Statins are agents used to reduce cholesterol. When used in a UK trial called MS-STAT they found that brain loss was slowed and suggested there was a benefical effect suggesting that nerves loss is inhibited by statins. “High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe”. So we now have MS-STAT2 on the go (NCT03387670)
Yeserday NDG posted a piece on neurofilaments (nerve protein that gets released after nerve damage) and in this study they looked for neurofilaments in the blood after statin treatment in MS-STAT and found no change, suggesting no saving of nerves. Should we say Oh heck?
There are over 1000 people in MS-STAT2. Whats going to happen?
I guess we have to wait and see, but because MS-STAT2 is a phase III trial it means the outcome is clinical. They ask does it stop disability progression, does it stop loss of mobility of the lower and upper limibs?
We will have to wait and see, but can we explain the result of a seemingly beneficical effect on brain shrinkage but no evidence to saving nerve loss. You can have read to see what you think. It suggests that “slowing of brain shrinkage is occuring independently of nerve loss”. I think NDG may say the problem is they were looking for nerve loss using the blood and they should be looking in spinal taps. Also it is hard to see a difference because they were not controlling inflammation in all people and adding statin on top. A good anti-inflammatory makes the neurofilament levels drop miles more than is ever seen from the nerve loss due to progression.
At the end of the day the clinical response is important. What do you think will happen?
However, one question is how could it work. The original idea was (a) It changed the pattern of T cell cytokines and (b) It block lesion formation by stopping trafficking across blood vessels. I know because we did the pioneering work with statins, but others got of the mark to do trials in RRMS and statins were not good enough so an SPMS trial was done, but what is the working mechanism. I think both (a) and (b) are not the answer indeed I never thought (a) was the answer, but how come the steroid pathway is the number one dysregulated pathway in chronic EAE, MS and Alzheimers. It isnt about T cell lesions..surely. Some may say de and (c) remyelination. There are other possibilities. I was going to write a review but never got round to it. One I wondered about was (d) the oxysterols that can be linked to neurodegneration and neuroprotection. Can one create a hypothesis for a role, I think you can and counter the effects of toxic accumulation of sodium and calcium, which we know have the capacity to kill nerves and oligodendrocytes via excitotoxicity.
Anyway blocking sodium channels did not have an effect on neurofilaments levels in the brain, but it did slow loss of mobility (PROXIMUS) so lets keep our fingers crossed
Williams TE, Holdsworth KP, Nicholas JM, Eshaghi A, Katsanouli T, Wellington H, Heslegrave A, Zetterberg H, Frost C, Chataway J. Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial. Neurol Neuroimmunol Neuroinflamm. 2022 Jan 14;9(2):e1130. doi: 10.1212/NXI.0000000000001130.
Background and objectives: Improved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.
Methods: The MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology.
Results: A total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.
Discussion: We found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.
COI: None really
Disclaimer. This is the authors view and does not represent theviews of any institution, notably mine.