The newer drugs for treating multiple sclerosis have had a dramatic effect on the way that new products are assessed in the NHS. This latest article in our series explores some of the issues surrounding these treatments
Multiple sclerosis (MS) is a slowly progressive, immunologically mediated disease of the central nervous system, characterised by inflammation and demyelination of white matter in the brain and spinal cord. This leads to a large number of signs and symptoms which can differ greatly between patients. Common problems include weakness affecting the arms and legs, spasticity, unco-ordinated speech, tremor and altered sensation, including paraesthesia and a feeling of burning, tearing and numbness in the limbs, trunk and face. Other problems include urinary incontinence, constipation, abnormal eye movements, optic neuritis (pain in one eye followed by visual disturbances and, rarely, partial blindness), cognitive impairment, depression and sexual dysfunction. Exposure to excessive heat (eg, bathing in hot water) and exercise commonly accentuates symptoms.
The disease is more common in women than men, and usually presents between the ages of 20 to 35 years. It is estimated that there are 80,000 patients with multiple sclerosis in the UK, with approximately 2,500 new cases per year.
The course of MS is highly varied and unpredictable. Many patients lead self-sufficient, productive lives, while others are severely disabled. The majority (80 per cent) present with relapsing/remitting multiple sclerosis (RR-MS), in which episodes of increased disability occur at random and for an unpredictable period, with a stable course in between. Recovery is invariably slower than the onset of an attack and may be incomplete. About 5 per cent of patients will remain symptom-free for over 20 years between their initial attack and their first relapse. However, the majority of patients will, at a later stage, enter a slowly progressive phase of the disease, accumulating varying degrees of disability over time. This is known as secondary progressive multiple sclerosis (SP-MS).
A minority of patients have benign MS, a form of multiple sclerosis that is not disabling. Their disease follows a relapsing/remitting pattern but with complete recovery from each episode. About 10 per cent of patients have no relapses but gradually progress over time, usually becoming wheelchair dependent. This is primary progressive multiple sclerosis (PP-MS).
The life expectancy of patients with multiple sclerosis is little different from the general population and a high proportion of patients die from unrelated causes. Occasionally, however, patients die from respiratory failure if a massive demyelination occurs in the medulla.
There are several scales for measuring the disability caused by multiple sclerosis. The most commonly used is the Expanded Standard Disability Status Scale (EDSS). This scale extends, in increments of 0.5, from 0 (normal neurology) to 10 (death from multiple sclerosis complications). Each point on the scale is defined by a functional score (0=normal, 6=maximum impairment) for pyramidal, cerebellar, brain stem, sensory, bladder, bowel, visual and mental functions. EDSS scores of 5 to 9.5 also include a score for impairment of ambulation.
Until recently, there has been no specific treatment for multiple sclerosis. Therapy has revolved around symptomatic control and the management of acute episodes with steroids. Symptomatic treatments may include analgesics, muscle relaxants, antidepressants and drugs for preventing urinary incontinence. Recent controversial therapies include the use of interferon-beta and glatiramer acetate (formerly known as copolymer-1) to prevent relapses, as well as the use of cannabis to control the pain and spasticity often associated with the disease.
Interferon-beta The first product licence to be granted for the use of interferon-beta as a treatment for multiple sclerosis was for interferon beta-1b (Betaferon). Although it became licensed for use in the management of RR-MS in early 1996, only 2 per cent of UK patients have been treated with the drug. This compares with 10 per cent in most European countries and the US. The difference may be because UK neurologists believe that the published clinical evidence is inadequate. This has encouraged health authorities to restrict funding by setting tight patient entrance criteria. Recently, evidence for the use of this group of drugs has become clearer for patients with RR-MS. Data have also been published showing efficacy in those with SP-MS. With 50 per cent of RR-MS patients developing SP-MS within 10 years of diagnosis, the number of patients now eligible for this therapy has risen dramatically.
| Table 1: Summary of trial results for treatment of multiple sclerosis with interferon beta | |||||
| Trial* | Duration | Number of patients; type of MS |
Type of interferon | Active arm | Relapse rate/year |
| IFBN,1 1993 | 2 years | 372; RR-MS | Beta-1b (Betaferon) |
1.6mIU or 8mIU | Placebo 1.27 |
| sc alternate days | 1.6mIU 1.17 | ||||
| 8mIU 0.84, P=0.0001 | |||||
| 8mIU v 1.6mIU, P<0.)1) | |||||
| MSCRG,2 1996 | 2 years | 301; RR-MS | Beta-1a (Avonex) | 6mIU im weekly | Placebo 0.9 |
| 6mIU 0.61, P=0.03 | |||||
| Relapse rate reduced at 2 years |
|||||
| PRISMS,31998 | 2 years | 560; RR-MS | Beta-1a (Rebif) | 6mIU or 12 mIU sc | Placebo 2.56 |
| three times a week | 6mIU 1.82 | ||||
| 12mIU 1.73, P<0.005 | |||||
| Time to confirmed disability |
|||||
| Placebo 11.9 months | |||||
| 6mIU 18.5 months, P<0.005 | |||||
| 12mIU 21.3 months, P<0.005 | |||||
| European SG,4 1998 |
Stopped at 2 years |
718; SP-MS | Beta-1b (Betaferon) |
8mIU alternate days | % with confirmed EDSS progression |
| Placebo 49.7 | |||||
| Interferon 38.9, P=0.0048 | |||||
*All trials were double blind, placebo controlled, multicentre and randomised
Clinical trial data for RR-MS The first study1 compared interferon beta-1b (Betaferon) 8mIU or 1.6mIU given on alternate days, subcutaneously, with placebo in RR-MS patients. The outcome was a 34 per cent reduction in relapse rate after two years in the 8mIU arm compared with placebo. There was an 8 per cent reduction in relapse rate in the 1.6mIU group over two years. The effects on progression of disability, which are probably the ultimate aim of therapy, were not significant.
A second study2 evaluated interferon beta-1a (Avonex), 6mIU given weekly by intramuscular injection over one to two years but only in patients with mild RR-MS. The result was a non-significant reduction in relapse after one year, with a significant 18 per cent reduction by the end of two years (P<0.005). There was also a significant delay in six month confirmed progression by one point on the EDSS, a result not demonstrated by the first study. Both of these studies have been open to much criticism. This included the fact that numbers of patients were low, many were lost to follow up and analysis was not by intention-to-treat.
The most recent trial3 showed that both 6mIU and 12mIU of interferon beta-1a (Rebif) significantly reduced relapse at one and two years. In the 6 and 12mIU group, time to first relapse was prolonged by three and five months, respectively, with the proportion of relapse-free patients significantly increasing (P<0.05). The study was well conducted, analysed well and demonstrated a delay in progression of disability, as well as a dose related effect.
Clinical trial data for SP-MS While initial attention focused on RR-MS, a European group targeted those with SP-MS to ascertain whether similar benefits could be established with interferon beta-1b (Betaferon).4 The primary endpoint showed the time taken to acheive a significant reduction in confirmed EDSS progression (increase of one point; P=0.0008), with delays in secondary endpoints such as time to become wheelchair bound, annual relapse rate and lesion volume detected by magnetic resonance imaging (MRI). This landmark study has created much excitement within neurology, as good clinical evidence now exists for interferon beta-1b (Betaferon) in both RR-MS and SP-MS.
Quality of life dataThe extensive side effect profile of the interferons, which includes fever, myalgia, fatigue, pain or swelling at the injection site, and depression or suicidal thoughts, has resulted in a cost-benefit analysis being conducted. The Extended Quality-Adjusted Time Without Symptoms and Toxicity (Q-TWiST) concluded that intervention with interferon beta-1b (Betaferon) in the management of RR-MS does not significantly improve quality of life.5
The rationale for this statement in the light of good clinical evidence is based on an evaluation of the World Health Organisation's definition of quality of life6 (QOL) over a 12 month period.
Analysis was conducted to evaluate the impact of interferon beta-1b (Betaferon) on QOL for seven separate dimensions, with the validated Q-TWiST analysis performed to assess change over time multidimensionally. Neurological symptoms, disability and psychosocial disabilities all improved in the treatment group, but this was dramatically offset by a significant decrease in functional status. Work disability, mental health and relapse all remained consistent during the study.
Numbers needed to treatEstablishing numbers needed to treat (NNT) can also be a useful tool, especially where drug costs are high. They have recently been calculated at 13 (7.2-49, 95 per cent CI) to prevent becoming wheelchair bound over two years (ie, 13 patients would need to be treated to prevent one becoming wheelchair bound), 9.2 (5.5 to 28) to prevent confirmed progression and 11 (6.0 to 46) to prevent moderate and severe relapse in SP-MS.7 With drug costs at around £10,000 per annum, a significant amount of resource would need to be directed into this area for results to be seen. In practical terms, the cost over two years of preventing one patient from experiencing confirmed disease progression would be around £200,000
Glatiramer acetate (copolymer-1)Glatiramer acetate is a mixture of synthetic peptides composed of four amino acids. Research into its use in multiple sclerosis dates back to the early 1980s, although most of the trials included only small numbers of patients. Glatiramer acetate was approved by the Food and Drug Administration (FDA) in the United States in December, 1996 and was launched in April, 1997. It is currently awaiting licensing by the UK authorities and may be available before the end of 1999. The cost is likely to be similar to that of interferon beta.
Clinical trial data for RR-MS There is now some evidence that glatiramer acetate can influence the immune response in RR-MS, causing a reduction in the number of acute exacerbations. In a double-blind trial,8 251 patients with RR-MS were randomised to receive glatiramer acetate (n=125) 20mg daily by subcutaneous injection or placebo (n=126). After two years the relapse rate was 1.19 (&#plusmn;0.13) for patients randomised to active treatment and 1.68 (&#plusmn;0.13) for those receiving placebo. This represents a 29 per cent reduction in relapse rate due to glatiramer acetate. When disability was measured using the EDSS, glatiramer acetate did not significantly reduce disability. However, when the number of patients who worsened, remained the same or improved by one or more EDSS points was evaluated after two years, significantly more patients receiving glatiramer acetate improved while more receiving placebo worsened. There was no significant effect on MRI measures of disease activity.9 Upon conclusion, this study was extended for a further 11 months.10 The extension showed that the benefits of glatiramer acetate were still present after nearly three years. Both of these trials8,10 showed that glatiramer acetate was well tolerated. The most common side effects included mild injection site reactions and a transient systemic reaction characterised by flushing, chest tightness, palpitations, dyspnoea and anxiety. A meta-analysis of the cumulative safety experience of glatiramer acetate11 confirmed these findings.
Although the 1995 study8 showed no significant change in disease activity on MRI, a more recent trial has contradicted this.12 Although small (n=10), it demonstrated a 57 per cent reduction in the frequency of new legions (0.92 versus 2.2 lesions per month) and a 49 per cent reduction per month in the mean area (ie, size) of lesions (22mm2 versus 43mm2). Patients acted as their own control, with a pre-treatment run-in phase of nine to 27 months followed by 10 to 14 months of glatiramer acetate.
Clinical trial data for PP-MSThere is more clinical trial data awaiting presentation and publication and a new trial evaluating the use of glatiramer acetate in PP-MS has just started. This trial will not be completed until 2002 and is aiming to recruit 900 patients.
CannabisCannabis has been used for hundreds of years as an intoxicant and, more recently, by patients suffering from multiple sclerosis, to provide symptomatic relief from spasticity and pain. It contains 66 cannabinoids, of which delta-9-tetrahydrocannabinol (THC) is the major active ingredient. While some anecdotal evidence13-16 of its benefits exists, there are few published trials which confirm its efficacy.
There is also evidence that cannabis impairs posture and balance.17 In people not affected by multiple sclerosis, both smoked and oral THC have been associated with distortion of reality, euphoria, dysphoria, changes in concentration and co-ordination, hallucinations, depersonalisation, paranoia and a loss of memory retrieval.18 Long-term exposure can affect the respiratory system and cause cardiovascular disturbances such as tachycardia and hypotension.18 Smoking cannabis exposes patients to 50 per cent higher levels of benz-α-pyrene, a potent carcinogen, than from tobacco smoke exposure.19 This can result in carboxyhaemoglobin levels that are five times higher20 and tar levels that are three times greater20 than those produced by cigarette smoking. The controversy that has arisen over the use of cannabis as a therapeutic agent in multiple sclerosis is that it is an illegal substance. For decriminalisation to take place, there must be clear evidence that cannabis is safe and effective as a medicine. This will only be confirmed with the completion of controlled trials. For these to take place and for cannabis to be categorised as a medicine it is necessary to have standardised pharmaceutical products. This would rule out the use of crude cannabis. With the recent discovery of a cannabinoid receptor and the mapping of brain areas with an affinity for the drug, it may be possible to develop synthetic cannabinoids with increased therapeutic benefits and minimal toxicity.18
More trial data with interferon beta and glatiramer acetate are expected shortly and there is no doubt that the results are likely to increase prescribing by neurologists for multiple sclerosis. If the total population of 80,000 MS sufferers in the UK were treated with interferon beta, the cost to the NHS would be likely to approach £1,000m, nearly a quarter of the primary care drug budget for England and Wales. Many will question whether this kind of resource should be used for pharmacological intervention, or to improve overall services for all MS patients.
References1. The IFNB multiple sclerosis study group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis; clinical results of a multicentre, randomised, double-blind, placebo-controlled trial. Neurology 1993;43:655.
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Mr Green is senior pharmacist for the medical directorate at Brighton Health Care NHS Trust and Mr Mynes is senior pharmacist, education and training at Brighton Health Care NHS Trust