Clinical trial explores whether the cholesterol-lowering drug Simvastatin may slow or stop Parkinson’s progression
The takeawaySimvastatin, a drug known for its cholesterol-lowering effects and prescribed for the prevention of cardiovascular disease, has important additional biochemical effects that may make it a viable disease-modifying therapy for Parkinson’s. It is currently being investigated as part of a clinical trial (PD-STAT) which commenced in 2015 and is currently recruiting at 23 hospitals across England.
Why is it important?The PD-STAT phase II trial will establish whether Simvastatin can slow or reverse the neurodegenerative process of Parkinson’s. Simvastatin has an excellent safety profile and has recently been shown to have neuroprotective effects in secondary progressive multiple sclerosis, in that it reduced brain degeneration compared to placebo. PD-STAT focuses on people with Parkinson’s with mid-stage disease who also experience alternating periods of good and poor response to medication; so it is directly relevant to people with Parkinson’s today.
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Impact OpinionThis is comprehensive review arguing that it is worth testing statins as disease-modifying drugs in Parkinson’s. A recently initiated trial will soon give us some answers as to whether this is a viable approach.
BackgroundSimvastatin is known widely for its use in cardiovascular disease due to its effects on regulating circulating cholesterol levels. However, over the last 20 years, increasing evidence from animal studies has been steadily showing that it has many additional biochemical effects, including:
- impacts on inflammation processes, and has neuroprotective effects by reducing neuronal programmed cell death (apoptosis)
- reduces harmful free radicals within nerve cells (neurons)
- enhances immune cells whose effects can also be neuroprotective
- reduces the accumulation of a-synuclein in neurons
- increases the expression of substances that promote the growth of neurons
The article reviews how each of these modes of action links directly to mechanisms known to be important in the development and progression of Parkinson’s.
Based on this large body of compelling findings, the International Parkinson’s Disease Linked Clinical Trials Committee, which comprises 15 internationally recognized Parkinson’s experts under the stewardship of The Cure Parkinson’s Trust, prioritised Simvastatin as a potential disease modifying treatment to be trialed for its potential to slow, halt or reverse disease progression.
The details198 people with mid-stage Parkinson’s who also experience “wearing off” symptoms are being enrolled into a double-blind, randomized, placebo controlled clinical trial. They will be randomly allocated to one of two groups. One group will be given Simvastatin to take orally, while the other group will receive an inactive placebo over 24 months, starting on a low dose (40mg) for one month and moving on to high dose (80mg) for 23 months. This dose of Compared to placebo, Simvastatin was shown to have excellent neuroprotective effects in a previous trial in people with multiple sclerosis.
At the start of the study, participants complete tests and questionnaires that assess their movement, mood and other symptoms. In the following six visits after 1, 6, 12, 18 and 24 and 26 months, these tests will be repeated. At four of these, participants will be asked to attend in the “OFF” medication state so that researchers can get a true picture of their disease.
The primary outcome measure is their MDS Unified Parkinson’s Disease Rating Scale (UPDRS) part III (Motor Examination) score, while secondary measures will include their MDS UPDRS part II (Motor Aspects of Daily Living) score and other tests including non-motor symptoms (NMSS).
To ensure that the effects observed are truly disease modifying rather than short-lived changes in symptoms, a two month “washout” period is included in the design, to allow the effects of the drug to disappear: after the end of the 24-month treatment period, the trial will continue for another two months off the trial medication, at the end of which the final assessment will be made.
Next stepsIf this phase II study is successful in showing that Simvastatin has neuroprotective potential in Parkinson’s, the next step may be a larger scale phase III trial, which is a critical step in moving this potential therapy into wider use.
Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, & Nicholas R (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet, 383, 2213-2221.
Poly TN, Islam MM, Walther BA, Yang HC, Nguyen PA, Huang CW, Shabbir SA, Li YJ (2017) Exploring the Association between Statin Use and the Risk of Parkinson’s Disease: A Meta-Analysis of Observational Studies Neuroepidemiology, 49, 142-151.