2 Ways To Overcome The Challenge Of Developing Neurological Rare Diseases Drugs
By Bruce Leuchter, MD, CEO, GRIN Therapeutics
Collectively, neurological rare diseases represent a complex and challenging area of medicine with significant unmet medical need. Drug development for neurological rare diseases can face unique challenges, including research based on small patient populations, heterogeneity in disease symptoms and progression, evolving understanding of disease mechanisms, subjective rater-based tools to assess drug efficacy, and global infrastructure required to advance clinical research. Despite these obstacles, the desperate need for new and better therapies continues to drive innovations — such as new technologies and business models — that can lead to important advances in treatment.
Individual Factors Compound Challenges In Clinical Trials
Neurological rare disease therapies often require tailored approaches in planning, designing, and executing clinical trials. The first issue in planning for clinical trials is the small and often geographically dispersed patient population. Patient recruitment can be slow and difficult because participants often have to travel to centers of excellence that serve as sites for these specialized trials.
In designing a clinical trial, the lack of disease-specific outcome measures and biomarkers for many neurological conditions complicates trial design and execution. Given the heterogeneity of patient populations affected by neurological diseases, trial endpoints assessed using rater-based outcomes can be prone to high degrees of variability and interpretation, making precise or holistic evaluations of efficacy and safety challenging.
Clinical research in neurological diseases can also require much higher levels of patient observation and analysis, in some cases over several years, to confirm efficacy benefits. This challenge can lead to longer timelines and affect associated costs.
In many cases, drug developers must work to develop innovative and previously untried trial designs, such as adaptive trials or protocols based on the use of real-world evidence. For instance, natural history studies and patient registries are increasingly used to gather baseline data and track disease progression, providing valuable insights that can better inform trial design. These approaches, while presenting the opportunity to address challenges in trial planning and execution, require a higher level of flexibility and deviation from standard procedures that regulatory agencies often prefer.
Regulatory Hurdles Make For A Moving Target
Drug developers must also consider the constantly evolving regulatory landscape for neurological rare disease drugs during the research and clinical development process. One example is the Inflation Reduction Act (IRA), which includes several strategies meant to reduce healthcare costs. While some changes might inspire new levels of collaboration in research, efforts to influence pricing could also help to expand access to treatment to more patients.
While the path to approval can be complex, programs such as the Orphan Drug Act have been crucial in incentivizing the development of more treatments for rare diseases. Recent efforts to streamline regulatory processes also have shown promise. For example, the new FDA guidance on rare disease clinical research emphasizes the importance of natural history studies and patient-focused drug development.1 These initiatives aim to reduce the burden on developers while ensuring that patients receive safe and effective treatments. The FDA also has supported initiatives such as the Rare Disease Clinical Trials Network (RDCTN),2 which connects rare disease researchers, patient advocates, and industry partners to enhance the design and conduct of clinical trials for rare diseases.3 The network focuses on helping streamline trial designs and improve recruitment efforts for studies assessing patients with rare diseases.
2 Ways Industry Is Accelerating Rare Disease Research Progress
Innovative Business Models
Industry leaders are developing customized approaches to identify and advance promising therapies and bring new treatments to patients, including the use of business models designed to streamline and improve development program protocols and timelines.
Some companies, including Neurvati Neurosciences, are advancing an approach based on a private equity (PE) model in the life sciences involving four key steps: identify, evaluate, invest, and develop. Compared to a classic venture-backed model that typically searches for and funds early-stage clinical research, the PE model is often designed to identify and advance later-stage assets supported by compelling clinical data. This approach can help avoid risks associated with development decisions based on translational and early-stage research. GRIN Therapeutics, the first affiliate company established by Neurvati Neurosciences, serves as an archetypal example.
In this approach, once an asset is vetted and acquired, the developer will often have multiple strategic options to consider, including a trade sale of an asset, the pursuit of an IPO, or continuing as a private company. In any case, a dedicated affiliate company is created to bring together the targeted resources necessary to advance development to commercialization. GRIN Therapeutics was established to advance radiprodil, an investigational drug candidate to treat GRIN-related neurodevelopmental disorder, a family of rare, genetically defined pediatric neurodevelopmental disorders.
One important advantage of this model is that it can identify later-stage drugs that have been studied extensively in prior research but did not advance to mid- to late-stage clinical trials and regulatory review, even though data show signs of biological activity and viability as a novel therapy. This process requires a team of specialists in neuroscience research to identify and thoroughly understand assets to confirm their potential for success in mid- to late-stage development. In addition, for the PE model to be successful, all parties, including investors, must understand and agree on the capital requirements, development timelines, competitive dynamics, and market opportunities these drugs represent.
Technological Advances
Advances in genetic technology are also making it possible for more drug developers to leverage human genetics, multi-omics, imaging, neurophysiology, and plasma and cerebral spinal fluid biomarkers to better understand the genetic components and underlying disease biology and how to target the disease more effectively.
For one, genomic sequencing technology that can process a large quantity of genetic material at a time provides unprecedented visibility of underlying DNA structures, making it possible to identify and confirm genetic mutations associated with many rare neurological diseases. This can include rare variants associated with neurodevelopmental disorders. Next-generation sequencing technology has transformed genomic research. Unlike traditional Sanger sequencing, which sequences DNA one fragment at a time, next-generation sequencing can sequence millions or even billions of DNA fragments simultaneously, enabling rapid and cost-effective analysis of large amounts of genomic data. Advanced multi-omics approaches, including transcriptomics and proteomics, can also analyze multiple layers of molecular information within cells or organisms simultaneously, providing a holistic view of their function and behavior. As a result, this can help identify patients with unique molecular signatures that influence disease progression and response to treatment, allowing researchers to better stratify patient populations and ensure therapies are being studied in the most relevant subgroups.
Looking Ahead In Rare Disease Drug Development
Integrating new business models and technological advances will be crucial to developing new treatments for rare neurological disorders, as will collaboration among researchers, regulators, industry leaders, and patient advocacy groups. By embracing these challenges with a multi-prong approach, we can advance more development programs and bring new treatments and hope to patients affected by often debilitating rare neurological conditions, many of which have limited or no disease-modifying treatments currently available.
References:
- U.S. Food and Drug Administration. Rare Diseases: Considerations for the Development of Drugs and Biological Products. Dec. 2023, www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-considerations-development-drugs-and-biological-products.
- U.S. Food and Drug Administration. FDA Requests Input on Rare Disease Clinical Trial Networks. 2023, www.fda.gov/news-events/fda-brief/fda-brief-fda-requests-input-rare-disease-clinical trial-networks.
- Rare Diseases Clinical Research Network. About Our Network. www.rarediseasesnetwork.org/about/our-network.
About the Author:
Bruce Leuchter, MD, is the CEO and president of GRIN Therapeutics, an affiliate of Neurvati Neurosciences, a Blackstone Life Sciences portfolio company. He has deep-rooted, wide-ranging experience spanning neuroscience, clinical neuropsychiatry, biotechnology equity research, healthcare investment banking, and entrepreneurship. A physician by training and neuropsychiatrist by specialty, Dr. Leuchter completed residency training in neurology and psychiatry at New York Presbyterian Hospital and Weill Cornell Medical College and is a diplomate of the American Board of Psychiatry and Neurology. Dr. Leuchter served as director of clinical neuropsychiatry at Weill Cornell Medical College and maintains a voluntary faculty appointment in the department of psychiatry. He serves as a member of the scientific advisory committee for the Daedelus Fund for Innovation at Weill Cornell Medical College, as a member of the Life Science Institute Leadership Council at the University of Michigan, and as a business advisory board member at FOXG1 Research Foundation.