered 30 to 60 minutes before each infusion, Pre-treatment with anti-h2, montelukast or corticosteroids could be administered to subjects with risk factors such as a history of allergies or adverse events related to infusions, Antipyretic treatments could be administered based on the decision of the investigators Primary efficacy endpoint Secondary endpoints included: Variation in the result of the 6-minute walk test (6MWT) 4 between inclusion and the end of treatment, at the 24th week. Variation between inclusion and the end of treatment in the 3-minute stair climb test (3MSCT) result: number of stairs climbed in 3 minutes. Two tests were done each time (only one test per day): at inclusion, during week 12, in week 24 and in the week following discontinuation of the trial. The test result was the average of the two scores. Urine KS concentration normalised for creatinine level Tertiary endpoint, exploratory Calculation of the number of subjects required Statistical analysis Forced vital capacity Based on a difference of 40 metres for the primary efficacy endpoint between the treatment groups and the placebo group, with a standard deviation of 65 metres, α=5% and β=10%, the number of subjects to be included in the study was 162 (54 patients per group). An analysis of covariance was performed for the primary efficacy endpoint, stratified on age group and on the result of the 6MWT at inclusion ( 200 metres and > 200 metres). Each treatment group was compared with placebo. The active treatment-placebo difference was considered significant if the significance level of the comparison between the two groups was < 0.05, or if this risk for one of the comparisons was < Missing data were replaced by the multiple imputation method. 4 The 6-minute walk test (6MWT) was done according to the recommendations of the American Thoracic Society: patients had to travel the greatest possible distance in 6 minutes. Walking aids were allowed (braces, crutches, canes, walkers), but had to be used for each test in the study. Two tests were done each time (only one test per day): at inclusion, during week 12, in week 24 and in the week following discontinuation of the trial. The test result was the average of the two scores. HAS - Medical, Economic and Public Health Assessment Division 7/23

8 Results Characteristics of the patients on inclusion: Patient characteristics on inclusion were similar between the groups (see Table 1 below): Table 1 Mean age in years (interval) 5-11 years old, n (%) years old, n (%) 19 years old, n (%) 6MWT (m) Mean ± standard deviation Min-max 3MSCT (number of stairs/min) Mean ± standard deviation Min-max Normalised urine KS (µg/mg) Mean ± standard deviation PLACEBO 15.0 (5-57) 30 (50.8%) 15 (25.4%) 14 (23.7%) ± ± mg/kg/2 weeks 15.3 (5-49) 31 (52.5%) 16 (27.1%) 12 (20.3%) ± ± mg/kg/week n= (5-42) 32 (55.2%) 16 (27.6%) 10 (17.2%) ± ± ± ± ± 14.1 Primary efficacy endpoint: Analysis of the variation in the 6-minute walk test (6MWT) between inclusion and W24 was performed on the ITT population (subjects randomised and having received at least one dose of the study treatment). The results are presented in Table 2 below. Table 2: 6MWT results Table 2: 6MWT (m) Week 24 Mean ± standard deviation Min-max Variation between inclusion and W24 Mean ± standard deviation Min-max ANCOVA - Active treatment-placebo difference between the least squares means - 95% CI - p PLACEBO ± mg/kg/2 weeks n= ± mg/kg/week n= ± ± ; ± ; ± ; * n=58* _ [-17.8, 18.9] [4.0, 40.9] *: 1 missing datum replaced; : difference between the least square means; CI: Confidence interval The lengthening increase of the distance walked by the 2 mg/kg/week group was higher than that of the placebo group. There was no difference in this endpoint between the 2 mg/kg/2 weeks group and the placebo group. Secondary endpoints: The results of the 3-minute stair climb test (3MSCT) in the ITT population showed no difference between the 2 mg/kg/week group and the placebo group (see Table 3). HAS - Medical, Economic and Public Health Assessment Division 8/23

9 Table 3: 3MSCT (no. stairs) Week 24 Mean ± standard deviation Min-max Variation between inclusion and W24 Mean ± standard deviation Min-max ANCOVA - Active treatment-placebo difference - 95% CI - p PLACEBO 33.6 ± ± ; 32.4 _ 2 mg/kg/2 weeks n= ± ± ; 45.8 * -0.5 [-3.7, 2.8] mg/kg/week n= ± ± ; 20.5 n=58* 1.1 [-2.1, 4.4] 0.49 *: 1 missing datum replaced; : difference between the least square means; CI: Confidence interval. The difference in forced vital capacity (FVC) of patients in the 2 mg/kg/week group versus that of the placebo group was 10.3% (95% CI [-1.8; 22.4], p=0.09) The urine concentration in urine keratan sulfate (uks) of the treatment groups was decreased compared with that of the placebo group (see Table 4 below) Table 4: uks ANCOVA - Estimated active treatment-placebo difference between the least square means (% of change compared with baseline) - 95% CI - p 2 mg/kg/2 weeks vs Placebo [-38.5, -22.0] < mg/kg/week vs Placebo n= [-49.0, -32.4] < MOR 005 study (extension of MOR 004) This is an efficacy and safety study that includes two phases: a comparative phase of 2 doses of elosulfase alfa (2 mg/kg every week or every 2 weeks), for a maximum of 48 weeks, and a non-comparative phase where all patients received elosulfase alfa at a dose of 2 mg/kg every week for a maximum of 240 weeks. The first phase is completed and the results are presented below. The second phase is in progress. HAS - Medical, Economic and Public Health Assessment Division 9/23

10 Method Primary objective of the study Method Study population Inclusion criteria Non-inclusion criteria Treatment groups Course of the study Study duration Primary efficacy endpoint Secondary endpoints included: MOR 005 study Extension study of the MOR 004 study, the objective of which is to evaluate the long-term efficacy and safety of elosulfase alfa. Comparative study of two doses of elosulfase alfa: 2 mg/kg every week or every 2 weeks for the 1st phase. Patients from the MOR 004 study For the 1st phase: - at a dose of 2 mg/kg/week - at a dose of 2 mg/kg/every 2 weeks For the 2nd phase: - at a dose of 2 mg/kg/week A randomised (1:1), double-blind first phase with two treatment groups. Patients who received active treatment in the MOR 004 study continued the same treatment regimen. Patients in the placebo group were randomised between the two treatment regimens, without stratification based on age or 6MWT results. This part of the study is completed. A second open-label phase includes a single dose regimen of 2 mg/kg/week. This part is in progress. The total planned duration of the study is 240 weeks. The planned duration of the first part was 36 to 48 weeks, i.e. at most 72 weeks of treatment since the start of the MOR 004 study. Variation in the result of the 6-minute walk test (6MWT) between inclusion and the end of treatment, at the 72nd week. 3-minute stair climb test (3MSCT) Urine KS concentrations Results In total, 173 subjects were included in this study out of the 175 who participated in the previous study. Characteristics of the patients on inclusion: Inclusion characteristics in the MOR 004 study are presented in Table 5 below: Table 5 Placebo 1 infusion/2 wk Placebo 1 infusion/wk 1 infusion/2 wk 1 infusion/wk n=56 Mean age (years) 16.7 ± 13.7* 13.5 ± 8.5* 15.3 ± 10.8* 12.8 ± 8.0* 6MWT (m) ± 74.2* ± 64.9* ± 81.2* ± 71.8* 3MSCT (m) 33.1 ± 15.6* 26.9 ± 12.1* 27.1 ± 15.8* 30.1 ± 16.2* Urine KS (µg/mg) 22.7 ± 15.3* 28.5 ± 14.9* 28.6 ± 21.2* 27.2 ± 14.2* *: standard deviation; HAS - Medical, Economic and Public Health Assessment Division 10/23

11 Endpoints: Once the analysis of the results of the MOR 004 study was available, all subjects included in the MOR 005 extension study began the second open-label part of this study (: 2 mg/kg/week) although many had not reached week 48 (week 24 of MOR 005). Therefore, the numbers of this last visit for part 1 are reduced. - The 6MWT results (ITT population) are presented in Table 6 below: 6MWT (m) Mean variation Placebo 1 infusion/2 wk* Placebo 1 infusion/wk* 1 infusion/2 wk Inclusion - W24 n=58 (W0 of MOR 005) 23.8 ± ± ± 40.8 Inclusion W36 n=28 n=28 n=58 (W12 of MOR 005) 31.2 ± ± ± 48.7 Inclusion W48 n=13 n=12 n=26 (W24 of MOR 005) 40.9 ± ± ± infusion/wk n= ± 58.5 n= ± 52.1 n= ± 64.9 *: i.e. 24 weeks on placebo and 24 weeks of treatment with ; : i.e. 48 weeks of treatment with ; : standard deviation - The 3MSCT results in the ITT population are presented in Table 7 below: Mean variation Placebo Placebo 1 infusion/2 wk* 1 infusion/wk* 1 infusion/2 wk Inclusion - W24 n=58 (W0 of MOR 005) 4.7 ± ± ± 10.2 Inclusion W36 n=28 n=28 n=58 (W12 of MOR 005) 6.8 ± ± ± 11.8 Inclusion W48 n=13 n=12 n=26 (W24 of MOR 005) 10.6 ± ± ± infusion/wk n= ± 8.1 n=54 5,9 ± 8,4 n= ± 10.8 *: i.e. 24 weeks on placebo and 24 weeks of treatment with ; : i.e. 48 weeks of treatment with ; : standard deviation - Urine KS concentration The results in the ITT population are presented in Table 8 below: Mean variation µg/mg Placebo 1 infusion/2 wk* Placebo - 1 infusion/wk* 1 infusion/2 wk Inclusion - W24 n=26 n=28 n=57 (W0 of MOR 005) -1.5 ± ± ± 16.3 Inclusion W36 n=27 n=28 n=54 (W12 of MOR 005) -9.0 ± ± ± 17.1 Inclusion W48 n=12 n=12 n=26 (W24 of MOR 005) -6.4 ± ± ± infusion/wk n= ± 9.6 n= ± 9.1 n= ± 10.6 *: i.e. 24 weeks on placebo and 24 weeks of treatment with ; : i.e. 48 weeks of treatment with ; : standard deviation HAS - Medical, Economic and Public Health Assessment Division 11/23

12 8.1.3 MOR 002 study (dose escalation) The objective of this non-comparative study was to study the safety of escalating doses of. Some secondary endpoints explored efficacy. Method: Primary objective of the study Method Study population Inclusion criteria Non-inclusion criteria MOR 002 Study The primary objective was to study tolerance to weekly escalating doses of in patients with MPS IVA. The study of the efficacy was a secondary objective. Open, non-comparative, dose-escalation study - subjects aged 5 to 18 years, - subjects with Morquio A disease diagnosed based on decreased GALNS enzyme activity or genetic testing. - history of haematopoietic stem cell transplant, - known allergy to, - use of any investigational medical product or device in the 30 days prior to inclusion or before the planned end of the study, - concomitant pathology, especially symptomatic cervical spine instability that could interfere with participation in the study or patient safety in the opinion of the investigator. Treatment groups Course of the study Associated treatments Patients received a weekly infusion over three 12-week periods: - week 1 to 12: 0.1 mg/kg/week - week 13 to 24: 1 mg/kg/week - week 25 to 36: 2 mg/kg/week At the end of the 36 weeks, patients who chose to continue the treatment received a dose of 1.0 mg/kg/week for an additional 36 to 48 weeks minutes to 1 hour before each infusion, each patient had to receive pre-treatment with an antihistamine, preferably non-sedating, and an antipyretic; - patients with histories of reaction to the infusion or allergies could receive pre-treatment with a sedating antihistamine, anti-h2, montelukast or corticosteroids. Primary efficacy endpoint Secondary endpoints included: Calculation of the number of subjects required Statistical analysis Tolerance to treatment Endurance measurement: - 6-minute walk test (6MWT), - 3-minute stair climb test (3MSCT), Respiratory function: - Forced vital capacity (FVC) Laboratory endpoints: - Urine GAG: Urine keratan sulfate (uks) Not applicable The study was exploratory. Data are presented in a descriptive manner. HAS - Medical, Economic and Public Health Assessment Division 12/23

13 Results Characteristics of the patients on inclusion: A total of 20 patients were included and participated in the first treatment period. Of these, 18 participated in the subsequent periods including the extension study. Their characteristics on inclusion are presented in Table 9 below: Mean age (years) 8.0 ± 2.89* Min max 4-16 Age classes n (%) 4 to < 8 10 (50.0%) 8 to < 10 6 (30.0%) 10 to 18 4 (20.0%) Use of a wheelchair 16 (80.0%) Use of walking aid 2 (10.0%) *Standard deviation; Efficacy endpoints: The mean distance travelled in the 6MWT at inclusion was 267 ± 137 m (0 to 511 m). The results for each period are presented in Table 10 below. At the Marketing Authorisation dose (2 mg/kg/week), the mean variation in walking distance between inclusion and the 25-36th week of treatment was 13.8 m. Table 10: 6MWT Mean variation at the end of the period compared to inclusion Period and dose Distance in m ± standard deviation week 1 to 12: 0.1 mg/kg/week m ± 85.9 week 13 to 24: 1 mg/kg/week 16.3 m ± 71.7 week 25 to 36: 2 mg/kg/week 13.8 m ± 63.2 *week 36 to 72: 1 mg/kg/week 4.0 m ± 87.2 *It should be noted that four patients underwent knee surgery just before the week 72 visit The mean number of stairs climbed at inclusion was 38.9 ± The results for each period are presented in Table 11 below. At the Marketing Authorisation dose (2 mg/kg/week), the mean variation in stairs climbed in 3 minutes between inclusion and the 25-36th week of treatment was 7.8. Table 11: 3MSCT Mean variation at the end of the period compared to inclusion Period and dose Distance in m ± standard deviation week 1 to 12: 0.1 mg/kg/week 0.3 ± 14.1 week 13 to 24: 1 mg/kg/week 6.1 ± 8.7 week 25 to 36: 2 mg/kg/week 7.8 ± 13.7 *week 36 to 72: 1 mg/kg/week 9.7 ± 13.9 *It should be noted that four patients underwent knee surgery just before the week 72 visit The uks/urine creatinine ratio was 26.4 ± µg/mg at inclusion. The results for each period are presented in Table 12 below. Table 12: uks Period and dose Mean variation at the end of the period compared to inclusion Concentration in µg/mg ± standard deviation week 1 to 12: 0.1 mg/kg/week -7.2 ± 7.3 week 13 to 24: 1 mg/kg/week -9.2 ± 7.6 week 25 to 36: 2 mg/kg/week ± 8.50 week 36 to 72: 1 mg/kg/week ± 7.42 HAS - Medical, Economic and Public Health Assessment Division 13/23

14 08.2 Safety/Adverse effects MOR 002 study All adverse events which occurred during the MOR 002 study are presented in Table 13 below: Adverse events no. patients (%) All adverse events - 20 (100.0) adverse events that occurred during the infusion 17 (85.0) treatment-related adverse events 14 (70.0) adverse events leading to definitive discontinuation of treatment 1 (5.0) serious adverse events 14 (70.0) treatment-related serious adverse events 3 (15.0) treatment-related serious adverse events following discontinuation of treatment 1 (5.0) There were no deaths during the study. The most common adverse events were fever (70%), nausea and cough (65% each), pain in the extremities (55%) and headache (45%). The most common treatment-related events were fever and headache (25%), vomiting and itchy rash (15%). Three patients had serious adverse events possibly or likely related to the study treatment: two patients had hypersensitivity reactions of which one was life-threatening; treatment was discontinued in these two patients. Another patient had a catheter infection. During the study, 7 infusions were stopped in 5 subjects (33.3%) and 18 were interrupted in 4 subjects (26.7%) due to the occurrence of adverse events. Medical treatment was necessary 4 times in 2 subjects (13.3%) MOR 004 study The distribution of adverse events is presented in Table 14 below: Placebo 2 mg/kg/2 wk 2 mg/kg/wk n=58 All AEs (n, %) 57 (96.6%) 59 (100.0%) 56 (96.6%) AEs deemed to be treatment-related 36 (61.0%) 42 (71.2%) 42 (72.4%) Serious AEs 2 (3.4%) 4 (6.8%) 9 (15.5%) Serious AEs deemed to be treatment-related 0 (0.0%) 1 (1.7%) 2 (3.4%) AEs: adverse events There was no discontinuation of treatment following an adverse event or death during the study. HAS - Medical, Economic and Public Health Assessment Division 14/23

15 The most common adverse events are presented in Table 15 below: Placebo 2 mg/kg/2 wk 2 mg/kg/wk n=58 Vomiting 21 (35.6%) 21 (35.6%) 26 (44.8%) Fever 17 (28.8%) 22 (37.3%) 25 (43.1%) Headache 21 (35.6%) 24 (40.7%) 24 (41.4%) Nausea 12 (20.3%) 14 (23.7%) 18 (31.0%) Cough 21 (35.6%) 17 (28.8%) 16 (27.6%) Abdominal pain 5 (8.5%) 8 (13.6%) 14 (24.1%) Diarrhoea 7 (11.9%) 12 (20.3%) 12 (20.7%) Oropharyngeal pain 7 (11.9%) 9 (15.3%) 12 (20.7%) Arthralgia 17 (28.8%) 9 (15.3%) 10 (17.2%) Pharyngitis 9 (15.3%) 12 (20.3%) 10 (17.2%) Upper respiratory infection 9 (15.3%) 10 (16.9%) 10 (17.2%) In the treatment groups, the most common adverse events were headache (40.7% and 41.4%), fever (37.3% and 43.1%), vomiting (35.6% and 44.8%), nausea (23.7% and 31.0%), and abdominal pain (13.6% and 24.1%). The most common adverse events considered to be treatment-related were fever (13.6% in the placebo group, 13.6% in the group treated every 2 weeks, 32.8% in the group treated every week), vomiting (6.8%, 11.9%, 31.0%), headache (15.3%, 13.6%, 25.9%) and nausea (6.8%, 11.9%, 24.1%). Serious adverse events considered to be treatment-related were 1 case of hypersensitivity, 1 case of vomiting and 1 case of anaphylactic reaction, which occurred in the groups treated with. Hypersensitivity reactions occurred more commonly in the treatment groups (11.9% in the placebo group, 27.1% in the group treated every 2 weeks and 20.7% in the group treated every week). There was 1 anaphylactic reaction in a treatment group, 4 cases of urticaria in each treatment group, and 8 cases of hypersensitivity (1, 4 and 3 subjects). Discontinuation or interruption of infusion was necessary for 13 (22.4%) of patients who received a weekly infusion and 9 (15.3%) of patients treated every 2 weeks. Medical treatment was necessary with discontinuation of infusion for 11 patients (19.0%) of the group treated every week and 6 patients (10.2%) of the group treated every 2 weeks, There was no interruption or discontinuation of infusion in the placebo group Studies in progress MOR 100 (extension study of the MOR 002 study) The objective of this open-label extension study was to evaluate the long-term efficacy and safety of a weekly infusion of, 2.0 mg/kg. All subjects who have participated in a clinical trial for, except the MOR 004 study, are eligible. The planned duration of the study was 240 weeks. This study was not completed at the time of the interim analysis: only the 17 patients who completed the MOR 002 study were included and no subject had completed the extension phase. At the time of database freeze, the mean duration of treatment during the MOR 100 study was 82.9 ± 3.5 weeks (74 to 87 weeks). The distribution of adverse events is presented in Table 16 below: HAS - Medical, Economic and Public Health Assessment Division 15/23

16 Adverse events no. patients (%) All AEs 17 (100.0%) Treatment-related AEs 14 (82.4%) AEs leading to definitive discontinuation of treatment 0 SAEs 9 (52.9%) Treatment-related SAEs 5 (29.4%) Treatment-related SAEs following discontinuation of treatment 0 AEs: adverse events; SAEs: serious adverse events There was no death during the study nor adverse event leading to a discontinuation of treatment. The most common adverse events ( 50% of subjects) were vomiting (70.6%), fever (58.8%), cough, pharyngitis and headache (52,9% each). The most common treatment-related adverse events were increase in blood levels of IgE (29.4%), fever (23.5%) and fatigue (17.6%). It should be noted that the IgE level was not measured in the MOR 002 study. The most common serious adverse events, which involved two subjects each (11.8%), were fever and an infusion site reaction. These adverse events were consistent with a hypersensitivity reaction. A discontinuation of the infusion with medical treatment was necessary for one subject. MOR 005 (MOR 004 extension study) Only the results for part 1 are presented. Patients included in part 2 had been treated for only an average of 5 weeks at the time of analysis of the safety results. The distribution of adverse events is presented in Table 17 below: Placebo 1 infusion/2 wk* Placebo 1 infusion/wk* 1 infusion/2 wk 1 infusion/wk n=56 All AEs - n (%) 29 (100.0%) 24 (82.8%) 56 (94.9%) 49 (87.5%) Treatment-related AEs - n (%) 18 (62.1%) 15 (51.7%) 22 (37.3%) 29 (51.8%) SAEs - n (%) 8 (27.6%) 7 (24.1%) 13 (22.0%) 7 (12.5%) Treatment-related SAEs - n (%) 1 (3.4%) *: i.e. 24 weeks on placebo and 24 weeks of treatment with ; : i.e. 48 weeks of treatment with ; : standard deviation; AEs: adverse events; SAEs: serious adverse events No adverse event led to discontinuation of treatment. There were no deaths during the study. The most common adverse events are presented in Table 18 below: Placebo Placebo Adverse events 1 infusion/2 wk* 1 infusion/wk* no. patients (%) 1 infusion/2 wk 1 infusion/wk n=56 Fever 11 (37.9%) 8 (27.6%) 11 (18.6%) 20 (35.7%) Headache 10 (34.5%) 9 (31.0%) 21 (35.6%) 19 (33.9%) Vomiting 12 (41.4%) 7 (24.1%) 10 (16.9%) 18 (32.1%) Pain in the extremities 4 (13.8%) 1 (3.4%) 6 (10.2%) 16 (28.6%) Arthralgia 9 (31.0%) 3 (10.3%) 10 (16.9%) 12 (21.4%) Nausea 6 (20.7%) 7 (24.1%) 8 (13.6%) 12 (21.4%) Upper respiratory 6 (20.7%) 5 (17.2%) 12 (20.3%) 12 (21.4%) infection Cough 7 (24.1%) 4 (13.8%) 10 (16.9%) 8 (14.3%) Diarrhoea 5 (17.2%) 5 (17.2%) 10 (16.9%) 7 (12.5%) The most common adverse events were vomiting (41.4 to 16.9% according to the group), fever (37.9 to 18.6%), headache (35.6 to 31.0%), nausea (24.1 to 13.6%), arthralgia (31.0 to 10.3%), and upper respiratory infections (21.4 to 17.2%). HAS - Medical, Economic and Public Health Assessment Division 16/23

17 The most common adverse events considered to be treatment-related were fever (17.9 to 1.7%), nausea (17.2 to 5.1%), vomiting (16.1 to 6.8%), and headache (13.8 to 8.5%). Hypersensitivity reactions were reported in 31.0 to 3.4% of subjects according to the group. The most common of these adverse events was urticaria (17.2 to 0%). All patients who had a hypersensitivity-type adverse event were able to continue the infusions. Discontinuations or interruptions of infusions due to adverse events are presented in Table 19 below: no. patients (%) Placebo 1 infusion/2 wk* Placebo - 1 infusion/wk* 1 infusion/2 wk 1 infusion/wk n=56 Discontinuation of infusion 11 (37.9%) 8 (27.6%) 13 (22.0%) 12 (21.4%) Interruption of infusion 4 (13.8%) 1 (3.4%) 2 (3.4%) 8 (14.3%) Discontinuation or interruption requiring medical treatment* 8 (27.6%) 3 (10.3%) 5 (8.5%) 8 (14.3%) *: intravenous antihistamine, corticosteroid or filling liquid, or oxygen. MOR 007 Study objectives: - The primary objective was to evaluate the medium- and long-term safety of infusions in children under 5 years of age with Morquio A disease. Study design: - open-label study Inclusion criteria: - children under 5 years of age with Morquio A disease Non-inclusion criteria: - history of haematopoietic stem cell transplant, - having already been treated by Primary efficacy endpoint: - Tolerance to treatment Treatment investigated: - 2 mg/kg/week over 52 weeks then 156-week extension phase with the same treatment Associated treatments: - Due to the possibility of hypersensitivity reactions, pre-treatment with antihistamines should be administered 30 to 60 minutes before each infusion, along with antipyretics on the decision of the investigator. The investigator may decide to discontinue pre-treatment with antihistamines for subjects who had no reaction to the infusions during the first 26 weeks. The study was exploratory. Analysis of the results is descriptive. The number of subjects to be included was assessed at 15. HAS - Medical, Economic and Public Health Assessment Division 17/23

18 Results All subjects were included. None had completed the first part of the study at the time of the interim analysis. The mean duration of treatment was 24.8 ± 9.12 weeks (8 to 44 weeks). The distribution of adverse events is presented in Table 20 below: Adverse events no. patients (%) All AEs 15 (100.0%) Treatment-related AEs 11 (73.3%) SAEs 3 (20.0%) Treatment-related SAEs 1 (6.7%) No adverse event led to discontinuation of treatment. There were no deaths during the study. The most common adverse events (reported in > 30% of patients) were vomiting (n=12; 80.0%), fever (n=11; 73.3%), cough (n=8; 53.3%), and nasal congestion (n=5; 33.3%) The most common treatment-related adverse events were vomiting (n=5; 33.3%), fever (n=4; 26.7%), abdominal pain (n=3; 20.0%), upper abdominal pain (n=3; 20.0%) One serious adverse event (immune system abnormality) was regarded as connected with the treatment. Hypersensitivity-type adverse events were reported in 4 patients (26.7%): urticaria in 2 patients (13.3%), hypersensitivity in 2 patients (13.3%) and wheezing in 1 patient (6.7%). Interruptions of infusions were necessary in 5 patients (33.3%) and discontinuations in 4 patients (26.7%). Medical treatment was necessary 4 times in 2 patients (13.3%). There was no definitive discontinuation of treatment. MOR 008 Study objectives: - The primary objective was to evaluate the safety of at doses of 2 mg/kg/week and 4 mg/kg/week Study design: - Double-blind study, randomised 2:1 in a first group of 15 patients and 1:1 in a second group of 10 patients Inclusion criteria: - Patients at least 7 years of age and able to walk at least 200 m in the 6MWT. Primary efficacy endpoint: - Tolerance to treatment Treatment investigated: - 2 mg/kg/week and 4 mg/kg/week over 27 weeks followed by a 130-week extension study. Associated treatments: - Antihistamine treatment is administered 30 min to 1 hr before each infusion. Antipyretic treatment can also be administered based on the decision of the investigator. Descriptive analysis Results None of the 25 subjects had completed the first phase of treatment at the time of analysis of data. Only the results of the group treated with 2 mg/kg/week (dosage recommended by the Marketing Authorisation) were taken into account. HAS - Medical, Economic and Public Health Assessment Division 18/23

19 At the time of this interim analysis, the mean duration of treatment was 11.7 weeks in the group treated with 2 mg/kg/week. Adverse events were observed in 14 patients (93.3%), 13 (86.7%) of which were considered to be treatment-related. There were no serious adverse events, no events that led to discontinuation of treatment, or deaths. The most common adverse events were headaches (73.3%) and fever (33.3%) The most common adverse events considered to be treatment-related were headache and fever (33.3% each) and vomiting (26.7%). Three patients (20.0%) reported a hypersensitivity-type adverse event: 1 peripheral oedema, 1 urticaria and 1 wheezing. There was no interruption of infusion. Discontinuation of infusion was necessary in 6 cases (40% of patients), with medical treatment needed in 3 cases (20%). There was no discontinuation of treatment Temporary authorisation for use by a cohort has been the subject of a temporary authorisation for use by a named patient [ATU nominative in French] since September 2013; one patient was treated. It has also been the subject of a temporary authorisation for use by a cohort since December 2013; in total, 12 patients were treated, including the patient initially treated under the temporary authorisation for use by a named patient [ATU nominative in French]. The first periodic summary report for the temporary authorisation for use by a cohort covers the period from 14 November 2013 to 14 February 2014: - during this period, 9 patients were included in the cohort, of which 3 began treatment at a dose of 2 mg/kg/week. - the median age of the 9 patients included was 6.1 years. - there was no death or discontinuation of treatment - one episode of fever considered to be serious (requiring hospitalisation) was reported Summary & discussion Primary efficacy data: The efficacy data for in Morquio A disease (MPS IVA) are primarily based on a randomised, placebo-controlled study (MOR 004) testing two doses including the dose chosen for the Marketing Authorisation: 2 mg/kg/week in patients aged 5 years or older in 176 patients (59, 59, 58 patients in the placebo, 2 mg/kg/2 wk and 2 mg/kg/wk groups, respectively). At inclusion, the patients had a 6-minute walk test (6MWT) distance of about 200 m. After 24 weeks of treatment at the dose of 2 mg/kg/week, the 6MWT improved by 22.5 m ([ ], p=0.017) compared with placebo. This should be compared with the rate of decrease of this distance without treatment, which is about 5 m per year. However, there is no established correlation to date between the reduction in decrease of this distance and the long-term progression of the disease. Efficacy results related to the stair climb test are not different between the groups. The decrease in urine keratan sulfate is more significant in the treatment groups than in the placebo group. For exploratory purposes, the forced vital capacity data show no difference between the 2 mg/kg/week and placebo groups. In the first phase of a follow-up study (MOR 005 study) of patients from the MOR 004 study, the variation in 6MWT between inclusion in the MOR 004 study and the 48th week was 33.4 ± 64.9 m HAS - Medical, Economic and Public Health Assessment Division 19/23

20 for patients who received elosulfase alfa from the start of the study and 15.0 ± 83.8 m for those who had previously received placebo. In a dose study (MOR 002) whose primary objective was to study the safety of elosulfase alfa, the 6MWT (secondary endpoint) improved from 13.8 m ± 63.2 between weeks 25 and 36 in the 2 mg/kg/week group. There are no longer-term efficacy data. Primary safety data: The most common adverse events considered to be treatment-related were fever, headache, and vomiting. In the study versus placebo, hypersensitivity reactions (urticaria, wheezing, anaphylactic reaction) were more common in the groups treated with (27.1% and 20.7%) than in the placebo group (11.9%). Hypersensitivity reactions involved 3.4 to 31% of patients according to the study and treatment group, despite systematic pre-treatment with antihistamines 30 to 60 minutes prior to infusion. Interruption (with subsequent resumption) or discontinuation of the infusion due to an adverse event was necessary in 15.3 to 40% of cases according to the study and group. Medical treatment (intravenous antihistamine, corticosteroid or filling liquid, or oxygen) was necessary for 8.5 to 27.6% of patients. Definitive discontinuation of treatment was necessary for one patient following an anaphylactic reaction. Discussion: (elosulfase alfa) is the only enzyme replacement therapy currently available for treatment of MPS IVA. The efficacy of this proprietary medicinal product has been assessed only on the 6-minute walk test in short-term studies. There is to date no clinical data showing a benefit in terms of clinical manifestations of the disease and long-term prognosis. Considering that data on the long-term efficacy and safety of must be completed, the EMA requested the establishment by the company of a registry for Morquio A disease (see paragraph 08.4). This registry may address questions on the long-term efficacy of. HAS - Medical, Economic and Public Health Assessment Division 20/23

21 08.4 Planned studies Risk management plan The EMA 5,6 requested that the company establish a Morquio A disease registry to study the long-term safety and efficacy of (elosulfase alfa): - The number of subjects included in studies is limited and rare adverse effects may not have been detected, in particular those related to a prolonged exposure to treatment, with a long latency of onset or related to a cumulative effect. - Given the potentially life-long use of elosulfase alfa therapy and the time needed to observe differences in clinically relevant outcomes, additional long-term efficacy data are required (e.g. increase in the time to dependency on wheelchair or before requiring respiratory support, decrease in need for orthopaedic surgery, and improvement in other parameters that impact the quality of life and length of life). The final report should be presented in March THERAPEUTIC USE Current treatment for Morquio A disease is symptomatic and limited to palliative procedures that do not modify the natural progression of the disease and that may, in certain cases, have a negative impact on mortality. Enzyme replacement therapy allows correction of the enzyme deficiency responsible for the disease and may modify the morbidity and mortality of patients. is the only treatment intended as replacement therapy for Morquio A disease that has demonstrated its efficacy in terms of improvement of the 6-minute walk distance. It should be initiated as first-line treatment and as early as possible, subject to verification of its long-term efficacy. 5 Public_assessment_report/human/ /WC pdf 6 plan_summary/human / /WC pdf HAS - Medical, Economic and Public Health Assessment Division 21/23

22 010 TRANSPARENCY COMMITTEE CONCLUSIONS In view of all the above information, and following the debate and vote, the Committee s opinion is as follows: Actual benefit MORQUIO A disease is a rare genetic multi-system multisystemic disease of autosomal recessive lysosomal overload due to a deficit of N-acetylgalactosamine-6-sulfatase (GALNS), an enzyme necessary for the breakdown of keratan sulfate (KS). The build-up of KS is responsible for generalised bone dysplasia, cardiac valve (mitral and/or aortic) disorders, and obstructive lung disease. Skeletal abnormalities include kyphoscoliosis, chest deformities, genu valgum and a short final height associated with ligamentous laxity. They are responsible, in particular, for pain, spinal cord compression which can cause early cervical myopathy, and risks of respiratory paralysis. They often require surgical treatment. There is significant heterogeneity in progression of the disease. The lifespan is reduced to 30 years, or 20 years in severe forms that affect approximately 70% of patients. In moderate forms, the life expectancy is longer, and can reach over 60 years. The main causes of death are respiratory failure of multi-factorial origin (obstructive lung disease, cervical myelopathy, chest deformations) and heart failure. This proprietary medicinal product is intended as replacement therapy. The efficacy/adverse effects ratio is high There are no treatment alternatives. This proprietary medicinal product is a first-line therapy. Public health benefit Mucopolysaccharidosis type IVA is a serious disease that constitutes a low public health burden because of its rarity (orphan disease). Improving the management of rare diseases is a public health need which is an established priority (Public Health Law 2004, Plan for Rare Diseases). The available data from clinical trials, in particular clinical improvement in terms of distance walked, and laboratory tests, observed at 24 weeks do not, however, allow the impact of this proprietary medicinal product to be quantified in terms of morbidity and quality of life compared with the usual care for bones and joint, heart, and lung disorders. Moreover, there is no evidence to predict any impact on the organisation of care. Therefore, it is not expected that the proprietary medicinal product will benefit public health. Consequently, the Committee considers that the actual benefit of is substantial in the Marketing Authorisation indication. The Committee recommends inclusion on the list of medicines approved for use by hospital use in the indication " is indicated for the treatment of mucopolysaccharidosis, type IVA (Morquio A Syndrome, MPS IVA) in patients of all ages" and at the dosages in the Marketing Authorisation. HAS - Medical, Economic and Public Health Assessment Division 22/23

23 010.2 Improvement in actual benefit (IAB) Considering the severity of the disease, the only available palliative treatment alternatives and the modest efficacy of elosulfase alfa on the walking distance, as demonstrated in the short term, the Committee considers that provides a moderate improvement in actual benefit (level III) to patients with Morquio A syndrome (mucopolysaccharidosis type IVA) Target population According to the Orphanet website, the prevalence of this disease is 1 to 9 per 1,000, According to INSEE estimates of the French population 1 to 60 years of age in 2014 (49,931,093 people), this would correspond to a target population of 50 to 450 people. According to experts, 80 to 100 patients with Morquio A disease have been diagnosed in France. Estimate/conclusion The target population would therefore be between 80 and 100 patients. 011 TRANSPARENCY COMMITTEE RECOMMENDATIONS Packaging Appropriate for the prescribing conditions as regards indication, dosage and treatment duration. Request for data The Committee would like to have follow-up data on the efficacy of elosulfase alfa in the longer term for all patients with Morquio A syndrome treated in France. If the registry provided for in the risk management plan, provided in the context of the Marketing Authorisation, addresses this question, it will not be necessary to set up an ad hoc study. The Committee will re-assess on the basis of these data, within a maximum of 5 years. The Transparency Committee raises the issue of newborn screening for Morquio syndrome which, although very rare, probably requires early initiation of replacement therapy, which would be facilitated by the screening. 7 (consulted on 17/07/2014) HAS - Medical, Economic and Public Health Assessment Division 23/23