Rationale:
Cannabidiol (CBD) is approved to treat seizures in patients with Dravet syndrome or Lennox-Gastaut Syndrome in the US and the EU. Due to low oral bioavailability, CBD is dosed as a large volume, oil-based oral solution, which carries the risk for hepatotoxicity and gastrointestinal (GI) adverse events. To address this challenge, SPT-310, an oral prodrug of cannabidiol, is being developed using the GlyphTM platform, a technology which reversibly conjugates a drug of interest to a dietary lipid molecule using proprietary chemistry to direct absorption toward the lymphatic system. Here, we evaluate the potential anti-convulsant activity of SPT-310 in the maximal electroshock seizure (MES) model in rodents, a validated and translatable preclinical model for anti-seizure drugs.
Methods:
Male Sprague Dawley rats (aged 6-8 weeks) were randomly assigned to one of the following groups (N=12/group): vehicle (5 mL/kg), valproate (250 mg/kg), oral CBD (50, 100, 150, 200, or 250 mg/kg), or SPT-310 (100, 150, 200, 250, 300, or 350 mg/kg). As SPT-310 has a ~3-fold higher molecular weight than CBD due to the prodrug moiety, the equivalent CBD content can be represented as a corresponding CBD-equivalent dose (36, 54, 72, 90, 110, and 130 mg/kg). Dosing of oral CBD and SPT-310 was completed in two separate experiments with each experiment including a vehicle group for comparison and valproate group as a positive control. Rats were assessed for the presence or absence of a tonic hindlimb extensor seizure following an electroshock (150 Ma; 50 Hz; 0.3 s duration). Significant differences between treatment groups were determined by a two-sided Fisher’s exact test versus vehicle.
Results:
Valproate treatment significantly reduced the number of animals exhibiting seizure activity. Oral CBD doses at 150, 200, and 250 mg/kg significantly increased the percent of animals protected from seizures (42%, 50%, 67%, respectively) vs vehicle. Oral SPT-310 at 54 mg/kg and 72 mg/kg CBD-equivalent doses protected animals from seizure activity (42% and 50%, respectively) while the 90 mg/kg CBD-equivalent dose protected a higher percent of animals (83%). Oral CBD at 50 and 100 mg/kg and SPT-310 at 36 mg/kg CBD-equivalent were not significantly different from vehicle. Additionally, the CBD equivalent ED50 of SPT-310 was lower (65mg/kg CBD equivalent) than oral CBD alone (180 mg/kg).Conclusions:
Oral CBD and SPT-310 both significantly inhibited tonic hindlimb extensor seizures in a rodent MES model compared to vehicle. Notably, SPT-310 protected a higher proportion of animals at the same CBD dose (83% vs 67%, respectively) and SPT-310 had a lower CBD-equivalent ED50. Importantly, this data suggests that SPT-310 enhances bioavailability of CBD and achieves similar seizure protection at lower doses compared to CBD, enabling oral dosing at a reduced volume, and reducing the risk for hepatoxicity and GI side effects. SPT-310 has the potential to expand the use of CBD to broader patient populations, particularly where higher doses are required to achieve a therapeutic effect.
Funding:
This study was supported by Seaport Therapeutics and, previously, Seaport Therapeutics’ predecessor, PureTech Health.