588. PMX30063-Clinical and Preclinical Investigations of Transient, Treatment Related Neurosensory Effects
Session: Poster Abstract Session: Novel Antimicrobial Agents
Friday, October 21, 2011
Room: Poster Hall B1
Background: PMX30063 is the first of a novel class of antibiotics, a non-peptidic, amphiphilic compound that mimics the properties and mechanism of action of the host defense proteins (HDP). Both the natural host defense proteins and PolyMedix’s HDP mimetics work by interacting with the bacterial membrane, disrupting its structure, and causing rapid bacterial death. PMX30063 has been tested in three Phase 1 clinical studies and the most frequent adverse event associated with the drug administration consisted of sensory disturbances defined as paresthesia. We have used two neurological scales in a phase 1 study to address the degree and reversibility of the paresthesia and we have investigated potential mechanisms underlying paresthesia in animals and in vitro.

Methods: Twenty subjects (16 active/4 placebo) were enrolled in a multiple-dose, safety and tolerability study of PMX30063. Subjects randomized to PMX30063 received a loading dose on day 1 of 1.0 mg/kg administered intravenously over 60 minutes followed by 0.35 mg/kg doses on days 2-14.  Specific assessments of neurological symptoms and objective neurological exams were performed in addition to other safety assessments.  In rats, the peripheral nerve electrophysiology studies were conducted at doses of 1, 3 and 10 mg/kg.  In vitro patch clamp assays were performed in cell lines to measure drug effect on ion channel activity.

Results: In the Phase 1 clincal trials the most frequent neurological symptoms were tingling and numbness that were resolved within 7 days after the last dose.  Neurological testing showed only minor, reversible abnormalities in tendon reflexes. In animals a small slowing of caudal nerve conduction velocity was observed only in the high dose animals and was fully reversed 30 days after the last dose. PMX30063 at 10 µM inhibited selected potassium, sodium and acid sensing channels present in sensory and sympathetic neurons.

Conclusion: Neurological symptoms observed in the clinical studies with PMX30063 were not severe and fully reversible. The results from animal testing and ion channel inhibition suggest that neurosensory symptoms associated with PMX30063 treatment is caused by affects on ion channel function and not direct neurotoxicity.


Subject Category: A. Antimicrobial agents and Resistance

Bozena Korczak, PhD1, Richard Scott, PhD1, Roger Echols, MD2 and Joseph Arezzo, PhD3, (1)PolyMedix, Inc., Radnor, PA, (2)Infectious Disease Drug Development Consulting, LLC, Easton, CT, (3)Albert Einstein College of Medicine, Bronx, NY

Disclosures:

B. Korczak, PolyMedix, Inc.: Employee, Salary

R. Scott, PolyMedix, Inc.: Employee, Salary

R. Echols, PolyMedix, Inc.: Consultant, Salary

J. Arezzo, None

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.