Abstract Details

Title Preclinical Evidence Supporting Pilavapadin as a Novel Oral Therapy for Spasticity

Topic Multiple Sclerosis

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 19-010

Objective To evaluate the effects of the adapter protein-2 associated kinase 1 (AAK1) inhibitor pilavapadin on spasticity endpoints in preclinical models of central nervous system injury.

Background Current oral therapies for spasticity, such as baclofen and tizanidine, provide only partial benefit and are often limited by sedation. By targeting AAK1, pilavapadin holds promise as a potential novel therapeutic option.

Design/Methods Spasticity was evaluated in a mouse model of multiple sclerosis (EAE model) and a rat model with complete spinal cord transection. Spasticity was assessed by transcranial motor-evoked potentials (tcMEPs) and electromyographic (EMG) fibrillation rates in mice and rate-dependent depression (RDD) of the Hoffmann reflex (H-reflex) and induced muscle spasms in rats.

Results In mice, pilavapadin significantly improved tcMEP latency (5.55 ± 0.22ms at 10 mg/kg; 5.32 ± 0.22ms at 3 mg/kg vs. 10.05 ± 2.59ms for vehicle; both p<0.05) and peak-to-peak amplitude (11,613.75 ± 1154.41 µV at 10 mg/kg; 11,321.67 ± 1321.68 µV at 3 mg/kg vs. 7681.17 ± 1505.12 µV for vehicle; both p<0.001) on day 10, with effects comparable to fingolimod and tizanidine. On day 21, EMG fibrillation was significantly lower with pilavapadin 10 mg/kg (1.22 ± 0.57 Hz) and 3 mg/kg (0.38 ± 0.38 Hz) compared with vehicle (4.69 ± 1.11 Hz; both p<0.05). In rats, pilavapadin 10 mg/kg reduced the mean relative H-reflex amplitude from 125.05 ± 13.43 (vehicle) to 83.15 ± 8.01 at 1 hour and 71.40 ± 9.58 at 6 hours (both p<0.05), while 30 mg/kg produced similar effects (77.90 ± 4.36 at 6 hours, p<0.05 at 1 Hz). Pilavapadin also significantly reduced chronic SCI-induced muscle spasms from 1-hour postdose onward without causing sedation.

Conclusions Pilavapadin demonstrated significant, sustained effects measures of spasticity in two validated preclinical models. These findings support further development of pilavapadin as a potential oral therapy for spasticity with a favorable tolerability profile.

Authors/Disclosures
Suma Gopinathan, PhD (Lexicon) PRESENTER	Dr. Gopinathan has received personal compensation for serving as an employee of Lexicon Pharmaceuticals. Dr. Gopinathan has or had stock in Lexicon Pharmaceuticals.
Qi M. Yang, PhD	Dr. Yang has nothing to disclose.
Sigal Meilin (MD Biosciences)	No disclosure on file
Praveen Tyle, PhD (Lexicon Pharmaceuticals)	Dr. Tyle has nothing to disclose.
Keren Kigel-Zur (MD Biosciences)	No disclosure on file
Isaac Levi, PhD	Dr. Levi has nothing to disclose.
Yoav Shulman (MD Biosciences)	No disclosure on file
Alan J. Main, PhD	Dr. Main has received personal compensation for serving as an employee of Lexicon Pharmaceuticals . Dr. Main has stock in Lexicon Pharmaceuticals .

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