You are currently viewing Terran Biosciences announces publication of four PCT patent applications covering breakthroughs in novel empathogens, including improved versions of methylone, ethylone, MDEA, MDAI, and MBDB

Terran Biosciences announces publication of four PCT patent applications covering breakthroughs in novel empathogens, including improved versions of methylone, ethylone, MDEA, MDAI, and MBDB

NEW YORK, May 11, 2023 /PRNewswire/ — Terran Biosciences (“Terran”), a biotech platform company dedicated to the development of transformational therapeutics for neurological and psychiatric diseases, has announced the publication of four PCT patent applications covering novel improvements to the empathogens methylone (also known as bk-MDMA or MDMC), ethylone, MDEA (also known as MDE), MDAI, and MBDB.  The discoveries include novel deuterated forms, enantiomerically pure forms, as well as novel salts, polymorphs, and co-crystals of racemic methylone, R-methylone and S-methylone. These PCT applications contain a body of work that spans several years and their publication unveils one of the most comprehensive novel empathogen development programs in the industry to date.

Because psychiatric disorders are incredibly diverse in their pathology and presentation, it is clear that a “one size fits all” therapeutic does not exist. Terran believes that therapeutic options for patients should be equally diverse, with unique psychedelics and empathogens tailored to specific patient needs. For example, patients with the most severe forms of PTSD may benefit from the most powerful empathogens such as MDMA and MDEA while patients with milder forms of PTSD, anxiety, or depression may benefit from medicines such as MDAI or MBDB.

Empathogens can be simply defined as compounds that increase feelings of empathy. MDMA is the most studied empathogen to date and has been shown to be an effective treatment for post-traumatic stress disorder (PTSD) in multiple phase 3 trials. Similar to MDMA, the compound methylone, (invented by the renowned chemists Alexander Shulgin and Peyton Jacob III), is also classified as an empathogen and has been described in the literature as efficacious in treating PTSD. Methylone has been shown to act rapidly and induce a milder sensorial experience than MDMA, which may be preferred by some patients.

The experiments detailed in the PCT outline Terran’s comprehensive approach to the study of racemic methylone in order to develop a stable formulation suitable for therapeutic use. Terran completed what is believed to be the first comprehensive salt and polymorph screen performed to date on this compound. Despite the challenges posed by methylone’s resistance to the formation of many salts, Terran’s solid state chemistry team was able to successfully create numerous novel salts, polymorphs, and co-crystals. Terran completed additional improvements including the synthesis of deuterated forms of racemic methylone, R-methylone, and S-methylone with improved pharmacokinetics.

Terran’s preclinical scientists put racemic methylone through a battery of tests in animal models and found that it did not follow a classic dose-dependent pattern as might be expected, but rather surprisingly produced a paradoxical increase in anxiety at lower doses. When the dose was increased, the effects were reversed and methylone acted as an effective anxiolytic, confirming that a sufficient dose level must be reached for a therapeutic effect while low doses may produce unwanted side effects.

Methylone exists typically as a racemate (a mixture containing half R-methylone and half S-methylone), so Terran developed a novel process to produce enantiomerically pure R-methylone and S-methylone and characterized their respective salts and polymorphs to explore potential advantages.  The team then tested racemic methylone head-to-head with R-methylone and S-methylone in animal models and showed that while S-methylone was more potent than R-methylone at producing therapeutic effects, it also produced the same paradoxical increase in anxiety at lower doses. Surprisingly, R-methylone was found to lack anxiety-inducing effects completely and it reduced anxiety in a consistent dose-dependent manner. Terran believes this is the first in vivo evidence to suggest that the side effects associated with racemic methylone at lower doses could be eliminated altogether by dosing pure R-methylone instead.

To enable the potential development of any of the various forms of methylone, Terran has also designed a safety protocol if a Risk Evaluation and Mitigation Strategy (REMS) program is required for the use of methylone in PTSD. This protocol is designed to help ensure that if racemic methylone or S-methylone were approved and selected by a treating physician it would be dosed in an effective range and avoid falling into a potentially harmful subtherapeutic range. However, due to the data obtained in Terran’s recent studies described above, R-methylone may represent a safer yet equally effective therapeutic option compared to racemic methylone or S-methylone.

A full description of this groundbreaking work is detailed in the PCT application “ISOTOPOLOGES, SALTS, CRYSTALLINE FORMS, STEREOISOMERS, OF METHYLONE AND ETHYLONE AND METHODS OF USE THEREOF” (WO2023081403)

As part of a comprehensive effort to discover empathogens that would be best suited for diverse use cases, Terran also developed improvements to the empathogens MDEA, MDAI, and MBDB, including novel deuterated forms with optimized pharmacokinetics in preclinical models. MDEA has been described in the literature as being a potential therapeutic alternative to MDMA with similar potency and ability to create strong empathogenic effects with some people reporting fewer undesirable side effects. The intense experience produced by MDMA requires administration and supervision by a trained professional and may ultimately limit therapeutic use to clinics. In contrast, MDAI and MBDB are described as very mild empathogens that may be more suitable for at home use in the outpatient setting. 

MDAI is not chiral and thus only exists in one form. However, MDEA and MBDB are chiral molecules, and exist as a racemic mixture of the R form and S form. Similar to methylone, Terran found that racemic MDEA and racemic MBDB do not follow a typical dose dependent response in animal models and produce increased anxiety at low doses. Thus Terran’s preclinical team again sought to investigate potential advantages of enantiomerically pure forms. Most surprisingly, the opposite effect was observed with MDEA, where the S-MDEA form was found to relieve anxiety in a classic dose dependent manner while the R-MDEA form was found to increase anxiety at low doses and reduce anxiety at high doses. Additionally, pure S-MBDB reduced anxiety with a potentially greater therapeutic index than racemic MBDB or R-MBDB.

While these findings in animal models show that all three of the forms of MDEA and MBDB have therapeutic effects, S-MBDB and S-MDEA appear to have significant safety advantages over the racemic form or other enantiomer. The comprehensive work detailed in these PCT applications demonstrates Terran’s commitment to developing empathogens for many diverse use cases, and can be reviewed in detail in the PCT applications: “ISOTOPICALLY ENRICHED ANALOGS OF 5,6-METHYLENEDIOXY-2-AMINOINDANE (MDAI)” (WO2023081895), “ISOTOPICALLY ENRICHED 3,4-METHYLENEDIOXY-N-ETHYLAMPHETAMINE (MDE) AND STEREOISOMERS THEREOF” (WO2023081897), and “ISOTOPICALLY ENRICHED N-METHYL-1,3-BENZODIOXOLYLBUTANAMINE (MBDB) AND STEREOISOMERS THEREOF” (WO2023081899).

Dr. Sam Clark, Terran’s CEO commented, “Developing these empathogens was a massive effort and I am very proud of how the different project teams came together to create these breakthroughs. We are honored to build upon Dr. Shulgin’s and Dr. Jacob’s pioneering work on methylone, and this new characterization of the therapeutic benefits of pure R-methylone along with S-MDEA and S-MBDB brings a new opportunity for these promising molecules. We believe empathogens could provide immense therapeutic benefit and it is our goal that the diversity of different empathogens developed at Terran will provide a wide variety of use profiles tailored to the specific needs of patients.”

About Terran Biosciences, Inc.

Terran is a biotech platform company developing a portfolio of therapeutics and technologies for patients with neurological and psychiatric diseases. Backed by a number of life-science and tech investors, Terran has built a CNS-focused, tech-enabled drug development platform, and is rapidly advancing of number of late-stage assets, which include novel psychedelic-based therapeutics.

Terran Contact

Investor Relations:
[email protected]

[email protected]

Licensing and Partnerships:
[email protected]

SOURCE Terran Biosciences, Inc.

Source link

Leave a Reply