|
What is the expected breakthrough discovery or innovation and how will it change the field? A therapy that can rapidly (<5 min), reliably, efficiently, and conveniently initiate urination or defecation, without lingering effects and without catheters or rectal digital stimulation/extraction, would provide a breakthrough therapy for individuals suffering from neurogenic bladder and bowel. We propose that a programmable, implantable, intrathecal drug delivery (IDD) device may provide on-demand control of neurogenic bladder, bowel, and sexual function for persons with severe, refractory, pelvic dysfunction by delivering drugs directly to the sacral spinal cord. Most of the sacral spinal drug targets in this proposal have been validated for control of bladder and colorectal function, but modulation by systemic drug administration is not possible due to systemic side-effects and absorption, distribution, metabolism, excretion, and pharmacokinetic/pharmacodynamic (PK/PD) issues that prevent rapid onset and offset of drug effects necessary for convenient on-demand urination, defecation, or arousal therapy. These issues have prevented many potentially efficacious drugs from being approved for human use. IDD circumvents these issues by providing direct administration to sacral spinal cord drug targets for very brief periods (e.g., ~5 minutes to induce urination, defecation, or arousal). When the IDD is deactivated, sacral drug concentrations drop very quickly, below effective levels, due to diffusion and/or metabolism. Plasma concentrations of intrathecal drugs remain well below systemic administration levels, thus minimizing side effects and PK/PD issues. Since IDD pumps are currently used to treat intractable pain and neurogenic spasticity, an Investigational Device Exemption (IDE) from the FDA to clinically test IDD as therapy for neurogenic bladder/bowel/arousal in an Early Feasibility Study could be obtained very rapidly. Thus, successful completion of this preclinical proof-of-concept project (which focuses on rapid-onset, short-duration, IDD-induced urination/defecation) could support intrathecal delivery of an extensive library of existing drugs, that are known to properly modulate sacral spinal reflexes to activate bladder, bowel, and sexual function, but cannot be administered systemically due to side effects or inappropriate PK/PD characteristics. With a clinically acceptable intrathecal route of drug administration, scientists and clinicians will be able to explore the therapeutic potential of known, and newly discovered, sacral spinal targets. Providing new targets, attracting more scientists, and using existing drugs; the IDD treatment modality may rapidly provide therapeutic benefits for treatment of severe pelvic dysfunction in people with spinal cord injury (SCI), multiple sclerosis, Parkinson’s disease, among others. IDD devices are now successfully implanted in many people with SCI for control of limb spasticity and chronic pain, and clinicians are competent with device implantation. Off-label delivery of drugs via IDD, as well as investigator-initiated IDD trials are not uncommon. Reimbursement codes are established, and managed care providers have experience with coverage of IDD-related clinical procedures and devices. Clinical IDD studies of approved drugs could begin quite rapidly, with efficacy and safety evaluated quickly (in 2-3 years), as opposed to development of new drugs (5-10 years). This accelerates development of a marketed product. Dignify Therapeutics has over 100 years of collective drug discovery/development experience and are leading experts in sacral spinal control of visceral function. We are joined by international key opinion leaders to accomplish future, long-term goals (letters of support received) for eventual clinical studies. Dr. Robert Gaunt, Univ. Pittsburgh, will provide his expertise with device implantation in telemetry-instrumented, chronic spinal cord injured animals for preclinical efficacy studies. Dr. Elias Viezi, Case Western Univ., will provide clinical expertise and guidance regarding implantation and use of IDD devices in patients, and Flowonix, a U.S. manufacturer of FDA- approved IDD pumps, will provide devices for future clinical studies.
|