Guest Column | September 11, 2023

Pursuing Smaller, Faster Clinical Trials For Progressive Neurological Disorders

By Zahid Ali, VP development lead, UCB

Doctors-human brain-GettyImages-1186854394

It’s easy to be pessimistic when it comes to investigating Parkinson’s disease. The condition, which causes progressive damage to brain cells over many years, has no therapy to halt its progression, with current treatments focusing only on symptom management.

The challenges in Parkinson’s drug development are diverse. Traditionally, clinical trials for progressive neurodegenerative disease are expensive, are time-consuming, and often require hundreds or even thousands of participants. Patients experience many individualized symptoms, and because of the often-debilitating nature of those experiences, their level of commitment throughout the duration of a clinical trial may waver, particularly as the benefits of any intervention that slows disease progression can take years to be revealed. What’s more, neurology is an area of calculated risk, and every new mechanism taken into clinical development has a high chance of failure, especially with the cost and complexity limiting the number of these trials.

Current progression measures of neurodegenerative disease are clinically focused, highly subjective, and can take years to reveal the effects of therapeutic intervention. Knowing that, the pursuit of smaller and faster clinical trials, particularly at the proof-of-concept stage, can be an innovative way to counteract some of these risks and sidestep the multiple limitations of larger trials. While these smaller trials are currently aspirational for the industry, it is hoped that new endpoints, new biomarkers, and advanced technology will bring us closer to delivering such trials with accuracy and efficiency.

The Pros And Cons Of Small Trials

Naturally, smaller trials are, in principle, more cost and time efficient, and potentially allow for a more in-depth understanding of a smaller group of patients and their disease. While the definition of a smaller trial’s size might depend on the levels of sub-groups in a patient population, if we are able to halve the typical trial count, this could yield huge increases in efficiencies, site use, and trial costs.

With smaller trials, there is the opportunity for the industry to work closely with patients — from increasing earlier and more meaningful patient engagement and advocacy to conducting direct interviews of HCPs, researchers, and patients during the drug development process. These can help uncover the myriad symptoms, small differences in disease pathobiology, biomarkers, and external factors that could affect the clinical manifestation of the disease and the impact of any therapeutic intervention. UCB’s Patient Engagement Council for Parkinson’s Research is a primary example of this collaborative effort. Patients and patient organizations are involved from the outset within our clinical development programs, sharing the reality of living with a complex progressive disease and advising on study design and communication considerations when engaging in the drug development process.

Smaller clinical trials are best engaged during the early stages of drug development when little is known about the investigational intervention. Phase 2 trials serve two distinct goals: to detect a signal that may be a biomarker, surrogate endpoint, or clinical endpoint that then gives confidence to move forward and to translate a signal in Phase 2 into the key clinical endpoints for later-stage development. In terms of signal detection, smaller trials and, in turn, a smaller population could allow for greater magnification of outliers and differences, spotting intricacies that wouldn’t necessarily be prioritized within larger groups. These intricate findings also can raise an alarm before entering larger populations in Phase 3 trials, which may lead to avoidance of missed endpoints and trial failures.

Naturally, smaller trials also have their limitations; a reduced research population also potentially reduces the diversity of the group, which may be important in Parkinson’s disease as no two diagnoses are the same. Furthermore, ensuring that any signal detected in Phase 2, particularly with respect to biomarkers or surrogate markers, eventually translates to a meaningful relevant signal for the internal decision making in late-stage development remains a risk.

To move us closer toward the goal of smaller and more agile clinical trials, progress is needed in in-depth understanding of the patient population and the creation of new endpoints and biomarkers, as well as the continued development of sophisticated technology to ensure smaller trials are as robust and meaningful as their larger counterparts. While we are not yet ready to establish these smaller trials in clinical development programs for Parkinson’s disease, when used in the right context they offer a very near and exciting future for clinical research.

The Need For A Multidisciplinary Approach To Jumpstart Smaller, Quicker Trials

A critical factor in the bid to improve the outlook for Parkinson’s research is the evolution of technology as it relates to biomarkers, imaging, and surrogate markers, in the clinical setting. A key tool in the digital transformation of Parkinson’s research is the use of wearable devices integrated with the devices many of us already have, such as smartwatches and smartphones, allowing for both passive and active monitoring of multiple tasks. For example, a wearable watch or device can measure involuntary movements, falls, energy expenditure, and posture for individuals with Parkinson’s disease, as well as capture the progression over an extended time period, without the disruption of daily routine or geographical barriers for data collection.

While this is an incredibly useful tool for developing symptomatic treatments and rehabilitation approaches, it also offers the opportunity to collect precise and continuous data on a large scale around the evolution of the disease as well as patient responses to treatment, both of which could drive earlier decision-making in clinical trials, particularly in the context of disease-modifying treatments. The ultimate goal here is for wearable technology to identify biomarkers or disease-specific markers in the diagnosis of Parkinson’s disease, a truly exciting prospect.

A pathobiologically-based classification using biomarkers has the potential to produce an increasingly homogenous and similar biological disease stage population, driving down the noise of other biases and allowing us to decrease the size and potentially the duration of a study. Perhaps among the most interesting development in Parkinson’s disease is the potential for biologically-based classifications of Parkinson’s disease, which would be an evolution from the purely clinical categorization that has existed thus far. Central to this is the use of the biomarker α-synuclein SAA within the cerebral spinal fluid and coupling it with imaging techniques to classify the different stages of Parkinson’s disease. The premise is that misfolded α-synuclein is the seminal pathobiology underlying Parkinson’s disease and imaging of a dopaminergic transporter is an indicator of loss of dopamine neurons. Importantly, it may be possible to target the development of therapeutic interventions based upon the biological stage of the disease rather than solely upon the temporal manifestation of clinical symptoms.

Clinical research and development need a multidisciplinary approach, and we recognize the significance of the notion that no one company or organization can tackle this mountain themselves. At UCB, we created — together with patients, The Parkinson’s Foundation, and Parkinson’s U.K.— patient-reported outcome tools to better reflect the experiences and potential impact of disease-modifying treatments in early Parkinson’s disease. In 2021, we formed our Patient Engagement Council for Parkinson’s Research (PECPR), a patient-led working group to help drive the key topics for clinical development in Parkinson’s, ensuring their priorities are factored into the clinical development of our treatment. We see similar activities across the spectrum with consortia such as Critical Path for Parkinson’s (CPP), composed of regulatory agencies, patient organizations, industry, and other key stakeholders coming together to address critical topics such as clinical endpoints for disease modification, utility of digital and imaging technologies, and biomarkers, to name but a few.  

Becoming Comfortable With Failure

With the combination of diverse partnerships, the involvement of passionate patient advocates, and the possibility of pursuing smaller, more agile trials, we are far from pessimistic about the future of Parkinson’s treatment innovation. Failure is the norm in drug development. But by leveraging innovation, overcoming key challenges through partnerships, and ensuring that we can separate promising from less-promising mechanisms by failing more quickly, we can get that much closer to the target of disease modification and eventually slow or halt the progression of neurodegenerative diseases such as Parkinson’s disease.

About The Author:

Zahid Ali is VP development lead in UCB early solutions. He is a seasoned early development specialist, having spent the majority of his career leading innovative small molecule and antibody programs in the neuroscience and pain space. Prior to joining UCB, he built his career at MSD, GSK, and Pfizer and went on to become the CSO of a U.K.-based semi-virtual biotech, Calchan Ltd. Zahid has a passion for innovative translational/clinical approaches in difficult to address therapeutic areas.