Designing Smarter Neuroimaging Studies to Support First-in-Human Trials for CNS Disorders

Introduction

Despite much progress in our understanding of the structures and function of the central nervous system (CNS) over the last decade, neuroscience clinical trials continue to have extremely high failure rates. First-in-human (FIH) clinical trials in central nervous system (CNS) drug development are associated with a much higher risk than many other therapeutic areas, driven by the biological complexity of the brain, and compounded by distinct clinical and logistical constraints. Early-phase CNS trial support is instrumental in the successful development of novel CNS therapeutics, facilitating the design of smarter preclinical neuroimaging studies with objective, quantifiable CNS biomarkers. This article will consider the challenges unique to FIH CNS clinical trials, considering how an experienced neuroimaging CRO can provide early-phase CNS trial support, fundamental for the approval of novel CNS therapeutics.

The challenge of first-in-human CNS drug development

More than 3 billion people worldwide are living with a neurological condition, with a large proportion of therapeutic approaches providing limited symptomatic relief rather than disease-modifying effects. The challenging CNS treatment landscape underscores a significant area of unmet medical need, spanning a wide range of conditions, including Parkinson’s and Alzheimer’s disease. Clinical progress in these areas is hampered by a combination of scientific and technical challenges, which complicate early clinical translation.

Challenges unique to CNS drug development include:

• Blood–brain barrier and target engagement uncertainty
• Translational gaps between preclinical and clinical CNS models
• Regulatory expectations for early CNS signals
• Long development times, with even longer post-development review
• The need for objective, mechanism-based biomarkers

Imaging as a bridge from preclinical to clinical development

During the early stages of drug development, clear evidence of CNS target engagement and pharmacodynamic effect can provide confidence that a therapeutic candidate should be advanced to first-in-human clinical trials. Preclinical imaging data not only informs dose selection but plays a key role in de-risking CNS drug development. Effective neuroimaging is central to smarter FIH CNS study design, providing insight into functional brain effects over time and enabling an objective assessment of target engagement.

Key benefits of preclinical and translational neuroimaging:

• Establishing disease biology prior to FIH studies
• Establishing target occupancy and receptor engagement
• Assessing functional pathway modulation
• Supporting minimum effective dose decisions
• Linking imaging readouts to PK/PD
• Enabling patient stratification and selection
• Reducing inter-subject variability
• Informing inclusion/exclusion criteria

Both baseline and longitudinal PET/fMRI support regulatory endpoints, dosing strategies, and patient selection in early clinical trials. These imaging approaches, often used in combination, offer complementary objective insights which underpin FIH clinical trial decision-making.

Positron emission tomography (PET) radiotracers are used to visualise protein aggregates, often the neuropathological hallmarks of neurological disease, without the use of invasive procedures such as biopsies. The use of functional magnetic resonance imaging (fMRI) alongside structural MRI facilitates the measurement of brain atrophy and functional connectivity over time. Baseline imaging data provides a reference point for clinical trial participants, providing an overview of initial disease biology, target expression, and functional brain activity before the administration of a developmental drug compound. Longitudinal imaging tracks changes in target engagement, receptor occupancy, and functional modulation over time, providing a dynamic understanding of therapeutic efficacy.

The combination of both baseline and longitudinal PET/fMRI imaging provides a high-level indication-agnostic view of therapeutic activity, strengthening regulatory submissions in support of FIH trials for CNS disorders. The development of PET tracers for amyloid β, and more recently tau tangles, has revolutionised Alzheimer’s disease clinical trials by facilitating longitudinal neuropathology in living people, guiding ongoing translational decisions. FIH PET Parkinson’s Alzheimer’s trials have demonstrated early target engagement and confirmed pathway modulation, providing regulators and sponsors with greater confidence in progression decisions.

A translational partner in early CNS Development

As our understanding of the central nervous system continues to evolve, sponsors need the support of an experienced neuroimaging CRO to drive the success of their CNS first-in-human imaging studies. With integrated preclinical and translational imaging capabilities, and experience supporting complex CNS clinical trials, Perceptive Disocvery supports advancement to first-in-human trials, and ultimately, the approval of novel CNS therapeutics. FIH CNS trial support includes appropriate imaging selection, site qualification and validation, and lead tracer development, and considers all of the operational and scientific design elements biotech sponsors must address within this complex area of research.

With over 750 neurology trials supported, including all major Alzheimer’s Disease trials over the last decade resulting in 18 FDA approvals, Perceptive Discovery is the preferred translational research partner for advancing novel CNS agents. Perceptive Discovery supports your Neuroscience studies with rigorous scientific expertise and operational excellence.

Reach out today and one of our solution experts will be in touch to learn about your trial needs.

Resources

The Lancet. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00038-3/fulltext

Neuropharmacology. https://pmc.ncbi.nlm.nih.gov/articles/PMC5820030/