TerXT: Combination of Xanomeline and Trospium Prodrugs for Schizophrenia

CLINICAL CONVERSATIONS

Terran has announced the development of TerXT, a combination of xanomeline and trospium for the long-acting treatment of schizophrenia.¹ To help share more on the announcement, Psychiatric Times sat down with Sam Clark, MD, PhD, the founder and CEO of Terran Biosciences.

PT: Tell us a little about TerXT in your own words.

Sam Clark, MD, PhD: TerXT is a novel fixed-dose combination therapeutic that consists of a prodrug of xanomeline and a prodrug of trospium. It was designed to enable longer-acting treatments for schizophrenia than would otherwise be possible with the older non-prodrug versions of xanomeline and trospium. Xanomeline and trospium were first developed in the 1990s and 1960s respectively, and in recent clinical trials they were tested as a fixed-dose combination given twice daily, which demonstrated safety and efficacy in treating schizophrenia. Terran was able to use a prodrug approach to overcome inherent pharmacokinetic and physical property limitations of the older forms of xanomeline and trospium with the goal of creating longer-acting combinations of the novel prodrugs, both for once-daily oral administration (“TerXT”) and also long-acting intramuscular injection with multi-month duration (“TerXT LAI”).

PT: What about TerXT sets it apart from other long-acting treatment options for schizophrenia? Can you share more on its mechanism of action, as well as its safety/efficacy data thus far?

Clark: Xanomeline is an agonist of the muscarinic M1 and M4 receptors. As a modulatory neurotransmitter, the muscarinic system is involved in modulating dopaminergic signaling. While activation of the M1/M4 receptors in the brain has an antipsychotic effect, activation of these receptors in the rest of the body leads to gastrointestinal adverse effects such as nausea and vomiting. To cancel out these peripheral effects, xanomeline is combined with trospium, which is a peripherally-restricted muscarinic receptor blocker. Trospium does not cross the blood brain barrier and thus only cancels out the effects of xanomeline in the rest of the body. This muscarinic mechanism is exciting as it represents the first truly novel antipsychotic mechanism in over 50 years.

The older non-prodrug twice-daily oral combination of xanomeline and trospium (called “KarXT”) has already passed 2 phase 3 studies with an excellent safety and efficacy profile and is currently under FDA review for approval, with a PDUFA date scheduled for September 26 of this year. There were 2 phase 3 trials conducted in adult schizophrenia patients, EMERGENT-2 with 252 patients and EMERGENT-3 with 256 patients. Patients were randomized 1:1 to receive KarXT (flexible dose) or placebo twice daily for 5 weeks. The primary endpoint measured was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline. In both studies KarXT was found to be well-tolerated and efficacious, with EMERGENT-2 showing a 9.6-point decline and EMERGENT-3 showing a 8.4-point decline in PANSS total scores from baseline.

What differentiates TerXT from KarXT is that TerXT utilizes a dual prodrug approach, and includes both a prodrug of xanomeline and a prodrug of trospium. In vitro and in vivo safety studies with TerXT have shown an excellent safety profile to date. Prodrug strategies have been widely used in the industry to improve older antipsychotics including aripiprazole lauroxil (Aristada®) and iloperidone palmitate (Invega Halfyera®) to make long-acting injectables with multi-month durations. Additionally, prodrug versions of antipsychotics are often approved via the 505(b)(2) accelerated regulatory pathway.

PT: What is the 505(b)(2) regulatory pathway? How does it differ from other approval processes? What makes TerXT a good candidate?

Clark: The FDA 505(b)(2) regulatory pathway is designed for the approval of drugs that have the same active ingredient as an FDA approved product, and allows the drug developer to reference all of the completed safety and efficacy studies of the approved drug as to not have to repeat those studies. The sponsor then must simply conduct bridging pharmacokinetic and safety studies to show bioequivalence with the approved drug, typically avoiding the need for large phase 2 and phase 3 clinical efficacy studies that are required in a standard 505(b)(1) process.

If the current non-prodrug form of xanomeline/trospium is approved on the 505(b)(1) pathway later this year, the FDA would grant a period of data exclusivity lasting approximately 5 years. After this period, TerXT would a good candidate for the 505(b)(2) pathway because it contains prodrugs of the active compounds. As mentioned previously, this prodrug approach is common, and antipsychotic prodrugs have been approved on the 505(b)(2) pathway many times before.

PT: Why should clinicians be excited about this treatment option? How do you anticipate it will change patient outcomes?

Clark: A twice-daily oral antipsychotic may pose a challenge for patients with schizophrenia as medication compliance is a known issue, and we believe clinicians would be excited by having access to improved formulations if available. The gold standard for oral antipsychotics is once-daily dosing, which we hope to achieve with TerXT. Additionally, multi-month duration is becoming the standard for long-acting injectable antipsychotics, which we hope to achieve with TerXT LAI. In comparison to the older twice-daily xanomeline/trospium, we believe longer-acting prodrug forms could potentially improve ease of dosing, increase compliance, and reduce psychotic episodes due to noncompliance.

PT: What are the next steps for TerXT?

Clark: After the approval of the older xanomeline/trospium therapeutic later this year, Terran plans to follow the well-established playbook for antipsychotic prodrugs, moving TerXT into pharmacokinetic bridging studies and toward a potential 505(b)(2) pathway to approval.

PT: Thank you!

Dr Clark is the founder and CEO of Terran Biosciences.

Reference

1. Terran Biosciences announces development of TerXT, a combination of xanomeline and trospium prodrugs for the treatment of schizophrenia, and intends to pursue accelerated 505(b)(2) approval pathway. News release. May 20, 2024. https://terranbiosciences.com/TerXT