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Published on 16 October 2015

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Latest treatments in the management of MS multiple sclerosis

 

 

The advent of disease-modifying therapies in the management of multiple sclerosis has provided novel approaches in affecting the progression of the disease
David Hellens MPharm PgD IP
Specialist Pharmacist in Delirium, 
Dementia and Frailty and Lead Pharmacist in Neurosciences
Addenbrooke’s Hospital,
Cambridge University Hospitals NHS Foundation Trust, UK
Email: david.hellens@addenbrookes.nhs.uk
Multiple sclerosis (MS) is a common central nervous system autoimmune disorder of unknown aetiology. It is characterised by scattered progressive demyelination of axons in the central nervous system, which results in deficits in motor control among other distinguishable symptoms, including imbalance and visual impairment.1 The lesions are perivenular in nature and have an established preference for specific sites within the brain and spinal cord, namely, the optic nerves, periventricular region, brainstem and its cerebellar connections and the cervical spinal cord.2
MS is a global issue. However, prevalence is directly proportional to the distance from the equator. At latitudes of 50–65 degrees north, which is from southern England to Iceland, prevalence is approximately 60–100 per 100,000 people. At latitudes less than 30 degrees north, the prevalence falls to less than 10 per 100,000 and at the equator is a rarity. Similar trends are noted in the southern hemisphere.2
MS phenotypes
There are four phenotypes that typically define the pathway of progression of MS. Analysis of the past course enables clinicians to attempt to forecast the future course. This is not only beneficial for the patients understanding of the disease and prognosis but also for deciding the most suitable pharmacotherapies.3
Relapsing-remitting MS (RRMS)
RRMS is the most prevalent phenotype thought to describe the initial course of 80% of patients with MS.4 Clearly distinct bouts of deteriorating neurologic function (flare-ups) are followed by partial or complete recovery (remissions), after which symptoms improve partially or completely and there is no ostensible advancement of disease.5
Secondary-progressive MS (SPMS)
SPMS emerges in approximately 65% of patients who were diagnosed at the outset with RRMS.4 Sporadic relapses and remission are observed as a general rule with disease progression in an established manner, although not inevitably at an increased rate.5
Primary-progressive MS (PPMS)
Steady deterioration in neurologic function from the outset is indicative of PPMS with no remission after the onset of the disease.3 Occurring in 10–20% of individuals, the rate of progression may vary over time with occasional plateaus and temporary, minor improvements.5
Progressive-relapsing MS (PRMS)
PRMS is the phenotype with the lowest prevalence and characterised as a steady deterioration in neurological function with the unfortunate addition of established exacerbating attacks.3 People with a diagnosis of PRMS may not recover following a relapse and progression often continues without remission.5
Drug treatments in the management of MS
Pharmacotherapy is one constituent of the multicomponent interventions in the management of MS. The three general categories of therapy include medications to treat relapses, medication that modifies the disease course and medications used to manage the symptoms of MS.
Relapses are routinely managed with pulse corticosteroid therapy over a few days. Evidence supports their effectiveness in accelerating recovery from a relapse although do not alter disease progression. The symptomatic management of MS is far-reaching and requires an individualised, patient-centred approach to therapy. Decisions are made depending on the presentation of deficits in balance, cognition, depression, erectile dysfunction, fatigue, foot drop, optic neuritis, pain, problems with walking, spasticity and spasms, speech problems and tremor.6
Medications shown to alter the disease course are the greatest motivation to people suffering with MS and there are several medications that remain in development through clinical trials that provide further encouragement. The disease-modifying drugs available in the UK decrease the incidence of relapses and have therefore only shown clinical benefit in people with RRMS and for a proportion with a diagnosis of SPMS. Unfortunately, they are not indicated in the phenotypes of progressive nature and care should therefore be centred on symptomatic therapies.6
The Risk Sharing Scheme in 2002 agreed to the use of beta interferons and glatiramer acetate as options in the management of relapsing MS based on evidence that although they ‘were not cost effective over the short-term, reducing disability over the longer-term might dramatically improve the cost effectiveness’.7 Since the advent of the Risk Sharing Scheme, there have been numerous disease-modifying therapies licensed for use in relapsing MS. Chronologically they include: natalizumab (2006) licensed for use in rapidly evolving severe RRMS; beta interferon 1b (Extavia; 2009); and Fingolimod (2011), licensed for use in rapidly evolving severe RRMS with two or more relapses per year, and for second-line therapy in people whose MS remains active, notwithstanding previous therapy with another of the disease-modifying medications.6 The influx of additional pharmacotherapies in 2014 was overwhelming and here we look to evaluate their benefits and use in practice.
Teriflunomide (Aubagio)
Approved by the National Institute for Health and Care Excellence (NICE) in March 2014, teriflunomide is ‘recommended as an option for treating adults with active RRMS (normally defined as two clinically significant relapses in the previous two years), only if they do not have highly active or rapidly evolving severe RRMS and the manufacturer provides teriflunomide with the discount agreed in the patient access scheme’8 as agreed with the Department for Health.
Teriflunomide’s mechanism of action is not fully understood. It is an anti-inflammatory immunomodulatory disease-modifying medication thought to diminish activated lymphocytes, thus reducing inflammation and destruction of myelin in the central nervous system. Beneficially, teriflunomide is administered orally as a 14mg tablet in a once-daily regime, which has the benefit in improving concordance in those people considered unsuitable for injectable therapies.
The clinical effectiveness of teriflunomide compared with placebo was considered in TEMSO, TOWER and a meta-analysis, which indicated a statistically significant decrease in adjusted annualised relapse rate in the favour of the treatment arm. TEMSO (teriflunomide 0.37 (95% CI 0.31–0.44), placebo 0.54 (95% CI 0.47–0.62), 31.5% relative risk reduction, p<0.001);9 TOWER trial (teriflunomide 0.32 (95% CI 0.27–0.38), placebo not stated; relative risk 0.637 (95% CI 0.512–0.793); p=0.0001).10
The cost of treatment per year, funded by the patient access scheme, is projected to be £13,500 per patient, although it is recognised that treatment length may vary depending on response to treatment and premature cessation of therapy. A home delivery service has been agreed to be provided at a cost to the manufacturer. The cost benefits per quality-adjusted life year (QALY) proved challenging to ascertain and NICE concluded that the most likely cost effectiveness estimate, given as an incremental cost effectiveness ratio, for teriflunomide compared with glatiramer acetate would be below £20,000 per QALY gained.11
Alemtuzumab (Lemtrada)
Approved in May 2014 by NICE, alemtuzumab is ‘recommended as an option, within its marketing authorisation, for treating adults with active RRMS’.12 Consequently, alemtuzumab can be implemented as an intervention at any point in the treatment pathway providing that the person has active RRMS.
The mechanism by which the antibody alemtuzumab rescues the rate of decline in RRMS is not precisely known. It causes obliteration of the B and T cells of the immune system by binding to proteins on their surface. Alemtuzumab is administered by intravenous infusion at 12mg per day for two treatment courses. The first course lasts five sequential days, followed one year later by a course over three sequential days.
The effectiveness of alemtuzumab was assessed in CAMMS223 and CARE-MS II. Although the clinical effectiveness was deemed somewhat uncertain due to the lack of clinical trials directly comparing other disease-modifying therapies, NICE concluded that ‘alemtuzumab was at least as effective as fingolimod and natalizumab for people with highly active RRMS despite beta interferon treatment and rapidly evolving severe RRMS respectively’.13 Consequently alemtuzumab is now licensed as an effective option in decreasing relapse rates with valuable outcome measures in disability at six months when compared with interferon beta 1a in active RRMS.
The cost of therapy is £7045 per 12mg vial, equating to approximately £56,000 for completing both courses of therapy. The cost benefits per QALY analysis by NICE concluded that the most likely cost effectiveness estimate, given as an incremental cost effectiveness ratio, for dimethyl fumarate compared with glatiramer acetate is likely to be between £13,600 and £24,500 per QALY gained.13
Dimethyl fumarate (Tecfidera)
Approved in August 2014 by NICE, dimethyl fumarate is ‘recommended as an option for treating adults with active RRMS (normally defined as two clinically significant relapses in the previous two years), only if they do not have highly active or rapidly evolving severe RRMS and the manufacturer provides dimethyl fumarate with the discount agreed in the patient access scheme’14 as agreed with the Department of Health. Consequently its use is limited to first line therapy only, or in people who exhibit no symptoms of progression but have terminated an alternative therapy due to adverse effects.
The defined mechanism of action of dimethyl fumarate is not fully understood. Inhibition of pro-inflammatory cytokines and adhesion molecules and promotion of anti-inflammatory effects is thought to reduce the incidence of relapses in patients with MS. Similar to teriflunomide, dimethyl fumarate is administered orally as a 120mg tablet in a twice-daily regime for one week, increasing to 240mg in a twice-daily regime thereafter providing the medication is well tolerated. To manage the transient side effects of gastrointenstinal disturbance and flushing, there is the option of temporarily reducing the dose to 120mg twice a day for up to a month.
The clinical effectiveness of dimethyl fumarate was considered in the DEFINE trial with a primary endpoint of the proportion of people with relapse at two years, and in the CONFIRM trial which measured the annualised relapse rate when compared to placebo. NICE acknowledged that analysis of the manufacturer’s data indicated that there was a statistically significant difference between dimethyl fumarate and placebo in that the treatment groups ‘reduced both the rate of relapses and the proportion of patients experiencing a relapse compared with placebo’.15
The cost of treatment per year, funded by the patient access scheme, is projected to be almost £18,000 per patient, although it is recognised that treatment length may vary depending on response to treatment and premature cessation of therapy. The cost benefits per QALY again proved challenging to ascertain and NICE concluded that the most likely cost effectiveness estimate, given as an incremental cost effectiveness ratio, for dimethyl fumarate compared with glatiramer acetate would be below £27,000 per QALY gained.15
Key points
  • There are four phenotypes that typically define the pathway of progression of multiple sclerosis (MS). Treatment decisions and appropriate interventions should be made depending based on diagnosis of phenotype.
  • Disease-modifying medications are not indicated for use in progressive forms of MS and management should be focused on symptomatic interventions.
  • Management of relapsing forms of MS should be based on clinical and cost effectiveness as outlined in the National Institute for Health and Care Excellence (NICE) guidelines, also considering the patients’ presenting symptoms and long-term prognostic benefits to therapy.
  • Peginterferon beta 1a (Plegridy) has been approved by the Scottish Medicines Consortium in January 2015 for use in NHS Scotland for the treatment of RRMS. The appraisal by NICE for the first pegylated form of beta interferon to be used in the management of MS is awaited.
References
  1. Berne R M, Levy MN. Physiology. St. Louis. Mosby, 2010.
  2. Kumar P, Clark M. Clinical Medicine. London. Saunders (W.B.) Co Ltd;2009.
  3. Lubdin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46(4):907–11.
  4. Compston A, Coles A. Multiple sclerosis. Lancet 2008;25;372(9648):1502–17.
  5. National Multiple Sclerosis Society. Types of MS. www.nationalmssociety.org/What-is-MS/Types-of-MS# (accessed 18 September 2015).
  6. Multiple Sclerosis Trust. Drugs and treatments used in the management of MS. Multiple Sclerosis Trust. www.mstrust.org.uk/atoz/drugs.jsp (accessed 18 September 2015).
  7. Palace J et al. UK multiple sclerosis risk-sharing scheme: a new natural history dataset and improved Markov model. BMJ Open 2014,4:e004073.
  8. National Institute for Health and Care Excellence. Teriflunomide for treating relapsing-remitting multiple sclerosis. Guidance. www.nice.org.uk/guidance/ta303/chapter/1-Guidance (accessed 18 September 2015).
  9. O’Connor P et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293–303.
  10. Confavreux C et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2014,3:247–56.
  11. National Institute for Health and Care Excellence. Teriflunomide for treating relapsing–remitting multiple sclerosis. Consideration of the evidence. www.nice.org.uk/guidance/ta303/chapter/4-Consideration-of-the-evidence (accessed 18 September 2015).
  12. National Institute for Health and Care Excellence. Alemtuzumab for treating relapsing remitting multiple sclerosis. Guidance. www.nice.org.uk/guidance/ta312/chapter/1-Guidance (accessed 18 September 2015).
  13. National Institute for Health and Care Excellence. Alemtuzumab for treating relapsing remitting multiple sclerosis. Consideration of the evidence. www.nice.org.uk/guidance/TA312/chapter/4-Consideration-of-the-evidence (accessed 18 September 2015).
  14. National Institute for Health and Care Excellence.. Dimethyl fumarate for treating relapsing remitting multiple sclerosis. www.nice.org.uk/guidance/ta320/chapter/1-Guidance (accessed 18 September 2015).
  15. National Institute for Health and Care Excellence. Dimethyl fumarate for treating relapsing remitting multiple sclerosis. Consideration of the evidence. www.nice.org.uk/guidance/ta320/chapter/4-Consideration-of-the-evidence (accessed 18 September 2015).


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