Modifying the Disease Course
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Five drug therapies are approved in Canada for the treatment of some forms of multiple sclerosis (MS). Four of these medications — Avonex®, Betaseron®, Copaxone® and Rebif® — are immune modulating medications. The fifth — Tysabri® — is a selective adhesion molecule inhibitor. In large clinical trials, all of these drugs have been found to have a direct influence on altering the course of MS. They are sometimes referred to collectively as disease-modifying therapies.
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The following summary provides brief information about each drug. It is not intended to be a comparison of the drugs to each other or to endorse or recommend any specific therapy. The summary has been prepared by the Multiple Sclerosis Society of Canada and reviewed for accuracy by the national medical advisor.
For more information about these therapies or for other information about MS management, please contact your physician, or the nearest Multiple Sclerosis Society of Canada division office
at 1-800-268-7582.
The cost of disease-modifying therapies for MS varies widely, from about $20,000 to $40,000 per year. The actual cost will depend on the treatment selected, the dosage, provincial pricing, pharmacy or clinic costs, dispensing fees, etc.
The MS Society is aware that the level of reimbursement and access criteria vary from province to province and is working to ensure that people who could benefit from treatment have access. For more information on these topics, contact your nearest division office at 1-800-268-7582.
Publication of this update was made possible by an unrestricted educational grant from Teva Neuroscience.
Avonex
Avonex (interferon beta-1a) is a type of protein called a beta-interferon that is produced from mammalian cells using recombinant DNA techniques (a series of procedures used to join together DNA segments). Beta-interferon occurs naturally in the human body in response to initiating factors such as viruses. In MS, the main effects of Avonex are to block the activity of certain immune
system cells and to reduce the passage of these immune cells into the central nervous system, where they cause inflammation and damage to myelin (the insulating material that protects nerves and helps them work properly).
INDICATIONS AND USE
Health Canada approved Avonex in 1998 for the treatment of relapsing forms of MS to slow the progression of disability, decrease the frequency of MS attacks, and reduce the number and volume of brain lesions seen on magnetic resonance imaging (MRI). MRI is a powerful tool that provides
images of the brain, spinal cord, or other areas of the body. It is often
used in MS to identify areas of inflammation.
Health Canada approved Avonex in 2003 for the treatment of people at
risk of developing clinically definite MS (CDMS), so as to delay the onset
of clinically definite MS and to decrease the number and volume of active
brain lesions on MRI. Before Avonex is initiated, people at risk of developing
CDMS must have brain lesions on MRI and other possible diagnoses
must be ruled out.
DOSAGE The recommended dose of Avonex is 30 mcg once per week.
ADMINISTRATION Avonex is self-injected once per week into the muscle (intramuscularly). The medication is now available as a pre-filled syringe.
SIDE EFFECTS The most common side effects of Avonex therapy include flu-like symptoms (fatigue, chills, fever, muscle aches, and sweating). Most of these
symptoms tend to improve over time. Less common side effects include injection site reactions (swelling, redness, discolouration, and pain), some liver, blood and thyroid problems, allergicreactions and depression.
NEUTRALIZING ANTIBODIES Some people taking a beta-interferon therapy develop neutralizing anti-bodies (NAb). It is not known if NAbs completely “neutralize” the clinical benefits of therapy. Some research has found that a higher NAb level may be associated with a lesser treatment effect. The level of NAbs associated with the use of Avonex is lower than that seen during treatment
with the other two beta-interferons. Studies are continuing in this area, as is the development of a standardized NAb test.
DRUG IDENTIFICATION NUMBER (DIN) 02237770; 02269201 for the pre-filled syringe
COST REIMBURSEMENT Much of the cost can be reimbursed through private and group health plans for people who meet the prescribing criteria, and through provincial drug programs for individuals who meet the prescribing criteria.
REIMBURSEMENT CRITERIA Assistance with treatment costs varies among provinces and private insurance companies. In most cases, to be reimbursed an individualmust have active relapsing-remitting MS (at least 1 or 2 MS attacks in the 1 or 2 years prior to starting treatment) and be ambulatory. The exact
definition of “ambulatory” varies among the provincial drug programs and private/group insurance plans. In Ontario and Quebec, Avonex can be
reimbursed for persons at high risk of developing MS who meet specific criteria. For more information on reimbursement, please contact your nearest division office at 1-800-268-7582, or your provincial government program office (telephone numbers are listed under For more information, Provincial Drug Programs).
CLINICAL TRIAL RESULTS Clinical Trials Note: Numerous clinical trials have been conducted for each of the disease-modifying therapies. The clinical trials included in this summary are those that have led to Health Canada approval for the therapy to be prescribed and sold in Canada, or that have led provincial health ministries to agree to reimburse the cost of that therapy or to make a significant
change to the reimbursement criteria.
Clinical Trials in Relapsing-Remitting MS
MSCRG Study
MSCRG: Multiple Sclerosis Collaborative Research Group Study
In this clinical trial, 301 people with relapsing-remitting MS were treated
with either Avonex at a dose of 30 mcg once per week or placebo (a treatment that has no active medication) for over 2 years. Results of the study showed that Avonex delayed the time to sustained progression of disability compared to placebo. The proportion of patients who progressed was reduced 37% (21.9% vs. 34.9%). Avonex reduced the annual attack rate by 18-32% compared to placebo and also reduced the number of brain lesions on MRI.1
[Jacobs et al. Ann Neurology 1996; 39: 285-294]
Clinical Trials: Single Event Suggestive of MS
CHAMPS Study
CHAMPS: Controlled High-Risk Subjects Avonex Multiple Sclerosis
Prevention Study
This study examined whether Avonex could reduce conversion to clinically definite MS in people who had a single neurological event suggestive of MS (an event involving the optic nerve, brain stem/cerebellum, or spinal cord) but who had not been diagnosed with MS. A total of 383 persons were treated with Avonex or placebo for up to 3 years. Treatment with Avonex resulted in a 44% reduction in the chance of having a second MS attack over the three-year period.2 [Jacobs et al. N Engl J Med 2000; 343: 898-904]
CURRENT CLINICAL TRIALS A number of clinical trials involving the five disease-modifying therapies are underway. The studies are examining the effectiveness at differentdoses and the possible benefits of combining therapies. For more information about clinical trials, please visit the MS Society of Canada website
by going to www.mssociety.ca and click on Research.
PHARMACEUTICAL COMPANY Biogen Idec Canada 3 Robert Speck Parkway
Mississauga, Ontario L4Z 2G5
FURTHER INFORMATION Further information for persons with MS is
available through MS Alliance at 1-888-456-2263.
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Betaseron
Betaseron (interferon beta-1b) is a beta-interferon that is produced from bacterial cells using recombinant DNA techniques (a series of procedures used to join together DNA segments). Beta-interferon is a protein that occurs naturally in the human body in response to initiating factors such as viruses. In MS, the main effects of Betaseron are to block the activity of certain immune system cells and to reduce the passage of these immune cells into the central nervous system, where they cause inflammation and damage to myelin (the insulating material that protects nerves and helps them
work properly).
INDICATIONS AND USE Health Canada approved Betaseron in 1995 for the treatment of people
with relapsing-remitting MS who are ambulatory (able to walk) to reduce
the frequency of attacks. Relapsing-remitting MS is characterized by
recurrent attacks followed by complete or incomplete recovery.
Betaseron was approved by Health Canada in 1999 for the treatment
of secondary-progressive MS to slow the progression of disability and
to reduce the frequency of MS attacks. About one-half of people with
relapsing-remitting MS start to worsen within 10 years of diagnosis, with
the possibility of increasing levels of disability and continued relapses.
This is known as secondary-progressive MS.
Health Canada has also approved Betaseron for the treatment of people
at risk of developing clinically definite MS (CDMS) accompanied by at
least two lesions on MRI to delay the progression to clinically definite MS.
Before Betaseron is initiated, alternative diagnoses must be ruled out.
DOSAGE The recommended dose of Betaseron for both relapsing-remitting and
secondary-progressive MS is 250 mcg every other day.
ADMINISTRATION Betaseron is self-injected every other day under the skin (subcutaneously).
Betaseron is available in a diluent pre-filled syringe. A diluent is a diluting
agent. With Betaseron, the syringes are pre-filled with a salt-water solution
to mix with the active medication, which is in a powder form.
SIDE EFFECTS The most common side effects of Betaseron therapy include flu-like
symptoms (fatigue, chills, fever, muscle aches, and sweating) and injection
site reactions (swelling, redness, discolouration, and pain). Most of these
symptoms tend to improve over time.
Less common side effects include some liver, blood and thyroid problems,
as well as allergic reactions and depression.
NEUTRALIZING ANTIBODIES Some people taking a beta-interferon therapy develop neutralizing anti-
bodies (NAb). It is not known if NAbs completely “neutralize” the clinical
benefits of therapy. Some research has found that a higher NAb level
may be associated with a lesser treatment effect. Studies are continuing
in this area, as is the development of a standardized NAb test.
DRUG IDENTIFICATION NUMBER (DIN) 02169649
COST REIMBURSEMENT Much of the cost can be reimbursed through private and group health
plans for people who meet the prescribing criteria, and through provincial
drug programs for individuals who meet the prescribing criteria.
In addition, a program called Bridging the Gap is available to provide
financial help for people with insurance or government program copayments
or deductibles. For more information, call 1-800-977-2770.
REIMBURSEMENT CRITERIA Assistance with treatment costs varies among provinces and private
CRITERIA insurance companies. In most cases, to be reimbursed an individual
must have active relapsing-remitting MS (at least 1 or 2 MS attacks in the
1 or 2 years prior to starting treatment) and be ambulatory. The exact
definition of “ambulatory” varies among the provincial drug programs and
private/group insurance plans. For more information on reimbursement,
please contact your nearest division office at 1-800-268-7582, or your
provincial government program office (telephone numbers are listed under
For more information, Provincial Drug Programs).
CLINICAL TRIAL RESULTS
Clinical Trials
Note: Numerous clinical trials have been conducted for each of the
disease-modifying therapies. The clinical trials included in this summary
are those that have led to Health Canada approval for the therapy to be
prescribed and sold in Canada, or that have led provincial health ministries
to agree to reimburse the cost of that therapy or to make a significant
change to the reimbursement criteria.
Clinical Trials in Relapsing-Remitting MS
Interferon Beta Multiple Sclerosis Study Group
In this clinical trial, 372 people with relapsing-remitting MS received
Betaseron at a dose of either 1.6 MIU or 8 MIU, or placebo (a treatment
that has no active medication) for 2 years. Compared to placebo,
Betaseron reduced the annual attack rate by about 30%.3 [The IFNB
Multiple Sclerosis Study Group. Neurology 1993; 43: 641-643]. Betaseron
also reduced disease activity, as measured by magnetic resonance
imaging (MRI), by 80% compared to placebo.4[Paty & Li. Neurology
1993; 43(4): 662-667] MRI is a powerful tool that provides images of the
brain, spinal cord, or other areas of the body. It is often used in MS to
identify areas of inflammation.
Clinical Trials in Secondary-Progressive MS
European Study in Secondary-Progressive MS
In this study, 718 people with secondary-progressive MS received either
Betaseron or placebo for up to 3 years. Compared to placebo, Betaseron
delayed progression of disability for 9-12 months. Betaseron also reduced
the attack rate by 31%.5 In this study, 718 people with secondary-progressive MS received either
Betaseron or placebo for up to 3 years. Compared to placebo, Betaseron
delayed progression of disability for 9-12 months. Betaseron also reduced
the attack rate by 31%.6 [Miller et al. Ann Neurol 1999; 46:
850–859] The final analysis (mean 35 month follow-up) of this study
confirmed the benefits of Betaseron over placebo with respect to
progression and relapses.7 [Kappos et al. Neurology 2001; 57: 1969-1975]
North American Study in Secondary-Progressive MS
The North American study of Betaseron involved 939 individuals with
secondary-progressive MS. In this trial, treatment with Betaseron failed
to show a significant difference in the time to progression compared to
placebo, although there were improvements in relapses and MRI brain
lesions.8 [North American Study Group
on Interferon Beta-1b in Secondary Progressive MS. Neurology
2004; 63: 1788-1795]
Clinical Trials: Single Event Suggestive of MS
BENEFIT trial
BENEFIT: Betaferon in Newly Emerging Multiple Sclerosis for Initial
Treatment
This study examined whether Betaseron could reduce conversion to clinically
definite MS in people who had a first clinical event suggestive of MS
(an event involving the optic nerve, brain stem/cerebellum, or spinal cord)
and at least two clinically silent brain lesions on MRI. A total of 468 were
treated with Betaseron or placebo for up to 2 years. The probability of
developing clinically definite MS over 2 years was 45% with placebo
compared to 28% with Betaseron, for an absolute risk reduction of 17%
and a relative risk reduction of 38%.9 [Kappos
et al. Neurology 2006; 67: 1242-1249]
CURRENT CLINICAL TRIALS A number of clinical trials involving the five disease-modifying therapies
are underway. The studies are examining the effectiveness at different
doses and the possible benefits of combining therapies. For more information
about clinical trials, please visit the MS Society of Canada website
by going to www.mssociety.ca and click on Research.
PHARMACEUTICAL COMPANY Bayer HealthCare Pharmaceuticals 77 Belfield
Rd. Toronto, Ontario M9W 1G6
FURTHER INFORMATION Further information for persons with MS is
available through MS Pathways at 1-800 977-2770.
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Copaxone
Copaxone (glatiramer acetate) is a synthetic protein made up of a combination of four amino acids
that chemically resemble a component of myelin (the insulating material that protects nerves and
helps them work properly). Copaxone induces the production of immune cells that are less damaging
to myelin.
INDICATIONS AND USE Health Canada approved Copaxone in 1997 for the treatment of people
with relapsing-remitting MS who are ambulatory (able to walk) to reduce
the frequency of attacks and to reduce the number and volume of active
brain lesions identified on MRI. Relapsing-remitting MS is characterized
by recurrent attacks followed by complete or incomplete recovery.
Health Canada approved Copaxone in 2009 for the treatment of people
at risk of developing clinically definite MS (CDMS) so as to delay the
onset of clinically definite MS, and to decrease the number and volume
of active brain lesions and overall disease burden on MRI. Before
Copaxone is initiated, people at risk of developing CDMS must have
brain lesions on MRI and other possible diagnoses must be ruled out.
DOSAGE The recommended dose of Copaxone is 20 mg per day.
ADMINISTRATION Copaxone is self-injected every day under the skin (subcutaneously).
Copaxone is available in pre-filled syringes that are ready for injection.
SIDE EFFECTS The most common side effects of Copaxone therapy are injection-site
reactions. Less common side effects include some of the following
symptoms immediately after an injection: flushing, chest pain, palpitations
(irregular beating of the heart), anxiety, and difficulty breathing.
However, these symptoms are usually temporary and do not require
specific treatment.
NEUTRALIZING ANTIBODIES GA-reactive antibodies are not neutralizing and do not alter the principal
immunological effects of GA.
DRUG IDENTIFICATION NUMBER (DIN) 02245619
COST REIMBURSEMENT Much of the cost can be reimbursed through private and group health
plans for people who meet the prescribing criteria, and through provincial
drug programs for individuals who meet the prescribing criteria.
In addition, a program called the Copaxone Assistance Program is
available to provide financial help for people with insurance or government
program co-payments or deductibles. For more information, contact
Shared Solutions at
1-800-283-0034.
REIMBURSEMENT CRITERIA AAssistance with treatment costs varies among provinces and private
CRITERIA insurance companies. In most cases, to be reimbursed an individual
must have active relapsing-remitting MS (at least 1 or 2 MS attacks in the
1 or 2 years prior to starting treatment) and be ambulatory. The exact
definition of “ambulatory” varies among the provincial drug programs and
private/group insurance plans. For more information on reimbursement,
please contact your nearest division office at 1-800-268-7582, or your
provincial government program office (telephone numbers are listed under
For more information, Provincial Drug Programs).
CLINICAL TRIAL RESULTS
Clinical Trials
Note:Note: Numerous clinical trials have been conducted for each of the
disease-modifying therapies. The clinical trials included in this summary
are those that have led to Health Canada approval for the therapy to be
prescribed and sold in Canada, or that have led provincial health ministries
to agree to reimburse the cost of that therapy or to make a significant
change to the reimbursement criteria.
Clinical Trials in Relapsing-Remitting MS
Phase III Trial of Copaxone
In this clinical trial, 251 persons with relapsing-remitting MS were
randomized to receive either Copaxone or placebo for 2 years. Study
participants treated with Copaxone showed a 29% reduction in relapses
compared to placebo.10
[Johnson et al.
Neurology 1995; 45: 1268-1276]
European/Canadian MRI Study
This study examined the effect of Copaxone on disease activity in 239
(continued) persons with relapsing-remitting MS. Patients were monitored by magnetic
resonance imaging (MRI). MRI is a powerful tool that provides images of
the brain, spinal cord, or other areas of the body. It is often used in MS to
identify areas of inflammation. Results of the study showed that treatment
with Copaxone was associated with fewer MRI brain lesions than was
placebo. The relapse rate was also reduced by one-third with Copaxone
compared to placebo.11 [Comi et al. Neurology 2001; 49: 290-297]
Clinical Trials: Single Event Suggestive of MS
PreCISe trial in Clinically Isolated Syndrome (CIS)
This study examined whether Copaxone could delay the conversion to
clinically definite MS in people who had a first clinical event suggestive of
MS (an event involving the optic nerve, brain stem/cerebellum, or spinal
cord) and at least two brain lesions on MRI. A total of 481 were treated
with Copaxone or placebo for up to 3 years. According to the pre-planned
interim analysis, the probability of developing clinically definite MS was
43% with placebo compared to 25% with Copaxone, for an absolute risk
reduction of 18% and a relative risk reduction of 45%.12 [Comi G.
Abstract LBS.003, AAN 2008.]
CURRENT CLINICAL TRIALS A number of clinical trials involving the five disease-modifying therapies
are underway. The studies are examining the effectiveness at different
doses and the possible benefits of combining therapies. For more information
about clinical trials, please visit the MS Society of Canada website
by going to www.mssociety.ca and click on Research.
PHARMACEUTICAL COMPANY Teva Neuroscience 999 Boul. de Maisonneuve
W., Suite 550 Montreal, Quebec H3A 3L4
FURTHER INFORMATION Further information for persons with MS is
available by contacting Shared Solutions at 1-800-283-0034.
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Rebif
Rebif (interferon beta-1a) is a beta-interferon that is produced from mammalian cells using recombinant
DNA techniques (a series of procedures used to join together DNA segments). Beta-interferon
is a protein that occurs naturally in the human body in response to initiating factors such as viruses.
In MS, the main effects of Rebif are to block the activity of certain immune system cells and to
reduce the passage of these immune cells into the central nervous system, where they cause
inflammation and damage to myelin (the insulating material that protects nerves and helps them
work properly).
INDICATIONS AND USE Health Canada approved Rebif in 1998 for the treatment of relapsing
forms of MS (in which persons still experience recurrent attacks, such
as relapsing-remitting MS and secondary-progressive MS with relapses)
to reduce the number and severity of attacks, slow the progression of
physical disability, reduce the need for steroids and the number of hospitalizations
due to MS, and to reduce the number of brain lesions seen on
magnetic resonance imaging (MRI).
Relapsing-remitting MS is characterized by recurrent attacks followed by
complete or incomplete recovery. About one-half of people with relapsing-remitting
MS start to worsen within 10 years of diagnosis, with the possibility
of increasing levels of disability and continued relapses. This is
known as secondary-progressive MS.
Although Rebif did not affect progression of disability in SPMS, clinical
trials have shown that people with SPMS with relapses experience benefits
with respect to relapses and MRI disease activity compared to those
receiving placebo.
DOSAGE The usual dose of Rebif is 44 mcg three times per week. It is also available
in a dose of 22 mcg three times per week.
ADMINISTRATION Rebif is self-injected three times per week under the skin (subcutaneously).
Rebif is available in a pre-filled syringe.
SIDE EFFECTS The most common side effects of Rebif therapy include flu-like symptoms
(fatigue, chills, fever, muscle aches, and sweating) and injection site reactions
(swelling, redness, discolouration, and pain). Most of these symptoms
tend to improve over time.
Less common side effects include some liver, blood and thyroid problems,
as well as allergic reactions and depression.
NEUTRALIZING ANTIBODIES Some people taking a beta-interferon therapy develop neutralizing anti-
bodies (NAb). It is not known if NAbs completely “neutralize” the clinical
benefits of therapy. Some research has found that a higher NAb level
may be associated with a lesser treatment effect. Studies are continuing
in this area, as is the development of a standardized NAb test.
DRUG IDENTIFICATION NUMBER (DIN)
Rebif 22 mcg 02237319
Rebif 44 mcg 02237320
Rebif Initiation Pk 02281708
Rebif 66 mcg Multi-dose 02318253
Rebif 132 mcg Multi-dose 02318261
COST REIMBURSEMENT Much of the cost can be reimbursed through private and group health
plans for people who meet the prescribing criteria, and through provincial
drug programs for individuals who meet the prescribing criteria.
In addition, a program called the Multiple Support Program is available
to assist persons in obtaining funding for Rebif therapy. For more information
on this program, contact 1-888-677-3243 (English) or
1-877-777-3243 (French).
REIMBURSEMENT CRITERIA Assistance with treatment costs varies among provinces and private
insurance companies. In most cases, to be reimbursed an individual
must have active relapsing-remitting MS (at least 1 or 2 MS attacks in the
1 or 2 years prior to starting treatment) and be ambulatory. The exact
definition of “ambulatory” varies among the provincial drug programs and
private/group insurance plans. For more information on reimbursement,
please contact your nearest division office at 1-800-268-7582, or your
provincial government program office (telephone numbers are listed under
For more information, Provincial Drug Programs).
CLINICAL TRIAL RESULTS
Clinical Trials
Note: Numerous clinical trials have been conducted for each of the
disease-modifying therapies. The clinical trials included in this summary
are those that have led to Health Canada approval for the therapy to be
prescribed and sold in Canada, or that have led to provincial health
ministries agreeing to reimburse the cost of that therapy or to make a
significant change to the reimbursement criteria.
Clinical Trials in Relapsing-Remitting MS
PRISMS Study PRIS
MS: Prevention of Relapses and Disability by Interferon beta-1a
Subcutaneously in Multiple Sclerosis
The PRISMS study compared the effects of Rebif at two doses (44
mcg and 22 mcg, three times per week) with placebo (a treatment
that has no active medication) in 560 persons with relapsing-remitting
MS. At 2 years, both doses of Rebif were shown to be more effective
than placebo in reducing the number and frequency of relapses.
With the higher dose of Rebif, the number of relapses was reduced
by about one-third. Rebif also delayed the progression of disability,
and a larger proportion of people were relapse-free with treatment
compared to placebo.13 [PRISMS Study Group. Lancet 1998; 352:
1498-1504] A separate report on MRI results found that Rebif
reduced the number of brain lesions compared to placebo.14 [Li
et al. Ann Neurol 1999; 46: 197-206]
Clinical Trials: Single Event Suggestive of MS
ETOMS Study
ETOMS: Effect of Early Treatment on Conversion to Definite MS
This study examined the effects of Rebif on the occurrence of
MS attacks in 308 persons who were at risk of developing clinically
definite MS, but who were not yet diagnosed with the disease.
After 2 years of treatment, fewer persons in the Rebif group
developed clinically definite MS (34%) compared to those in the
placebo group (45%), which represents a 24% reduction in risk.
Rebif was also found to have a positive effect on the relapse
rate and MRI measures compared to placebo.15 [Comi et al. Lancet
2001; 357: 1576-1582]
Clinical Trials in Secondary-Progressive MS
SPECTRIMS Study
SPECTRIMS: Secondary-Progressive Efficacy Clinical Trial of Recombinant
Interferon beta-1a in MS
In the SPECTRIMS study, 618 persons with secondary-progressive
MS were treated with either Rebif or placebo for 3 years. The
study found that Rebif did not slow disease progression in people
with secondaryprogressive MS. Rebif treatment was associated
with fewer relapses.16 [SPECTRIMS Study Group. Neurology 2001;
56: 1496-1504] Rebif was also associated with fewer brain lesions
as measured by MRI.17 [Li et al. Neurology 2001; 56: 1505-1513]
CURRENT CLINICAL TRIALS
A number of clinical trials involving the five disease-modifying therapies
are underway. The studies are examining the effectiveness at different
doses and the possible benefits of combining therapies. For more information
about clinical trials, please visit the MS Society of Canada website
by going to www.mssociety.ca and click on Research.
PHARMACEUTICAL COMPANY EMD Serono Canada Inc. 1075 North Service
Rd W., Suite 100 Oakville, Ontario L6M 2G2
FURTHER INFORMATION Further information for persons with MS is
available through the Multiple Support Program at 1-888-677-3243
(English) or 1-877-777-3243 (French).
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Tysabri
Tysabri (natalizumab) is a type of protein called a monoclonal antibody that is produced from
mammalian cells using recombinant DNA techniques (a series of procedures used to join together
DNA segments). Tysabri is the first in a class of agents called selective adhesion molecule inhibitors.
In MS, inflammatory T cells enter the central nervous system by attaching to the blood-brain barrier
with “sticky molecules”, called alpha-4 integrins. Tysabri blocks alpha-4 integrin and prevents T cells
from entering the central nervous system, where they cause inflammation and damage to myelin (the
insulating material that protects nerves and helps them work properly).
INDICATIONS AND USE Health Canada approved Tysabri in 2006 for people with relapsing-
remitting MS to reduce the frequency of relapses, delay the progression
of disability and reduce the number and volume of brain lesions seen on
magnetic resonance imaging (MRI).
Tysabri is indicated as a monotherapy (not combined with other therapies).
It is generally recommended for people with MS who have not responded
adequately to other disease-modifying therapies or who are unable to
tolerate them. This is because of an increased risk of progressive multifocal
leukoencephalopathy (PML). PML is a rare brain disease caused by the
JC virus that can cause severe disability or death. The condition usually
affects people with suppressed immune systems. Three cases of PML
were reported in clinical trials of Tysabri. There were two deaths: one in
a person with MS who was also taking Avonex, and one in a person with
Crohn’s disease who was also taking immunosuppressants. Ten additional
cases of PML have been reported to date (July 2009). The risk of PML in
people taking Tysabri has been estimated to be 1 in 1000 (0.1%) during
18 months of treatment.18 A large-scale study (TYGRIS) is currently investigating
the risk of PML in people receiving natalizumab monotherapy for
several years.There are no known treatments if PML occurs. The drug’s
manufacturers recommend that people who take Tysabri should enrol in
the Canadian Tysabri Care Program at 1-888-827-2827.
DOSAGE The recommended dose of Tysabri is 300 mg every 4 weeks.
ADMINISTRATION Tysabri is administered as an intravenous (into the vein) injection over
time (an infusion) in a specialized infusion centre by a health professional.
SIDE EFFECTS The most common serious side effects of Tysabri therapy are infections
and allergic reactions (rash, swelling, difficulty breathing). Three cases of
PML, including 2 deaths, have been reported. Treatment may also be
associated with infusion-related reactions (headache, dizziness, fatigue,
rash). Less common side effects include anemia, cough, muscle cramps
and depression.
Treatment with Tysabri (natalizumab) has been associated with an
increased risk of progressive multifocal leukoencephalopathy (PML).
PML can cause disability or death.
Healthcare professionals must monitor people on Tysabri for any new
sign or symptom that may be suggestive of PML. Tysabri should be
withheld immediately at the first sign or symptom suggestive of PML. |
NEUTRALIZING ANTIBODIES Some people taking Tysabri develop “neutralizing” antibodies (NAb).
Persistent NAbs to Tysabri are associated with a lesser treatment effect
and an increased risk of hypersensitivity reactions and/or infusion-related
reactions (rigors, nausea/vomiting and flushing). Antibody testing should
be performed if NAbs are suspected. The occurrence of NAbs may be
transient. If they persist, discontinuation of treatment should be considered.
DRUG IDENTIFICATION NUMBER (DIN) 02286386
COST REIMBURSEMENT Private and group health plans may provide some coverage for people
who meet the prescribing criteria. Financial assistance through the
Canadian Tysabri Care Program may be available to people who
cannot afford the drug. For more information, call 1-888-827-2827.
REIMBURSEMENT CRITERIA Assistance with treatment costs varies among provinces and private
insurance companies. In most cases, to be reimbursed an individual
must have active relapsing-remitting MS (at least 1 or 2 MS attacks in the
1 or 2 years prior to starting treatment) and be ambulatory. The exact
definition of “ambulatory” varies among the provincial drug programs and
private/group insurance plans. For more information on reimbursement,
please contact your nearest division office at 1-800-268-7582, or your
provincial government program office (telephone numbers are listed under
For more information, Provincial Drug Programs).
CLINICAL TRIAL RESULTS
Clinical Trials
Note: Numerous clinical trials have been conducted for each of the
disease-modifying therapies. The clinical trials included in this summary
are those that have led to Health Canada approval for the therapy to be
prescribed and sold in Canada, or that have led provincial health ministries
to agree to reimburse the cost of that therapy or to make a significant
change to the reimbursement criteria.
Clinical Trials in Relapsing-Remitting MS
AFFIRM Study
AFFIRM: Natalizumab Safety and Efficacy in Relapsing Remitting
Multiple Sclerosis
This clinical trial involved 942 people with relapsing-remitting
MS who were treated with either Tysabri or placebo (a treatment
that has no active medication) for over 3 years. Results of the
study showed that Tysabri reduced the risk of sustained progression
of disability compared to placebo. Tysabri reduced the annual
relapse rate by 68% compared to placebo and also reduced the
number of brain lesions on MRI.19 [Polman et al. N Engl J Med
2006; 354: 899-910]
SENTINEL Study
SENTINEL: Safety and Efficacy of Natalizumab in Combination with
Interferon
Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis
This study examined whether the combination of Tysabri and Avonex
was safe and more effective than Avonex alone in people who were
continuing to have relapses while on Avonex monotherapy. A total
of 1,171 people taking Avonex for relapsing-remitting MS were
treated with Tysabri or a placebo infusion for up to 120 weeks.
The study was stopped one month early after two cases of PML
had been reported. At 1 and 2 years, the annual relapse rate
was reduced about 54% with the Tysabri/Avonex combination compared
to Avonex alone. Combination therapy also reduced the probability
of disease progression at 2 years, and reduced the number of
brain lesions seen on MRI compared to Avonex alone.20 [Rudick
et al. N Engl J Med 2006; 354: 911-923]
CURRENT CLINICAL TRIALS A number of clinical trials involving the five disease-modifying therapies
are underway. The studies are examining the effectiveness at different
doses and the possible benefits of combining therapies. For more information
about clinical trials, please visit the MS Society of Canada website
by going to www.mssociety.ca and click on Research.
PHARMACEUTICAL COMPANY Biogen Idec Canada Inc. 3 Robert Speck
Parkway Mississauga, Ontario L4Z 2G5
FURTHER INFORMATION Further information for persons with MS is
available through the Canadian Tysabri Care Program at 1-888-827-2827.
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References
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Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular
interferon beta-1a for disease progression in relapsing multiple
sclerosis.
The Multiple Sclerosis Collaborative Research Group (MSCRG).
Ann Neurology 1996; 39: 285-294.
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Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon
beta-1a therapy initiated during a first demyelinating event
in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;
343: 898-904.
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The IFNB Multiple Sclerosis Study Group. Interferon beta-1b
is effective in relapsing-remitting multiple sclerosis. I.
Clinical results of a multicenter, randomized, double-blind,
placebo-controlled trial. Neurology 1993; 43: 641-643.
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Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting
multiple sclerosis. II. MRI analysis results of a multicenter,
randomized, double-blind, placebo-controlled trial. UBC MS/MRI
Study Group and the IFNB Multiple Sclerosis Study Group.
Neurology 1993; 43: 662-667.
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European Study Group on Interferon Beta-1b in Secondary-Progressive
MS. Placebo-controlled multicentre randomised trial of interferon
beta-1b in treatment of secondary-progressive multiple sclerosis.
Lancet 1998; 352: 1491-1497.
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Miller DH, Molyneux PD, Barker GJ, et al. Effect of interferon-beta1b
on magnetic resonance imaging outcomes in secondary progressive
multiple sclerosis: results of a European multicenter,
randomized, double-blind, placebo-controlled trial. Ann Neurol
1999; 46: 850–859.
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Kappos L, Polman C, Pozzilli C, et al. Final analysis of
the European multicenter trial on IFNbeta-1b in secondary-progressive
MS. Neurology 2001; 57: 1969-1975.
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North American Study Group on Interferon Beta-1b in Secondary
Progressive MS. Interferon beta-1b in secondary progressive
MS: results from a 3-year controlled study. Neurology 2004;
63: 1788-1795
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Kappos L, Polman CH, Freedman MS, et al. Treatment with
interferon beta-1b delays conversion to clinically definite
and McDonald
MS in patients with clinical isolated syndromes. Neurology
2006; 67: 1242-1249.
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Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces
relapse rate and improves disability in relapsing-remitting
multiple sclerosis: results of a phase III multicenter, double-blind
placebocontrolled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45: 1268-1276.
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Comi G, Filippi M, Wolinsky JS. European/ Canadian multicenter,
double-blind, randomized, placebocontrolled study of the
effects of glatiramer acetate on magnetic resonance imaging-measured
disease activity and burden in patients with relapsing multiple
sclerosis. European/ Canadian Glatiramer Acetate Study Group.
Ann Neurology 2001; 49: 290-297.
Comi G. Treatment with glatiramer acetate delays
conversion to clinically definite multiple sclerosis
(CDMS) in patients with clinically isolated syndromes.
Abstract LBS.003. 60th annual meeting of the
American Academy of Neurology, Chicago IL,
April 12-19, 2008.
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PRISMS Study Group. Randomised double-blind placebo-controlled
study of interferon beta-1a in relapsing/remitting multiple
sclerosis. Lancet 1998; 352: 1498-1504.
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Li DKB, Paty DW, and the UBC MS/MRI Analysis Research
Group and the PRISMS Study Group. Magnetic resonance imaging
results of the PRISMS trial: a randomized, double-blind, placebo-controlled
study of interferon-beta1a in relapsing-remitting multiple
sclerosis. Ann Neurol 1999; 46: 197-206.
-
Comi G, Filippi M, Barkhof F, et al. Effect of early interferon
treatment on conversion to definite multiple sclerosis: a
randomised study Lancet 2001; 357: 1576-1582.
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SPECTRIMS Study Group. Randomized controlled trial of
interferon beta-1a in secondary progressive MS. Neurology
2001; 56: 1496-1504.
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Li DKB, Zhao GJ, Paty DW, et al. Randomized controlled
trial of interferon beta-1a in secondary progressive MS: MRI
results.
Neurology 2001; 56: 1505-1513.
-
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation
of patients treated with natalizumab for progressive multifocal
leukoencephalopathy. N Engl J Med 2006; 354: 924-933.
-
Polman CH, O’Connor PW, Havrdova E, et al. A randomized,
placebo-controlled trial of natalizumab for relapsing multiple
sclerosis. N Engl J Med 2006; 354: 899-910.
-
Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab
plus interferon beta-1a for relapsing multiple sclerosis.
N Engl J
Med 2006; 354: 911-923.
The drug information contained in this publication has
been obtained from the manufacturers’ product
monographs. Consult the package insert for more
detailed information about the product’s indications,
contraindications, medical use and side effects. If you are
taking any of the medications listed above, do not change
the dose or stop taking your medication without
consulting your physician first.
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For more information
PROVINCIAL DRUG PROGRAMS
Alberta
Alberta Blue Cross: 1-800-661-6995
British Columbia
Pharmacare Special Authority Process: 1-800-554-0250
Manitoba
Pharmacare Exceptional Drug Status: (204) 788-6388
New Brunswick
MS Prescription Drug Program: 1-800-332-3692 or (506) 867-4515
Newfoundland and Labrador
Prescription Drug Program: (709) 729-6507
Nova Scotia
Special MS Therapy Program MS Clinic: (902) 422-7817
Ontario
Ontario Drug Benefits Section 8 Mechanism: 1-866-811-9893 or
(416) 327-8109
Prince Edward Island
MS Program: 1-877-577-3737 or (902) 368-4947
Québec
Régie de l’assurance-maladie du Québec (RAMQ) — service
de l’expertise pharmaceutique:
1-800-561-9749 or (514) 864-3411
Saskatchewan
MS Drugs Program: (306) 655-8400
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