In May 2024, we sat down with Sam Clark, CEO of Terran Biosciences, to discuss the exciting developments in their pipeline, particularly their latest schizophrenia therapeutic, TerXT. This new treatment is designed to be a significant competitor to Karuna’s KarXT. Since our last interview, Terran has made remarkable strides, including the development of new forms of psilocybin, MDMA, and 5-MeO-DMT, each with unique properties aimed at improving therapeutic outcomes. However, the highlight of our conversation is TerXT, a novel combination of prodrugs xanomeline and trospium, engineered to offer long-acting formulations in both a once-daily oral pill and a multi-month intramuscular injection.
Since we last spoke it looks like there have been some significant updates at Terran, including several new assets in the psychedelic space and in schizophrenia, could you highlight some of these breakthroughs?
Over the past year, we have announced several innovations across our pipeline. First, we created the world’s first new forms of psilocybin (psilocybin HCl and psilocybin edysilate), the first new form of MDMA (MDMA hemifumarate), as well as the first orally-active prodrugs of 5-MeO-DMT. The patent office has now granted us patents for all of these inventions and we are planning to pursue the 505(b)(2) pathway to approval.
Our biggest update, however, is the recent unveiling of our schizophrenia therapeutic TerXT, which is a combination of novel prodrugs of the compounds xanomeline and trospium, designed with the goal of creating long-acting formulations, including a once-daily oral pill and an intramuscular injection with a multi-month duration.
Karuna Therapeutics’ drug “KarXT” (the original non-prodrug xanomeline/trospium combination) was quite successful in clinical trials of schizophrenia, leading to Karuna’s acquisition by Bristol Myers Squibb (BMS) for $14B just a few months ago. In the context of KarXT’s success, could you provide some background on the space and what differentiates “TerXT”?
Patients with schizophrenia are in dire need of novel therapeutic options and the advent of xanomeline and trospium (muscarinic receptor modulators) provides the first new antipsychotic mechanism in over 50 years. The non-prodrug version of xanomeline/trospium (KarXT), is currently under FDA review with a decision expected in September of this year. While it was found to be safe and effective in trials for schizophrenia, it needs to be dosed twice daily, which may not be an ideal dosing regimen for patients with a difficult disease like schizophrenia. Once-daily oral pills and intramuscular injections with multi-month duration are becoming important in the standard of care for patients, as their decreased dosing frequency may aid in medication adherence, and could potentially lead to a reduction in breakthrough psychotic episodes and improve the overall impact on the lives of patients and their families. A long-acting profile is the key differentiator we hope to bring to patients with our novel prodrugs of xanomeline/trospium (TerXT).
What is a prodrug exactly? Why take this approach?
A prodrug is simply a modified and inactive form of a drug which is metabolized in the body to release the active form of the drug. Some of the most effective antipsychotics to date, including Aristada®, and Invega Sustena®, Maintena®, Trinza®, and Hafyera® are prodrugs. Xanomeline itself was first invented in the 1990s and trospium was invented in the 1960s, and we realized that the physical properties of these molecules, such as low colonic absorption and high water solubility, could make longer-acting formulations very challenging. We designed a strategy to apply the best modern prodrug designs with the goal of improving these older molecules and hope that TerXT will ultimately provide patients with a longer-acting therapeutic option, such as a once-daily pill and an intramuscular injectable with a multi-month duration.
Can you tell us about the work that went into this innovation?
This was a massive effort from our team, which resulted in over 10,000 new prodrug designs. We had a team of 200 chemists working to synthesize over 500 prodrugs, which were tested in over 500 preclinical studies, both in vivo and in vitro. We also developed a predictive PK model of both xanomeline and trospium across a vast spectrum of different formulation designs and release profiles to determine the optimal pharmacokinetic parameters and ratios.
What is the potential regulatory pathway to approval that Terran plans to take?
Antipsychotic prodrugs have utilized the FDA’s accelerated 505(b)(2) regulatory pathway to achieve rapid approval with a significantly abbreviated development plan. This pathway could allow Terran to use pharmacokinetic bridging studies and potentially leverage existing KarXT trial data to bring the next-generation TerXT to patients approximately five years after KarXT’s approval.
Is Terran pursuing this same pathway with the other pipeline programs (e.g. psychedelic compounds)?
We have indeed created a number of novel psychedelic compounds with the goal of pursuing the 505(b)(2) pathway. As I noted earlier, for psilocybin and MDMA we created the world’s first new salts and polymorphs, (psilocybin HCl and MDMA hemifumarate), and we also created orally-active prodrugs of 5-MeO-DMT. We intend to pursue the accelerated 505(b)(2) regulatory pathway to bring these novel forms to patients approximately 5 years after any of these psychedelic compounds are approved by the FDA.
What’s next for Terran and the TerXT program?
We are planning to move forward with Phase I pharmacokinetic studies after the pending approval of KarXT. We’re excited to be working in a very dynamic space and are honored to be able to push forward our next-generation TerXT prodrugs for patients living with schizophrenia.
The innovative approach Terran is taking with prodrugs represents a potential game-changer for patients with schizophrenia, promising improved adherence and outcomes. Terran’s commitment to pushing the boundaries of therapeutic development is evident not only in their work with TerXT but also in their advancements within the psychedelic space. Stay updated on Terran’s groundbreaking work by visiting their website at www.terranbiosciences.com, the TerXT product page at www.TerXT.com, and by following them on LinkedIn and X.
