ACT-PD: Accelerating clinical treatments for Parkinson's disease

Parkinson's Disease (PD) remains a relentlessly progressive condition with no current therapies that can slow or stop it; treatments remain symptomatic and have undesirable side effects which worsen with long term use often becoming severely debilitating. There are however significant advances in the understanding of some of the mechanisms associated with the condition as a result of which a wealth of potential therapeutic interventions is being identified. Preclinical models assist in their selection but are flawed and ultimately only clinical trials can determine their potential. As a slowly progressive condition with complex and individual characteristics, trials of some length are generally required (more than a year) in a large number of patients. Individual trials are very slow to set up and the sophisticated infrastructure that delivers them is then lost as single trials deliver their results; this is just too slow to advance the breakthroughs in disease modifying treatments that could be achieved and which patients need and deserve.
The proposal is to develop an innovative platform to rapidly and efficiently evaluate a large number of therapies (in a phase II and phase III sense) and utilizing and capitalizing on the valuable expertise and research framework in the UK. This new platform will efficiently deliver results, evaluating the most promising candidates whether identified and progressed by philanthropic or commercial partners. Over the last twenty years the typical approach to evalution of Phase I, II and III trials with a few disease modifying therapies (DMT's) have led to costly and drawn out failure and disappointment. Critical features include long delays especially between phases and failure in efficacy in late stage. The proposal is to do things differently, to learn from this history and approaches utilized in other areas. University College London (UCL) and Professor Max Parmar have pioneered innovative trial designs including multi arm multi stage (MAMS) with practice changing results in prostate cancer and other areas. Such approaches are now being developed for neurological applications including progressive Multiple Sclerosis and Motor Neuron Disease; it is timely for PD to be part of this revolution and for the UK to spearhead the process becoming the "go to" place for evaluation of therapies in PD.
The Cure Parkinson's Trust (CPT)has already supported this project through funding a position to develop ideas of MAMS further and is an integral part of the core consortium. The basis for an international collaboration supporting a MAMS platform has also already been established by CPT with its International Linked Clinical Trials program (iLCT); this initiative involves international experts in PD who meet annually to identify and rank suitable candidates for clinical testing (Brundin & Wyse, 2019). The prioritized candidates are then moved forward into clinical trials by the charity, involving multiple funding sources. This established program ensures that drug candidates tested in the MAMS trial are evaluated, prioritized and endorsed by the global PD community.
The application is for support to second a dedicated individual from the Trust to continue to facilitate its input and ensure that the skills developed are embedded in the Trust for the future development of its work to find a cure, facilitating input from CPT and associated patients and assisting with the development of the platform to reflect input from patients, clinicians, clinical trial managers, academic and commercial opinion leaders and the expertise in statistics and trial design embedded in the UCL CTU. The project is further supported by collaboration with Professor Camille Carrol, a lead investigator in PD from the University of Plymouth and the input of the Edmund J Safra Foundation and the Pistoia Alliance.

The wealth of mechanistic data that has emerged from genetics and experimental medicine has revealed dozens of new targets and drugs with promise as potential Parkinson's disease modifying therapies (DMTs); to evaluate these rapidly and efficiently is essential by avoiding the slow sequential trials and late stage failures seen to date.
Trial designs that rapidly facilitate drug discovery/patient benefit have been achieved in cancer (STAMPEDE), infectious diseases (COVID-RECOVERY) and neurological diseases. A consortium of partners with requisite experience has been created to provide a solution for PD; UCL MDC, providing a large patient/clinician base and experience in trials; University of Plymouth, that has generated key research and UCL MRC Clinical trials unit that has successfully delivered the type of trials envisaged. The Cure Parkinson's Trust (CPT) having previously funded work at Plymouth to develop the proposal is an integral part of the consortium. International collaboration has been established by CPT with its International Linked Clinical Trials program; experts in PD meet annually to identify and rank candidates for clinical testing (Brundin & Wyse, 2019). They are then taken into clinical trials by CPT, involving multiple funding sources. Candidates tested in MAMS are thus evaluated, prioritized and endorsed by the global PD community. The application is for support to second a dedicated individual from CPT to continue to facilitate input and embed skills developed for the future.
(MAMS)= multiple treatments tested in parallel arms compared against a single placebo control arm. At checkpoints, analyses determine whether treatments are safe and show enough promise to continue evaluation; if not removed/replaced.
Three-year workplan, 3 key objectives:
Infrastructure for a MAMS neuroprotective trial in PD: stakeholders build framework.
Protocol - encompassing design, selection, biomarkers, outcomes
Initiate MAMS in PD: a 'proof of concept'