J. Chataway, A. Alsanousi, D. Chan, D. MacManus, K. Hunter, J. Foster, C. Bangham, D. Wilkie, J. Nicholas, S. Clegg, C. Nielsen, N. Scheurer, V. Calder, J. Greenwood, C. Frost, R. Nicholas. The MS-STAT trial: high dose simvastatin demonstrates neuroprotection without immune-modulation in secondary progressive multiple sclerosis (SPMS) – a phase II trial
Background: Statins are widely used and well tolerated for the treatment of hyperlipidemia and have reduced cardiovascular morbidity and mortality. In addition, they have multiple effects on the nervous system, both anti-inflammatory and neuroprotective, that include increasing endothelial nitric oxide synthase activity, reducing excitotoxicity and augmenting remyelination.
Objectives: To assess whether high dose simvastatin can slow the rate of whole brain atrophy, and/or disability in secondary progressive multiple sclerosis SPMS.
Methods: In a double-blind, placebo-controlled phase II trial, 140 patients, with evidence of progression for 2 years prior to enrolment, EDSS 4.0-6.5, 6 months off disease-modifying treatment, were randomised in a 1:1 ratio, to 80mg simvastatin (40mg first month) or placebo for 2 years. Primary outcome was the rate of whole brain atrophy per year, measured using brain boundary shift integral (BSI). Secondary outcomes included Expanded Disability Status Score (EDSS), new or enlarging T2 lesions, relapse count and adverse event profile.
Results: 140 patients were randomised as planned (70 per arm), with 9 patients lost from final follow-up. Cohort demographics: 70% female, age 51 yrs (mean), duration of MS 21yrs, and SPMS 7 yrs. Baseline median (IQR) EDSS 6 (5.5 to 6.5). The simvastatin group had a statistically significant benefit over the placebo group for the EDSS at 2 years: difference -0.246; 95% CI: -0.453 to -0.064). There was no difference in relapse rate or T2 lesion activity between the arms. At the time of abstract submission, the BSI data is not available, but will be presented at the meeting
Conclusions: This trial, in actively progressing SPMS demonstrates a positive effect on clinical disability and a putative neuroprotective role. No anti-inflammatory effect was seen. A phase III trial is warranted. ClinicalTrials.gov, number NCT00647348
Statins must be working on something else
Team G started working on statins with Prof. John Greenwood (one of the authors above), who came up with the idea that statins may be useful for MS, many years ago. At that time we thought that statins may control blood brain barrier dysfunction (See figure), some other guys in the USA thought it was cytokine control, fitting the dogma of the time.
This appears not to be the case as the drug does not seem to be affecting the relapse rate, although there is some support for this from other studies. Importantly in the context of this study my fear of disease worsening in progressive MS has not being realized. What did I mean? Well statins can block the action of a molecule called Rho. This is involved in the movement of a cells skeleton called actin. So statins could affect growth cones of of nerve processes and so could impair new synapses from being formed. This would block compensation mechanisms called plasticity during MS. This has not happened which is great.
What appears to have happened is that there is benefit in progressive MSers.
According to reports the annualized rate of brain volume loss was just 0.298% compared to 0.589% among those given placebo (P=0.003). There was also significant reductions, as measured by EDSS and MS Impact score.
Whilst this is clear that this is not a cure and the drug does not halt progression but it is slowing the rate of progression, which is a good start. Couple this with an immunomodulator and I would predict there is even more activity.
However, this looks promising, statins are cheap drugs, are commonly used for cholestrerol-lowering effects. Not all statins will be useful because some of them do not get into the brain and so would be unlikely to be nerve protecting. This study looked at the affect of one of them.
So now it is time to get a phase III in SPMS and a phase II in PPMS to take this forward. Now here comes the problem.
Who is going to pay for the trials? This study was supported by Charitable cash and funds from the UK National Institute of Health Research. Phase III studies add a further significant layer of cost. It is not only this but also who funds the cost of gaining regulatory approval with the FDA and EMA?
Pharma have teams of people doing this and they still sometimes mess up and delay things. Academics have no expertise in this area. This study was not done by pharma and the statin is now generic, because it is out of patent. So moving this forward will be much slower than would occur with Pharma involvement.
Let us hope that Dr. Jeremy Chataway, the clinician who led the trial has got the midas touch for controlling progressive MS, as he will probably be involved in a number of trials for progressive MSers in the near future (However, that is another story)