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PharmaTher Announces Positive Results from Study For Ketamine Microneedle Patch

PharmaTher Announces Positive Results from Study For Ketamine Microneedle Patch

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 — 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 Chianelli
Chief Executive Officer
PharmaTher Holdings Ltd.
Tel: 1-888-846-3171
Email: 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:
1.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.

2.     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.

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PharmaTher Announces Positive Results from Study of KETABET™ for Depression

PharmaTher Announces Positive Results from Study of KETABET™ for Depression

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 depressionTORONTO, June 7, 2022 — 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 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 Chianelli
Chief Executive Officer
PharmaTher Holdings Ltd.
Tel: 1-888-846-3171
Email: 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:

  1. 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) 3223–32
  2. Krystal et al. 1994; Perry et al. 2007
  3. Murrough et al. 2013; Wan et al. 2014
  4. Ionescu et al. 2015; Nugent et al. 2014; Rybakowski et al. 2013
  5. Aligeti et al. 2014; Thakurta et al. 2012; Zigman and Blier 2013
  6. Feder et al. 2020
  7. ​Freed 1984; 1985
  8. Kim et al. 2013; Di Pierro et al. 2015
  9. Percy and Lane 2005
  10. van der Westhuyzen and Metz 1984
  11. ​Chai et al. 2013
  12. 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.
  13. 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.
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PharmaTher To Develop and Commercialize Novel Wearable Ketamine Delivery Device in Collaboration with CCBIO

PharmaTher To Develop and Commercialize Novel Wearable Ketamine Delivery Device in Collaboration with CCBIO

Wearable ketamine delivery device complements PharmaTher’s ketamine product portfolio, including injectable, intravenous, and microneedle patch
​
PharmaTher aims to become a leader in specialty ketamine products for mental health, neurological and pain disorders

TORONTO, May 25, 2022 — PharmaTher Holdings Ltd. (the “Company” or “PharmaTher”) (OTCQB: PHRRF) (CSE: PHRM), a company focused on the development and commercialization of specialty ketamine products, and CC Biotechnology Corporation (“CCBIO”), a leader in the design and manufacturing of wearable, pen and auto injectors, today announced they have entered into a development agreement to combine PharmaTher’s ketamine formulation with CCBIO’s Felice Dose wearable delivery device to create a proprietary wearable ketamine delivery solution for mental health, neurological and pain disorders. The Company expects to conduct clinical studies with its wearable ketamine delivery device in Q1-2023.

Currently, ketamine is delivered predominately by intravenous (“IV”) and intramuscular (“IM”) means in a controlled healthcare setting (i.e. hospital or clinic) for analgesia, sedation and anesthetic induction and is also emerging as a viable treatment option for various mental health, neurological and pain disorders. The Company believes that in the natural evolution of chronic disease management, a logical progression from IV and IM to wearable injection systems and microneedle patches could increase the convenience, compliance, and dose flexibility for both caregivers and patients.

PharmaTher’s proposed wearable ketamine delivery device aims to convert IV and IM delivery of ketamine to a subcutaneous format, which may improve safety and efficacy, reduce side effects, enhance patient comfort and adherence, and reduce the time burden of treatment on patients and healthcare providers whether at hospital, clinic or home, and therefore may expand the adoption of ketamine for unmet medical needs.

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CCBIO’s Felice Dose on-body wearable device

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CCBIO’s Felice Dose on-body wearable device prototype worn on a person

Fabio Chianelli, Chief Executive Officer of PharmaTher, commented: “We are excited to work with CCBIO, a leader in wearable delivery injectors, to develop and commercialize a proprietary wearable ketamine delivery device that aims to change the way ketamine is given to potentially reduce the treatment burden of patients and healthcare providers. In addition, the current, evolving, and future therapeutic use of ketamine is dependent on the control of ketamine dosing to deliver pharmacokinetic profiles specific to each indication. Therefore, our goal is to become a leader in specialty ketamine solutions, which include injectable, intravenous, microneedle patch and now a ketamine wearable device that each serve a unique solution to enable tailored pharmacokinetic profiles for various mental health, neurological, and pain disorders.”

Edgar Yeh, Vice General Manager of CCBIO commented: “We are thankful to have the opportunity to work with PharmaTher to provide a patient-centric ketamine on-body injector device for patients. CCBIO’s in-house design, V/V, RA, and patenting capabilities enable us to produce competitive high-end medical devices for multiple applications. We are eager to partner with PharmaTher to generate and market a convenient ketamine wearable device that supports the needs of patients and caregivers using ketamine therapies.”    

CCBIO’s Felice Dose is a delivery motor system-based on-body subcutaneous injector device that can deliver various drug volumes, concentrations and viscosities over variable- and long-duration injections. Felice Dose can deliver a stable dose of drug per unit time under discontinuous pressure, reducing the swelling underneath the skin during injection and thus decreasing patient pain. Discontinuous pressure for a high-dose container is important.  Otherwise, if a drug delivery system continually places a positive linear compression pressure on the container, pressure will accumulate and increase patient pain during the injection process. In addition, the delivery motor system can adapt to the primary drug container, providing a very stable displacement unit for the drug, and the duration for filling and delivery can be programmed to suit the drug formulation. The Felice Dose user interface includes options for WiFi, near-field communication and Bluetooth connectivity, an LED display, fully-customizable programmability, a robust delivery motor system and a lithium battery. The device’s smart program functionality can help patients take control of their treatment, make their daily lives easier and more comfortable, and reduce the need for hospital visits and the involvement of healthcare providers.

Under the agreement, PharmaTher will cooperate with CCBIO to develop PharmaTher’s wearable ketamine delivery device. CCBIO will be responsible for the development and clinical manufacturing activities and support PharmaTher’s regulatory submissions.

About CC Biotechnology Corporation

Founded in 2012, CCBIO is a Taiwan-based medical device designer and manufacturer of wearable, pen and auto injectors and follows ISO13485, FDA21 CFR820 and GMP requirements. Learn more at CCbio.com.tw.

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 Chianelli
Chief Executive Officer
PharmaTher Holdings Ltd.
Tel: 1-888-846-3171
Email: 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.

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PharmaTher Announces Grant of U.S. Patent on Formulation and Production Process of Ketamine and Ketamine Analogs

PharmaTher Announces Grant of U.S. Patent on Formulation and Production Process of Ketamine and Ketamine Analogs

TORONTO, May 5, 2022 — PharmaTher Holdings Ltd. (the “Company” or “PharmaTher”) (OTCQB: PHRRF) (CSE: PHRM), a leader in specialty ketamine pharmaceuticals, is pleased to announce that the United States Patent and Trademark Office granted US Patent No: 11,286,230, titled “Ketamine Flow Synthesis” (the “Patent”), which refers to a continuous-flow process technology for the preparation of ketamine and ketamine analogs. The Company gained exclusive worldwide development and commercial rights of the Patent along with Europe patent no. 3700887B1 and patent applications in China and Canada from Gesval S.A., a public limited company incorporated by the University of Liège, Belgium.

Fabio Chianelli, Chief Executive Officer of PharmaTher, commented: “Our goal is to become the leader in specialty ketamine pharmaceuticals.  The recent grant of the U.S. patent strengthens our patent portfolio of novel uses, delivery forms, formulations, and production processes of ketamine and ketamine analogs to serve the unmet medical needs for mental health, neurological and pain disorders, and surgery.”

The Patent strengthens the Company’s global intellectual property portfolio of ketamine, which consists of novel uses (i.e. Parkinson’s disease, Amyotrophic Lateral Sclerosis), delivery forms (i.e. microneedle patch, injection, infusion and wearable pump), formulations (i.e. ketamine and betaine, analogs), production (i.e. process flow synthesis), and the Company’s FDA orphan drug designation portfolio of ketamine for Amyotrophic Lateral Sclerosis, Complex Regional Pain Syndrome and Status Epilepticus.

As part of its short-term product strategy, the Company is developing its own Ketamine Injection and Infusion product to support the Company’s expected pivotal clinical studies for Parkinson’s disease and Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease), future FDA 505(b)(2) regulatory submissions in mental health, neurological and pain disorders, and its commercialization plans in the U.S. via an FDA Abbreviated New Drug Application (“ANDA”) for anesthesia and procedural sedation. The Company expects to file the ANDA in Q4-2022 for commercialization in the U.S. In addition, the Company’s long-term product strategy is to develop novel ketamine formulations and drug delivery systems, including its patented microneedle patch and proposed wearable pump device for the intradermal and subcutaneous delivery of ketamine, respectively.

Ketamine was approved by the FDA in 1970 and is clinically used for analgesia, sedation, and anesthetic induction. Ketamine is also emerging as a viable treatment option for various mental health, neurological and pain disorders. However, the methods generally used for the production of ketamine are time-consuming and typically based on stepwise macroscopic batch processes resulting in low productivity, reproducibility and flexibility due to poor mixing and heat transfer.

Developed at the Center for Integrated Technology and Organic Synthesis (CiTOS, ULiège) headed by Professor Jean-Christophe Monbaliu, the Patent relates to a scalable, safe and efficient continuous-flow process in micro/mesofluidic reactors for the production of ketamine and ketamine analogs, thereby addressing the shortcomings of the ketamine batch processes to improve yield production, reproducibility, purity profile, and requiring smaller footprint for production. In addition to improving the production process of racemic ketamine, the Patent provides various methods for synthesizing ketamine analogs (i.e. arylcycloalkylamine derivatives) by using continuous-flow conditions with a drastically improved efficiency relative to batch procedures, which is of paramount importance for developing next-generation ketamines.

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 Chianelli
Chief Executive Officer
PharmaTher Holdings Ltd.
Tel: 1-888-846-3171
Email: 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.

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PharmaTher Signs Exclusive Worldwide License Agreement for Patented Formulation and Production Process of Ketamine and Ketamine Analogs

PharmaTher Signs Exclusive Worldwide License Agreement for Patented Formulation and Production Process of Ketamine and Ketamine Analogs

PharmaTher to file ANDA and 505(b)(2) regulatory submissions with the FDA for novel uses, delivery forms and formulations of ketamine for mental health, neurological and pain disordersTORONTO, April 12, 2022 — PharmaTher Holdings Ltd. (the “Company” or “PharmaTher”) (OTCQB: PHRRF) (CSE: PHRM), a leader in specialty ketamine pharmaceuticals, is pleased to announce that PharmaTher has entered into an exclusive worldwide license agreement with Gesval S.A., a public limited company incorporated by the University of Liège, Belgium, for the development and commercialization of a patented continuous-flow process technology for the preparation of ketamine and ketamine analogs (the “Ketamine Technology”). The Ketamine Technology strengthens the Company’s patent portfolio of ketamine and it will complement the Company’s expanding ketamine pharmaceutical pipeline for use in hospitals, clinics and homes.

PharmaTher is developing and commercializing novel uses, delivery forms and formulations of ketamine and ketamine analogs. As part of its short-term product strategy, the Company is developing its own Ketamine Injection and Infusion product to support the Company’s expected pivotal clinical studies for Parkinson’s disease and Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease), future FDA 505(b)(2) regulatory submissions in mental health, neurological and pain disorders, and its commercialization plans in the U.S. via an FDA Abbreviated New Drug Application (“ANDA”) for anesthesia and procedural sedation. The Company expects to file the ANDA in Q4-2022 for commercialization in the U.S. In addition, the Company’s long-term product strategy is to develop novel ketamine formulations and drug delivery systems, including its patented microneedle patch and proposed wearable pump device for the intradermal and subcutaneous delivery of ketamine, respectively.

Ketamine was approved by the FDA in 1970 and is clinically used for analgesia, sedation, and anesthetic induction.  Ketamine is also emerging as a viable treatment option for various mental health, neurological and pain disorders. However, the methods generally used for the production of ketamine are time-consuming and typically based on stepwise macroscopic batch processes resulting in low productivity, reproducibility and flexibility due to poor mixing and heat transfer.

The Ketamine Technology, developed at the Center for Integrated Technology and Organic Synthesis (CiTOS, ULiège) headed by Professor Jean-Christophe Monbaliu, relates to a scalable, safe and efficient continuous-flow process in micro/mesofluidic reactors for the production of ketamine and ketamine analogs, thereby addressing the shortcomings of the ketamine batch processes to improve yield production, reproducibility, purity profile, and requiring smaller footprint for production. In addition to improving the production process of racemic ketamine, the Ketamine Technology provides various methods for synthesizing ketamine analogs (i.e. arylcycloalkylamine derivatives) by using continuous-flow conditions with a drastically improved efficiency relative to batch procedures, which is of paramount importance for developing next-generation ketamines.

“We are excited to advance patented technology for the novel development and production process of ketamine and ketamine analogs from the University of Liège,” said Fabio Chianelli, CEO of PharmaTher. “We remain committed to our goal of becoming a leader in the development and commercialization of novel ketamine pharmaceuticals and this license not only strengthens our global patent portfolio for ketamine, but also complements our strategy in commercializing novel uses, delivery forms and formulations of ketamine and ketamine analogs to serve the unmet medical needs for mental health, neurological and pain disorders.”

In addition, the Company expects to form partnerships with research labs, ketamine clinics and pharmaceutical companies that are: seeking a secure supply of cGMP ketamine and ketamine products for current portfolios; exploring alternative dosage forms for multiple existing indications; developing novel ketamine analogs; and requiring support to develop and eventually commercialize specific ketamine products for new indications.

Under the terms of the Agreement, PharmaTher gained exclusive worldwide development and commercial rights to an intellectual property portfolio consisting of a granted patent (Europe patent: 3700887B1) and patent applications (PCT/EP2018/097033) titled, “Methods for the preparation of arylcycloalkylamine derivatives” in the U.S., China and Canada.

Consistent with industry standards, PharmaTher paid a one-time fee for entering into the Agreement, and all other future payments are based on clinical trial and revenue milestones reached by PharmaTher. 

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 Chianelli
Chief Executive Officer
PharmaTher Holdings Ltd.
Tel: 1-888-846-3171
Email: 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 period of November 30, 2021 (“MD&A”), dated January 27, 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.

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Ketamine + Parkinson’s meds

PharmaTher Announces Positive Topline Results from Clinical Study of Ketamine for Parkinson’s Disease

The most common Parkinson’s medication, Levodopa, causes involuntary muscle movements in most patients who take it long-term.

PharmaTher (PHRM) found that a low dose of ketamine reduces these muscle spams in 100% of Parkinson’s patients — but it’s unclear by how much or for how long…

However, a separate study from 2016 found that low doses of ketamine reduced this side effect for up to one month and also eased depression.

PharmaTher is confident that the results will pave the way for a Phase 3 trial. 

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PharmaTher Announces Positive Topline Results from Clinical Study of Ketamine for Parkinson’s Disease

PharmaTher Announces Positive Topline Results from Clinical Study of Ketamine for Parkinson’s Disease

100% of patients treated with ketamine demonstrated reduction in dyskinesias as measured by the Unified Dyskinesia Rating Scale

Ketamine was well tolerated with no serious adverse events reported

Study results are adequate to give an effect size in powering a Phase 3 clinical study

PharmaTher planning a Phase 3 clinical study to allow for FDA approval of KETARX™ (ketamine) for Parkinson’s disease under the 505(b)(2) regulatory pathwayTORONTO, March 23, 2022 — PharmaTher Holdings Ltd. (the “Company” or “PharmaTher”) (OTCQB: PHRRF) (CSE: PHRM), a leader in specialty ketamine pharmaceuticals, is pleased to announce positive topline results from the dose-finding and tolerability clinical study (the “Study”) of ketamine for the treatment of levodopa-induced dyskinesia (“LID”) in patients with Parkinson’s disease. The Study results are adequate to give an effect size in powering a Phase 3 clinical study which is expected to bridge the design with increased treatment duration relative to the Company’s Phase 2 clinical study (NCT04912115).

The Study evaluated the safety, tolerability and efficacy of low-dose ketamine infusion for the treatment of LID in patients with Parkinson’s disease. Efficacy data from the Study demonstrated that 100% of patients treated with ketamine demonstrated a reduction in dyskinesias as measured by the Unified Dyskinesia Rating Scale during the Study period compared to the pre-treatment baseline. Safety data from the Study demonstrated that ketamine was well tolerated with no serious adverse events reported. All adverse events were mild or moderate and reflected the expected side-effects of ketamine administration. This Study further supports the previous findings in the observational study publication, titled “Case Reports Showing a Long-Term Effect of Subanesthetic Ketamine Infusion in Reducing l-DOPA-Induced Dyskinesias,” regarding the positive impact of ketamine in reducing LID.  Full results of the Study are expected to be submitted for presentation at a medical congress by June 2022.

Dr. Scott Sherman, MD, PhD, Principal Investigator of the Study, commented: “The results of this clinical study further support that ketamine is well-tolerated even in an older population of patients with advanced Parkinson’s disease. This opens the door to a fast-track development of a novel non-surgical treatment for levodopa-indued dyskinesia, that will fill a major gap in the existing therapeutic arsenal.” Dr. Scott Sherman is the Associate Professor of Neurology and Director of the Movement Disorders Center at the University of Arizona College of Medicine, Medical Director of the Arizona Chapter of American Parkinson’s Disease Association, and Director of the Parkinson’s Disease Program of the HealthSouth Rehabilitation Institute of Tucson.

Fabio Chianelli, CEO of PharmaTher, commented: “We are very pleased with the results from this clinical study as it gives us further confidence that ketamine can safely and effectively reduce levodopa-induced dyskinesia in patients with Parkinson’s disease and it paves the way for a potential Phase 3 clinical study to support FDA approval via the 505(b)(2) regulatory pathway.”

Based on the Study results, the Company is preparing to engage the FDA to establish the next steps for a planned Phase 3 clinical study to allow for ketamine’s approval for Parkinson’s disease under the 505(b)(2) regulatory pathway. The Company plans to use its proprietary ketamine intravenous product, KETARX™, for the planned Phase 3 clinical study.

Ketamine’s Potential In Parkinson’s Disease

Parkinson’s disease is a debilitating disorder that affects over 1 million people in the U.S. and more than 7 million people worldwide. The global Parkinson’s disease market is expected to grow from USD $5 billion in 2019 to USD $7.5 billion by the end of 2025 [360iResearch 2020] and it is estimated that the potential market opportunity for LID Parkinson’s disease to be over USD $3 billion in the U.S. alone.

Ketamine is an FDA-approved N-methyl-D-aspartate receptor-modulating (NDMA) drug that is widely used as an anesthetic agent either alone or in combination with other anesthetic agents [Smith et al, 1987; Pacheco et al, 2014]. The possible therapeutic effect of low-dose ketamine on levodopa-induced dyskinesia was noted in a retrospective analysis of Parkinson’s disease patients who received ketamine for pain relief. During this analysis, it was observed that the patients experienced an improvement in LID lasting several weeks beyond treatment [Sherman et al, 2016]. These results were corroborated in a test of low-dose ketamine in a rodent LID model, and this possible effect has also been examined in a controlled study [Bartlett et al, 2016]. Ketamine may also have additional benefits in the treatment of pain [Niesters et al, 2014] and depression [Diamond et al, 2014; Murrough et al, 2013], which are frequent comorbidities of Parkinson’s disease.

About Parkinson’s Disease   

There is currently no cure for Parkinson’s disease, although some drug combinations are used to treat the disease symptoms. Although the etiology of Parkinson’s disease is not fully understood, it is thought to result from loss of pigmented dopaminergic neurons in the Substantia nigra and their striatal projections, leading to dopamine deficiency in the striatum [Schapira and Jenner, 2011]. This ultimately affects the cortico-striatal system that controls movement. As a progressive neurogenerative disorder of the central nervous system that primarily affects the motor nerve system, symptoms of Parkinson’s disease may emerge slowly and include tremors, rigidity, bradykinesia, and postural instability [Paulson and Stern, 2004]. Also, patients may experience non-motor symptoms such as autonomic dysfunction (orthostatic hypotension, constipation, bladder dysfunction), psychiatric (depression), cognitive and sensory symptoms (pain) [Olanow, et al, 2009]. These non-motor symptoms become more common as the disease progresses. Treatments, including levodopa and dopamine agonists, which restore the dopamine deficits in the brain, have been employed for almost 50 years. However, with continued treatment using levodopa, dose-limiting motor side-effects often emerge. This includes the emergence of abnormal involuntary movements termed Levodopa Induced Dyskinesias, which can be identified in about 50% of patients within five years after initiation of levodopa treatment and in almost all patients within ten years post-treatment initiation. These side effects often limit further dose increases in dopaminergic therapy.

There can be no assurance that the FDA will support any potential request for an expedited path to approval or further development for ketamine in the treatment of Parkinson’s disease.

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 Chianelli
Chief Executive Officer
PharmaTher Holdings Ltd.
Tel: 1-888-846-3171
Email: 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 period of November 30, 2021 (“MD&A”), dated January 27, 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.

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PharmaTher Announces Grant of U.S. Patent on Ketamine Formulation

PharmaTher Announces Grant of U.S. Patent on Ketamine Formulation

PharmaTher (PHRM) was granted a US patent for its formulation of ketamine and betaine anhydrous, a chemical that occurs naturally in the human body and may increase ketamine’s antidepressant effect. The formulation is already patented in Japan and Taiwan, and the company expects to receive patents in Europe, Canada, Israel and China in the near future.

PharmaTher Holdings Ltd. Ketamine

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Treating rare disorders with ketamine

PharmaTher Granted FDA Orphan Drug Designation for Ketamine to Treat Status Epilepticus

PharmaTher (PHRM) is developing a treatment for a rare, seizure-inducing disorder called Status Epilepticus using ketamine. This week, it was granted a designation that will save them millions of dollars in the process. 

It’s called an Orphan Drug Designation and it gives the company potential tax credits, grant eligibility, and marketing exclusivity, and waives a $2.4M New Drug Application fee. It’s designed to incentivize R&D of treatments for rare conditions.

PharmaTher previously received the designation for ketamine to treat ALS and complex regional pain syndrome too!

PharmaTher Inc.

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