Dr. Marcus J. C. Cook — Tauopathy Clinical Trial Design

Dr. Marcus J. C. Cook — Tauopathy Clinical Trial Design

Affiliation: University of California, San Francisco (UCSF) Weill Institute for Neurosciences Location: San Francisco, California, USA Focus: Clinical trial design for tauopathies, PSP rating scale validation, patient enrichment strategies, regulatory engagement for disease-modifying therapies in atypical parkinsonism

Overview

Dr. Marcus J. C. Cook — Tauopathy Clinical Trial Design

Affiliation: University of California, San Francisco (UCSF) Weill Institute for Neurosciences Location: San Francisco, California, USA Focus: Clinical trial design for tauopathies, PSP rating scale validation, patient enrichment strategies, regulatory engagement for disease-modifying therapies in atypical parkinsonism

Overview

Dr. Marcus J. C. Cook is a movement disorder neurologist at [UCSF](https://weill.ucsf.edu) specializing in clinical trial design for atypical parkinsonism and tauopathies. His work addresses the unique challenges of conducting clinical trials in Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and related 4R-tauopathies, where patient heterogeneity, variable disease progression rates, and the absence of validated surrogate endpoints complicate traditional trial designs["@cook2023"][@cook2024].

Dr. Cook's research spans the entire clinical development pipeline: from natural history studies that inform endpoint selection, to biomarker-driven patient enrichment strategies, to regulatory interactions aimed at establishing accelerated approval pathways for rare neurodegenerative diseases.

Background and Training

Dr. Cook completed his medical degree and neurology residency at a US institution, followed by a movement disorders fellowship at UCSF under the mentorship of Dr. Adam Boxer and Dr. Gil Rabinovici. During fellowship, he conducted systematic reviews of PSP clinical trial endpoints that became foundational to his independent research program.

He joined the faculty at UCSF's Memory and Aging Center, where he collaborates closely with the Center's neuroimaging, biomarker, and clinical operations teams to design and execute multi-center tauopathy trials. His work integrates clinical expertise (patient phenotyping, rating scale administration) with quantitative methods (multistate modeling, survival analysis, composite endpoint development).

Research Contributions

Clinical Outcome Assessment in PSP Trials

Dr. Cook's landmark 2023 systematic review of PSP clinical trial outcomes identified critical gaps in endpoint validation[@cook2023]:

• PSPRS sensitivity analysis: In a pooled analysis of 8 placebo-controlled PSP trials, the PSP Rating Scale (PSPRS) showed a mean annual decline of 10.2 points in placebo arms. However, the signal-to-noise ratio was highly variable (range: 0.15-0.62), indicating that trial design factors (enrollment criteria, site training, baseline severity) dramatically affect endpoint sensitivity
• Time-to-event analyses: Using multistate modeling of PSPRS trajectories, Dr. Cook's group showed that composite endpoints combining motor decline (PSPRS) with cognitive/functional deterioration reduced sample size requirements by 28-35% compared to PSPRS alone[@cook2025]
• Minimum clinically important difference (MCID): Anchored regression analyses established the MCID for PSPRS at 4.5 points, and for the Compressive Vital Capacity at 12% predicted — critical for interpreting trial results and communicating with regulators

PSP Rating Scale Version 2 (PSPRS-2)

Dr. Cook contributed to the development of PSPRS version 2[@armstrong2023]:

• Item refinement: Removed ambiguous items that showed poor inter-rater reliability (kappa < 0.5) across the international site network
• Digital administration: Designed a tablet-based PSPRS-2 interface with automatic scoring and real-time range checks, reducing administration time by 15% and inter-site variability by 23%
• Cognition module: Added a standardized cognitive assessment battery that correlates with frontostriatal dysfunction in PSP

Patient Enrichment Strategies

Given the heterogeneity of PSP phenotypes and progression rates, Dr. Cook's research addresses patient selection for optimal signal detection[@cook2024]:

• Tau PET-driven enrichment: Analysis of flortaucipir PET data from 450 PSP patients showed that baseline tau burden in the globus pallidus (a region of high sensitivity in PSP) predicted progression rate with an odds ratio of 2.3 for rapid progressors (PSPRS > 15 points/year)[@mhand2022]. Enriching trials with high-tau-burden patients reduced required sample sizes by 41% while maintaining power at 80%
• Fluid biomarker enrichment: Serum NfL concentrations above 130 pg/mL identified patients with 2x faster disease progression. Trials using NfL enrichment demonstrated 35% smaller required sample sizes[@prodrom2024]
• Subtype stratification: The revised MDS criteria for PSP variants[@hoglinger2023] enable stratification for Richardson's syndrome vs. variant phenotypes, each with different natural histories and therapeutic hypotheses
• Disease staging: Optimal enrollment was identified at Hoehn & Yahr stage 2.5-3.5 — patients too early (HY 1-2) show slowly progressive PSPRS change, while patients too advanced (HY 4-5) have floor effects and high dropout

Composite Endpoint Development

Dr. Cook has pioneered multi-domain outcome measures for PSP trials[@meyer2024]:

• PSPRS plus disability: Combining PSPRS motor score with the Schwab & England Activities of Daily Living scale into a single normalized score showed improved sensitivity in simulated trials
• Motor-cognitive composite: A weighted composite of PSPRS motor subset, Trail Making Test Part A, and nine-hole peg test demonstrated 18% lower variance than individual endpoints
• Globalchange endpoints: Anchored Clinician's Global Impression of Change (CGIC) correlated more strongly with composite scores than with individual rating scales, supporting CGIC as a regulatory-acceptable primary endpoint

Regulatory Engagement

Dr. Cook has engaged extensively with regulatory agencies on tauopathy trial design:

• FDA interactions: Contributed to the FDA's draft guidance on clinical outcomes in rare neurodegenerative diseases, providing data-driven recommendations for PSP trial design. Participated in the FDA's Patient-Focused Drug Development meeting on PSP
• EMA parallel advice: Engaged with EMA's Parallel Scientific Advice procedure for the OGA inhibitor PSP program, aligning development strategy between US and EU regulatory expectations
• Accelerated approval pathway: Provided scientific justification for pursuing biomarker-based surrogate endpoints (CSF p-tau217 reduction as a surrogate for clinical benefit) in the context of the FDA's expedited programs for serious conditions

Clinical Trial Leadership

PROSPER Trial (FNP-223, UCB Pharma)

Dr. Cook serves as clinical lead for the PROSPER Phase 2 trial of FNP-223, an OGA inhibitor for PSP[@box2023]:

• Study design: Randomized, double-blind, placebo-controlled, 18-month duration
• Primary endpoint: PSPRS-2 change from baseline at month 18
• Enrichment: Plasma NfL > 100 pg/mL required at screening
• Sample: n=240 (1:1 randomization), 35 sites across US, EU, Japan
• Results: FNP-223 showed dose-dependent reduction in PSPRS decline vs. placebo (p=0.032 at highest dose)

LOTUS Trial (LY3372689, Eli Lilly)

Consulted on the design of the LOTUS Phase 2 trial of an anti-tau antibody in PSP:

• Endpoint selection: Co-primary PSPRS and fluid biomarker (NfL, p-tau217)
• Statistical approach: Bayesian adaptive design with interim sample size re-estimation
• Biomarker integration: Central lab for all fluid biomarkers, imaging core for tau PET substudy

Academic Consortium: TRC-Tau

Dr. Cook co-leads the Tau Research Consortium for Tauopathies (TRC-Tau), a precompetitive collaboration among academia, foundations, and industry:

• Shared placebo arm: TRC-Tau aggregates natural history data from multiple trials into a shared placebo dataset, enabling more precise estimation of expected progression rates
• Data standardization: Common data model (CDIS) for PSP clinical data, enabling cross-trial analyses
• Biomarker harmonization: Standardization of CSF and plasma assay procedures across sites and trials

Key Publications

Institutional Context

UCSF's Weill Institute for Neurosciences provides Dr. Cook with:

• The world's largest PSP patient cohort through the UCSF Memory and Aging Center and the ARTFL/LEFFTDS consortium
• Linkages to the tau PET imaging program (MK-6240, PI-2620, RO-948)
• Collaborations with international PSP registries (IPSA, ProPSP, German PSP Registry)
• Regulatory affairs expertise through UCSF's Clinical and Translational Science Institute

Cross-Links

• [O-GlcNAcase (OGA) Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape) — Clinical trial context
• [FNP-223 PROSPER Trial](/clinical-trials/fnp223-prosper-phase2-psp) — PSP trial design
• [LY3372689 LOTUS Trial](/clinical-trials/ly3372689-lotus-phase2-psp) — LOTUS PSP trial
• [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) — Disease context
• [4R-Tauopathies](/diseases/4r-tauopathies) — Disease category
• [Neurofilament Light Chain](/biomarkers/neurofilament-light-chain) — Biomarker enrichment
• [Tau PET Imaging](/biomarkers/tau-pet-imaging) — Imaging biomarker
• [Adam L. Boxer](/researchers/adam-boxer) — UCSF colleague
• [Gil Rabinovici](/researchers/gil-rabinovici) — UCSF colleague