We can accelerate neuroscience research with courage and urgency

Over the past two decades, I’ve witnessed neuroscience advances from multiple vantage points: As head of the Neuroimmunology Unit and a principal investigator at University Hospital in Brussels, as head of Medical Affairs at Ipsen and Sanofi Genzyme, and as co-founder of an international non-profit organization dedicated to multiple sclerosis (MS) patients.

I believe neuroscience research is nearing a tipping point: poised to accelerate scientifically, clinically, and commercially much as cardiology and oncology did decades ago. Three trends underpin my conviction. The gathering speed of small, incremental advances in understanding the mechanisms and pathophysiology of neurologic and psychiatric diseases. A new sense of urgency as the personal and societal burdens of illnesses such as Alzheimer’s disease (AD) and major depressive disorder (MDD) rise globally and become more apparent. Finally, recent positive clinical trials and marketing approvals in challenging indications and growing evidence that regulators are considering a more flexible approach to surrogate neuroscience endpoints. On September 26, 2024, the FDA approved the first schizophrenia drug with a novel mechanism of action in over 30 years.¹

I believe neuroscience research is nearing a tipping point: poised to accelerate scientifically, clinically, and commercially much as cardiology and oncology did decades ago.

At a tipping point, progress becomes unstoppable, but we are not there yet. We still face significant challenges in delivering safe and effective treatments to the patients who need them.

What is holding us back?

Conservatism: Neuroscience sponsors and regulators remain risk averse despite recent trial data and discoveries. This is understandable; neuroscience trials have had high failure rates, leading to an exodus of large pharmaceutical companies from neurologic and psychiatric research. ²

Unequal healthcare access and infrastructure: People suffering from neurologic and psychiatric illnesses have unequal access to diagnostics and treatments. Global healthcare systems and providers lack the tools, knowledge, and training to diagnose and treat people. This is an infrastructure problem. Alzheimer’s Disease International (ADI) estimates that 75% (41 million) of people with dementia are undiagnosed, and 70% of people with cognitive decline do not even know they have AD.³ Moreover, many people with cognitive decline do not have access to clinics with experts who can differentiate between, say, vascular dementia, frontotemporal dementia, AD, or impairment due to depression. 

Incomplete scientific knowledge: Oncology and cardiology offer roadmaps for how precision medicine can benefit patients. However, we cannot compare neuroscience to oncology. Despite recent progress, the brain is still a black box, and finding and validating actionable biomarkers has proven more difficult.

What will carry us forward?

Better endpoints. Endpoint selection and interpretation remain significant challenges in neurology and psychiatry clinical trials due to subjectivity, complexity, slow disease progression, heterogeneity, the placebo effect, meaningfulness, regulatory limitations, sensitivity, cultural and linguistic barriers, comorbidities, ceiling/floor effects, and inter-rater variability. We can take hope from MS, where limitations of the mainstream Expanded Disability Status Score (EDSS) and Annualized Relapse Rate (ARR) led researchers and patients to advocate for more sensitive, disease mechanism-related, and patient-relevant endpoints. Trials now include new endpoints, such as the simple digit modality test (SDMT), the timed 25-foot walk test (T25WT), the 9-hole peg test (9HPT), and composite scores, such as the MS Functional Composite (MSFC), NEDA (non-evidence of disease activity), PIRA (progression independent of relapses) and, more recently, smouldering-associated-worsening (SAW). MRI (MS lesions and brain volume loss) and other biomarkers, such as serum neurofilament light chain (sNfL) levels, are also incorporated into MS trials.

More reliable biomarkers. There is a lack of reliable and easy-to-access biomarkers for early diagnosis and disease treatment monitoring. In AD, for example, many individuals do not have access to a PET scan, which is, anyway, not 100% reliable for many reasons. Recently, researchers reported that a simple blood test analyzed in a lab, the amyloid probability score 2 (APS2), detected AD pathology accurately 91% of the time versus 73% for dementia specialists and 61% for primary care physicians.⁴ We must still confirm the APS2’s validity as a biomarker for AD risk prediction.⁵  However, more reliable biomarkers hold tremendous potential for optimizing drug development and patient care across many conditions. 

Patient-guided trial design. Neuroscience clinical trials are more burdensome and last longer than other therapeutic areas. Recruitment and retention are critical challenges that can be overcome with studies that are feasible and realistic for patients and sites. Recently, we conducted a patient burden analysis of schizophrenia trials and found that patient-centric strategies to reduce study visit complexity and duration and support patients and caregivers can increase interest in schizophrenia studies and boost retention.⁶ Patients are experts in which symptoms matter most, enabling sponsors and regulators to choose relevant endpoints. At Parexel, our research shows that existing clinical outcome assessments fail to capture treatments’ effects on salient symptoms and quality of life for people with MS.⁷ Our ability to accommodate patients’ insights and daily realities into efficient, well-designed clinical trials with meaningful endpoints has grown dramatically in recent years. 

Artificial intelligence. We are not where we should be regarding precision neuroscience, but the field is advancing. Biomarkers are essential for this to happen, but there are other means. At Parexel, we help sponsors of psychiatric treatments explore how to incorporate precision medicine techniques, such as more precisely grouping and stratifying patient populations. Clinical trials now routinely divide heterogeneous indications such as depression and schizophrenia into discrete symptom clusters that better represent biological pathways and provide clear drug targets. AI-based algorithms have been recently developed to help select those patients at high risk of progression, which could shorten timelines in neuroscience trials.

Boldness and courage. Understanding comes with trial and error, including high-profile, expensive failures. It comes with a committed investment in research. At Parexel, we advise sponsors on how to take calculated risks, such as utilizing innovative trial designs and novel endpoints. A well-designed adaptive or basket trial with suitable indications and outcomes can keep early development programs small and enable smarter go-no-go decisions. Working closely with regulators and conducting rigorous feasibility testing can mitigate the risks in these approaches. Small biotech companies pioneered cancer innovations, and we see the same pattern in neuroscience. For example, all nine publicly disclosed Breakthrough Therapy Designations granted to neuroscience compounds in 2024 went to compounds originated by emerging companies.⁸

At Parexel, we advise sponsors on how to take calculated risks, such as utilizing innovative trial designs and novel endpoints.

Urgency. Oncology researchers, patients, and regulators adopted a “time matters” approach to R&D, transforming the field and benefiting patients. Likewise, the neuroscience community must communicate an urgency commensurate with the burdens and crises these diseases impose on individuals and societies. ADI estimates that if ‘dementia’ were a country, it would be the 17th largest economy in the world because its worldwide cost is 1.3 trillion dollars.⁹ Neurological and psychiatric diseases often progress slowly, but time matters; we must treat them early. The World Health Organization estimates that half of adult mental health disorders start by age 14, and depression and anxiety are a leading cause of illness and disability among adolescents globally.¹⁰ Yet most cases go undetected and untreated—creating incalculable future societal costs. Nothing could be more urgent than slowing this vicious cycle of dysfunction.

Oncology researchers, patients, and regulators adopted a ‘time matters’ approach to R&D, transforming the field and benefiting patients. Likewise, the neuroscience community must communicate an urgency commensurate with the burdens and crises these diseases impose on individuals and societies.

Contributing Experts