HOLLYWOOD, FLA. – An investigational intranasal spray antidepressant known for now as PH10 shows early promise in addressing two major unmet needs in the treatment of major depressive disorder: faster-acting drugs with novel mechanisms of action.
PH10 showed a large antidepressant effect in a small phase II study after just 1 week, when the first scheduled assessment took place. Future studies will look for an antidepressant effect even sooner, perhaps as early as day 1 of treatment, Dr. Michael R. Liebowitz said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.
PH10 is a proprietary pherine. The pherines are a class of intranasally administered psychoactive therapeutic agents that bind locally on nasal chemosensory receptors and trigger responses in the hypothalamus, amygdala, prefrontal cortex, and hippocampus. They have an excellent safety and tolerability profile, are effective in nanogram quantities, and do not circulate systemically in the blood. Instead, they initiate neural impulses that follow defined pathways in order to directly affect brain function, explained Dr. Liebowitz, professor of clinical psychiatry at Columbia University, New York.
He presented an 8-week, phase II, double-blind, single-site pilot randomized trial involving 30 patients with major depressive disorder. None had treatment-resistant depression. The participants were randomized to two self-administered inhalations in each nostril twice daily at a dose of 3.2 mcg/day of PH10 from a metered-dose spray device, or a high-dose group receiving 6.4 mcg/day, or placebo spray.
Baseline scores on the 17-item Hamilton Rating Scale for Depression (HAM-D) were in the low to mid 20s. After 8 weeks of treatment, mean HAM-D scores dropped by 10.9 points in the placebo-treated controls, 16.3 points in the low-dose PH10 group, and 17.8 points in the high-dose arm, said Dr. Liebowitz, also managing director and founder of the Medical Research Network.
Particularly intriguing were the results after just 1 week: a 4.2-point drop with placebo, compared with decreases of 8.4 and 10.1 points, respectively, in the low- and high-dose PH10 arms.
"The effect sizes are pretty substantial," Dr. Liebowitz noted. He cited the Cohen’s d value of 1.01 for the comparison between high-dose PH10 and placebo, indicative of a large effect size; and a Cohen’s d of 0.71, indicative of a moderate to large effect size, for low-dose PH10 vs. placebo.
Baseline scores on the patient self-rated Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ) averaged 40 but improved by a mean of 20.3 points in the high-dose PH10 group, 15.3 points in the low-dose group, and 10.1 points in controls.
Remission as defined by a final HAM-D score of 7 or less occurred in 80% of the low-dose PH10 group in this small study, in 60% of those on high-dose therapy, and 20% on placebo.
The most common side effects reported in patients on PH10 were daytime sleepiness, nasal irritation, and headache. Three patients on high-dose PH10 reported an increase in appetite, as did one patient in the low-dose arm and two patients on placebo. No significant changes in body weight were seen in the 8-week study.
As was frequently noted at the NCDEU meeting, depression is the mental illness with the largest prescription drug market in the United States. The need for antidepressants with new mechanisms of action is underscored by the observation that 50%-70% of patients do not experience remission on selective serotonin reuptake inhibitor/selective norepinephrine reuptake inhibitor therapy.
Pherin Pharmaceuticals, which is developing PH10 as a treatment for depression, also has a handful of other intranasal pherines in its pipeline. Furthest along is aloradine, now in phase III clinical trials for social anxiety disorder. Meanwhile, phase II studies have been completed for an intranasal spray used to treat premenstrual dysphoric disorder called PH80-PMD, and phase III studies for this product are gearing up. Salubrin-HF is currently in phase II studies for menopausal hot flashes. And PH15 is in preclinical testing as a cognitive enhancement agent.
Dr. Liebowitz serves as a consultant to and holds stock options in Pherin Pharmaceuticals. He receives research grants from more than 20 pharmaceutical companies.