Key Point: Phase 2 trials suggest extended-release oral ketamine formulations could be alternative to clinic-administered treatment for resistant depression.
Phase 2 trials suggest extended-release oral ketamine formulations could provide antidepressant efficacy for patients with treatment-resistant depression (TRD), without the requirement for parenteral administration, or the degree of dissociative adverse effects associated with injectable ketamine and intranasal esketamine.
In the phase 2 trial results of R-107 (Douglas Pharmaceuticals) recently published in Nature Medicine1, and of KET01 (Ketabon, collaboration of HMNC Brain Health andDevelco Pharma) presented in May at the American Society of Clinical Psychopharmacology Annual Meeting in Miami,2 both extended-release oral formulations of ketamine were associated with statistically significantly more improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) measure of depressive symptoms than placebo when added to the antidepressant regimens of outpatients whose symptoms were unremitting despite their current, and at least 2 previously tried, antidepressants.
In the published randomized placebo-controlled trial with R-107, Paul Glue, MD, of the University of Otago in Dunedin, New Zealand, and colleagues applied a cohort enrichment design; randomizing only the 168 participants who had initially responded to the addition of the investigational agent out of the 231 who had received the agent in the initial open-label, 8-day phase.
"We chose this design owing to observations that acute antidepressant clinical trials in non-TRD have high failure rates—inability to separate clinical response between active and placebo arms," Glue et al explained.
"Failure rates can be reduced by using an enrichment design, in which nonresponders are excluded, followed by a subsequent relapse-prevention phase in treatment responders," the investigators observed, noting that the design has been found to reduce failure rates to as low as 25%.
All participants met criteria for TRD and presented with depressive symptoms that had persisted despite treatment with 2 or more antidepressants. At baseline, all participants had MADRS scores greater than or equal to 20. The cohort included those currently on antidepressants (n=165) and others who had stopped taking, or had their antidepressant discontinued (n=60). Most participants took the R-107 while at home.
The trial primary endpoint was statistically significantly greater improvement of MADRS score with drug than placebo at week 13. Secondary outcomes included rates of remission (MADRS total score less than or equal to 10) and response (greater than or equal to 50% reduction MADRS from baseline), and the rates and types of adverse events. In addition to comparing drug effect with placebo, the investigators sought to determine optimal dose of the investigational ketamine formulation, and so participants were randomized to receive double-blind R-107 in doses of 30, 60, 120, or 180 mg or placebo twice weekly for 12 weeks.
Glue told Psychiatric Times that the 180 mg dose twice weekly was found to be the closest to a minimum effective dose that could maintain a durable response over 3 months.
"This is consistent with trends we have seen in the 6-month pen label safety study and in the compassionate use program, where most patients take 180mg twice a week," he said, adding, "Some patients may benefit from lower doses."
The investigators reported that the primary endpoint was met, with a least square mean difference of MADRS score for the 180 mg tablet vs placebo at 13 weeks of -6.1 (05% CI 1.0-11.16). Although the rates of response with R-107 at week 13 were numerically higher, and rates of relapse numerically lower than with placebo, the differences were not statistically significant. Relapse rates during the double-blind phase ranged from 70.6% for placebo to 42.9% with 180 mg of R-107.
Glue noted that the primary endpoint of reduction in MADRS with the active agent, and separation from placebo were both statistically and clinically significant. "The minimum clinically important difference in placebo-controlled antidepressant trials using the MADRS varies between 2-4 points, depending on which studies are included in meta-analyses.”
"The 6-point difference reported in... (this) study would therefore be clinically significant. The reduction in MADRS at 92 for the 180 mg dose group compared to placebo had a positive P value, which also demonstrates clinical significance. This result informs the dose to be used in phase 3," Glue explained.
Glue anticipates that the phase 3 clinical testing will provide sufficient evidence of safety and efficacy to warrant product registration. "In phase 3 we will treat a nonenriched population of patients with TRD, randomized and double-blinded to test or placebo study arms. The primary efficacy endpoint will be MADRS separation between the 2 groups at 5 weeks," he said.
The investigators characterized the tolerability of R-107 as "excellent," with no observed changes in blood pressure and minimal reports of sedation. The most common adverse events were headache, dizziness, and anxiety. The occurrences of dissociation were also described as "minimal"; reported by 26 participants (11.6%), with mean dissociation (Clinician-Administered Dissociative States Scale) scores of less than 3. The relatively few reports of dissociation, compared with that associated with ketamine injection, is attributed to a low systemic concentration from the slow-release dosage form.
Peter Surman, PhD, Chief Scientific Office, Douglas Pharmaceuticals, and a coauthor of the phase 2 trial report, commented that while he is confident that R-107 will proceed to pivotal registrational clinical studies and ultimately prove safe and effective for home administration, he anticipates that protocols for its use will include specific restrictions and monitoring.
"There will likely be restrictions on the quantity of tablets that can be dispensed to a patient. Douglas Pharmaceuticals are anticipating a risk evaluation and mitigation plan for the commercial product focused on mitigation of abuse and diversion of R-107," Surman told Psychiatric Times. "At the same time, we are planning to include elements that will aid treatment adherence such as notification when it is time to take your medication. "We are anticipating that patients who respond to R-107 will self-administer R-107 at home. We expect that many doctors will prefer their patients to come to clinic for their first few doses to determine how they respond, and to monitor safety and tolerability.”
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