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Simvastatin as a Potential Disease-Modifying Therapy for Patients with Parkinson's Disease: Rationale for Clinical Trial, and Current Progress.

ABSTRACT: Many now believe the holy grail for the next stage of therapeutic advance surrounds the development of disease-modifying approaches aimed at intercepting the year-on-year neurodegenerative decline experienced by most patients with Parkinson's disease (PD). Based on recommendations of an international committee of experts who are currently bringing multiple, potentially disease-modifying, PD therapeutics into long-term neuroprotective PD trials, a clinical trial involving 198 patients is underway to determine whether Simvastatin provides protection against chronic neurodegeneration. Statins are widely used to reduce cardiovascular risk, and act as competitive inhibitors of HMG-CoA reductase. It is also known that statins serve as ligands for PPAR?, a known arbiter for mitochondrial size and number. Statins possess multiple cholesterol-independent biochemical mechanisms of action, many of which offer neuroprotective potential (suppression of proinflammatory molecules & microglial activation, stimulation of endothelial nitric oxide synthase, inhibition of oxidative stress, attenuation of ?-synuclein aggregation, modulation of adaptive immunity, and increased expression of neurotrophic factors). We describe the biochemical, physiological and pharmaceutical credentials that continue to underpin the rationale for taking Simvastatin into a disease-modifying trial in PD patients. While unrelated to the Simvastatin trial (because this conducted in patients who already have PD), we discuss conflicting epidemiological studies which variously suggest that statin use for cardiovascular prophylaxis may increase or decrease risk of developing PD. Finally, since so few disease-modifying PD trials have ever been launched (compared to those of symptomatic therapies), we discuss the rationale of the trial structure we have adopted, decisions made, and lessons learnt so far.

SUBMITTER: Carroll CB

PROVIDER: S-EPMC5676977 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Simvastatin as a Potential Disease-Modifying Therapy for Patients with Parkinson's Disease: Rationale for Clinical Trial, and Current Progress.

Carroll Camille B CB Wyse Richard K H RKH

Journal of Parkinson's disease 20170101 4

Many now believe the holy grail for the next stage of therapeutic advance surrounds the development of disease-modifying approaches aimed at intercepting the year-on-year neurodegenerative decline experienced by most patients with Parkinson's disease (PD). Based on recommendations of an international committee of experts who are currently bringing multiple, potentially disease-modifying, PD therapeutics into long-term neuroprotective PD trials, a clinical trial involving 198 patients is underway ...[more]

PMID: 29036837

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Project description:Parkinson's disease is the second most common age-related neurodegenerative disorder, typified by the progressive loss of substantia nigra pars compacta dopamine neurons and the consequent decrease in the neurotransmitter dopamine. Patients exhibit a range of clinical symptoms, with the most common affecting motor function and including resting tremor, rigidity, akinesia, bradykinesia and postural instability. Current pharmacological interventions are palliative and largely aimed at increasing dopamine levels through increased production and/or inhibition of metabolism of this key neurotransmitter. The gold standard for treatment of both familial and sporadic Parkinson's disease is the peripheral administration of the dopamine precursor, levodopa. However, many patients gradually develop levodopa-induced dyskinesias and motor fluctuations. In addition, dopamine enhancement therapies are most useful when a portion of the nigrostriatal pathway is intact. Consequently, as the number of substantia nigra dopamine neurons and striatal projections decrease, these treatments become less efficacious. Current translational research is focused on the development of novel disease-modifying therapies, including those utilizing gene therapeutic approaches. Herein we present an overview of current gene therapy clinical trials for Parkinson's disease. Employing either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors, these clinical trials are focused on three overarching approaches: augmentation of dopamine levels via increased neurotransmitter production; modulation of the neuronal phenotype; and neuroprotection. The first two therapies discussed in this article focus on increasing dopamine production via direct delivery of genes involved in neurotransmitter synthesis (amino acid decarboxylase, tyrosine hydroxylase and GTP [guanosine triphosphate] cyclohydrolase 1). In an attempt to bypass the degenerating nigrostriatal pathway, a third clinical trial utilizes rAAV2 to deliver glutamic acid decarboxylase to the subthalamic nucleus, converting a subset of excitatory neurons to GABA-producing cells. In contrast, the final clinical trial is aimed at protecting the degenerating nigrostriatum by striatal delivery of rAAV2 harbouring the neuroprotective gene, neurturin. Based on preclinical studies, this gene therapeutic approach is posited to slow disease progression by enhancing neuronal survival. In addition, we discuss the outcome of each clinical trial and discuss the potential rationale for the marginal yet incremental clinical advancements that have thus far been realized for Parkinson's disease gene therapy.

Project description:ImportanceCurrent treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy.ObjectiveTo determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD.Design, setting, and participantsThis randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021.InterventionsParticipants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period.Main outcomes and measuresThe prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event.ResultsOf 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE.Conclusions and relevanceIn this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial.Trial registrationISRCTN Identifier: 16108482.

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Simvastatin as a Potential Disease-Modifying Therapy for Patients with Parkinson's Disease: Rationale for Clinical Trial, and Current Progress.

Publications

Simvastatin as a Potential Disease-Modifying Therapy for Patients with Parkinson's Disease: Rationale for Clinical Trial, and Current Progress.

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