INDICATION: Major depressive disorder (MDD)
INDICATION: Benzodiazepine dependency, anxiety and spasticity
INDICATION: Early stage COVID-19
STATUS: Randomized, double-blind, placebo controlled trial, powered for Phase 3 registration
AREA: HPV GENITAL (Female)
INDICATION: HPV Cervical High grade intraepithelial lesion (HSIL)
STATUS: Phase 2
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.
SARS CoV 2 coronavirus causes COVID 19. SARS CoV viruses block interferon production in infected cells, allowing the virus to continue replicating unabated ¹.
Treatment with interferon may overcome that block, potentially restoring cells normal anti viral activity.
Interferon alpha 2b (IFNa2b) is a potential treatment for COVID 19 ².
IFNa2b (inhaled) has been used in China on COVID 19 patients.
AP-003 may be given by inhalation at the first signs of COVID 19 with following projected outcomes according to Altum Clin Protocol ALT 003 COV 01 2020 05 04 rationale:
AP-001 is a topical delivery system that incorporates interferon alpha-2b in Altum’s patented BiPhasix™ technology. The BiPhasix system uniquely enables efficient delivery of biomolecules across the mucosa.
Interferon alpha-2b is a potent, broad acting anti-viral agent, with established anti-HPV activity. Intron A® is approved for treatment of HPV induced genital warts (condylomata acuminate). Treatment requires intra-lesional injections three times a week. This administration makes it very difficult to use in indications such as HPV-cervical neoplasia, where lesions are not readily visible and the multiple local injections impair patient quality of life on many levels. There is also the cost and inconvenience of repeated healthcare professional visits for the injections. Intron A has therefore not been developed in this indication. Intravenous interferon results in systemic toxicities which precludes its use for treatment of cervical HPV. HPV-cervical dysplasia is a local disease ideally treatment with the local delivery of interferon alpha-2b. The delivery should be easy to use and self-administered at home and safe, without systemic and local side effects). AP-001 is intended to fulfill this need.
AP-001 is a self-administered intra-vaginal cream. It fills the vagina in proximity to the cervix following self- administration. The product’s viscosity prevents vaginal leakage of the cream following administration, thereby allowing prolonged coating the cervix for optimal drug delivery. AP-001 has completed Phase 1 and Phase 2 clinical trials, where it was shown to be active (in cervical neoplasia regression) and safe (no systemic or local side effects). A randomized Phase 2b clinical trial in HPV-cervical CIN2/3 patients is projected to be initiated by Q1 2021.
Clinical Outcome of Topical Interferon Alpha-2b Cream in Phase II Trial for LSIL/CIN 1 Patients – PDF
Stabilization of Interferon alpha-2b in a Topical Cream – PDF
By design, the skin is a formidable barrier to penetration by external agents. In order to reach their target site within the underlying layers of the skin or beyond the skin to the systemic circulation, topical drugs must first penetrate the stratum corneum, the outermost layer of the skin. It is this layer which is considered to be the rate-limiting barrier to drug absorption.
The goal is to have a safe delivery system that does not irritate or damage the skin barrier after repeated usage in patients.
Altum is developing its proprietary BiPhasix™ liposomal delivery system which has greatly improved the features of traditional liposomes. In contrast to traditional liposomes that entrap a single, aqueous phase, our system is a complex system where the lipid bilayers entrap both aqueous and oil phases in the form of a stabilized emulsion.
BiPhasix™ is constructed with multi-compartmental lipid vesicles. BiPhasix™ makes it possible to achieve greater formulation versatility than previously attainable with traditional creams, gels or ointments – or even conventional liposomal delivery systems. Thus, BiPhasix™ dermal delivery system combines the advantages of liposomes and micro-emulsions, offering a wider range of formulation options for a variety of drug substances:
The lead product from the BiPhasix™ platform is AP-001.
BetterLife has assembled a highly experienced management team that has clinical, commercial, product development and financial experience