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Qualification Opinion on Dopamine Transporter Imaging As an Enrichment Biomarker for Parkinson’S Disease Clinical Trials in Patients with Early Parkinsonian Symptoms

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Qualification Opinion on Dopamine Transporter Imaging As an Enrichment Biomarker for Parkinson’S Disease Clinical Trials in Patients with Early Parkinsonian Symptoms 29 May 2018 EMA/CHMP/SAWP/765041/2017 Committee for Medicinal Products for Human Use (CHMP) Qualification opinion on dopamine transporter imaging as an enrichment biomarker for Parkinson’s disease clinical trials in patients with early Parkinsonian symptoms Draft agreed by Scientific Advice Working Party 26 October 2017 Adopted by CHMP for release for consultation 09 November 20171 Start of public consultation 24 January 20182 End of consultation (deadline for comments) 07 March 20183 Adoption by CHMP 26 April 2018 Biomarker, Molecular neuroimaging, Parkinson’s disease Keywords 1 Last day of relevant Committee meeting. 2 Date of publication on the EMA public website. 3 Last day of the month concerned. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Executive summary Critical Path Global Ltd.’s Critical Path for Parkinson’s (CPP) is a multinational consortium of the Critical Path Institute supported by Parkinson’s UK and industry. This broad collaboration of pharmaceutical companies, government agencies, academic institutions, and charities aims to accelerate the development of therapies for Parkinson’s disease (PD). The CPP Imaging Biomarker team aims to achieve a qualification opinion by EMA Committee for Medical Products for Human Use (CHMP) for the use of low baseline Dopamine Transporter levels for subject enrichment in clinical trials in early stages of PD. This package reports the results of the Critical Path Global Ltd. CPP Imaging Biomarker team’s analysis of baseline levels of Dopamine Transporter (DAT) density as assessed by Single-Photon Emission Computed Tomography (SPECT) neuroimaging as an enrichment biomarker in clinical trials for the treatment of PD. The biomarker proposed for qualification is molecular imaging of DAT, a transporter protein that is located on the presynaptic nerve terminal of dopaminergic neurons. Molecular imaging of the DAT protein represents a viable method of assessing the integrity of dopamine nerve terminal function in living human brain. The aim of this work is to demonstrate the predictive accuracy of visual assessment of DAT neuroimaging scans at baseline for identifying those subjects with high likelihood of progressing in clinical motor disability. By excluding subjects from clinical trials who are classified as having a “Scan Without Evidence of Dopaminergic Deficit” (SWEDD), subjects more likely to have PD can be more accurately identified for inclusion in future clinical trials. Patients with striatal dopamine deficit will be identified at the earliest signs of clinical motor impairment, when candidate therapeutic drugs presumably would more effectively disrupt the neurodegenerative process and declining clinical trajectory. It is proposed that confirming reduction of DAT expression levels by SPECT neuroimaging of subjects with early motor deficits is a useful means of enriching clinical trials of PD therapeutic agents, as this facilitates excluding patients who are unlikely to show disease progression from enrolment in a PD clinical trial. Patient-level imaging and clinical data were acquired and analyzed from two large multicenter global PD clinical cohorts focused on patients at early motor stages. The studies include a large randomized, double-blind, placebo-controlled, clinical trial (Parkinson Research Examination of CEP-1347 Trial - PRECEPT) and a longitudinal observational cohort focused on biomarker discovery and validation (Parkinson’s Progression Markers Initiative - PPMI). In the integrated PPMI and PRECEPT studies, DAT levels assessed visually at baseline accurately predicted that SWEDD subjects were unlikely to progress in motor disability. Results suggested that SWEDD subjects have a statistically significant slower rate of motor worsening compared to subjects with DAT deficit as shown by the harmonized Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score. The imaging biomarker is appropriate for assessing dopamine deficiency consistent with Parkinsonism as a tool to aid in subject selection for clinical trials. Reproducibility and reliability have been addressed by including a detailed methodology section recommended for use by sponsors. Several published studies have addressed the issue of test-retest reliability of DAT-SPECT imaging (1,2). There is a high degree of inter observer agreement in the visual interpretation of (123)I-FP-CIT images (3). Zaknun et al. (4) evaluated the effects of different scanners on DAT imaging results and reported that the spatial distribution and image quality of [123I]FP-CIT on different high-resolution systems applying Qualification Opinion on Dopamine Transporter Imaging as an Enrichment Biomarker for Parkinson’s Disease Clinical Trials in Patients with Early Parkinsonian Symptoms EMA/CHMP/SAWP/765041/2017 Page 2/39 standardized acquisition and reconstruction protocols is less operator dependent and did not affect visual rating of striatal DAT loss. Morton et al. (5) reported no statistical variation between operators. Such results support that the biomarker can be deployed with confidence in clinical trials of PD subjects to enable early intervention while ensuring patient safety and sparing subjects without dopaminergic deficit from being exposed to test therapeutic candidates. This document communicates the degree of enrichment one expects from using the biomarker in prospective clinical trials according to the proposed context-of-use. Background information as submitted by the applicant Background on the disease Drug development for the treatment of PD is being pursued aggressively by industry, biotech and non- profit organizations. Challenges that all drug developers face for PD therapeutics include the prolonged duration of disease progression, the heterogeneity of the patient population, the risk of adverse drug reactions in an elderly patient population and paucity of biomarkers to differentiate subtypes of Parkinsonism. There is increasing recognition that novel disease-modifying therapies will be most efficacious if treatment is initiated very early in the course of the disease. Significant challenges exist in advancing treatments for very early-stage PD subjects in that it is difficult to accurately diagnose patients based upon clinical evaluations alone. Clinical symptoms of early motor PD overlap with many different conditions and the true percent of atypical Parkinsonism or other non-PD cases in legacy PD clinical trials is still not known. Novel biomarker approaches are needed to accurately identify PD patients for subject selection in clinical trials. Background on the biomarker The biomarker proposed for qualification is molecular imaging of DAT, a transporter protein that is located on the presynaptic nerve terminal of dopaminergic neurons. Reductions of DAT radiotracer binding correlate with the loss of presynaptic nigrostriatal neurons in nonclinical PD models and in humans (6). Ligands specific for in vivo imaging of DAT directly measure the functional integrity of the dopamine nerve terminal and are used to monitor neurodegeneration in both nonclinical and clinical studies. Significant clinic pathologic findings illustrate that reductions in DAT assessed by neuroimaging reflect dopaminergic nerve terminal degeneration in animal models and in patients with Parkinson’s disease and that such reductions precede the onset of clinical symptoms. At present, the ligand approved by regulatory agencies for use in humans is the DAT-selective radioligand [123I]N-omega-fluoropropyl-2β-carbomethoxy-3β-[4-iodophenyl] nortropane (FP-CIT) [the brand name for this biomarker in the European Union (EU) is DaTSCANTM]. 123I-ioflupane (123I-FP- CIT) is a SPECT tracer, licensed by the European Medicines Agency and available in Europe since 2000. In the United States, 123I-ioflupane was approved by the Food and Drug Administration in January 2011 and is commercially available (7). The approved use for 123I-ioflupane is to aid in the differential diagnosis between essential tremor and other parkinsonian disorders in clinical practice (like progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, vascular Parkinsonism, etc). Assessment of DAT levels can be carried out by visual read (dichotomous classification), semiquantiative or quantitative measurements of striatal binding uptake. The approved clinical use of this marker for differential diagnosis is based on visual assessment. This document is aimed at qualification of the biomarker itself, as opposed to a specific tracer. Multiple tracers exist for in vivo imaging of dopamine transporter levels yet only 123I-ioflupane [(123I-FP-CIT); Qualification Opinion on Dopamine Transporter Imaging as an Enrichment Biomarker for Parkinson’s Disease Clinical Trials in Patients with Early Parkinsonian Symptoms EMA/CHMP/SAWP/765041/2017 Page 3/39 DaTscanTM] is approved for use in EU and US. Other tracers are used as research-only tools. Therefore, the focus for this technical document is on the approved tracer, given that it will be the tool of choice for prospective clinical trials and has been employed successfully in the multisite PPMI observational cohort study. Role in drug development There is an urgent need for biomarkers to be used as tools that can be successfully
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