Med Check: Opioid Overdose, Ketamine Side Effects, Schizophrenia

FDA Takes Action on Two Potential Opioid Overdose Treatments

The Food and Drug Administration (FDA) has taken action on two potential treatments for opioid overdose.

First, in late October the agency gave fast track designation to Cessation Therapeutics’ CSX-1004, an investigational therapy for the prevention of fentanyl-related overdose. CSX-1004 is a human IgG1 monoclonal antibody specific for fentanyl and fentanyl analogs that neutralizes the substances in the blood before they reach the brain. The FDA fast track is a process designed to facilitate the development of drugs that treat serious conditions and fill an unmet medical need and to expedite their review.

The fast-track designation was based in part on nonhuman primate data demonstrating that a single dose of CSX-1004 can block the life-threatening, respiratory depressant effects of high doses of fentanyl for up to 28 days. Cessation has initiated a phase 1a trial to evaluate the safety, tolerability, and pharmacokinetics of CSX-1004 in healthy volunteers.

Second, in November, the FDA accepted for review Orexo’s New Drug Application for OX124, a nasal rescue medication containing a high dose of naloxone. The submission includes data from a study in healthy volunteers, which showed OX124 showed a significantly faster and higher absorption of naloxone compared with intramuscular dosing with an injection reference product.

Fewer Dissociative Symptoms Reported With Prolonged-Release Ketamine

In a head-to-head trial, KET01—a prolonged-release oral formulation of ketamine—produced significantly fewer dissociative symptoms than Spravato, the FDA-approved esketamine nasal spray, Ketabon announced in November.

KET01 is the lead drug asset of Ketabon, a joint venture between HMNC Brain Health and Develco Pharma. The findings were presented at the 2023 CNS Summitt in November.

This comparison study involved 26 adult participants without depression who received either a KET01 pill (240 mg) and intranasal placebo nasal spray, or intranasal esketamine (84 mg) and a placebo pill; the treatments were spaced two to four weeks apart. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS).

The participants who took KET01 exhibited significantly lower CADSS scores in the hours after administration compared with those receiving esketamine spray, the company noted in a press release.

FDA to Review Karuna’s Schizophrenia Drug KarXT

In November Karuna Therapeutics announced that the FDA has accepted for review the New Drug Application for KarXT (xanomeline-trospium) for the treatment of schizophrenia in adults.

The NDA submission includes data from the EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials, which evaluated the efficacy and safety of KarXT compared with placebo. In all three placebo-controlled trials, the drug met its primary endpoint, demonstrating a statistically significant and clinically meaningful reduction in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo.

Karuna Therapeutics also announced in November that KarXT was not associated with increases in blood pressure.

In a safety study, 133 adults aged 30 to 65 years with schizophrenia received KarXT twice daily for up to eight weeks, and 80% of the participants were at the highest dose level at the end of the study (125mg xanomeline/30mg trospium).

After eight weeks, average ambulatory systolic blood pressure across 24 hours dropped by 0.59 mmHg among the participants, with the highest range being a gain of 1.60 mmHg (The FDA considers an increase in blood pressure to be clinically meaningful if it is 3 mmHg or more, according to the company press release). ■