Oral Prolonged-Release Ketamine in Treatment-Resistant Depression

Key Takeaways

• Adjunctive KET01 240 mg/d did not meet the prespecified day 21 MADRS endpoint versus placebo in adults with treatment-resistant depression.
• Earlier MADRS reductions were observed after the first 240 mg dose, with between-group differences at days 4 and 7 and a numerical difference at 4 weeks, but these remained time-point signals.
• Intranasal esketamine was associated with significant dissociation, while KET01 showed limited cardiovascular change, lower peak plasma levels, and higher metabolite exposure.

Across two randomized clinical trials of oral prolonged-release KET01, adjunctive 240 mg/d did not separate from placebo on the prespecified phase 2 endpoint in treatment-resistant depression. At day 21, the LS mean MADRS difference for 240 mg/d KET01 versus placebo was -1.82 points (95% CI, -6.21 to 2.57; P = .41).

KET01-03 was an active-comparator, double-blind, double-dummy, crossover phase 1 randomized clinical trial conducted at a single site in Germany. It enrolled 26 healthy male volunteers aged 18 years or older, with a median age of 32 years, and compared oral KET01 240 mg with intranasal esketamine 84 mg. Maximum CADSS change within 24 hours was the primary endpoint. KET01-02 was a placebo-controlled, double-blind phase 2 randomized clinical trial across 29 sites in the Czech Republic, Germany, and Poland among adult outpatients with treatment-resistant depression receiving ongoing standard therapy. It enrolled 122 outpatients and tested KET01 120 mg/d or 240 mg/d against placebo for 3 weeks, with LS mean MADRS change to day 21 as the primary endpoint.

In KET01-02, the prespecified day 21 comparison for adjunctive 240 mg/d KET01 versus placebo was negative. MADRS scores decreased 7 hours after the first 240 mg dose. The LS mean difference versus placebo was -3.66 points at day 4 (95% CI, -6.74 to -0.59; nominal P = .02). At day 7, the LS mean difference versus placebo was -3.95 points (95% CI, -7.75 to -0.15; nominal P = .04). At 4 weeks, the LS mean difference was -3.35 points (95% CI, -7.62 to 0.93; nominal P = .13).

In KET01-03, intranasal esketamine 84 mg, but not KET01, induced significant dissociation within 24 hours after dosing. Mean maximum CADSS change was 29.6 [12.5] points with intranasal esketamine versus 0.7 [1.7] points with KET01 (P < .001). Pulse and blood pressure did not change markedly in the KET01 group in both trials, whereas rapid increases followed intranasal esketamine in KET01-03. Maximum plasma concentration was 39.1 ng/mL for KET01 and 104.1 ng/mL for esketamine, while norketamine AUC was 3.5 µg × h/mL versus 1.4 µg × h/mL for norketamine.