Ok abit of a melodramatic title of something that started in one.place and ended up somewhere else.
But once the idea was mooted that statins inhibited progression loads of people with MS got their hands on them as why wait for 5 years for a trial to be done. So how do you get on statins….scoff loads of eggs to get you cholesterol up (statins are used to reduce cholesterol levels) go to the docs to get a prescription. If you are over sixty you seem to get donated a Statin even if your cholesterol isn’t high:-(. Anyway the statin trial has failed and so you can stop eating your eggs.
We did the first experiments on relapsing EAE to show an effect of statins on blood brain barrier function. The best experiment was never put in the paper as you could only have a few figures, but the rest was put out in supplementary online. There was an effect on EAE. We had shown this with Prof Greenwood but it had also been shown by the Group of Prof. Nature….the person who has had more nature papers than I have had scrambled eggs. However, the explanations were different. One was based on how they could impact on migration of cells into the brain the other on a cytokine switch which was dogma for the week at the time. So I suggested going to Nature with back to back papers the mediocre paper on the yawn cytokine switch flew in because it was written by the demigods of MS and ours got binned because we hadn’t done the work in a knockout mouse to prove the mechanism. FYI this mouse would have never been born as it would been lethal but negative comments by one referee is enough to sink papers and it doesn’t matter if the comments are coming from a place where the sun don’t shine. Anyway the best experiment that was destined for supplementary was that MD2 got EAE going blocked relapse for weeks and then two days after it was stopped which is the time taken for the drug to clear….relapse occurred in all the beasties….the cytokine switch idea was clearly cobblers because the cytokine switch would not be reversible….What the referee from Nature didn’t get is you don’t prove your idea, you prove the idea is rubbish. The cytokine switch concept was flawed in its thinking and was later shown to be disastrous in MS…5 minutes of thinking in a certain way was all you needed.
Anyway there were too many trials in relapsing MS and so secondary progressive MS was targeted after a whiff of an effect on atrophy in a phase II. MSSTAT2 was conceived and it is reported here.
It failed….
I have always said trials kill drugs and this is perhaps another example. I have said this and given reasons before and there is no point having a postmortem. The big question for me was how could a Statin inhibit progressive MS?
What was the biology?..I didn’t buy the idea that it had anything to do with blood brain barrier…..I did have a idea and wanted to develop it with a bloke and lady from France who worked on Alzheimer’s we never got it funded. Anyway all in the past now. This is a sad day and so all them Cool Hand Luke’s can stop.
Chataway J, Williams T, Blackstone J, John N, Braisher M, De Angelis F, Bianchi A, Calvi A, Doshi A, Apap Mangion S, Wade C, Bordea E, Merry R, Barton G, Lyle D, Jarman E, Mahad D, Shehu A, Arun T, McDonnell G, Geraldes R, Craner M, Hillier C, Ganesalingam J, Fisniku L, Hobart J, Spilker C, Robertson NP, Kalra S, Pluchino S, Harikrishnan S, Mattoscio M, Harrower T, Young C, Lee M, Chhetri SK, Ahmed F, Rog D, Silber E, Gallagher P, Duddy M, Straukiene A, Nicholas R, Rice C, Tebbs S, Hawton A, Hunter R, Giovannoni G, Ciccarelli O, Beveridge J, Nixon S, Thompson AJ, Greenwood J, Pearson OR, Evangelou N, Sharrack B, Galea I, Gray E, Pavitt S, Chandran S, Ford HL, Frost C, Nicholas JM; MS-STAT2 Investigators. Effect of repurposed simvastatin on disability progression in secondary progressive multiple sclerosis (MS-STAT2): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2025 Oct 1:S0140-6736(25)01039-6. doi: 10.1016/S0140-6736(25)01039-6. Epub ahead of print. PMID: 41045938.
Background: Despite the success of immune modulation in the treatment of relapsing multiple sclerosis, disability progression is a major problem driven by multiple mechanisms. Comorbidities (eg, vascular risk) and ageing are thought to augment these neurodegenerative pathologies. In the phase 2b MS-STAT trial of simvastatin (80 mg) versus placebo in secondary progressive multiple sclerosis (SPMS), the adjusted difference in brain atrophy rate between groups was -0·254% per year: a 43% reduction. In this phase 3 MS-STAT2 trial, we aimed to assess the efficacy of simvastatin versus placebo in slowing the progression of disability in SPMS.
Methods: This phase 3, randomised, double-blind, parallel group, placebo-controlled clinical trial was conducted at 31 neuroscience centres and district general hospitals in the UK. Participants aged 18-65 years with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) of between 4·0 and 6·5 were eligible and randomly assigned (1:1) to oral simvastatin (80 mg) or matched placebo for up to 4·5 years, based on a minimisation algorithm within an independent and secure online randomisation service. All participants, site investigators, and the trial coordinating team were masked to treatment allocation. The primary outcome was time to 6-month EDSS confirmed disability progression (an increase of at least 1 point if EDSS score at baseline visit was less than 6·0 or an increase of 0·5 point if EDSS score at baseline visit was 6·0 or more) assessed in all randomly assigned participants (intention-to-treat analysis) without imputation. This study is registered with ClinicalTrials.gov (NCT03387670) and is on the ISRCTN registry (ISRCTN82598726). The study is completed.
Findings: Between May 10, 2018, and July 26, 2024, 1079 patients were screened for eligibility and 964 participants were randomly assigned, with 482 (50%) in the placebo group and 482 (50%) in the simvastatin group. Of all 964 participants, 704 (73%) were female and 260 (27%) were male, with a mean age of 54 years (SD 7). 173 (36%) of 482 participants in the placebo group and 192 (40%) of 482 participants in the simvastatin group had 6-month confirmed disability progression (adjusted hazard ratio 1·13 [95% CI 0·91 to 1·39], p=0·26). Although no emergent safety issues were seen, there was one serious adverse reaction (rhabdomyolysis) in the simvastatin group. 12 (2%) of 482 participants in the placebo group and five (1%) of 482 participants in the simvastatin group had a cardiovascular serious adverse event.
Interpretation: The MS-STAT2 trial did not show a treatment effect of simvastatin in slowing disability progression in SPMS. Simvastatin use in multiple sclerosis should be confined to existing vascular indications.
Source: multiple-sclerosis-research.org