Vitamin B12 Deficiency Anaemia

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.

By now everyone knows that virtual care usage exploded over the last year, forging a new competitive era of telehealth. While more choice and greater access are generally good things for consumers in any industry (and this is also true for healthcare where patients, our “consumers,” have historically had neither) the growing virtual care market also has the potential to lead to a more fragmented experience. This will only happen if virtual care entities do not integrate and coordinate patient care by working across the industry with brick-and-mortar and other traditional healthcare provider partners. First, let me be clear: Americans still need much more care access, and telemedicine is helping to fill some of the many gaps people face today in seeking care. A recent survey found that more than half of U.S. adults have now tried telemedicine, yet a majority indicated they still face significant barriers, such as cost and broadband access – problems that were more pronounced in minority and other underserved communities. Telemedicine is not a panacea for solving the U.S. healthcare shortage, but it certainly can help to reach more people, fill care gaps and add resources to the woefully overwhelmed healthcare system. Ultimately though, what patients also need from virtual care providers are more serious efforts to create increasingly sophisticated and coordinated integrations with brick-and-mortar healthcare partners. While the relationship between virtual care platforms and traditional healthcare providers has been sometimes characterized as competitive or adversarial, judging the success of the telehealth revolution should be contingent on the success of these partnerships. While there are types of conditions that will always be better managed by in-person healthcare, virtual care providers are becoming more experienced at identifying health issues in patients who might not have physically visited a doctor in person otherwise. However, what good is that ability if that patient never follows up? Many times the reason a patient lands on a virtual care provider’s doorstep is that they didn’t like the friction that seeing a provider in person can entail, including taking time off to get to an appointment and long waits to see a provider. So we shouldn’t expect a patient who prefers to see only a doctor conveniently from home to suddenly take the initiative to go to a healthcare provider in person because their virtual doctor recommended they do so. For instance, consider a patient who sees a virtual care provider for sexual health. Part of that visit many times includes screening for cardiovascular health issues – screenings that this patient might not have ever gotten elsewhere. If a problem is detected, the patient is then frequently advised to seek specialty care in person. But then what? We assume the patient that didn’t want the “hassle” of seeing a doctor in person suddenly is ready to jump through the hoops they’ve been avoiding? That patient deserves a virtual care provider that’s willing to forge community-level partnerships that identify and remove as many points of friction as possible. Otherwise, that patient is likely left with more health silos and fragmented care. Clinical lab testing is another critical point between in-person and virtual care providers where patients deserve much better integration. A patient who can’t as easily make it to a doctor’s office might find the same issues with visiting a clinical testing location. So, virtual care providers likewise need to pursue ways to more deeply integrate with the testing industry to reduce patient pain points in seeking care. Ironically, the COVID-19 pandemic did some good on this front, sparking incremental changes. In the early days of the pandemic, testing was a major problem, and many virtual care providers partnered with testing operations to bring COVID-19 screening into the home. These partnerships, born out of a national emergency, provided the “testing” grounds that have opened the door to greater – and smarter – telehealth opportunities. If primary care medical professionals can consult with a patient online, order tests that are delivered to patients’ homes and monitor their progress with subsequent virtual visits, then virtual care is an effective modality for bringing down costs and reducing patient friction – all while still ensuring high-quality care. But, those providers still need integrations with brick-and-mortar healthcare providers who can take on more complex cases that may require in-person care. Consider a regular virtual care patient with medication-managed diabetes who begins to present with increasing levels of lightheadedness and fatigue. While these are not uncommon side effects of some diabetes medications, a subsequent at-home blood test uncovers B12-deficiency anemia, which has been linked to long-term use of certain diabetes medications. Even though both conditions – diabetes and B12 deficiency anemia – can technically be treated via telehealth as separate conditions, a virtual care provider may be able to recognize that the two could be linked – an instance that would likely cause the virtual care provider to recommend a specialist. That’s where deep integrations between virtual care and traditional healthcare providers lead to better outcomes by creating a seamless transition for the patient and their data. However, it shouldn’t stop there. We are entering a brave new world of possibilities as the remote patient monitoring technology market matures. A whole ecosystem of connected smart devices opens the door for virtual care providers to not only treat more conditions, but also work with health systems in communities across the nation to address population-level health. Virtual care providers have the potential to bring more patients into the system – especially in harder-to-reach communities – and then, via partnerships with health systems and remote patient monitoring technologies, collectively work to bring more relevant care to patients. As one expert pointed out, remote patient monitoring technologies enable a swifter migration to "truly personalized care,” and both virtual and brick-and-mortar providers should consider a strategy to leverage them in order to better serve patient populations. Ultimately, it’s not just in the expansion of telehealth as a care-delivery modality where virtual care providers have the greatest opportunity to evolve. It’s also through the innovative partnerships they strike with traditional brick-and-mortar healthcare providers – integrations that ensure patients get easy access to comprehensive, integrated care. While we’ve seen some of this already happen, which has led to greater care access overall, we’re only scratching the surface. Patients deserve more, better and deeper integrations between virtual and in-person care providers. About the author: Dr. Patrick Carroll is the chief medical officer at Hims & Hers, a direct-to-consumer virtual health company.