The legally binding text is the original French version
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."
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Actual Benefit
Substantial.
Improvement 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 sclerosis. The results of the network meta-analysis showing, through an indirect comparison, a reduction in the annualised relapse rate with TECFIDERA 240 mg x 2/day compared with interferon beta, glatiramer acetate and teriflunomide can not be considered as sufficient to 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 of the availability of an additional oral proprietary medicinal product indicated as disease modifying therapy in relapsing remitting multiple sclerosis.
in
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01
ADMINISTRATIVE AND REGULATORY INFORMATION
Marketing Authorisation (centralised procedure) Prescribing and dispensing conditions/special status
ATC Classification
02
30/01/2014
List I Medicine requiring special monitoring during treatment. Prescription restricted to NEUROLOGY specialists and departments
N N07 N07XX N07XX09
Nervous system Other nervous system drugs Other nervous system drugs dimethyl fumarate
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.
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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 2 3 4
C. Confavreux et S. Vukusic. "L'évolution naturelle de la sclérose en plaques" Rev. Prat 2006; 56:1313-20. Moreau T. Vie quotidienne et sclérose en plaques. Rev Neurol (Paris) 2001; 157(8-9): 1157-62. HAS. Re-assessment of interferon beta and glatiramer acetate in multiple sclerosis. July 2010. www.has-sante.fr. 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.
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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. Proprietary medicinal product (INN) COMPANY AVONEX (IFN beta-1a) BIOGEN IDEC
List of proprietary medicinal products indicated for the treatment of MS. Date of TC opinion
AB
IAB
02/06/2010
Substantial
IAB III treatment
02/06/2010 20/06/2012
Substantial Substantial
IAB III in treatment IAB V in treatment
Yes Yes
02/06/2010
Substantial
IAB III in treatment
Yes
21/07/2010
Substantial
IAB V compared with BETAFERON
Yes
RRMS Patients with a single demyelinating event at high risk of MS. RRMS
02/06/2010 06/04/2011
Substantial Substantial
IAB III in treatment IAB V in treatment
Yes Yes
05/03/2014
Substantial
IAB V in treatment
In progress
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 Substantial
IAB III in the treatment of patients with aggressive § RRMS
Yes
IAB IV in treatment
Yes
Admin.
Indications*
IM 1/week
• •
REBIF (IFN beta-1a) MERCK SERONO
SC 3/week
• •
BETAFERON (IFN beta-1b) BAYER SANTE
SC 1 day/2
• •
EXTAVIA (IFN beta-1b) NOVARTIS PHARMA COPAXONE (glatiramer acetate) TEVA PHARMA AUBAGIO (teriflunomide) GENZYME TYSABRI (natalizumab) BIOGEN IDEC
SC 1 day/2
•
SC 1/day
• •
Oral
•
IV infusion 1/month
•
RRMS Patients with demyelinating high risk of MS. RRMS Patients with demyelinating high risk of MS.
$
a single event at
a single event at
RRMS Patients with a single demyelinating event at high risk of MS. Secondary progressive MS
• GILENYA Oral 20/07/2011 (fingolimod) NOVARTIS * refer to the SPC of the proprietary medicinal products for the detailed wording of the indications.
Reimbur sement
$
in
Yes
$
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. §
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Conclusion The comparators of TECFIDERA are medicinal products indicated as disease modifying therapies in RRMS.
HAS - Medical, Economic and Public Health Assessment Division
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07 07.1
ANALYSIS OF AVAILABLE DATA 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".
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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 the DEFINE study.
Premature treatment discontinuation, n (%) Relapse Progression of MS Adverse event Lost to follow-up Withdrawal of consent Decision of the investigator Non-compliance Death Other Premature withdrawal from the study, n (%)
Dimethyl fumarate 240 mg x 2/day n = 410
Dimethyl fumarate 240 mg x 3/day n = 416
Placebo n = 408
126 (31)
127 (31)
143 (35)
4 (
