Ketamine+betaine microneedle patch (PharmaTher)

Successfully delivered ketamine and KETABET™ (ketamine and betaine) via microneedle patch, unlocking the potential for desired dosage forms and pharmacokinetic profiles Pursuing Phase 2 clinical studies in treatment-resistant depression and pain indications in Q4-2022 TORONTO, June 29, 2022 (GLOBE NEWSWIRE) -- PharmaTher Holdings Ltd. (the “Company” or “PharmaTher”) (OTCQB: PHRRF) (CSE: PHRM), a leader in specialty ketamine pharmaceuticals, is pleased to announce that it has successfully completed its research study evaluating the Company’s patented hydrogel-forming microneedle patch, PHARMAPATCH™, to deliver ketamine and KETABET™ (ketamine and betaine anhydrous), which aims to prevent the potential side effects of repeated ketamine treatment for depression and other indications, including suicidal ideation, substance abuse, post-traumatic stress disorder, neurological disorders, and chronic pain. PHARMAPATCH™ has been shown to successfully deliver esketamine, the S(+) enantiomer of ketamine, which may overcome the drawbacks associated with ketamine administration in an intravenous or nasal spray format. Research results were published in a paper titled “Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery”1. The aim of the research program led by Prof Ryan Donnelly at Queens University Belfast (“QUB”) was to develop and characterize PHARMAPATCH™ for the transdermal delivery of ketamine and KETABET™ in a sustained manner and finalize production scale-up processes for clinical studies. Characterization of drug recovery and stability before drug permeation from films via hydrogel-forming microneedle array patches (“MAP”) was assessed in vitro using the Franz cell apparatus. Based on the findings from in vitro permeation investigations, lead candidate MAP formulations were selected and brought forward for in vivo testing using Sprague-Dawley rats to assess the ability to achieve sustained plasma concentrations of ketamine and betaine within the therapeutic range for potential antidepressant therapy over the course of 48 hours. PHARMAPATCH™ is an alternative platform that allows ketamine to be delivered transdermally in a sustained and de-risked manner. The results from this study represent the first time that multiple formulations of PHARMAPATCH™ for the delivery of ketamine and betaine have been developed, characterized and tested in an animal model. Extensive characterisation of each drug-containing polymeric film and hydrogel-forming MAP combination in terms of swelling capacity, insertion capabilities, drug recovery, stability, and ultimately in vitro drug permeation using the Franz cell apparatus allowed the selection of the most promising candidate formulations for in vivo testing. Hydrogel-forming MAP-mediated delivery of ketamine and betaine were compared with intramuscular injection and orally administered solution, respectively. At regular time intervals during the 48-hour rat study, blood sample results demonstrated that PHARMAPATCH™ was able to deliver plasma levels of ketamine (between 70-200 ng/mL) in a controlled manner throughout the study. The findings of this work support PHARMAPATCH™ as a promising drug delivery platform through which effective, de-risked, and safe ketamine therapies can be delivered. Considering the high degree of flexibility possessed by this delivery system in terms of formulation, the potential for effective treatment regimens extending beyond 48 hours could be developed through further alterations in surface area, application time, and drug loading of these polymeric patches. The Company is preparing for a planned Phase 2 clinical study to allow for ketamine and KETABET™ microneedle patch evaluation in treatment-resistant depression and chronic pain under the FDA 505(b)(2) regulatory pathway. The Company is manufacturing its ketamine microneedle patches at LTS LOHMANN Therapie-Systeme AG for upcoming GLP pre-clinical pig studies to demonstrate the delivery, dosing and safety profile of ketamine in a comparable animal model to support regulatory filings to conduct human clinical studies in Q4-2022. In addition, scale up of the manufacturing process to support GMP and commercial production is currently underway. About PHARMAPATCH™ Microneedle-enhanced intradermal delivery is an elegant, efficient and painless method for increasing the skin permeation of many drugs, including ketamine. Transdermal delivery systems offer several advantages over inhalation and intravenous administration. PharmaTher‘s approach with ketamine consists of a 2-part system comprised of a drug-loaded reservoir placed on top of the hydrogel microneedle array. After administration into the skin (i.e. intradermal delivery), the microneedles become hydrated and swell, creating pores for the reservoir to release the drug content into the tissue over the treatment course. Upon removal, the needles are intact, yet rounded, and do not need to be disposed of as sharps. The drug enters the systemic circulation circumventing absorption and first-pass barriers typical for oral delivery. Studies have shown that systemic drug concentrations are reached minutes after administration and maintained over multiple days with transdermal delivery. This system addresses a major unmet need by offering greater ease of administration and including patients with pre-existing conditions that exempt them from oral or inhalation dosing. In addition, it avoids syringe needles, eliminating pain and patient visits to a clinician. Potential of the Ketamine Microneedle Patch The Company’s patented hydrogel-forming microneedle (“MN”) patch aims to deliver ketamine for intradermal administration to treat various mental health, neurological and pain disorders. The MN patch consists of hydrogel-forming microneedle arrays and an accompanying reservoir that will overcome limitations by the quantity of drug loaded into the needles or onto the needle surfaces. As such, the MN patch can significantly increase the amount of drug that can permeate through the microneedle array and into the skin.2 The MN patch is tailored for ketamine due to the required drug volume to maximize their therapeutic utility and increase potential market opportunities. The ketamine MN patch aims to empower patients to dose their medication remotely, safely and conveniently rather than being supervised by a healthcare provider at a certified medical office. The ketamine MN patch has the potential for enabling continuous delivery of ketamine (without pain) with minimal formulation manipulation into systemic circulation while maintaining constant plasma levels for more than 24 hours, which will improve efficacy and compliance for patients.1-2 Also, the ketamine MN patch will incorporate anti-tampering and anti-abuse features that parallel the approach used by commercially available tamper-resistant transdermal fentanyl patches. About PharmaTher Holdings Ltd. ​PharmaTher Holdings Ltd. (OTCQB: PHRRF) (CSE: PHRM) is focused on the development and commercialization of specialty ketamine pharmaceuticals for mental health, neurological, and pain disorders. Learn more at PharmaTher.com. For more information about PharmaTher, please contact: Fabio ChianelliChief Executive OfficerPharmaTher Holdings Ltd.Tel: 1-888-846-3171Email: info@pharmather.com Website: www.pharmather.com Neither the Canadian Securities Exchange nor its Regulation Services Provider have reviewed or accept responsibility for the adequacy or accuracy of this release. Cautionary Statement This press release contains 'forward-looking information' within the meaning of applicable Canadian securities legislation. These statements relate to future events or future performance. The use of any of the words "could", "intend", "expect", "believe", "will", "projected", "estimated", "potential", "aim", “may” and similar expressions and statements relating to matters that are not historical facts are intended to identify forward-looking information and are based on PharmaTher Holdings Ltd. (the "Company") current belief or assumptions as to the outcome and timing of such future events. Forward-looking information is based on reasonable assumptions that have been made by the Company at the date of the information and is subject to known and unknown risks, uncertainties, and other factors that may cause actual results or events to differ materially from those anticipated in the forward-looking information. Given these risks, uncertainties and assumptions, you should not unduly rely on these forward-looking statements. The forward-looking information contained in this press release is made as of the date hereof, and Company is not obligated to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as required by applicable securities laws. The foregoing statements expressly qualify any forward-looking information contained herein. Factors that could cause actual results to differ materially from those anticipated in these forward-looking statements are described under the caption "Risk Factors" in Company's management's discussion and analysis for the three and nine month periods ended February 28, 2022 and 2021 ("MD&A"), dated April 25, 2022, which is available on the Company's profile at www.sedar.com. This news release does not constitute an offer to sell or the solicitation of an offer to buy, and shall not constitute an offer, solicitation or sale in any state, province, territory or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state, province, territory or jurisdiction. Sources: Courtenay, et al. Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery, Journal of Controlled Release, Volume 322, 2020, Pages 177-186.Donnelly R.F. Hydrogel-forming microneedles prepared from "super swelling" polymers combined with lyophilised wafers for transdermal drug delivery. PLoSONE. 2014 doi: 10.1371/journal.pone.0111547.

KETABET™ (Ketamine and Betaine) shown effectiveness as measured by the Clinician Administered Dissociative States Scale Study results are adequate to give an effect size in powering a placebo-controlled clinical study PharmaTher planning a Phase 2 clinical study to incorporate KETABET™ in its proprietary microneedle patch for depression TORONTO, June 07, 2022 (GLOBE NEWSWIRE) -- PharmaTher Holdings Ltd. (the “Company” or “PharmaTher”) (OTCQB: PHRRF) (CSE: PHRM), a leader in specialty ketamine pharmaceuticals, is pleased to announce positive results from an investigator-led observational study (the “Study”) evaluating the impact of KETABET™, a patented drug combination of FDA-approved ketamine and betaine anhydrous, on the unwanted ketamine side effects seen post ketamine treatment for subjects with depression. KETABET™ aims to prevent the potential adverse psychiatric effects of repeated ketamine treatment for depression and other indications, including suicidal ideation, substance abuse, post-traumatic stress disorder, and chronic pain. The investigator-led observational study is a randomized crossover study with subjects suffering from unmanageable depression and currently receiving ketamine treatment but experiencing unwanted side effects of ketamine. The study enrolled 10 subjects and aimed to determine if the administered oral betaine anhydrous before ketamine treatment can reduce some or all of the unwanted side effects observed in the first few hours of ketamine therapy as determined by the Clinician Administered Dissociative States Scale (“CADDS”). Alleviation or reduction of side effects would support further progression of this product strategy. The CADDS is currently the standard scale used for studies assessing acute psychoactive effects of ketamine. It is used to measure present-state dissociative symptoms and assess treatment-emergent dissociative symptoms. The CADDS is comprised of 23 questions each evaluated on a 5-point scaling system (0 = “not at all”, 1 = “mild”, 2 = “moderate”, 3 = “severe”, and 4 = “extreme”). Assessment is based on three components, including depersonalization, derealization and amnesia, and an overall total score representing the severity of the condition. Depersonalization is a state in which one loses a sense of identity relative to thoughts and feelings. Derealization is a state where one feels detached from their surroundings. The Study’s data support the benefit of pre-treatment with oral anhydrous betaine prior to ketamine administration for certain side effects measured by CADDS, including depersonalization and derealization. A reduction in mean of 66% at 40 minutes following ketamine infusion initiation was seen for each of these measures in the Study. Ketamine and betaine were well tolerated with no serious adverse events reported. Although the Study was not meant for statistical significance, it supports the Company’s planned placebo-controlled phase 2 clinical study incorporating KETABET™ in the Company’s proprietary microneedle patch and will further evaluate betaine anhydrous dose, timing of pre-treatment, and duration of effect on depersonalization and derealization effects of low-dose ketamine. Reduction in the depersonalization and derealization side effects associated with low-dose ketamine infusion will potentially improve treatment compliance, treatment dose range, and treatment duration associated with ketamine therapy. Additional influence of pre-treatment with betaine prior to low-dose ketamine administration will further define the Company’s KETABET™ product scope for this and potentially other indications. Complete results of the Study are expected to be submitted for presentation at a medical congress by 2H-2022. Dr. Raul Cruz, MD, Principal Investigator of the Study, commented: “The results of this pilot observational study were very promising as the pre-treatment with betaine prior to ketamine administration demonstrated a better recovery from ketamine effects and higher dose tolerability for patients that typically experience dose limiting side effects. In general, patients that typically experienced nausea during treatment had a notable reduction and improved recovery. We are encouraged by the increase in alertness and decreased dizziness with pre-treatment of betaine and look forward to incorporating this combination into our practice for patients that require ketamine therapy for depression.”Fabio Chianelli, CEO of PharmaTher, commented: “We are very pleased with the results from this Study as it provides support for advancing our microneedle patch program in a potential Phase 2 clinical study evaluating KETABET™ for mental health and pain disorders.” Based on the Study results, the Company is preparing to engage the FDA to establish the next steps for a planned Phase 2 clinical study to allow for KETABET™ evaluation in depression under the 505(b)(2) regulatory pathway. The Company intends to use its proprietary hydrogel-forming microneedle patch for the planned Phase 2 clinical study. Granted patents of KETABET™ are issued in the U.S. (Patent No. 11,213,495), Japan (Patent no. 6967532) and Taiwan (Patent no. I648049). The Company expects to convert the current patent applications in Europe, Canada, Israel and China into granted patents. Patent protection is expected to expire in 2036. Potential of KETABET™ KETABET™, a patented drug combination of FDA-approved ketamine and betaine anhydrous, has been shown in research to enhance the antidepressant effect while having the potential to reduce the known negative side effects of ketamine significantly.1 Side effects such as hallucinations, confusion, memory loss and abuse liability compromise the compliance and potential therapeutic value of ketamine.2 The combination of ketamine and betaine anhydrous produced more robust antidepressant-like responses than their individual effects and that the combination blocked the psychotomimetic effects of ketamine.1 This suggests that betaine anhydrous can be considered as an add-on therapy to ketamine or as a fixed-dose combination therapy for treatment-resistant depression, treatment-resistant bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder and chronic pain. More than 300 million people suffer from major depressive disorder and 100 million people are resistant to available treatments worldwide. Ketamine is emerging as a viable treatment option for depression. Recent clinical studies have shown that low dose ketamine produces a rapid-acting and sustained antidepressant effect in major depressive disorder,3 bipolar depression,4 depression with suicidal ideation5 and post-traumatic stress disorder.6 Despite this, the potential for abuse and misuse of ketamine and the adverse mental effects of ketamine leads to its limited clinical use and discontinuation. Betaine anhydrous (CYSTADANE®) was approved by the FDA in 1996 to treat homocystinuria to decrease elevated homocysteine blood concentrations. There is growing evidence that betaine plays a critical role in regulating brain functions and has an antidepressant-like effect.7 Betaine has been reported to prevent seizures in rodents,8 to improve symptoms of Rett syndrome,9 and to delay the onset of neurologic impairment due to vitamin B12 deficiency10 clinically. Furthermore, betaine attenuates memory deficits induced by homocysteine.11 Potential of the Hydrogel-forming Microneedle Patch The Company’s patented hydrogel-forming microneedle (“MN”) patch aims to deliver ketamine and KETABET™ for intradermal administration to treat various mental health, neurological and pain disorders. The MN patch consists of hydrogel-forming microneedle arrays and an accompanying reservoir that will overcome limitations by the quantity of drug loaded into the needles or onto the needle surfaces. As such, the MN patch can significantly increase the amount of drug that can permeate through the microneedle array and into the skin.12 The MN patch is specifically tailored for ketamine and KETABET™ due to the volume of drug that is required to maximize their therapeutic utility and increase potential market opportunities. The KETABET™ MN patch aims to empower patients to dose their medication remotely, safely and conveniently rather than being supervised by a healthcare provider at a certified medical office. KETABET™ MN patch has the potential for enabling continuous delivery of KETABET™ (without pain) with minimal formulation manipulation into systemic circulation while maintaining constant plasma levels for more than 24 hours that will improve efficacy and compliance for patients.12-13 Also, PharmaTher's KETABET™ MN patch will incorporate anti-tampering and anti-abuse features that parallel the approach used by commercially available tamper-resistant transdermal fentanyl patches. About PharmaTher Holdings Ltd. ​PharmaTher Holdings Ltd. (OTCQB: PHRRF) (CSE: PHRM) is focused on the development and commercialization of specialty ketamine pharmaceuticals for mental health, neurological, and pain disorders. Learn more at PharmaTher.com. For more information about PharmaTher, please contact:Fabio ChianelliChief Executive OfficerPharmaTher Holdings Ltd.Tel: 1-888-846-3171Email: info@pharmather.com Website: www.pharmather.com Neither the Canadian Securities Exchange nor its Regulation Services Provider have reviewed or accept responsibility for the adequacy or accuracy of this release. Cautionary Statement This press release contains 'forward-looking information' within the meaning of applicable Canadian securities legislation. These statements relate to future events or future performance. The use of any of the words "could", "intend", "expect", "believe", "will", "projected", "estimated", "potential", "aim", “may” and similar expressions and statements relating to matters that are not historical facts are intended to identify forward-looking information and are based on PharmaTher Holdings Ltd. (the "Company") current belief or assumptions as to the outcome and timing of such future events. Forward-looking information is based on reasonable assumptions that have been made by the Company at the date of the information and is subject to known and unknown risks, uncertainties, and other factors that may cause actual results or events to differ materially from those anticipated in the forward-looking information. Given these risks, uncertainties and assumptions, you should not unduly rely on these forward-looking statements. The forward-looking information contained in this press release is made as of the date hereof, and Company is not obligated to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as required by applicable securities laws. The foregoing statements expressly qualify any forward-looking information contained herein. Factors that could cause actual results to differ materially from those anticipated in these forward-looking statements are described under the caption "Risk Factors" in Company's management's discussion and analysis for the three and nine month periods ended February 28, 2022 and 2021 ("MD&A"), dated April 25, 2022, which is available on the Company's profile at www.sedar.com. This news release does not constitute an offer to sell or the solicitation of an offer to buy, and shall not constitute an offer, solicitation or sale in any state, province, territory or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state, province, territory or jurisdiction. Sources: J.-C. Lin, M.-Y. Lee, M.-H. Chan, Y.-C. Chen, H.-H. Chen, Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice, Psychopharmacology (Berl). 233 (2016) 3223–32Krystal et al. 1994; Perry et al. 2007Murrough et al. 2013; Wan et al. 2014Ionescu et al. 2015; Nugent et al. 2014; Rybakowski et al. 2013Aligeti et al. 2014; Thakurta et al. 2012; Zigman and Blier 2013Feder et al. 2020​Freed 1984; 1985Kim et al. 2013; Di Pierro et al. 2015Percy and Lane 2005van der Westhuyzen and Metz 1984​Chai et al. 2013Donnelly R.F. Hydrogel-forming microneedles prepared from "super swelling" polymers combined with lyophilised wafers for transdermal drug delivery. PLoSONE. 2014 doi: 10.1371/journal.pone.0111547.Courtenay, et al. Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery, Journal of Controlled Release, Volume 322, 2020, Pages 177-186.