Background: One in 36 children and 1 in 45 adults are estimated to have Autism Spectrum Disorder (ASD). The two approved drugs to treat irritability associated with ASD, risperidone and aripiprazole, are atypical antipsychotics with significant adverse effects that often lead to discontinuation. AJA001 Oral Solution is a full-spectrum hemp-derived botanical drug product consisting of cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and other minor cannabinoids and terpenes in glyceryl monolinoleate (a winterized oil composed of long-chain mono-, di-, and triglycerides) being developed for ASD. The present study evaluated the safety and tolerability of AJA001 in healthy adults and characterized its pharmacokinetic (PK) and subjective pharmacodynamic (PD) effects in fed and fasted conditions.

Methods: The study included single-ascending dose (SAD) cohorts to assess the acute effects of AJA001 in fasted conditions with doses from 1.1 mL (62.5 mg CBD, 2.5 mg THC) to 8.8 mL (500 mg CBD, 20 mg THC). One SAD cohort also received 1.1 mL under fed conditions to determine food effects on safety, PK, and PD. Next, 7-day multiple-ascending dose (MAD) cohorts were provided fasted doses beginning at 1.1 mL twice daily and escalating to 3.2 mL twice daily. In each cohort, participants were randomized 3:1 to receive AJA001 or placebo (6 AJA001 and 2 placebo per cohort). Safety and tolerability were evaluated by monitoring adverse events (AEs), electrocardiograms (ECGs), vital signs, clinical laboratory tests, suicidality, and use of concomitant medications. Blood samples for PK plasma analysis of CBD, THC, and their respective metabolites were drawn 45 minutes before dosing and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, 72, and 168 hours post-dose for the SAD cohorts. For the MAD cohorts, blood samples were drawn on Day 1 at 45 minutes before dosing and at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours following initial dosing, on Days 2-6 pre-morning dose, and on Day 7, 45 minutes prior to pre-morning dose as well as at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 96 hours following morning dose. To assess subjective PD effects, the Drug Effects Questionnaire (DEQ; scaled 0-100) was completed before dosing and at 1, 2, 4, 6, 8, and 12 hours post-dose in the SAD cohorts and on Days 1, 3, and 7 in the MAD cohorts. The study was approved by the Alfred Hospital Ethics Committee in Australia, where the study was conducted (ClinTrials ID: NCT06019065).

Results: 70 participants were enrolled (38 SAD; 32 MAD). Treatment emergent AEs were greater in the groups receiving AJA001 relative to placebo, and there was one treatment-related serious adverse event (SAE) following 8.8 mL SAD dosing (500 mg CBD, 20 mg THC). The SAE did not require treatment with concomitant medication and resolved without sequelae. AEs at > 5% for AJA001 included somnolence, anxiety, sinus tachycardia, dizziness, nausea, abdominal discomfort, affect lability, and diarrhea. Most AEs were mild and transient and resolved spontaneously. There were no clinically significant changes in vital signs or clinical chemistry evaluations (including liver function tests) in either study phase. Data from the fasted SAD cohorts revealed: (1) 1.1mL of AJA001 (62.5 mg CBD and 2.5 mg THC) resulted in Cmax=14.7 ng/mL, Tmax=2.6h (CBD); Cmax=0.8 ng/mL, Tmax=2.5h (THC), (2) 2.2 mL of AJA001 (125 mg CBD, 5 mg THC) resulted in Cmax=34.3 ng/mL, Tmax=2.2h (CBD); Cmax=1.5 ng/mL, Tmax=2.2h (THC), (3) 4.4 mL of AJA001 (250mg CBD, 10mg THC) resulted in Cmax=67.2 ng/mL, Tmax=3.7h (CBD); Cmax=2.6 ng/mL, Tmax=2.1h (THC), (4) 6.6 mL of AJA001 (375mg CBD, 15mg THC) resulted in Cmax=92.6 ng/mL, Tmax=3.7h (CBD); Cmax=5.0 ng/mL, Tmax=3.5h (THC), and (5) 8.8 mL of AJA001 (500mg CBD, 20mg THC) resulted in Cmax=80.2 ng/mL, Tmax=2.6h (CBD); Cmax=3.3 ng/mL, Tmax=2.7h (THC). Those receiving 1.1 mL of AJA001 in the fed condition demonstrated a 2-fold increase in the Cmax of CBD (30.3 ng/mL fed vs. 14.7 ng/mL fasted) and THC (1.41 ng/mL fed vs. 0.84 ng/mL) though measured metabolites were 2-fold higher in the fasted vs. fed conditions (e.g., 7-OH-CBD = 8.7 ng/mL (fed) vs. 16.3 ng/mL (fasted)). The MAD study also revealed a dose-response escalation in PK parameters. PD data from the DEQ showed that the intensity of subjective drug effects followed a dose-related pattern in the SAD, with mean maximum drug effects (Emax) ranging from 6.2 (SD = 26.9) in the 1.1 mL cohort to 74.3 (SD = 37.6) in the 8.8 mL cohort (pooled placebo drug effects Emax was 36.1 [SD = 39.1]). Similar dose-related PD findings occurred in the MAD.

Conclusions: Data from our study revealed an upper limit for acute and repeated dosing of AJA001 of ~6.6 mL daily (375mg CBD, 15mg THC) based on safety and tolerability assessments. PK analyses demonstrated that AJA001 is associated with higher CBD bioavailability than in prior studies of similar oral CBD doses under fasted conditions. Levels of THC in plasma were similar to those observed in prior oral dosing studies. Food improved bioavailability of CBD and THC by ~2-fold. Of note, our data highlight greater levels of metabolites under fasted vs. fed conditions. PD results showed that subjective drug effects tended to be dose-related and similar to data collected in other studies of oral cannabis and cannabinoid-based products. The safety, PK, and PD profiles of AJA001 are optimized for the ASD population given its high bioavailability and relatively mild side effect profile up to a dose of 6.6 mL daily.

Keywords: Phase 1, Pharmacokinetics, Pharmacodynamics, Cannabidiol, delta9-tetrahydrocannabinol

Disclosure: Charlotte’s Web: Employee (Self). DeFloria, Board Member (Self)