Opinion 7 May 2014 TECFIDERA 120 mg, gastro-resistant hard ... · 20/06/2012 Substantial IAB V in treatment Yes BETAFERON (IFN beta-1b) BAYER SANTE SC 1 day/2 • RRMS • Patients

HAS - Medical, Economic and Public Health Assessmen t Division 1/24

The legally binding text is the original French ver sion

TRANSPARENCY COMMITTEE Opinion

7 May 2014

TECFIDERA 120 mg, gastro-resistant hard capsule B/14 (CIP: 34009 274 978 8 9)

TECFIDERA 240 mg, gastro-resistant hard capsule B/56 (CIP: 34009 274 979 4 0)

Applicant: BIOGEN IDEC FRANCE

INN Dimethyl fumarate

ATC code N07XX09 (other nervous system drugs)

Reason for the request

Inclusion

Lists concerned National Health Insurance (French Social Security Code L.162-17) Hospital use (French Public Health Code L.5123-2)

Indication concerned "TECFIDERA is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis."


Actual Benefit Substantial.

Improvement in Actual Benefit

In the absence of a superiority study versus an active treatment, TECFIDERA does not provide an improvement in actual benefit ( Level V, non-existent) in the treatment of relapsing remitting multiple scler osis. The results of the network meta-analysis showing, t hrough an indirect comparison, a reduction in the annualised relapse r ate with TECFIDERA 240 mg x 2/day compared with interferon beta, glati ramer acetate and teriflunomide can not be considered as sufficient t o draw any conclusions concerning the superior efficacy of TECFIDERA at a dose of 240 mg x 2/day compared with these treatments. The Transparency Committee recognises the benefit o f the availability of an additional oral proprietary medicinal product indi cated as disease modifying therapy in relapsing remitting multiple sclerosis.


01 ADMINISTRATIVE AND REGULATORY INFORMATION

Marketing Authorisation (centralised procedure)

30/01/2014

Prescribing and dispensing conditions/special status

List I Medicine requiring special monitoring during treatment. Prescription restricted to NEUROLOGY specialists and departments

ATC Classification

N Nervous system N07 Other nervous system drugs N07XX Other nervous system drugs N07XX09 dimethyl fumarate

02 BACKGROUND

This is a request for the inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use of TECFIDERA (dimethyl fumarate), a new orally administered medicinal product indicated as disease modifying therapy for adult patients with relapsing remitting multiple sclerosis.

03 THERAPEUTIC INDICATION

"TECFIDERA is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis."

04 DOSAGE

"The starting dose is 120 mg twice a day. After 7 days, the dose is increased to the recommended dose of 240 mg twice a day. Temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and gastrointestinal adverse reactions. Within 1 month, the recommended dose of 240 mg twice a day should be resumed. TECFIDERA should be taken with food. For those patients who may experience flushing or gastrointestinal adverse reactions, taking TECFIDERA with food may improve tolerability." Please refer to the SPC for more detailed information.


05 THERAPEUTIC NEED

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system. It is a progressive, incapacitating neurological condition that is the primary cause of non-traumatic disability in young adults in France.1 Its general progress and prognosis are heterogeneous and not considered very predictable.2 Within the progressive forms of MS, we can distinguish: - Relapsing-remitting forms (RRMS), , which occur the most and are characterised by the

presence of relapses without any progression in the disability observed between relapses; - So-called secondary progressive multiple sclerosis (SPMS), secondary to the

relapsing-remitting forms and characterised by a sustained build-up of disability, completely independent of any relapses;

- Primary progressive multiple sclerosis (PPMS) characterised by symptoms which gradually get worse following their onset with no remission, completely independent of any relapses.

The long-term treatment for RRMS is based on first-line interferon beta (interferon beta-1a and 1b) and glatiramer acetate. The aim of these treatments is to reduce the frequency of relapses and progression of disability in the short-term. Currently, it has not been demonstrated that these products alter the progression of disability in the long-term.3 Natalizumab (TYSABRI) and fingolimod (GILENYA) have Marketing Authorisation indications that are restricted to highly active forms of RRMS.4

1 C. Confavreux et S. Vukusic. "L'évolution naturelle de la sclérose en plaques" Rev. Prat 2006; 56:1313-20. 2 Moreau T. Vie quotidienne et sclérose en plaques. Rev Neurol (Paris) 2001; 157(8-9): 1157-62. 3 HAS. Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis. July 2010. www.has-sante.fr. 4 Higlhy active forms of RRMS correspond to the following disease groups:

- patients with high disease activity despite treatment with interferon beta, which is complete and well conducted, usually lasting at least one year. The patients must have presented with at least one relapse during the previous year whilst under treatment and must present with at least nine T2 hyperintense lesions shown on a cerebral MRI or at least one Gd-enhancing lesion. A "non-responder" may also be defined as a patient for whom the level of relapses has not changed or has increased compared with the previous year or who continues to have severe relapses, - patients with rapidly evolving severe RRMS, defined by two or more disabling relapses within one year combined with one or more Gd-enhancing lesion(s) shown on the cerebral MRI or a significant increase in the T2 lesion load compared with a recent previous MRI scan.


06 CLINICALLY RELEVANT COMPARATORS

06.1 Medicinal products

The comparators of TECFIDERA are medicinal products indicated as disease modifying therapies in RRMS. First-line treatments are interferon beta (AVONEX, REBIF, BETAFERON, EXTAVIA) and glatiramer acetate (COPAXONE). They are administered subcutaneously or intramuscularly at varied rhythms (1 to 7 times a week). Natalizumab (TYSABRI) and fingolimod (GILENYA) have an indication restricted to highly active forms of RRMS.4 Another orally administered proprietary medicinal product, teriflunomide (AUBAGIO) obtained Marketing Authorisation in the treatment of RRMS, however it is not yet marketed in France. Table 1. List of proprietary medicinal products ind icated for the treatment of MS.

Proprietary medicinal product (INN) COMPANY

Admin. Indications* Date of TC opinion AB$ IAB$ Reimbur

sement

AVONEX (IFN beta-1a) BIOGEN IDEC

IM 1/week

• RRMS • Patients with a single

demyelinating event at high risk of MS.

02/06/2010 Substantial IAB III in treatment

Yes

REBIF (IFN beta-1a) MERCK SERONO

SC 3/week

• RRMS 02/06/2010 Substantial IAB III in treatment Yes • Patients with a single


20/06/2012 Substantial IAB V in treatment Yes

BETAFERON (IFN beta-1b) BAYER SANTE

SC 1 day/2

• RRMS • Patients with a single


• Secondary progressive MS

02/06/2010 Substantial IAB III in treatment Yes

EXTAVIA (IFN beta-1b) NOVARTIS PHARMA

SC 1 day/2

21/07/2010 Substantial IAB V compared with BETAFERON

Yes

COPAXONE (glatiramer acetate) TEVA PHARMA

SC 1/day

• RRMS 02/06/2010 Substantial IAB III in treatment Yes • Patients with a single


06/04/2011 Substantial IAB V in treatment Yes

AUBAGIO (teriflunomide) GENZYME

Oral • RRMS 05/03/2014 Substantial IAB V in treatment In progress

TYSABRI (natalizumab) BIOGEN IDEC

IV infusion 1/month

• Patients with a highly active form of RRMS despite interferon beta treatment.

• Rapidly evolving severe RRMS

29/02/2012 Substantial in the aggressive forms of RRMS

IAB III in the treatment of patients with aggressive RRMS§

Yes

GILENYA (fingolimod) NOVARTIS

Oral 20/07/2011 Substantial IAB IV in treatment Yes

* refer to the SPC of the proprietary medicinal products for the detailed wording of the indications. $ refer to the Transparency Committee Opinion for the full wording of the AB and the IAB. § defined by the occurrence of two or more disabling relapses within one year, and with one or more Gadolinium-enhancing lesion(s) shown on the cerebral MRI or a significant increase in the T2 lesion load compared with a recent previous MRI scan.


�� Conclusion The comparators of TECFIDERA are medicinal products indicated as disease modifying therapies in RRMS.


07 ANALYSIS OF AVAILABLE DATA

07.1 Efficacy

The dossier submitted by the company is based on the following studies: - Two phase III, randomised, double-blind, placebo-controlled superiority studies, DEFINE and

CONFIRM that evaluated the efficacy of dimethyl fumarate over two years in patients with RRMS; the CONFIRM study included an active control arm, treated with glatiramer acetate;

- The pooled analysis of the results of the DEFINE and CONFIRM studies; - The ENDORSE study, the aim of which was to evaluate the long-term safety of dimethyl

fumarate in patients who participated in the DEFINE and CONFIRM studies (this study is in progress);

- A network meta-analysis in which the efficacy and the safety of dimethyl fumarate was compared with other RRMS treatments;

- A phase II dose research study that evaluated the efficacy of dimethyl fumarate (120 mg x 1/day, 120 mg x 3/day and 240 mg x 3/day) versus placebo on MRI parameters in patients with recurrent MS over 24 weeks. The results from this phase II study will not be included here.

7.1.1 DEFINE Study

7.1.1.1 Study design

The DEFINE study is a multi-centric, randomised, double-blind, placebo-controlled superiority study with the aim of evaluating the efficacy and the safety of dimethyl fumarate at doses of 240 mg x 2 and 3/day in patients with RRMS. The primary objective was to demonstrate the efficacy of dimethyl fumarate in reducing the proportion of patients with relapses during the two-year study period. The inclusion criteria were as follows: - To be between 18 and 55 years old; - A confirmed RRMS diagnosis, defined according to the McDonald criteria with a EDSS score

≤ 5;5 - To have presented with at least one relapse in the year prior to inclusion or to have gadolinium

enhancing cerebral lesions in the six weeks prior to inclusion; - To not have been treated with corticosteroids in the four weeks before randomisation, or by

glatiramer acetate or an interferon in the three months prior to inclusion. Patients were randomised to three groups (1:1:1 ratio): - Dimethyl fumarate 240 mg x 2/day; - Dimethyl fumarate 240 mg x 3/day; - Placebo. Treatment was started with the administration of a dose of 120 mg x 2 or 3/day for one week, changing to a dose of 240 mg x 2 or 3/day from Day 8. The treatment lasted 96 weeks.

5 The EDSS (Expended disability status scale) enables the severity of disability to be assessed. The neurological examination is divided into eight functional areas (FA). A severity score increasing from 0 to 6 or 7 is attributed to each FA (four major: pyramidal function, cerebellar function, sensitivity function and brain stem function; four minor: bowel and bladder, vision, mental and others). The overall EDSS score ranges from 0 (normal neurological examination) to 10 (death). The overall score of the scale is measured on a 20-point scale (0 to 10 by half-points). Up to level 3.5, the score obtained in each FA and the number of FS achieved automatically determines the EDSS score. From 4 to 7, the definition of each level is also indicated by inability to walk (ability to walk without stopping, need for assistance). A score of 5.5 is " without ambulatory aid or rest for about 100 metres: disability severe enough to preclude full daily activities".


The primary efficacy endpoint was the percentage of patients with relapses (Kaplan-Meier analysis). Relapses were diagnosed by the examining neurologist, treated by the treating neurologist and confirmed by a neurological independent review board. The principal secondary endpoints were: - The annualised relapse rate; - Disability progression, defined by an increase in EDSS score of at least 1 point compared with

baseline and maintained over 12 weeks for a EDSS score ≥ 1 at inclusion, or an increase by at least 1.5 points for an EDSS score = 0 at inclusion;

- Disability progression with continued deterioration in EDSS score over 24 weeks; - MRI parameters: number of new hyper-intense or enlarging T2 lesions at two years and the

number of gadolinium-enhancing lesions at two years.

7.1.1.2 Results

A total of 1234 patients were included in the intention to treat (ITT) analysis and 540 in the MRI cohort (patients in the ITT population with MRI data in the centres approved by the study). Finally, the rate of premature discontinuation of treatment was 31% in both the dimethyl fumarate 240 mg x 2/day and 240 mg x 3/day groups and 35% in the placebo group (see Table 2). Table 2 Reasons for treatment discontinuation in th e DEFINE study.

Dimethyl fumarate

240 mg x 2/day n = 410

Dimethyl fumarate 240 mg x 3/day

n = 416

Placebo n = 408

Premature treatment discontinuation, n (%) 126 (31) 127 (31) 143 (35)

Relapse 4 (<1) 10 (2) 31 (8) Progression of MS 7 (2) 7 (2) 14 (3) Adverse event 61 (15) 56 (13) 22 (5) Lost to follow-up 9 (2) 11 (3) 7 (2) Withdrawal of consent 18 (4) 18 (4) 34 (8) Decision of the investigator 4 (<1) 2 (<1) 4 (<1) Non-compliance 3 (<1) 9 (2) 3 (<1) Death 0 1 (<1) 0 Other 20 (5) 13 (3) 28 (7) Premature withdrawal from the study, n (%) 95 (23) 96 (23) 91 (22)

Patient characteristics The mean age of patients was 39 years and the median time since initial MS diagnosis was four years (minimum: 0; maximum: 32). The median EDSS score at inclusion was 2 (minimum: 0; maximum: 6.5); 204 patients (16.5%) had an EDSS score > 3.5 at inclusion. Finally, 45% of patients were naive to previous MS treatment. Primary efficacy endpoint: The estimated percentage of patients with relapses during the two years was significantly reduced in the dimethyl fumarate groups compared with the placebo group: the percentage of patients with relapses was 46% in the placebo group versus 27% in the dimethyl fumarate 240 mg x 2/day group (Hazard ratio [HR]: 0.51; 95% CI [0.40 to 0.66]) and 26% in the dimethyl fumarate x 3/day group (HR: 0.50; 95% CI [0.39 to 0.65], see Figure 1).


Figure 1: Risk of relapse in the DEFINE study (ITT population ).

Secondary endpoints - Annualised relapse rate The annualised relapse rate at two years was reduced in the dimethyl fumarate groups compared with placebo: the adjusted annualised relapse rate at two years6 was 0.36 (95% CI [0.30 to 0.44]) in the placebo group versus 0.17 (95% CI [0.14 to 0.21]; p versus placebo < 0.0001) for the dimethyl fumarate 240 mg x 2/day group and 0.19 (95% CI [0.15 to 0.23]; p versus placebo < 0.0001) for the dimethyl fumarate 240 mg x 3/day group. - Disability progression The risk of disability progression at two years with deterioration in EDSS score confirmed at 12 weeks was reduced in the dimethyl fumarate groups in comparison with the placebo group: the estimated percentage of patients with disability progression at two years (Kaplan-Meier) was 0.271 in the placebo group versus 0.164 (p < 0.01) and 0.177 (p < 0.05) in the dimethyl fumarate 240 mg x 2/day and 240 mg x 3/day groups respectively. Reduction in disability progression with deterioration in EDSS confirmed at 24 weeks was not demonstrated. - MRI parameters The number of new or enlarging T2 lesions at two years compared with baseline was reduced in the dimethyl fumarate groups compared with placebo: the mean number of new or enlarging T2 lesions was 16.5 in the placebo group versus 3.2 (p < 0.0001) and 4.9 (p < 0.0001) in the dimethyl fumarate 240 mg x 2/day and x 3/day groups respectively. The risk of having more gadolinium-enhancing lesions at two years was reduced in the dimethyl fumarate groups compared with placebo: OR versus placebo 0.10 (95% CI [0.05 to 0.22]) for dimethyl fumarate 240 mg x 2/day and 0.27 (95% CI [0.15 to 0.46]) for dimethyl fumarate 240 mg x 3/day.

6 The annualised relapse rate was adjusted based on the EDSS score on inclusion, age, geographical area and the number of relapses in the year prior to inclusion.


7.1.2 CONFIRM Study


The CONFIRM study is a multi-centric, randomised, placebo-controlled superiority study with the aim of evaluating the efficacy and safety of dimethyl fumarate at doses of 240 mg x 2/day and x 3/day in patients with RRMS. The CONFIRM study includes an active validation arm, treated with glatiramer acetate. The primary objective was to demonstrate the efficacy of dimethyl fumarate in reducing the frequency of relapses during the two-year study period. The inclusion criteria were as follows: - To be between 18 and 55 years old; - A confirmed RRMS diagnosis, defined according to the McDonald criteria with a EDSS score

≤ 5;5 - To have presented with at least one relapse in the year prior to inclusion or have

gadolinium-enhancing cerebral lesions in the six weeks prior to inclusion; - To not have been treated with glatiramer acetate; to not have been treated with corticosteroids

in the four weeks before randomisation or by interferon in the three months prior to inclusion. Patients were randomised into four groups (ratio 1:1:1:1): - Dimethyl fumarate 240 mg x 2/day; - Dimethyl fumarate 240 mg x 3/day; - Placebo; - Glatiramer acetate, SC administration of 20 mg/day. Patients in the dimethyl fumarate and placebo groups started treatment by the administration of one dose of 120 mg x 2 or 3/day for one week, changing to a dose of 240 mg x 2 or 3/day from Day 8. Dimethyl fumarate and placebo were administered blind, whereas glatiramer acetate was administered on an open-label basis. The treatment lasted 96 weeks. The primary efficacy endpoint was the annualised relapse rate at two years. Relapses were diagnosed by the examining neurologist, treated by the treating neurologist and confirmed by a neurological independent review board. The principal secondary endpoints were: - Disability progression, defined by an increase in EDSS score of at least 1 point compared with

baseline and maintained over 12 weeks for a EDSS score ≥ 1 at inclusion, or an increase by at least 1.5 points for an EDSS score = 0 at inclusion;

- Disability progression with continued deterioration in EDSS score over 24 weeks; - MRI parameters: number of new or enlarging hyper-intense T2 lesions at two years and the

number of new hypo-intense T1 lesions at two years. The direct comparison between dimethyl fumarate and glatiramer acetate was carried out as a post hoc analysis.


7.1.2.2 Results

A total of 1417 patients were included in the ITT analysis and 681 in the MRI cohort. Finally, the rate of premature discontinuation of treatment was 30% in the dimethyl fumarate 240 mg x 2/day group, 28% in the dimethyl fumarate 240 mg x 3/day group and 36% in the placebo group (see Table 3). Table3. Reasons for treatment discontinuation in th e CONFIRM study.

Dimethyl fumarate

240mg x 2/day n = 359

Dimethyl fumarate 240mg x 3/day

n = 345

GA n = 350

Placebo n = 363

Premature treatment discontinuation, n (%) 106 (30) 96 (28)

86 (25) 129 (36)

Relapse 3 (<1) 6 (2) 6 (2) 18 (5) Progression of MS 7 (2) 5 (1) 8 (2) 8 (2) Adverse event 36 (10) 38 (11) 27 (8) 21 (6) Lost to follow-up 8 (2) 4 (1) 8 (2) 7 (2) Withdrawal of consent 9 (3) 15 (4) 10 (3) 14 (4) Decision of the investigator 2 (<1) 1 (<1) 2 (<1) 3 (<1) Non-compliance 4 (1) 3 (<1) 3 (<1) 9 (2) Death 0 0 1 (<1) 0 Other 34 (9) 27 (8) 21 (6) 49 (13) Premature withdrawal from the study, n (%) 75 (21) 72 (21) 58 (7) 85 (23)

GA: glatiramer acetate.

Patient characteristics The mean age of patients was 37 years and the median time since initial MS diagnosis was three years (minimum: 0; maximum: 33). The median EDSS score at inclusion was 2.5 (Minimum: 0; maximum: 5.5); 236 patients (16.6%) had an EDSS score > 3.5 at inclusion. Finally, 60% of patients were naïve to previous MS treatment. Primary efficacy endpoint: The frequency of relapses was significantly reduced in the dimethyl fumarate groups compared with placebo: the adjusted annualised relapse rate6 was 0.40 (95% CI [0.33 to 0.49]) in the placebo group versus 0.22 (95% CI [0.18 to 0.28]) in the dimethyl fumarate 240 mg x 2/day group (p < 0.02) and 0.20 (95% CI [0.16 to 0.25]) in the dimethyl fumarate 240 mg x 3/day group (p < 0.0001, see Table 4). Table 4. Annualised relapse rate in the CONFIRM stu dy.

Placebo n = 363


n = 359


n = 345

GA n = 350

Number of patients with ≥ 1 relapse, n (%)

140 (38.6) 93 (25.9) 76 (22.0) 104 (29.7)

Total number of relapses 212 124 106 163

Total number of patient-years 561.4 552.9 529.8 569.6

Adjusted annualised relapse rate6

%

[95% CI]

0.401

[0.329 to 0.488]

0.224

[0.179 to 0.282]

0.198

[0.156 to 0.252]

0.286

[0.232 to 0.353]

Rate ratio

[95% CI]

0.560

[0.423 to 0.740]

0.495

[0.369 to 0.662]

0.714

[0.548 to 0.931]

p value < 0.0001 < 0.0001 0.0128 GA: glatiramer acetate.


Secondary endpoints - MRI parameters The number of new or enlarging T2 lesions at two years and the number of hypo-intense T1 lesions was reduced in the dimethyl fumarate groups and the glatiramer acetate group compared with placebo. - Disability progression The reduction in disability progression with deterioration in EDSS confirmed at 12 or 24 weeks was not demonstrated. Direct comparison with glatiramer acetate ( post hoc analysis) The exploratory results of the comparison between dimethyl fumarate and glatiramer acetate are as follows (see Figure 2): - there was no difference observed between dimethyl fumarate 240 mg x 2/day and glatiramer

acetate in annualised relapse rate at two years, however there was a difference in favour of dimethyl fumarate observed with dimethyl fumarate 240 mg x 3/day;

- regarding disability progression, no difference was observed between dimethyl fumarate and glatiramer acetate.

Figure 2. Comparison of the efficacy of dimethyl fu marate versus glatiramer acetate. Post hoc analysis. 7

7 European public assessment report. www.ema.europa.eu.


7.1.3 Pooled analysis of the DEFINE and CONFIRM studies


A pooled analysis of the DEFINE and CONFIRM studies was carried out. The primary efficacy endpoint was the annualised relapse rate at two years. The principal secondary endpoints were: - Disability progression, defined by an increase in EDSS score of at least 1 point compared with

baseline and maintained over 12 weeks for an EDSS score ≥ 1 at inclusion, or an increase by at least 1.5 points for an EDSS score = 0 at inclusion;

- MRI parameters: number of new hyper-intense or enlarging T2 lesions at two years and the number of gadolinium-enhancing lesions at two years.

Sub-group analyses according to baseline patient characteristics (gender, age, relapse history, McDonald criteria, treatment history, EDSS score, MRI parameters) were carried out. At the request of the European Medicines Agency a post hoc analysis of patients presenting with a highly active form of RRMS was carried out. Highly active forms of RRMS were defined according to the following criteria: - treatment with interferon beta for at least 12 months, with:

• the occurrence of at least one relapse on interferon beta and at least nine T2 lesions or a gadolinium-enhancing lesion shown on a cerebral MRI; • or an unchanged or increased relapse rate over a year compared with the two previous years;

- or the occurrence of at least two relapses in the previous year combined with at least one gadolinium-enhancing lesion shown on a cerebral MRI.

7.1.3.2 Results

Primary efficacy endpoint: The frequency of relapses was significantly reduced in the dimethyl fumarate groups compared with placebo: the adjusted annualised relapse rate was 0.37 (95% CI [0.33 to 0.42]) in the placebo group versus 0.19 (95% CI [0.16 to 0.22]) in the dimethyl fumarate 240 mg x 2/day group (p < 0.0001) and 0.20 (95% CI [0.16 to 0.25]) in the dimethyl fumarate 240 mg x 3/day group (p < 0.0001). Secondary endpoints - Disability progression The risk of disability progression at two years with deterioration in EDSS score confirmed at 12 weeks was reduced in the dimethyl fumarate groups in comparison to the placebo group: the estimated percentage of patients with disability progression at two years (Kaplan-Meier) was 0.222 in the placebo group versus 0.146 (p < 0.01) in the dimethyl fumarate 240 mg x 2/day group and 0.155 (p < 0.01) in the dimethyl fumarate 240 mg x 3/day group. Likewise, the risk of disability progression with deterioration in EDSS score confirmed at 24 weeks was reduced in the dimethyl fumarate groups compared with placebo: The estimated percentage of patients with disability progression at two years was 0.148 in the placebo group versus 0.105 (p < 0.05) in the dimethyl fumarate 240 mg x 2/day group and 0.104 (p < 0.05) in the dimethyl fumarate 240 mg x 3/day group. - MRI parameters The number of new or enlarging T2 lesions at two years compared with inclusion and the number of gadolinium-enhancing lesions was reduced in the dimethyl fumarate groups and the glatiramer acetate group compared with placebo.


Sub-group analysis A reduction in the annualised relapse rate versus placebo was found in the different sub-groups defined according to baseline patient characteristics (see Figure 3).

BG12: dimethyl fumarate Figure 3. Annualised relapse rate as a function of baseline patient characteristics. In the post hoc analysis carried out on the sub-group of patients with highly active RRMS, according to the two definitions of highly active RRMS used, the annualised relapse rate was reduced in the dimethyl fumarate groups compared with placebo: - according to the definition "treatment with interferon beta for at least 12 months with at least

one relapse on interferon beta and at least nine T2 lesions or a gadolinium-enhancing lesion shown on a cerebral MRI or an unchanged or increased relapse rate" (20% of the population treated with dimethyl fumarate 240 mg x 2/day; n = 318), the annualised relapse rate ratio versus placebo was 0.57 (95% CI [0.39 to 0.84]);

- according to the definition "the occurrence of at least two relapses in the previous year combined with at least one gadolinium-enhancing lesion shown on a cerebral MRI" (6% of the population treated with dimethyl fumarate 240 mg x 2/day; n = 93), the annualised relapse rate ratio versus placebo was 0.40 (95% CI [0.22 to 0.71]).

In this group of patients with highly active RRMS, reduction in disability progression with deterioration in EDSS score confirmed at 12 or 24 weeks was not demonstrated (see Table 5).


Table5. Sub-group analysis of patients presenting w ith highly active RRMS.

Pooled analysis DEFINE + CONFIRM Placebo Dimethyl fumarate

240mg x 2/day

Ratio (95% CI) Dimethyl fumarate

240 mg x 2/day versus placebo

Interferon beta for ≥ 12 months AND ≥1 relapse on IFN and ≥ 9 T2 or 1 Gd+ lesion(s) OR Unchanged or increased relapse rate (total n = 318) Annualised relapse rate 0.36 0.20 0.57* (0.39; 0.84) EDSS disability progression (EDSS confirmed at 12 weeks)

0.16 0.18 1.19$ (0.66; 2.15)

≥2 relapses in previous year and Gd+ (total n = 93) Annualised relapse rate 0.58 0.23 0.40* (0.22; 0.71) EDSS disability progression (EDSS confirmed at 12 weeks)

0.33 0.26 1.11$ (0.47; 2.60)

* Annualised relapse rate ratio; $ Hazard ratio.

7.1.4 Network meta-analysis


The aim of this network meta-analysis was to make an indirect comparison of the efficacy and the safety of dimethyl fumarate 240 mg x 2/day to those of other RRMS immunomodulator treatments. A systematic review was performed on the MEDLINE, EMBASE databases and the Cochrane Library up to November 2012. Manual research of studies on clinicaltrials.gov, the meta-registry of controlled studies, and congress reports was also carried out. Two independent examiners gathered and extracted data. The studies included were randomised, controlled studies evaluating an immunomodulator treatment on patients with RRMS or in a population where at least 80% of patients have RRMS. The immunomodulator treatments included in the analysis were as follows: interferons beta-1a and beta-1b, glatiramer acetate, teriflunomide, natalizumab, fingolimod and dimethyl fumarate. The endpoints were the annualised relapse rate, disability progression, the time between relapses and the severity of the relapses, adverse effects and premature discontinuation of the study. Only the results for the annualised relapse rate and disability progression are presented here.

7.1.4.2 Results

A total of 27 randomised studies were included in the analysis. On the whole these were placebo-controlled, with 18 studies versus placebo and 9 studies including direct comparisons between two immunomodulator treatments. The two studies that evaluated dimethyl fumarate were the DEFINE and CONFIRM studies. Therefore, the only direct comparison available between dimethyl fumarate and an active treatment was versus glatiramer acetate in the CONFIRM study (the network of comparisons for the annualised relapse rate is presented in Figure 4). The duration of the studies was between 13 and 260 weeks. The number of patients included varied between 31 and 2244. In the 27 studies, the patients included presented with RRMS, had a mean EDSS score of between 1.9 and 3.2 on inclusion and had had one relapse in the year prior to inclusion or two relapses


during the two years prior to inclusion. The median time since MS diagnosis was between 0.9 years and 10.6 years. The percentage of patients who had received a previous MS treatment was a maximum of 56% in the nine studies for which this information was available. Inclusion of treatment naive patients was mentioned in only one study.

Placebo

IFN beta-1a 44 mcg tiw

IFN beta-1a 30 mcg once

weekly

Calabrese 2011EVIDENCE trialEtemadafir 2006

IFN beta-1b, 250 mcg EOD

GA 20 mg od

BG00012, 240 mg bid

Natalizumab 300 mg q4w

Fingolimod0.5 mg od

IFN beta-1a 22 mcg tiw

Figure 4. Network of comparisons of MTC for the ann ualised relapse rate. Annualised relapse rate Dimethyl fumarate 240 mg x 2/day was superior to placebo, to interferons beta-1a and beta-1b, to glatiramer acetate and to teriflunomide for annualised relapse rate (see Figure 5). There was no difference observed between dimethyl fumarate and fingolimod. Natalizumab was more effective than dimethyl fumarate. Disability progression: Dimethyl fumarate 240 mg x 2/day was more effective than placebo for disability progression at two years with deterioration of EDSS score confirmed at 12 weeks. No difference was observed between dimethyl fumarate and other active RRMS treatments for disability progression confirmed at 12 weeks (see Figure 6). No difference was observed between dimethyl fumarate and placebo for disability progression confirmed at 24 weeks (relative risk [RR]: 0.670; 95% CI [0.421 to 1.066]).


vs. IFN beta-1a 30 mcg once weekly

vs. IFN beta-1b 250 mcg EOD

vs. GA 20 mg od

vs. IFN beta-1a 22 mcg tiw


vs. Teriflunomide 7 mg od


vs. Fingolimod 0.5 mg od

vs. Natalizumab 300 mg q4w

vs. Placebo

Comparison

0.679 (0.557 - 0.826)

0.781 (0.646 - 0.943)

0.807 (0.677 - 0.961)

0.734 (0.595 - 0.905)

0.791 (0.656 - 0.953)

0.767 (0.610 - 0.965)

0.773 (0.614 - 0.974)

1.159 (0.948 - 1.419)

1.535 (1.232 - 1.913)

0.527 (0.450 - 0.616)

ARR ratio (95% CI)

<- Favors BG00012 240 mg bid Favors comparator -> 10.3 3 Figure 5. Annualised relapse rate ratio of dimethyl fumarate 240 mg x 2/day versus the other RRMS treatments.

vs. IFN beta-1b 250 mcg EOD

vs. GA 20 mg od





vs. Fingolimod 0.5 mg od

vs. Natalizumab 300 mg q4w

vs. Placebo

Comparison

0.746 (0.412 - 1.352)

0.781 (0.481 - 1.270)

0.871 (0.431 - 1.763)

0.889 (0.437 - 1.809)

0.799 (0.439 - 1.453)

0.877 (0.478 - 1.607)

0.786 (0.480 - 1.290)

1.143 (0.644 - 2.029)

0.592 (0.405 - 0.866)

RR (95% CI)

<- Favors BG00012 240 mg bid Favors comparator -> 10.3 3 Figure 6. Relative risk of dimethyl fumarate 240 mg x 2/day versus other treatments on disability progression at two years confirmed at 12 weeks.


07.2 Adverse effects

7.2.1 Data from the DEFINE and CONFIRM clinical studies

7.2.1.1 Common adverse effects

During the DEFINE and CONFIRM studies, a total of 1529 patients were treated with dimethyl fumarate for a maximum duration of 24 months, corresponding to an exposure of 2371 patient-years. The most commonly reported adverse effects in the dimethyl fumarate groups compared with placebo were flushing and gastrointestinal adverse effects (diarrhoea, nausea and abdominal pain, see Table 6). Table6. Adverse events during the DEFINE and CONFIR M studies.


n = 769

Placebo n = 771

Blood and lymphatic system disorders Lymphopenia 2% <1%

Gastrointestinal disorders Diarrhoea 14% 10% Nausea 12% 9% Upper abdominal pains 10% 6% Abdominal pain 9% 4% Vomiting 8% 5% Dyspepsia 5% 3%

Vascular disorders Flushing 34% 4% Hot flushes 7% 2%

Skin and subcutaneous tissue disorders Pruritus 8% 4% Rash 8% 3% Erythema 5% 1%

Investigations Albumin urine present 6% 4% Aspartate aminotransferase increased 4% 2%

7.2.1.2 Specific risks

Flushing

In the DEFINE and CONFIRM studies, the incidence of flushing (34% versus 4%) and hot flushes (7% versus 2%) was higher in patients treated with dimethyl fumarate than in patients receiving placebo. According to the SPC, flushing tended to occur at the start of treatment (mainly during the first month) and then continue to occur intermittently throughout the whole treatment course with dimethyl fumarate. In the majority of cases, flushing was mild to moderate in severity. A total of 3% of patients treated with dimethyl fumarate discontinued treatment as a result of flushing. The incidence of serious flushing, characterised by generalised erythema, rash and/or pruritus was observed by less than 1% of patients treated with dimethyl fumarate. Gastrointestinal effects The incidence of gastrointestinal effects (diarrhoea [14% versus 10%], nausea [12% versus 9%], upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%] and dyspepsia [5% versus 3%]) was higher in patients treated with dimethyl fumarate than in patients on placebo. Gastrointestinal effects tended to begin at the start of treatment (primarily during the first month) and then could occur intermittently throughout the whole treatment course.


A total of 4% of patients treated with dimethyl fumarate discontinued treatment due to gastrointestinal effects. The incidence of serious gastrointestinal effects, in particular gastroenteritis and gastritis, was less than 1 %. Haematological adverse effects After treatment with dimethyl fumarate, the mean number of lymphocytes reduced during the first year then plateaued. On average, the number of lymphocytes reduced by approximately 30% compared with the initial value. The mean and median number of lymphocytes remained within the limits of normal. A number of lymphocytes < 0.5 x109/l was observed for < 1% of patients on placebo and for 6% of those treated with dimethyl fumarate. A number of lymphocytes < 0.2 x 109/l was observed for one patient treated with dimethyl fumarate compared with no patients on placebo. The incidence of infections (58% versus 60%) and serious infections (2% versus 2%) was similar for patients on placebo and those treated with dimethyl fumarate. The incidence of infections and serious infections did not increase for patients, with the number of lymphocytes being < 0.8 x 109/l or 0.5 x 109/l. A transient increase in the mean number of eosinophils was observed during the first two months of treatment. Hepatic transaminases An increase in alanine aminotransferase and aspartate aminotransferase ≥ 3 times the upper limit of normal (ULN) was observed for 5% and 2% of patients on placebo and for 6% and 2% of patients treated with dimethyl fumarate respectively. In the majority of patients, these increases were < 3 times the ULN. This increase was primarily observed during the first six months of treatment. None of these cases were associated with an increase in total bilirubin levels > 2 times the ULN. Discontinuation of treatment due to elevated hepatic transaminase levels was less than 1% and comparable for patients treated with dimethyl fumarate and those on placebo. Renal adverse effects The incidence of proteinuria was higher in patients treated with dimethyl fumarate (9%) compared with those on placebo (7%). The overall incidence of renal and urinary adverse events was similar for patients treated with dimethyl fumarate and for those on placebo. There were no reports of serious renal impairment.

7.2.2 ENDORSE Study (in progress)

The ENDORSE study is an extension study over five years of both the DEFINE and the CONFIRM studies, with the aim of evaluating the long-term safety of dimethyl fumarate. This study is currently in progress (end of study scheduled for June 2016). Within the scope of an interim analysis on 30 March 2012, 1736 patients were included in the ITT analysis: - 1002 patients treated with dimethyl fumarate during the DEFINE and CONFIRM studies, for whom treatment continued at the same dosage; - 734 patients who received the placebo or glatiramer acetate and randomised to receive

dimethyl fumarate 240 mg x 2/day or x 3/day. In total, follow-up involved 1960 patient-years, close to 63% of patients received at least one years' follow-up and 15% for at least two years. No new adverse events were identified on the date of the interim analysis.


7.2.3 Post-marketing experience of FUMADERM

In Germany, the company, BIOGEN IDEC, has marketed a proprietary medicinal product in 1994 containing a mixture of fumaric acid (including dimethyl fumarate), FUMADERM, in the treatment of moderate to severe psoriasis. The accumulated exposure to FUMADERM since its launch in 1994 to the end of January 2012 is estimated as being approximately 165,000 patient-years. The safety profile of TECFIDERA and FUMADERM appears, overall, to be the same (flushing and gastrointentinal disorders, leucopenia and moderate lymphopenia, proteinuria and elevated serum creatinine). Three cases of progressive multifocal leukoencephalopathy (PML) have been reported for patients treated with FUMADERM. Two of these patients had identified risk factors (one patient had received treatment with efalizumab [RAPTIVA] for which the Marketing Authorisation has been suspended due to the occurrence of PML and one patient had sarcoidosis).


07.3 Summary & discussion

�� Two studies (DEFINE, 1234 patients and CONFIRM, 1417 patients) compared the efficacy of dimethyl fumarate 240 mg x 2/day (Marketing Authorisation dosage) and 240 mg x 3/day with that of a placebo for two years in patients with RRMS. In the DEFINE study, the estimated percentage of patients with relapse (primary endpoint) was 27% in the group treated with dimethyl fumarate 240 mg x 2/day versus 46% in the placebo group (HR: 0.51; 95% CI [0.40 to 0.66]). In the CONFIRM study, the annualised relapse rate (primary endpoint) was significantly reduced compared with placebo: 0.22 (95% CI [0.18 to 0.28]) in the dimethyl fumarate 240 mg x 2/day group versus 0.40 (95% CI [0.33 to 0.49]) in the placebo group (p < 0.02). The results for disability progression were more variable. In the DEFINE study, the risk of disability progression at two years with deterioration of EDSS score confirmed at 12 weeks was reduced with dimethyl fumarate 240 mg x 2/day compared with placebo; however no difference was observed between dimethyl fumarate and placebo for the risk of disability progression confirmed at 24 weeks. In the CONFIRM study, no difference was observed between dimethyl fumarate and placebo for the risk of disability progression. The pooled analysis of the two studies enabled a reduction in the risk of disability progression at two years with deterioration in EDSS score confirmed at 12 and at 24 weeks to be highlighted. �� Data for highly active forms of RRMS are based on a sub-group analysis of the DEFINE and CONFIRM studies, carried out a posteriori. According to two definitions of highly active RRMS, similar to the wording of the indications for GILENYA and TYSABRI, the annualised relapse rate was reduced in the dimethyl fumarate 240 mg x 2/day group compared with placebo: - according to the definition "treatment with interferon beta for at least 12 months with at least

one relapse on interferon beta and at least nine T2 lesions or a gadolinium-enhancing lesion shown on a cerebral MRI or an unchanged or increased relapse rate," which represented 20% of patients treated with dimethyl fumarate 240 mg x 2/day (n = 318), the annualised relapse rate ratio was 0.57 (95% CI [0.39 to 0.84]);

- according to the definition "the occurrence of at least two relapses in the previous year combined with at least one gadolinium-enhancing lesion shown on a cerebral MRI," which represented 6% of patients treated with dimethyl fumarate 240 mg x 2/day (n = 93), the annualised relapse rate ratio was 0.40 (95% CI [0.22 to 0.71]).

These results are exploratory and should be interpreted with caution. �� The CONFIRM study included an active validation arm, treated with glatiramer acetate. Within the scope of a comparison carried out a posteriori, no difference in efficacy was observed between dimethyl fumarate 240 mg x 2/day and glatiramer acetate for the annualised relapse rate (annualised relapse rate ratio: 0.78; 95% CI [0.59 to 1.05]) and the risk of disability progression (HR: 0.85; 95% CI [0.56 to 1.29]). �� The efficacy of dimethyl fumarate 240 mg x 2/day was indirectly compared to that of other immunomodulators indicated in the treatment of RRMS within the scope of a network meta-analysis. A total of 27 studies were included, mainly placebo-controlled (18 studies versus placebo and 9 direct comparison studies between other active treatments). In this meta-analysis, the efficacy of dimethyl fumarate 240 mg x 2/day on the annualised relapse rate was superior to placebo, interferons beta-1a and beta-1b, glatiramer acetate and teriflunomide. No difference was observed for the risk of disability progression between dimethyl fumarate and other treatments. Interpretation of the results of this network meta-analysis should be considered with caution, given the lack of direct comparisons available and the disparity of characteristics between the studies. Although of good quality, this network meta-analysis cannot replace the conclusions from well carried out direct comparison studies.


�� According to the SPC, the most commonly reported adverse effect for patients treated with dimethyl fumarate in the clinical studies were flushing and gastrointestinal effects (diarrhoea, nausea and abdominal pain).

08 THERAPEUTIC USE

The disease medifying treatment for RRMS is based on first-line interferon beta-1a (AVONEX and REBIF), interferon beta-1b (BETAFERON and EXTAVIA) and glatiramer acetate (COPAXONE). These treatments are administered subcutaneously (BETAFERON, EXTAVIA, REBIF, COPAXONE) or intramuscularly (AVONEX) at various rhythms (1 to 7 times per week). Natalizumab (TYSABRI) and fingolimod (GILENYA) have an indication restricted to highly active forms of RRMS. Another orally administered proprietary medicinal product, teriflunomide (AUBAGIO) obtained Marketing Authorisation in the treatment of RRMS, however it is not yet marketed in France. TECFIDERA, administered orally, is an alternative to other disease modifying therapies indicated in RRMS. Data on the highly active forms of RRMS are limited. The carrying out of a complete blood count on starting treatment with TECFIDERA, then every 6 to 12 months and in the presence of clinical signs is recommended. TECFIDERA is an alternative to other disease modify ing therapies indicated in RRMS.


09 TRANSPARENCY COMMITTEE CONCLUSIONS

In view of all the above data and information, and following the debate and vote, the Committee’s opinion is as follows:

09.1 Actual Benefit

� Multiple sclerosis is a debilitating, progressive chronic neurological disorder. It involves the selective, chronic inflammation and demyelinisation of the central nervous system. There are multiple clinical signs: sensitivity and motor issues, sensory, bladder and sphincter and sexual impairment and issues with cognitive function and mood. These disorders may considerably reduce patients’ autonomy and impair their quality of life. The severity of the disease is very variable from mildly disabling forms which lead to severe disabilities within a few years. Relapsing remitting forms (RRMS), on the whole, are characterised by the presence of relapses without any progression in the disability observed between the relapses. � TECFIDERA is a disease modifying therapy, with the aim of preventing relapses in RRMS. � The efficacy/adverse effects ratio for this medicinal product is high. � The alternative treatments are other medicinal products indicated as disease modifying therapies in RRMS.

� Public health benefit At the present time, MS affects between 70,000 and 90,000 patients in France, with a probable annual incidence of 4 to 6 per 100,000 inhabitants. Starting on average at the age of 30 (20-40 years) with a female preponderance, it is the leading non-traumatic cause of severe disability in young subjects. The severity of the disease is due to the disabilities it causes, their impact on quality of life and their socio-economic impact. The burden in terms of public health of relapsing remitting forms of MS is considered as moderate. Reducing the functional limitations introduced by multiple sclerosis and improving the quality of life of patients with the disease are a public health need within the framework of established priorities (objective 65 of the act of 9 August 2004 on French public health policy, plan for improvement in quality of life of patients with chronic illnesses 2007-2011). In view of the results from the DEFINE and CONFIRM studies, TECFIDERA has demonstrated a significant reduction in morbidity (reduction in relapses) compared with placebo. The impact on disability progression has only been evaluated in the short-term. However, in the absence of a superiority study versus an active comparator, and given the post-hoc nature of the comparison versus glatiramer acetate and the inherent limitations to the comparison based on the network meta-analysis, the additional impact of dimethyl fumarate in relation to the alternatives can not be formally determined. Likewise, a statistically significant improvement, although not clinically relevant (<5 points) in quality of life for the physical component of the SF-36 questionnaire, was demonstrated versus placebo. Furthermore, the commonly reported adverse effects in the pivotal studies were flushing, gastrointestinal disorders and haematological toxicity. As the result of making an oral form available, avoiding repeated subcutaneous or intramuscular injections, an impact on the organisation of care (nursing care) may be presumed, however this impact is difficult to assess given that self-injection is carried out.


TECFIDERA will therefore not provide an additional response to the identified public health need. Consequently, in the current state of knowledge, it is not expected that TECFIDERA will benefit public health in its indication.

Taking account of these points, the Committee considers that the actual benefit of TECFIDERA is substantial "in the treatment of adult patients with relapsing remitting multiple sclerosis".

09.2 Improvement i

09.3 n actual benefit (IAB)

In the absence of a superiority study versus an act ive treatment, TECFIDERA does not provide an improvement in actual benefit (level V, non-existent) in the treatment of relapsing remitting multiple sclerosis. The results of a network meta-analysis, showing, th rough an indirect comparison, a reduction in the annual relapse rate with TECFIDERA 240 mg x 2/day compared with interferon beta, glatiramer acetate and teriflunomi de, can not be considered as sufficient to draw conclusions as to the superior efficacy of TEC FIDERA at a dose of 240 mg x 2/day compared with these treatments. The Transparency Committee recognises the benefit o f the availability of an additional oral proprietary medicinal product indicated as disease modifying therapy in relapsing remitting multiple sclerosis.

09.4 Target population

The prevalence of people with chronic multiple sclerosis was 126/100,000 on 31 December 2012 for patients subscribed under the general health plan.8 Applying this prevalence to the general population, the number of persons currently treated for multiple sclerosis in France is estimated to be about 83,000. Of these, approximately 60% would have remitting relapsing MS,9 which is nearly 50,000 patients.

010 TRANSPARENCY COMMITTEE RECOMMENDATIONS

�� Proposed reimbursement rate: 65 % �� Packaging It is not appropriate for the prescribing conditions according to the indication. The Committee wishes to reiterate that, in accordance with its deliberations of 20 July 2005, it recommends standardisation of pack sizes for treatments lasting one month to the equivalent of 30 days of treatment. �� Specific requests inherent to reimbursement Exception drug status

8 Statistical data from National Health Insurance. www.ameli.fr. Affections de Longue Durée 9 HAS. Transparency Committee. Re-assessment of interferon beta and glatiramer acetate. July 2010. www.has-sante.fr.

Documents

Opinion 7 May 2014 TECFIDERA 120 mg, gastro-resistant hard ... · 20/06/2012 Substantial IAB V in treatment Yes BETAFERON (IFN beta-1b) BAYER SANTE SC 1 day/2 • RRMS • Patients