PIPELINE OVERVIEW

TD-0148A is a non-hallucinogenic second-generation Lysergic Acid Diethylamide (“LSD”) derivative molecule that mimics the projected therapeutic potential of LSD in the treatment of disorders such as depression, post-traumatic stress disorder (“PTSD”), and migraines. TD-0148A’s chemical name is 2-bromo-LSD. Due to its non-hallucinogenic nature, TD-0148A is being developed as a patient self-administered oral medication prescribed by a psychiatrist.

LSD has been studied for the treatment of people with a number of psychiatric conditions, including depression, alcoholism, and PTSD throughout the 1950s and 1960s and research is currently experiencing a renaissance, with a number of publications referencing the efficacy of LSD to alleviate or reverse certain mental health conditions.  In 2-bromo-LSD, the modification on the LSD structure is proposed to alter the pharmacological effect of compound on the serotonin 5HT2A receptor, and lead to its non-hallucinogenic properties compared to LSD. 2-bromo-LSD has been tested in studies in humans, mainly in healthy subjects, where no hallucingonic effects were reported.  BetterLife plans to develop TD-0148A to treat mental health disorders including Treatment-resistant Depression (“TRD”) and migraines.  TRD is a term used in clinical psychiatry to describe a condition that affects patients diagnosed with major depressive disorder who do not respond adequately to a course of appropriate antidepressant medication within a certain time.  Studies have shown TRD has been associated with lower long-term quality of life as well as more instances of relapse than depression that is responsive to treatment. BetterLife also plans to develop TD-0148A for treatment of migraines (cluster headaches). In 2010 a case series study in cluster headaches was reported showing that treatment with 2-bromo-LSD was effective against cluster headaches. 2-bromo-LSD has not been investigated in TRD in any of the previously published studies.

Research to date on 2-bromo-LSD has been hindered as it usually is synthesized from LSD. The very strict controlled substance classification of LSD (Schedule 1) has been a hindrance to research in this arena. BetterLife’s TD-0148A issued patent is a manufacturing process pathway to make 2-bromo-LSD via non-controlled pathways, i.e. it does not start with nor generate LSD at any stage. TD-0148A synthesis is therefore not subject to Schedule 1 controlled substance restrictions, and BetterLife can move ahead with TD-0148A large scale synthesis and clinical trials without these restrictions.  TD-0148A’s patented synthesis process allows for cost effective manufacturing of TD-0148A.  TD-0148A is orally administered and is a BetterLife proprietary oral formulation of 2-bromo-LSD. In addition to its synthesis and formulation patents, TD-0148A is also protected by other BetterLife TD-0148A method of use patents (provisional).

While 2-bromo-LSD has been tested in human studies, most of these human studies were conducted at the end of the 1950’s and early 1960’s. Therefore, for purposes of US Food and Drug Administration (“FDA”) or other health regulatory authority purposes to start human clinical trials, TD-0148A is at preclinical stage of development.  BetterLife is setting up GMP manufacturing of TD-0148A, and in parallel plans to conduct the necessary preclinical and IND enabling toxicology studies. Currently, the TD-0148A IND filing is projected to be by Q1 of 2022, with the start of a randomized placebo controlled Phase 1 clinical trial in healthy subjects to begin on approval of IND. The Phase 1 will be followed in 2022-2023 with initiation of two randomized placebo controlled Phase 2 trials: one trial in TRD and trial one in cluster headaches.

TD-010 is novel formulation of a derivative of dihydrohonokiol, a known anti-anxiety compound, with potential for treatment of benzodiazepine dependency, anxiety and spasticity. TD-010’s active pharmaceutical ingredient is dihydrohonokiol-B (“DHH-B”). DHH-B is a derivative of honokiol, which is the active anxiolytic (anti-anxiety) ingredient of magnolia bark extracts. Magnolia bark extracts have been used in traditional Chinese medicines for centuries as anxiolytic medication. Several animal studies on safety and anxiolytic efficacy of honokiol/magnolia bark extract have been published . Only two human clinical trials have been published on honokiol (given as magnolia bark extract). Magnolia bark extract/honokiol is sold as a nutraceutical. DHH-B has been shown in animal studies to have significantly (20x) more anxiolytic activity than its parent molecule honokiol . Animal studies have also shown that DHH-B does not have the side effects of benzodiazepines and not to be addictive like benzodiazepines . No human clinical trials have been conducted on DHH-B. TD-010 is DHH-B formulated in BetterLife’s patented formulation (provisional) to overcome DHH-B’s insolubility and poor bioavailability for potential treatment of anxiety and other neuro-psychiatric disorders.

TD-010 has not been tested in human studies. It is currently in preclinical stage of development. BetterLife intends to set up GMP manufacturing of TD-010, and alongside complete all the necessary preclinical and IND enabling toxicology studies. The TD-010 IND filing is projected to be in 2022, with the start of a randomized placebo controlled Phase 1 clinical trial to begin on approval of IND. The Phase 1 will be followed with a randomized placebo controlled Phase 2 trial treating benzodiazepine dependency.

For health regulatory authority purposes to start human clinical trials, AP-003 is considered to be at preclinical stage of development.  The manufacturing and formulation work is currently ongoing. A pre-IND discussion has been conducted with the FDA for use of AP-003 inhalation in COVID-19. Based on FDA feedback, an inhalation GLP toxicology study in rats using AP-003, is under planning.  Given the advent of effective SARS-CoV-2 vaccines, the AP-003 development timing and path are being currently reassessed. IFNa2b is a broad acting anti-viral agent, and studies show that it is effective against many viruses. Importantly, viruses have not been seen to develop resistance to IFN. AP-003 is therefore a potential treatment for mutant SARS-CoV-2 viruses that bypass the current vaccines, or other new coronavirus pandemics that may arise in the future. The timing of AP-003 IND and clinical trials is currently under reassessment.