Politics: lessons from the simvastatin trial

What can we learn from the positive Simvastatin trial? #MSBlog #MSResearch

"At last it has been published; the MS-STAT study. Jeremy Chataway presented the results at the ECTRIMS meeting in Lyon, in October 2012. We have had a lot of discussion about these results on this blog in the past. The good news is that this phase 2 study shows that high dose simvastatin reduces the rate of brain atrophy in SPMSers and delays disease progression. Is this a eureka moment? No. Three issues need to be addressed. (1) How does simvastatin work? (2) Is there a dose effect? (3) Where to from here?"

"(1) How does simvastatin work? Why do I ask this? There have been several other trials of statins in MS that have been negative or equivocal. Some of these studies have used doses that are of similar potency to the dose used here, i.e. 80mg. Therefore is simvastatin working via MS-specific mechanisms, MS non-specific mechanisms but as a neuroprotective agent, or is it targeting the so called comorbidities such as vascular disease that may speed up MS disease progression. It is important to identify the mechanisms before this strategy is taken forward."

" (2) Is there a dose effect? 80mg per day is a very large dose and is more likely to be associated with side effects, in particular adverse effects on muscle function (weak muscles called a myopathy). It is important to know if lower doses are effective. This will allow dose titration to minimise side effects. In addition, the EMA and FDA tend to require a dose titration as part of any of development programme when they consider drugs for licensing."

"(3) Where to from here? Who is going to take simvastatin forward? With the current level of risk associated with drug development and the amount of regulatory red-tape it seems unlikely that an alternative, or competitor, to the current pharmaceutical industry model will emerge. The current big pharma model does not facilitate repurposing of existing drugs, i.e. the development of drugs that have been discarded or that have too short a patent life to encourage investment. Big Pharma may be tempted to innovate in areas where patent protection is achievable, but obviously show no interest in developing off-patent drugs for new indications. Simvastatin for progressive MS is just such an example. The questions at this point are: (i) Who is going to fund a phase III clinical development programme of simvastatin in progressive MS, for a drug that costs £2.06 per month (80 mg, 28-tab pack, British National Formulary)? The development costs will be many millions of pounds, even for investigator-led studies. Pharma did not even support the phase II study, so the likelihood of substantial pharma investment, for a drug out-of-patent is slim. (ii) Will regulatory approval be required for risk averse neurologists to prescribe simvastatin? Even if neurologists decide to prescribe simvastatin would NHS England and insurance companies pay for an unlicensed drug? (iii) Will regulatory approval of simvastatin require one or two phase III studies, as is currently required of Pharma? (iv) Even if a phase 3 programme was funded, who will take responsibility for licensing, and maintaining the license, for simvastatin for people with SPMS? (iv) Who will monitor safety aspects once approved? Without a licence would the health providers also be at risk of legal action should side-effects become manifest or if licenced products became available. As simvastatin is off-patent there is no incentive for an investor to undertake such studies. Will government funding agencies or medical charities step in to do this?"

"In 2012, The Wellcome Trust and the Department of Health launched a drug repurposing initiative as part of a “Health Innovation Challenge Fund”. Whilst this initiative is commendable, the funds available were simply not large enough to complete phase III clinical trials in slowly progressive neurological disorders and importantly – there is no allowance for subsequent funding to take the drug through the regulatory process to obtain and maintain a license. Furthermore there was no clear path other than getting pharma support, past clinical trials which is some way off delivering medicines to patients . In reality, the repurposing initiative is to fund proof-of-concept studies, presumably to find new targets using existing drugs that can then be exploited by Big Pharma with pro-drugs or new chemical or biological entities. However, without changing the regulatory framework there may be no incentive for this to happen. If it is not feasible to develop licensed drugs to the stage that they can actually be prescribed for a new indication, we surely cannot justify – neither ethically nor economically – the undertaking of such proof-of-concept studies. They become little more than an academic exercise, creating false hopes for people in desperate need of treatments. Although the National Institute of Clinical Excellence (NICE) should surely have no quarms about supporting the cost-effectiveness of cheap generic drugs, their role would become superfluous if non-expensive drugs became the norm. In contrast the Medical and Healthcare products Regulatory Agency (MHRA) has no interest in the cost of drugs. They concern themselves with safety and so are unlikely to support cost- cutting or creating any unfair advantage over their pharma paymasters."

"An alternative to the system Big Pharma currently uses is required that enable the repurposing of existing drugs to the point that doctors can actually prescribe such drugs to their patients. Firstly, regulators and politicians need to acknowledge that we have a problem. The time for reflection may be right; in this age of austerity when drug budgets are soaring, repurposing of existing drugs could and should help contain costs. The cost of the current Pharma model are simply too high to be sustainable in the long-term, certainly as long as society remains committed to the NHS’ core principles, including that healthcare “be free at the point of delivery”.

"Putting the issue of privatisation and private prescriptions of drugs to one side, one proposal could be a new tax or levy on the sale of pharmaceuticals to pay for the costs of non-profit drug development. However, this is unlikely to work if the navigation of the regulatory red-tape remains so complex and expensive. In addition, the skills needed to apply for, and maintain a license generally reside in industry. Hypothecated or ring-fenced taxation as a way of paying for initiatives may not work as spending of such revenues tends to inefficient and the electorate may not support it." 

"A market-driven solution would be preferable. However, to achieve this regulators and politicians need to lower the bar for the repurposing of drugs. Only then can repurposing be done by non-profit organisations and/or academic institutions, and partners from the pharmaceutical industry could be incentivised to contribute to this process. Governments could create such incentives in a similar way they did for orphan drug development. In the US and EU it is easier to gain marketing approval for an orphan drug. There are other financial incentives, such as an extended exclusivity period, to encourage the development of drugs which might otherwise lack a sufficient profit motive. In the UK the collective buying power of the NHS, could be used to ring-fence the supply compounds to the NHS. Another possibility is to allow adaptive phase III programmes; i.e. long-term efficacy and safety data could be collected from post-marketing studies, once a drug has been given a provisional marketing authorisation. For example, the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) had concerns about the long-term safety of oral cladribine in people with MS and hence requested additional data. Rather than producing such data, Merck-Serono, the manufacturer of oral cladribine, withdrew oral cladribine from markets in Russia and Australia where it had been licensed. This decision is particularly disappointing given their subsequently completed phase III trial of oral cladribine in clinically isolated syndrome suggestive of demyelination (CIS) study. In that study lasting two years the 3.5mg/kg dose of cladribine reduced the risk of conversion to clinically definite MS by 67% when compared to placebo and there were no new safety signals. Had cladribine been given a provisional license the drug could have been used on condition that every MSer taking the drug was registered in a pharmacovigilance study to assess long-term risks of the drug. The control group for this study could have been subjects treated with the licensed first line therapies (interferon-beta, glatiramer acetate and, more recently, teriflunomide and dimethyl-fumarate). The lack of flexibility to grant a conditional license by key regulatory authorities, threw the baby out with the bathwater and as a result people with MS have been denied a potentially highly effective – and safe – drug. Academia could take up the baton to repurpose the off-patent, generic, subcutaneous formulation of cladribine as a highly-effective and low cost (£1000/per lifetime) induction treatment for MS. However, without more flexibility of the licensing procedures any attempt to that effect will be in vain. Thus, in effect ensuring that the NHS pays high and recurrent drug costs and perpetuates rationing of access to expensive drugs."

"We therefore feel a new movement should be formed to support a “Big Pharma Alternative” ( BPA). The BPA should lobby politicians to change direction and create an alternative to the current Big Pharma model to develop drugs for MS and other diseases. The working model could be a non-profit, or social entrepreneurship, with the aim of getting legislation enacted similar to that for orphan-diseases. The primary objective is to create the environment that will allow academic institutions and non-profit organisations to develop drugs. The aim is to get drugs that are off-patent, or do not have sufficient patent life for Big Pharma to recoup development costs and make a profit, to the market under a provisional marketing authorisation, whilst the long-term safety data is being collected for a definitive marketing authorisation. As an alternative, the central buying power of the NHS, and closed market of the United Kingdom, makes it an ideal place for innovation to help deliver effective treatments to UK citizens in a cost-efficient manner, from which others can benefit. The BPA can work hand-in hand with pharma for many of these developments. With the introduction of legislation to support granting time-restricted exclusivity for supply and effectively extending the patent life and possible allowing some price adjustment, this could incentivise pharma to undertake the studies This is a political problem that requires a political solution, and it is a problem we literally cannot afford to ignore."

Chataway et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. The Lancet, 19 March 2014. doi:10.1016/S0140-6736(13)62242-4.

Background: Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in MSers. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive MS.

Methods: We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18—65 years with secondary progressive MS were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. MSers, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348.

Findings: 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in MSers in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was −0·254% per year (95% CI −0·422 to −0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]).

Interpretation: High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing.

CoI: multiple, Jeremy Chataway is a member of MS@UCLP

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