CNS-targeted therapies are changing every day. It’s important to stay ahead of the curve and learn about some of the highlighted new approaches being developed in the CNS rare disease space.
Richard Scheyer, MD, Vice President, Medical Affairs at Medpace answers some questions about his upcoming presentation about CNS-targeted therapies at DIA 2018.
How has imaging been used in confirming CNS diagnoses?
For diseases that affect the CNS, it is rarely possible to collect tissue samples capable of confirming diagnosis, measuring disease progression or monitoring the effectiveness of a treatment. For example, a tissue biopsy is often used to study samples in oncology, but clinicians are often unable to take a biopsy of the brain or spinal cord, except in the case of a post-mortem. Imaging, such as molecular PET, is increasingly being used to confirm diagnosis of diseases like Alzheimer’s and Parkinson’s, but target limitations and concerns over radiation exposure have limited its ability to probe specific pathophysiology. Cerebrospinal fluid (CSF), while more invasive, can provide complementary information.
Delivery of therapeutics to the CNS has been a challenge for generations of medicinal chemists, exacerbated by recent trends towards macromolecular and genetic therapies. What are some successful approaches?
One partially successful approach has been intrathecal delivery, this is particularly useful for targets adjacent to CSF space. Another increasingly popular approach has been to link the therapeutic to a ligand for an endogenous receptor mediated transport. Confirming brain entry remains a challenge. CSF is a product of the choroid plexus, and even without the confound of intrathecal delivery, concentrations do not necessarily mirror those within the brain. PET imaging can be highly informative, but is expensive and applicable for only a fraction of current targets. Fortunately, a new generation of tools has emerged to monitor not only drug penetration, but also target engagement, using readily obtained circulating samples, supplementing and potentially replacing CSF sampling.
Beyond disease monitoring is the opportunity to rapidly confirm that a putative treatment has engaged its target and measure downstream pharmacologic activity. What are some challenges with this opportunity?
Initial efforts to measure circulating CNS markers were hampered by marker instability, challenging assays, and lack of CNS specificity. These challenges may be addressed in part by measuring markers contained within CNS-derived extracellular vesicles. Nevertheless, careful consideration of marker selection, collection, assay, and interpretation are critical.
Where can I learn more about novel approaches to confirming CNS penetration and target engagement?
Attend the session “Novel Approaches for Accessing the CNS: Nonclincial and Clinical Challenges” at DIA on Tuesday, June 26th at 8:00am.