The Linked Clinical Trials (LCT) initiative is a drug repurposing programme specifically aimed at identifying drugs that can slow the progression of Parkinson's disease (PD). Tom Isaacs was one of ...the key people behind the idea of LCT in 2011. He ensured it became a priority of The Cure Parkinson's Trust (CPT), a philanthropic funding body based in the UK which Tom had co‐founded 7 years earlier. During the latter 6 years of his life, Tom Isaacs was heavily involved in the LCT initiative and held the programme dear to his heart. This article describes the genesis of LCT and how the LCT scientific committee evaluates candidate drugs. From 2012, this committee has met annually to prioritise drugs suitable for repurposing in PD. This article does not catalogue every clinical trial within the LCT programme, but describes the 10 clinical trials that emerged either directly, or as an offspring from discussions, at the first meeting of the LCT scientific committee. Some, but not all, are funded by CPT, and all 10 trials are now either completed or ongoing. These trials use drugs developed to address one of the four therapeutic targets: glucagon‐like peptide 1 receptor, iron, and c‐abl tyrosine kinase. We conclude the LCT programme has already sparked a large number of promising clinical trials aimed at slowing PD progression. In doing so, it is a major legacy of Tom Isaacs, carrying the torch he once lit and conveying a sense of urgency for new and life‐transforming therapies for people with PD.
This diagram briefly describes how the Linked Clinical Trials (LCT) program selects compounds to move forward to clinical trials with the aim of achieving disease modification in Parkinson’s disease. The numbers indicate the total numbers of compounds evaluated at each step during 2012‐2018. The LCT scientific committee carefully considers a range of important pre‐clinical, pharmaceutical, biochemical and clinical criteria, and some of these imperatives are illustrated in the bulleted lists.
Statins and Parkinson's: A complex interaction Carroll, Camille B.; Wyse, Richard K.H.; Grosset, Donald G.
Movement disorders,
July 2019, 2019-07-00, 20190701, Letnik:
34, Številka:
7
Journal Article
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 PPARα, 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 α-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.
The international Linked Clinical Trials (iLCT) program for Parkinson's to date represents one of the most comprehensive drug repurposing programs focused on one disease. Since initial planning in ...2010, it has rapidly grown - giving rise to seven completed, and 15 ongoing, clinical trials of 16 agents each aimed at delivering disease modification in Parkinson's disease (PD). In this review, we will provide an overview of the history, structure, process, and progress of the program. We will also present some examples of agents that have been selected and prioritized by the program and subsequently evaluated in clinical trials. Our goal with this review is to provide a template that can be considered across other therapeutic areas.
The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models
and
. In Japan, Fasudil has been approved for the treatment of ...subarachnoid haemorrhage since 1995 and shows a favourable safety profile.
To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD.
We plan to include 75 patients with at least 'probable' PD (MDS criteria), Hoehn and Yahr stages 1-3, and age 30-80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration.
After positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.
As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of ...Parkinson's disease (PD) in 2021. This progress included both "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD), which can be categorised further based on their mechanisms of action and class of drug.
This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT - in clinical trials for PD during 2021- 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community.
We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next.
There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%).
Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute.
The primary neuropathological characteristics of the Parkinsonian brain are the loss of nigral dopamine neurons and the aggregation of alpha synuclein protein. Efforts to development potentially ...disease-modifying treatments have largely focused on correcting these aspects of the condition. In the last decade treatments targeting protein aggregation have entered the clinical pipeline. In this chapter we provide an overview of ongoing clinical trial programs for different therapies attempting to reduce protein aggregation pathology in Parkinson's disease. We will also briefly consider various novel approaches being proposed-and being developed preclinically-to inhibit/reduce aggregated protein pathology in Parkinson's.
Since 2020, annual reports on the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) have been generated. These reviews have followed the ...progress of both "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Additional efforts have been made to further categorize these experimental treatments based on their mechanisms of action and class of drug.
A dataset of clinical trials for drug therapies in PD was obtained using trial data downloaded from the ClinicalTrials.gov online registry. A breakdown analysis of all the studies that were active as of January 31st, 2023, was conducted.
There was a total of 139 clinical trials registered on the ClinicalTrials.gov website as active (with 35 trials newly registered since our last report). Of these trials, 76 (55%) were considered ST and 63 (45%) were designated DMT. Similar to previous years, approximately a third of the studies were in Phase 1 (n = 47; 34%), half (n = 72, 52%) were in Phase 2 and there were 20 (14%) studies in Phase 3. Novel therapies again represented the most dominant group of experimental treatments in this year's report with 58 (42%) trials testing new agents. Repurposed drugs are present in a third (n = 49, 35%) of trials, with reformulations and new claims representing 19% and 4% of studies, respectively.
Our fourth annual review of active clinical trials evaluating ST and DMT therapeutics for PD demonstrates that the drug development pipeline is dynamic and evolving. The slow progress and lack of agents transitioning from Phase 2 to Phase 3 is concerning, but collective efforts by various stakeholders are being made to accelerate the clinical trial process, with the aim of bringing new therapies to the PD community sooner.
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