There have been more advances in treating multiple sclerosis (MS) in the last 21 years than in the previous century – there were no treatments at all until 1993. But researchers fear that the traditional big-pharma model for developing new therapies may be unsustainable due to cost.
The Association of the British Pharmaceutical Industry (ABPI) says that it typically costs £1.5 billion to bring a single drug to market. So, instead of investigating new compounds, researchers are relying more on drugs developed to treat other conditions.
For example, the MS-SMART trial is comparing three drugs against a dummy treatment or placebo to see if they slow or halt disability. Amiloride, Ibudilast and Riluzole are respectively used to treat heart disease, asthma (in Japan) and motor neurone disease. All three have the potential to protect nerves from the damage of MS and ultimately stop or slow secondary progression, the worst form of the disease.
Testing all three drugs at once is much quicker and cheaper than running three individual trials because unlike new compounds, “repurposed drugs” already have well-established safety records.
Using repurposed drugs also avoids the need to find new compounds. The ABPI claims that for every marketed medicine that makes enough money to pay for its development, 25,000 compounds are tested. On average, 25 of these go into clinical trials that typically involve four different phases and thousands of patients. It can take 12 years or more to bring a drug to market and much longer than that to discover what may work. The multi-billion-dollar game of pharmaceutical roulette is more drip drip than big bang.
The discovery in 1957, for example, of naturally occurring interferon led to the first treatment for MS, but this did not become generally available until 1993. So called because it interferes with virus reproduction, beta interferon is a blockbuster. Beta interferon-based MS treatments include Avonex, which generated sales of $751.5 million in 2013 for Biogen Idec, whose total revenue exceeded $190 billion, representing a 39 per cent rise.
A further five drug therapies emerged between 1993 and 2004. Five more have come on stream in the last five years. In April the National Institute for Health and Care Excellence (NICE) approved the most expensive of these new products for NHS use.
Instead of investigating new compounds, researchers are relying more on drugs developed to treat other conditions
Lemtrada (Alemtuzumab) costs £56,000 for just two sets of infusions over one year, but in the long run this may actually be cheaper than pre-existing treatments costing £6,000 to £12,000 a year. Marketed under trade names including Campath (after the Department of Pathology at the University of Cambridge), MabCampath and Campath-IH, Alemtuzumab also treats chronic lymphocytic leukaemia and other cancers.
Like other effective new therapies, Lemtrada carries a greater risk of side effects. These include so-called secondary auto-immunity, which affected 47.7 per cent of patients, mostly with thyroid problems, in a seven-year follow-up study published earlier this year.
Other repurposed drugs offer far cheaper options and the prospect, like the drugs in the MS-Smart trial, of developing treatments for secondary progressive MS (SPMS) – the Holy Grail of MS research. More than half of patients with the relapsing-remitting disease ultimately develop SPMS. This can mean life in a wheelchair and premature death as MS reduces life expectancy by eight years, and death is more likely to occur in advanced MS
The Lancet medical journal recently reported that a statin has been found to significantly reduce brain shrinkage in a study of people with SPMS. Simvastatin is usually used to lower cholesterol levels in people at risk from heart attack and stroke.
The culmination of two decades of research, this seven-year investigation was a so- called phase II “proof of concept” study with 140 people, comparing simvastatin with a placebo or dummy treatment. Researchers are now hoping for a successful Phase III study, the prerequisite for a marketing licence. This may take several years, during which time treatment will be largely restricted to clinical-trial patients.
Lead author of The Lancet study, Dr Jeremy Chataway, of University College London, reported that the treatment had been very well tolerated and reduced the rate of brain shrinkage by about 40 per cent, which was “really quite dramatic”.
Researchers are also investigating combination therapies or cocktails of more than one drug. Klaus Schmierer, of The Blizard Institute at Barts and the London School of Medicine, says: “What we really need are combinations of drugs that are both neuro-protective and prevent inflammation.”
Developing combination therapies bypasses the large cost of developing new compounds. More than ten different combinations have been tested in recent clinical trials. For example, beta interferon has been tested in combination with a statin. No one knows exactly how interferons work in treating MS, but naturally occurring interferons play a key role in controlling immune responses. Beta interferon 1 is believed to control the abnormal immune responses that apparently appear in MS, while statins can reduce brain shrinkage.
These approaches may help to delay or even prevent the development of SPMS. Dr Schmierer adds: “It may be possible to produce an effective generic combination therapy at a tenth – or even less – of the price of a new branded therapy.”
Branded therapies are protected under patent rights to allow drug companies to recoup development costs and make profits. When patents on drugs expire other companies can market cheaper generic versions. In the UK a standard patent lasts for 20 years. It may take ten to fifteen years to develop a drug, giving a company limited patent protection. Many MS drug patents have expired recently or are about to, opening up a huge generic market as there are an estimated 2.5 million people with MS worldwide.
Generic alternatives will reduce costs, but patients who may fare better on newer branded products may be prescribed cheaper generics. Whatever happens, there will be unprecedented choice, maybe 20 or more different treatments.
But when patients are treated may be as important as what they are treated with. As Dr Schmierer says: “We now know it is critical to provide early treatment to have a big impact on MS.”