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.