Tag: $PHRX

PharmaDrug Announces Positive Findings for the Combination of Cepharanthine and Frontline Chemotherapy for IND-Enabling Esophageal Cancer Study

• Results show that oral cepharanthine plus paclitaxel (combination therapy) significantly reduced tumor volume and increased tumor growth inhibition at day 28, the final day of dosing compared to paclitaxel alone (p=0.0049)
• Dose range finding demonstrates that oral cepharanthine-alone was well tolerated in the current in vivo study

Toronto, Ontario – June 16, 2022 – PharmaDrug Inc. (CSE: PHRX) (OTCQB: LMLLF) (“PharmaDrug” or the “Company“), a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics and naturally-derived approved drugs, is pleased to announce that the Company’s enteric coated, oral formulation of cepharanthine (PD-001), when combined with paclitaxel, reduces tumor volume and provides improved esophageal cancer tumor growth inhibition. These results support the Company’s continued oncology focus for orally administered PD-001 and serve to substantially leverage the FDA-granted orphan drug designation (ODD) for cepharanthine as a therapeutic to treat esophageal cancer.

In 2021 the Company initiated a series of cancer screening studies aimed at uncovering therapeutic opportunities for cepharanthine when used alone or in combination with standard of care (SoC) chemotherapy drugs. Results from these in vitro studies revealed that of all cancer types screened, cepharanthine displayed the greatest growth inhibition against esophageal cancer. For those studies, the concentration of cepharanthine required to inhibit 50% growth for esophageal cancer was determined to be 1.51µM; a concentration well below that which has previously been used safely in humans¹. Here the Company is pleased to report that a once-per-day oral regimen of PD-001, in combination with paclitaxel significantly reduced tumor volume and improved tumor inhibition at the scheduled end of dosing (day 28 post implantation) in its recently completed esophageal cancer efficacy study. For the current study, the chemotherapeutic paclitaxel served as a clinically relevant positive control agent. Following 28 days of paclitaxel administration tumor volume was reduced by 53% compared to the untreated control group. Significantly, paclitaxel provided robust tumor growth inhibition in the early portion of the study, but during the second half, the rate of tumor growth tended to accelerate. This observation mirrors that which is often noted in the clinical treatment of esophageal cancer patients; with the development of chemoresistance often noted after a period of treatment. PD-001 delivered at a dose of 27 mg/kg/day combined with paclitaxel provided an improvement of 41% in tumor volume reduction beyond that of paclitaxel alone (day 28 post tumor implantation). This result was found to be statistically significant versus paclitaxel alone (p=0.0049). PD-001 (27 mg/kg/day) tended to provide tumor growth inhibition as early as day 17 post implantation (40% greater than paclitaxel alone), that peaked at day 20 (84% greater than paclitaxel alone). Persistence of effects for PD-001 in combination with paclitaxel was measured during the ten day study recovery phase during which time drugs were not administered. During this period, those animals that had previously received paclitaxel with PD-001 at 27mg/kg/day (combination therapy) demonstrated a weeklong, statistically significant improvement in tumor volume compared to those treated with paclitaxel alone.

Daniel Cohen, CEO and Chairman of PharmaDrug commented, “We are extremely excited to continue to broaden the use case for PD-001 as a treatment for esophageal cancer. This study outcome serves to further support our goal of moving towards an FDA clinical trial and will provide the Company with the opportunity to fully leverage the benefits of the previously granted FDA orphan drug designation for cepharanthine-based treatment of esophageal cancer. We believe that cepharanthine will ultimately show a wider potential use in the treatment of cancers, specifically in situations where chemoresistance becomes an obstacle to optimal outcome.”

About PD-001 (Enteric-coated Oral Cepharanthine)

Cepharanthine is a natural product and an approved drug used for more than 70 years in Japan to successfully treat a variety of acute and chronic diseases. In clinical research, cepharanthine has been shown to exhibit multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic effects^2,3. However, historically cepharanthine’s low oral bioavailability has represented a major obstacle to realizing its full clinical potential.

The Company is focused on advancing the clinical development of an improved and patented enteric-coated oral formulation of cepharanthine (PD-001) to treat responsive cancers and COVID-19. Compared to generic cepharanthine, PD-001 has been shown in rodent and non-rodent models to possess markedly improved oral bioavailability (more easily absorbed). These findings support the development of an orally administered formulation, and in so doing, removes the undesirable requirement for frequent intravenous dosing to maintain therapeutic levels of drug in circulation. Despite enormous research efforts, esophageal cancer has a 5-year survival of only 20%⁴. Through subsequent rounds of refinement to optimize PD-001 dose and dose interval, the Company endeavours to develop an efficacious, oral therapeutic add-on option to potentially improve outcomes for esophageal cancer patients using SoC treatment.

PD-001 for Cancer

PharmaDrug’s cancer program is based on cepharanthine’s known anti-cancer activities. Cepharanthine has been shown in multiple preclinical efficacy models to inhibit cancer cell proliferation, induce cancer cell apoptosis (death) and restore cancer cell sensitivity to multiple unrelated classes of chemotherapy. Multidrug resistance continues to represent a considerable clinical challenge. As such, preclinical cancer studies aimed at elucidating the mechanisms that underlie chemoresistance; including the critical role drug efflux pumps play in this phenomenon by reducing the intracellular concentration of chemotherapeutic drugs, are of particular interest to PharmaDrug. Cepharanthine has been shown in preclinical studies to potently reverse chemoresistance by downregulating expression of ABCB1, the transcript of which codes for multidrug resistance protein 1, (MDR1, aka P- glycoprotein). Importantly, several prior in vitro and in vivo studies have shown that cepharanthine-mediated reductions in ABCB1 expression restores cancer cell sensitivity to a range of chemotherapeutics including taxanes, vinca alkaloids and platinum-based drugs^5-8.

Collectively the two in vitro screening studies already completed by the Company, the noted in vivo efficacy results noted for prostate cancer when combined with cabazitaxel, and the current esophageal cancer study results reported here, continue to reinforce the potential therapeutic opportunities in oncology for PD-001 when used in combination with SoC chemotherapy drugs to provide additive or synergistic benefit to existing SoC treatments. For reference to previous press releases related to PharmaDrug’s ongoing efforts in the oncology space please see previous press releases April 19, April 1, Feb 1, 2022 and Nov 18, Oct 15 and July 28, 2021. The Company plans to fully leverage the streamlined path to approval which comes by way of a FDA Orphan Drug Designation PD-001 for the treatment of esophageal cancer.

Potential of PD-001 to treat Esophageal Cancer

Despite standard, targeted and immunotherapy options, survival from esophageal cancer is dismal. The 5-year survival rate of people with cancer located only in the esophagus is 47%. The 5-year survival rate for those with disease that has spread to surrounding tissues or organs and/or the regional lymph nodes is 25%. If it has spread to distant parts of the body, the survival rate is 5%^9,10. Cepharanthine is a natural alkaloid extracted from S. cepharantha Hayata that has been used in Japan to treat several acute and chronic diseases with only rare reports of safety issues and side effects¹⁰. The Company previously announced positive results for the combination of cepharanthine and cabazitaxel, a second generation taxane, for the treatment of prostate cancer. Treatment of esophageal cancer is highly varied based on clinical presentation and the physician’s own preference/experience. Treatment with taxane family member, paclitaxel remains a common approach for esophageal cancer, however chemoresistance to paclitaxel represents a significant clinical challenge¹¹. The observation that cepharanthine can decrease or overcome development of chemoresistance, in particular to taxanes points to the potential of PD-001 to be a novel targeted therapy for use as a neoadjuvant and/or adjuvant treatment which could provide increased survival benefit.

About PharmaDrug Inc.
PharmaDrug is a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs. PharmaDrug owns 100% of Pharmadrug Production GmbH (“Pharmadrug Production”), a German medical cannabis distributor, with a Schedule I European Union narcotics license and German EuGMP certification allowing for the importation and distribution of medical cannabis to pharmacies in Germany and throughout the European Union. PharmaDrug owns 100% Sairiyo Therapeutics (“Sairiyo”), a biotech company that specializes in researching and reformulating established natural medicines with a goal of bringing them through clinical trials and the associated regulatory approval process in the US and Europe. Sairiyo is currently developing its patented reformulation of cepharanthine, a drug that has shown substantial third party validated potential for the treatment of Covid-19 and rare cancers. Sairiyo is also conducting R&D in the psychedelics space for the treatment of non-neuropsychiatric conditions. The Company also owns 100% of Super Smart, a company building a vertically integrated retail business with the goal to elevate the use of functional mushrooms, and psilocybin mushrooms where federally legal, as natural based medicines.

For further information, please contact:

Daniel Cohen, Chairman and CEO
dcohen@pharmadrug.co
(647) 202-1824

Caution Regarding Forward-Looking Information:

THE CANADIAN SECURITIES EXCHANGE HAS NOT REVIEWED NOR DOES IT ACCEPT RESPONSIBILITY FOR THE ADEQUACY OR ACCURACY OF THIS RELEASE.

This press release contains “forward-looking information” within the meaning of applicable securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. Generally, forward-looking information may be identified by the use of forward-looking terminology such as “plans”, “expects” or “does not expect”, “proposed”, “is expected”, “budgets”, “scheduled”, “estimates”, “forecasts”, “intends”, “anticipates” or “does not anticipate”, or “believes”, or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. In particular, this press release contains forward-looking information in relation to: the development and commercialization of cepharanthine. This forward-looking information reflects the Company’s current beliefs and is based on information currently available to the Company and on assumptions the Company believes are reasonable. These assumptions include, but are not limited to the ability of the Company to successfully execute on its plans for the Company and its affiliated entities; the ability to obtain required regulatory approvals and the Company’s continued response and ability to navigate the COVID-19 pandemic being consistent with, or better than, its ability and response to date.

Forward-looking information is subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of the Company to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; the actual results of the Company’s future operations; competition; changes in legislation affecting the Company; the ability to obtain and maintain required permits and approvals, the timing and availability of external financing on acceptable terms; lack of qualified, skilled labour or loss of key individuals; risks related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to try to limit the pandemic, including travel restrictions, border closures, non-essential business closures, service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, economic activity, financing, supply chains and sales channels, and a deterioration of general economic conditions; and a deterioration of financial markets that could limit the Company’s ability to obtain external financing.

A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in the Company’s disclosure documents on the SEDAR website at www.sedar.com. Although the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Accordingly, readers should not place undue reliance on forward-looking information. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated.

The Company’s securities have not been registered under the U.S. Securities Act of 1933, as amended (the “U.S. Securities Act”), or applicable state securities laws, and may not be offered or sold to, or for the account or benefit of, persons in the United States or “U.S. Persons”, as such term is defined in Regulations under the U.S. Securities Act, absent registration or an applicable exemption from such registration requirements. This press release shall not constitute an offer to sell or the solicitation of an offer to buy nor shall there be any sale of the securities in the United States or any jurisdiction in which such offer, solicitation or sale would be unlawful.

Forward-looking information contained in this press release is expressly qualified by this cautionary statement. The forward-looking information contained in this press release represents the expectations of the Company as of the date of this press release and, accordingly, are subject to change after such date. However, the Company expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law.

References:

1. Yasuda, K., Moro, M., Akasu, M., and Ohnishi, A. (1989). Pharmacokinetic disposition of cepharanthin following single and multiple intravenous doses in healthy subjects. Jpn. J. Clin. Pharmacol. Ther. 20, 741-749.
2. Bailly C. Cepharanthine: An update of its mode of action, pharmacological properties and medical applications. Phytomedicine. 2019 Sep;62:152956. doi: 10.1016/j.phymed.2019.152956. Epub 2019 May 10. PMID: 31132753; PMCID: PMC7126782.
3. Rogosnitzky M, Danks R. Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions. Pharmacol Rep. 2011;63(2):337-47. doi: 10.1016/s1734-1140(11)70500-x. PMID: 21602589.
4. https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-digestive-system-tumors/esophageal#:~:text=The%20overall%20five%2Dyear%20survival,year%20survival%20rate%20is%20higher.
5. Saito T, Hikita M, Kohno K, Tanimura H, Miyahara M, Kobayashi M. Enhanced expression of the multidrug resistance gene in vindesine-resistant human esophageal cancer cells. Oncology. 1994 Sep-Oct;51(5):440-5. doi: 10.1159/000227380. PMID: 8052486.
6. Zhou P, Zhang R, Wang Y, Xu D, Zhang L, Qin J, Su G, Feng Y, Chen H, You S, Rui W, Liu H, Chen S, Chen H, Wang Y. Cepharanthine hydrochloride reverses the mdr1 (P-glycoprotein)-mediated esophageal squamous cell carcinoma cell cisplatin resistance through JNK and p53 signals. Oncotarget. 2017 Nov 27;8(67):111144-111160. doi: 10.18632/oncotarget.22676. Erratum in: Oncotarget. 2021 Jan 05;12(1):61-62. PMID: 29340044; PMCID: PMC5762312.
7. Huang CZ, Wang YF, Zhang Y, Peng YM, Liu YX, Ma F, Jiang JH, Wang QD. Cepharanthine hydrochloride reverses P glycoprotein-mediated multidrug resistance in human ovarian carcinoma A2780/Taxol cells by inhibiting the PI3K/Akt signaling pathway. Oncol Rep. 2017 Oct;38(4):2558-2564. doi: 10.3892/or.2017.5879. Epub 2017 Aug 4. PMID: 28791369.
8. Zahedi P, De Souza R, Huynh L, Piquette-Miller M, Allen C. Combination drug delivery strategy for the treatment of multidrug resistant ovarian cancer. Mol Pharm. 2011 Feb 7;8(1):260-9. doi: 10.1021/mp100323z. Epub 2010 Dec 17. PMID: 21166459.
9. Esophageal Cancer Stat Facts 2020, National Cancer Institute Surveillance, Epidemiology and Endresults Program (SEER), accessed August 20, 2020 https://seer.cancer.gov/statfacts/html/esoph.html
10. Survival Rates for Esophageal Cancer. American Cancer Society, accessed August 26, 2020,
    https://www.cancer.org/cancer/esophagus-cancer/detection-diagnosis-staging/survival-rates.html
11. Shen Z, Chen M, Luo F, Xu H, Zhang P, Lin J, Kang M. Identification of Key Genes and Pathways Associated With Paclitaxel Resistance in Esophageal Squamous Cell Carcinoma Based on Bioinformatics Analysis. Front Genet. 2021 Aug 11;12:671639. doi: 10.3389/fgene.2021.671639. PMID: 34456964; PMCID: PMC8386171.

PharmaDrug Announces Execution Of an Agreement to Sell Its German Cannabis Asset to Khiron

Toronto, Ontario – May 31, 2022 – PharmaDrug Inc. (CSE: PHRX) (OTCQB: LMLLF) (“PharmaDrug” or the “Company“), is pleased to announce that it has entered into an agreement on May 31, 2022 with Khiron Life Sciences Corp. (TSXV: KHRN) (“Khiron“) to sell all of the outstanding securities of Pharmadrug Production GmbH, (“Pharmadrug GMBH“) the Company’s wholly-owned German subsidiary, a medical cannabis distributor, with a Schedule I European Union narcotics license and German EuGMP certification allowing for the importation and distribution of medical cannabis to pharmacies in Germany and throughout the European Union (the “Transaction“).

Under the terms of the share purchase agreement the Company has agreed to sell 100% of the securities of Pharmadrug GMBH for consideration consisting of 5,500,000 common shares in the capital of Khiron and a non-interest bearing promissory note in the principal amount of $1,100,000 which note will be payable one year from the date of issue. The agreement provides for an adjustment to the purchase price at closing to account for certain payments that may be made between the date of signing of the share purchase agreement and the date of closing.

Daniel Cohen, the Company’s Chairman and Chief Executive Officer commented, “We are excited to be entering into this transaction with Khiron as it is a major step towards the company’s shift into a pure play biotech strategy. We believe Khiron is perfectly positioned to take full advantage of the asset and believe PharmaDrug should ultimately yield the most value for Pharmadrug Production through and equity ownership in Khiron.”

The closing of the proposed Transaction is subject to the satisfaction of customary closing conditions including receipt of all necessary regulatory approvals. The parties are targeting a closing on or before the end of July, 2022. There can be no assurance that the Transaction will be completed as proposed or at all.

Rationale for the Sale

The decision to sell Pharmadrug Production was driven by two main issues. Firstly, the Board of Directors and Management believes that the cannabis industry is at a point in maturity where critical mass as well as vertical expertise is needed to be able to execute on a successful strategy. Secondly, Pharmadrug production was a cash drag and unlike The Company’s biotech efforts, management did not believe the cash burn in the German operations added any value to shareholders.

The Company is of the opinion that Khiron is perfectly positioned to yield the appropriate value from Pharmadrug Production. Khiron has vertical experience in growing and in building and operating medical clinics. A successful strategy in Germany requires a knowledgeable sales force to be able to educate both physicians and patients. Khiron possesses that knowledge and has an active medical sales force. Management believes that by taking an equity position in Khiron, PharmaDrug shareholders have the opportunity to potentially realize further value by being able to participate in the upside that management still expects to arise form a growing cannabis market in Germany as well as Khiron’s ability to potentially outperform in said market. Upon closing of the divestiture, PharmaDrug will have exited from the Cannabis Industry and all European operations.

About PharmaDrug Inc.

PharmaDrug is a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs. PharmaDrug owns 100% of Pharmadrug Production GmbH (“Pharmadrug Production”), a German medical cannabis distributor, with a Schedule I European Union narcotics license and German EuGMP certification allowing for the importation and distribution of medical cannabis to pharmacies in Germany and throughout the European Union. PharmaDrug owns 100% Sairiyo Therapeutics (“Sairiyo”), a biotech company that specializes in researching and reformulating established natural medicines with a goal of bringing them through clinical trials and the associated regulatory approval process in the US and Europe. Sairiyo is currently developing its patented reformulation of cepharanthine, a drug that has shown substantial third party validated potential for the treatment of infectious disease and rare cancers. Sairiyo is also conducting R&D in the psychedelics space for the treatment of non-neuropsychiatric conditions. The Company also owns 100% of Super Smart, a company building a vertically integrated retail business with the goal to elevate the use of functional mushrooms as natural based medicines.

For further information, please contact:

Daniel Cohen, Chairman and CEO
dcohen@pharmadrug.co
(647) 202-1824

Caution Regarding Forward-Looking Information:

THE CANADIAN SECURITIES EXCHANGE HAS NOT REVIEWED NOR DOES IT ACCEPT RESPONSIBILITY FOR THE ADEQUACY OR ACCURACY OF THIS RELEASE.

This press release contains “forward-looking information” within the meaning of applicable securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. Generally, forward-looking information may be identified by the use of forward-looking terminology such as “plans”, “expects” or “does not expect”, “proposed”, “is expected”, “budgets”, “scheduled”, “estimates”, “forecasts”, “intends”, “anticipates” or “does not anticipate”, or “believes”, or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. In particular, this press release contains forward-looking information in relation to the timing of the closing of the Transaction and the Company’s future plans. This forward-looking information reflects the Company’s current beliefs and is based on information currently available to the Company and on assumptions the Company believes are reasonable. These assumptions include, but are not limited to the ability of the Company to successfully execute on its plans for the Company and its affiliated entities; the ability to obtain required regulatory approvals and the Company’s continued response and ability to navigate the COVID-19 pandemic being consistent with, or better than, its ability and response to date.

Forward-looking information is subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of the Company to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; the actual results of the Company’s future operations; competition; changes in legislation affecting the Company; the ability to obtain and maintain required permits and approvals, the timing and availability of external financing on acceptable terms; lack of qualified, skilled labour or loss of key individuals; risks related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to try to limit the pandemic, including travel restrictions, border closures, non-essential business closures, service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, economic activity, financing, supply chains and sales channels, and a deterioration of general economic conditions; and a deterioration of financial markets that could limit the Company’s ability to obtain external financing.

A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in the Company’s disclosure documents on the SEDAR website at www.sedar.com. Although the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Accordingly, readers should not place undue reliance on forward-looking information. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated.

The Company’s securities have not been registered under the U.S. Securities Act of 1933, as amended (the “U.S. Securities Act”), or applicable state securities laws, and may not be offered or sold to, or for the account or benefit of, persons in the United States or “U.S. Persons”, as such term is defined in Regulations under the U.S. Securities Act, absent registration or an applicable exemption from such registration requirements. This press release shall not constitute an offer to sell or the solicitation of an offer to buy nor shall there be any sale of the securities in the United States or any jurisdiction in which such offer, solicitation or sale would be unlawful.

Forward-looking information contained in this press release is expressly qualified by this cautionary statement. The forward-looking information contained in this press release represents the expectations of the Company as of the date of this press release and, accordingly, are subject to change after such date. However, the Company expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law.

PharmaDrug Announces Closing of the First Tranche of Non-Brokered Private Placement

Toronto, Ontario – May 27, 2022 – PharmaDrug Inc. (CSE: PHRX) (OTCQB: LMLLF) (“PharmaDrug” or the “Company“), a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs, is pleased to announce the closing of the first tranche (the “First Tranche“) of a non-brokered private placement (the “Offering“) of units in the capital of the Company (the “Units“). Pursuant to the closing of the First Tranche, the Company issued 7,000,000 Units at a price of $0.04 for aggregate gross proceeds of $280,000.

Each Unit consists of one common share (a “Common Share”) and one Common Share purchase warrant (a “Warrant”). Each Warrant entitles the holder to acquire one Common Share at a price of $0.05 for a period of 24 months from the closing of the Offering.

In connection with the closing of the First Tranche, the Company paid a finder (the “Finder”) a cash commission of $1,600 and issued an aggregate of 40,000 broker warrants (“Broker Warrants”). Each Broker Warrant entitles the Finder to purchase one Common Share of the Company at a price of $0.04 for a period of twenty-four (24) months from the closing of the First Tranche.

PharmaDrug intends to use the net proceeds from the Offering to assist the Company in production of pharmaceutical grade cepharanthine intended to be used in Phase I and Phase II clinical trials and general working capital.

The securities issued via the Offering are subject to a statutory four month and one day hold period.

Daniel Cohen, Chairman and Chief Executive Officer of the Company (the “Interested Person”) purchased or acquired direction and control over an aggregate of 1,250,000 Units under the First Tranche. The Interested Person is considered a “related party” of PharmaDrug and the sale of Units under the Offering to the Interested Person constitutes a “related party transaction” within the meaning of Multilateral Instrument 61-101 – Protection of Minority Security Holders in Special Transactions (“MI 61-101”). The Interested Person will now beneficially own or control 5,246,045 Common Shares (23,255,798 Common Shares assuming conversion of all convertible debentures and securities held by the Interested Person). The “related party” portion of the Offering was exempt from the minority approval requirement of Section 5.6 and the formal valuation requirement of Section 5.4 of MI 61-101 as neither the fair market value of the “related party” portion of the Offering, nor the fair market value of the consideration of the “related party” portion of the Offering, exceeded 25% of Pharmadrugs’s market capitalization. A material change report will be filed in connection with the related party participation in the Offering less than 21 days in advance of closing of the First Tranche as approval of the Offering occurred less than 21 days prior to closing. This shorter period was reasonable and necessary in the circumstances as the Company wished to complete the First Tranche in a timely manner.

About PharmaDrug Inc.

PharmaDrug is a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs. PharmaDrug owns 100% of Pharmadrug Production GmbH (“Pharmadrug Production”), a German medical cannabis distributor, with a Schedule I European Union narcotics license and German EuGMP certification allowing for the importation and distribution of medical cannabis to pharmacies in Germany and throughout the European Union. PharmaDrug owns 100% Sairiyo Therapeutics (“Sairiyo”), a biotech company that specializes in researching and reformulating established natural medicines with a goal of bringing them through clinical trials and the associated regulatory approval process in the US and Europe. Sairiyo is currently developing its patented reformulation of cepharanthine, a drug that has shown substantial third party validated potential for the treatment of infectious disease and rare cancers. Sairiyo is also conducting R&D in the psychedelics space for the treatment of non-neuropsychiatric conditions. The Company also owns 100% of Super Smart, a company building a vertically integrated retail business with the goal to elevate the use of functional mushrooms as natural based medicines.

For further information, please contact:

Daniel Cohen, Chairman and CEO
dcohen@pharmadrug.co
(647) 202-1824

Caution Regarding Forward-Looking Information:

THE CANADIAN SECURITIES EXCHANGE HAS NOT REVIEWED NOR DOES IT ACCEPT RESPONSIBILITY FOR THE ADEQUACY OR ACCURACY OF THIS RELEASE.

This press release contains “forward-looking information” within the meaning of applicable securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. Generally, forward-looking information may be identified by the use of forward-looking terminology such as “plans”, “expects” or “does not expect”, “proposed”, “is expected”, “budgets”, “scheduled”, “estimates”, “forecasts”, “intends”, “anticipates” or “does not anticipate”, or “believes”, or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. In particular, this press release contains forward-looking information in relation to the use of proceeds of the Offering. This forward-looking information reflects the Company’s current beliefs and is based on information currently available to the Company and on assumptions the Company believes are reasonable. These assumptions include, but are not limited to the ability of the Company to successfully execute on its plans for the Company and its affiliated entities; the ability to obtain required regulatory approvals and the Company’s continued response and ability to navigate the COVID-19 pandemic being consistent with, or better than, its ability and response to date.

Forward-looking information is subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of the Company to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; the actual results of the Company’s future operations; competition; changes in legislation affecting the Company; the ability to obtain and maintain required permits and approvals, the timing and availability of external financing on acceptable terms; lack of qualified, skilled labour or loss of key individuals; risks related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to try to limit the pandemic, including travel restrictions, border closures, non-essential business closures, service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, economic activity, financing, supply chains and sales channels, and a deterioration of general economic conditions; and a deterioration of financial markets that could limit the Company’s ability to obtain external financing.

A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in the Company’s disclosure documents on the SEDAR website at www.sedar.com. Although the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Accordingly, readers should not place undue reliance on forward-looking information. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated.

The Company’s securities have not been registered under the U.S. Securities Act of 1933, as amended (the “U.S. Securities Act”), or applicable state securities laws, and may not be offered or sold to, or for the account or benefit of, persons in the United States or “U.S. Persons”, as such term is defined in Regulations under the U.S. Securities Act, absent registration or an applicable exemption from such registration requirements. This press release shall not constitute an offer to sell or the solicitation of an offer to buy nor shall there be any sale of the securities in the United States or any jurisdiction in which such offer, solicitation or sale would be unlawful.

Forward-looking information contained in this press release is expressly qualified by this cautionary statement. The forward-looking information contained in this press release represents the expectations of the Company as of the date of this press release and, accordingly, are subject to change after such date. However, the Company expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law.

PharmaDrug Advances Oncology Program with Filing of Provisional Patent Following Positive Findings for the Combination of PD-001 and Frontline Chemotherapy in Prostate Cancer Study

• Provisional patent filed (April 14, 2022) to support use of PD-001 plus cabazitaxel for primary, metastatic and chemotherapy-resistant prostate cancer
• Final study results show that oral cepharanthine (PD-001) plus cabazitaxel combination therapy significantly reduced tumor volume and increased tumor growth inhibition
• Dose range finding demonstrates that oral cepharanthine-alone was well tolerated
• Addition of PD-001 to cabazitaxel dosing regimen did not increase toxicity

Toronto, Ontario – April 19, 2022 – PharmaDrug Inc. (CSE: PHRX) (OTCQB: LMLLF) (“PharmaDrug” or the “Company“), a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs, is pleased to announce that the Company’s enteric coated, oral formulation of cepharanthine (PD-001), when combined with cabazitaxel, significantly reduces tumor volume and provides improved prostate cancer tumor growth inhibition. Accordingly, the Company has filed a second provisional patent application to support new claims specifically related to the in vivo dosing of cepharanthine in combination with taxane-family members for the treatment of prostate cancer. The current patent application aims to complement the previous provisional patent filing, built around the Company’s in vitro study findings, which set forth claims related to the use of cepharanthine plus cabazitaxel and/or other taxane family members used in combination to treat primary, metastatic and chemotherapy-resistant prostate cancer.

Daniel Cohen, CEO and Chairman of PharmaDrug commented, “With our new provisional patent filing we continue to broaden the use case for PD-001 as a treatment for prostate cancer. While esophageal cancer continues to be our main focus with a goal to move towards an FDA clinical trial, we believe that cepharanthine will ultimately show a wider potential use in the treatment of cancers, specifically in combination with the current standard of care chemotherapies”.

In 2021 the Company initiated a series of cancer screening studies aimed at uncovering therapeutic opportunities for cepharanthine when used alone or in combination with standard of care (SoC) chemotherapy drugs. Results from these in vitro studies revealed that the combination of cepharanthine and cabazitaxel, a SoC used for castration-resistant, metastatic prostate cancers, provided unexpectedly synergistic reduction in prostate tumor cell survival. Here the Company is pleased to report that a once-per-day oral regimen of PD-001, in combination with cabazitaxel provided statistically significant benefit from day 10 through to the end of dosing (day 21) in its recently completed prostate efficacy study. Throughout the study, the degree of tumor growth inhibition continued to improve for those groups receiving the combination of PD-001 and cabazitaxel versus cabazitaxel-alone, suggesting that perhaps a more sustained dosing regimen might result in greater efficacy. Upon completion of study dosing, PD-001 delivered at doses of 3, 9, or 27 mg/kg/day combined with cabazitaxel (3mg/kg/Q3D) provided up to a 64% tumor growth inhibition compared to 37% noted for treatment with cabazitaxel alone. Based on these results, the addition of PD-001 to the SoC, cabazitaxel was found to improve tumor growth inhibition by 73% compared to cabazitaxel-alone. These results were deemed to be highly statistically significant, with a p-value less than 0.001 (day 21). Addition of PD-001 to cabazitaxel did not notably increase toxicity compared to cabazitaxel alone.

About PD-001 (Enteric-coated Oral Cepharanthine)

Cepharanthine is a natural product and an approved drug used for more than 70 years in Japan to successfully treat a variety of acute and chronic diseases. In clinical research, cepharanthine has been shown to exhibit multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic effects^1,2. However, historically cepharanthine’s low oral bioavailability has represented a major obstacle to realizing its full clinical potential.

The Company is focused on advancing the clinical development of an improved and patented enteric-coated oral formulation of cepharanthine (PD-001) to treat responsive cancers and COVID-19. Compared to generic cepharanthine, PD-001 has been shown in rodent and non-rodent models to possess markedly improved oral bioavailability (more easily absorbed). These findings support the development of an orally administered formulation, and in so doing, removes the undesirable requirement for frequent intravenous dosing to maintain therapeutic levels of drug in circulation. Despite enormous research efforts, metastatic prostate cancer has a 5-year survival of only 31%³. Through subsequent rounds of refinement to optimize PD-001 dose and dose interval, the Company endeavours to develop an efficacious, oral therapeutic add-on option to potentially improve outcomes for prostate cancer patients using SoC treatment.

The Company is not making any express or implied claims that its product has the ability to eliminate, cure or contain the Covid-19 (or SARS-2 Coronavirus) at this time.

PD-001 for Cancer

PharmaDrug’s cancer program is based on cepharanthine’s known anti-cancer activities. Cepharanthine has been shown in multiple preclinical efficacy models to inhibit cancer cell proliferation, induce cancer cell apoptosis (death) and restore cancer cell sensitivity to multiple unrelated classes of chemotherapy. Multidrug resistance continues to represent a considerable clinical challenge. As such, preclinical cancer studies aimed at elucidating the mechanisms that underly chemoresistance; including the critical role drug efflux pumps play in this phenomenon by reducing the intracellular concentration of chemotherapeutic drugs, are of particular interest to PharmaDrug. Cepharanthine has been shown in preclinical studies to potently reverse chemoresistance by downregulating expression of ABCB1, the transcript of which codes for multidrug resistance protein 1, (MDR1, aka P- glycoprotein). Importantly, several prior in vitro and in vivo studies have shown that cepharanthine-mediated reductions in ABCB1 expression restores cancer cell sensitivity to a range of chemotherapeutics including taxanes, vinca alkaloids and platinum-based drugs^4–7. Collectively the two in vitro screening studies already completed by the Company and the interim in vivo efficacy results provided here, continue to reinforce the potential therapeutic opportunities in oncology for PD-001 when used in combination to provide additive or synergistic benefit to existing SoC treatments. For reference to previous press releases related to PharmaDrug’s ongoing efforts in the oncology space please see previous press releases dated Feb 1, 2022 and Nov 18, Oct 15, July 28, 2021. In addition to its ongoing investigations of PD-001 for prostate cancer, the Company plans to fully leverage the streamlined path to approval which comes by way of a FDA Orphan Drug Designation PD-001 for the treatment of esophageal cancer.

Potential of PD-001 to treat Prostate Cancer

According to the American Cancer Society, in 2021 there were approximately 248,530 new cases of prostate cancer and about 34,130 deaths from prostate cancer in the United States, and it is the second leading cause of cancer death in American men. Metastatic prostate cancer is commonly treated using androgen deprivation therapy (ADT), including surgical or medical castration, but metastatic castration-resistant prostate cancer (mCRPC) commonly emerges⁸. The taxanes docetaxel and cabazitaxel are approved for the treatment of mCRPC, however resistance to taxanes is known to develop over time. Agents such as PD-001 which show synergistic benefit when combined with taxanes for the treatment of prostate cancer are sorely needed. The Company’s forthcoming in vivo studies are specifically designed to address the potential of PD-001 to overcome taxane-based chemoresistance in vivo.

About PharmaDrug Inc.

PharmaDrug is a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs. PharmaDrug owns 100% of Pharmadrug Production GmbH (“Pharmadrug Production”), a German medical cannabis distributor, with a Schedule I European Union narcotics license and German EuGMP certification allowing for the importation and distribution of medical cannabis to pharmacies in Germany and throughout the European Union. PharmaDrug owns 100% Sairiyo Therapeutics (“Sairiyo”), a biotech company that specializes in researching and reformulating established natural medicines with a goal of bringing them through clinical trials and the associated regulatory approval process in the US and Europe. Sairiyo is currently developing its patented reformulation of cepharanthine, a drug that has shown substantial third party validated potential for the treatment of Covid-19 and rare cancers. Sairiyo is also conducting R&D in the psychedelics space for the treatment of non-neuropsychiatric conditions. The Company also owns 100% of Super Smart, a company building a vertically integrated retail business with the goal to elevate the use of functional mushrooms, and psilocybin mushrooms where federally legal, as natural based medicines.

For further information, please contact:

Daniel Cohen, Chairman and CEO
dcohen@pharmadrug.co
(647) 202-1824

Caution Regarding Forward-Looking Information:

THE CANADIAN SECURITIES EXCHANGE HAS NOT REVIEWED NOR DOES IT ACCEPT RESPONSIBILITY FOR THE ADEQUACY OR ACCURACY OF THIS RELEASE.

This press release contains “forward-looking information” within the meaning of applicable securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. Generally, forward-looking information may be identified by the use of forward-looking terminology such as “plans”, “expects” or “does not expect”, “proposed”, “is expected”, “budgets”, “scheduled”, “estimates”, “forecasts”, “intends”, “anticipates” or “does not anticipate”, or “believes”, or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. In particular, this press release contains forward-looking information in relation to: the development and commercialization of, and research and development relating to, cepharanthine, the results of the Company’s research and development in the psychedelics space and the development of the Supersmart business. This forward-looking information reflects the Company’s current beliefs and is based on information currently available to the Company and on assumptions the Company believes are reasonable. These assumptions include, but are not limited to the results of its research and development activities, the ability of the Company to successfully execute on its plans for the Company and its affiliated entities; the ability to obtain required regulatory approvals and the Company’s continued response and ability to navigate the COVID-19 pandemic being consistent with, or better than, its ability and response to date.

Forward-looking information is subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of the Company to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; the actual results of the Company’s future operations; competition; changes in legislation affecting the Company; the ability to obtain and maintain required permits and approvals, the timing and availability of external financing on acceptable terms; lack of qualified, skilled labour or loss of key individuals; risks related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to try to limit the pandemic, including travel restrictions, border closures, non-essential business closures, service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, economic activity, financing, supply chains and sales channels, and a deterioration of general economic conditions; and a deterioration of financial markets that could limit the Company’s ability to obtain external financing.

A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in the Company’s disclosure documents on the SEDAR website at www.sedar.com. Although the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Accordingly, readers should not place undue reliance on forward-looking information. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated.

The Company’s securities have not been registered under the U.S. Securities Act of 1933, as amended (the “U.S. Securities Act”), or applicable state securities laws, and may not be offered or sold to, or for the account or benefit of, persons in the United States or “U.S. Persons”, as such term is defined in Regulations under the U.S. Securities Act, absent registration or an applicable exemption from such registration requirements. This press release shall not constitute an offer to sell or the solicitation of an offer to buy nor shall there be any sale of the securities in the United States or any jurisdiction in which such offer, solicitation or sale would be unlawful.

Forward-looking information contained in this press release is expressly qualified by this cautionary statement. The forward-looking information contained in this press release represents the expectations of the Company as of the date of this press release and, accordingly, are subject to change after such date. However, the Company expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law.

References:

1. Bailly C. Cepharanthine: An update of its mode of action, pharmacological properties and medical applications. Phytomedicine. 2019 Sep;62:152956. doi: 10.1016/j.phymed.2019.152956. Epub 2019 May 10. PMID: 31132753; PMCID: PMC7126782.
2. Rogosnitzky M, Danks R. Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions. Pharmacol Rep. 2011;63(2):337-47. doi: 10.1016/s1734-1140(11)70500-x. PMID: 21602589.
3. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/survival-rates.html
4. Saito T, Hikita M, Kohno K, Tanimura H, Miyahara M, Kobayashi M. Enhanced expression of the multidrug resistance gene in vindesine-resistant human esophageal cancer cells. Oncology. 1994 Sep-Oct;51(5):440-5. doi: 10.1159/000227380. PMID: 8052486.
5. Zhou P, Zhang R, Wang Y, Xu D, Zhang L, Qin J, Su G, Feng Y, Chen H, You S, Rui W, Liu H, Chen S, Chen H, Wang Y. Cepharanthine hydrochloride reverses the mdr1 (P-glycoprotein)-mediated esophageal squamous cell carcinoma cell cisplatin resistance through JNK and p53 signals. Oncotarget. 2017 Nov 27;8(67):111144-111160. doi: 10.18632/oncotarget.22676. Erratum in: Oncotarget. 2021 Jan 05;12(1):61-62. PMID: 29340044; PMCID: PMC5762312.
6. Huang CZ, Wang YF, Zhang Y, Peng YM, Liu YX, Ma F, Jiang JH, Wang QD. Cepharanthine hydrochloride reverses P glycoprotein-mediated multidrug resistance in human ovarian carcinoma A2780/Taxol cells by inhibiting the PI3K/Akt signaling pathway. Oncol Rep. 2017 Oct;38(4):2558-2564. doi: 10.3892/or.2017.5879. Epub 2017 Aug 4. PMID: 28791369.
7. Zahedi P, De Souza R, Huynh L, Piquette-Miller M, Allen C. Combination drug delivery strategy for the treatment of multidrug resistant ovarian cancer. Mol Pharm. 2011 Feb 7;8(1):260-9. doi: 10.1021/mp100323z. Epub 2010 Dec 17. PMID: 21166459.
8. Komura K, Sweeney CJ, Inamoto T, Ibuki N, Azuma H, Kantoff PW. Current treatment strategies for advanced prostate cancer. Int J Urol. 2018;25(3):220-231. doi:10.1111/iju.13512

Pharmadrug Advances PD-001, Its Patented, Improved Version of Cepharanthine for Oncology and Infectious Disease

• Committed to the ‘pipeline-in-a-pill’ approach with PD-001 for certain cancers and COVID-19
• Advances cGMP manufacturing of clinical drug supply with Southwest Research Institute
• Receives final positive data for recently conducted prostate cancer model and evaluates opportunities to broaden claim set for PD-001 in the treatment of cancer
• Initiates IND-enabling efficacy study of PD-001 to treat esophageal cancer
• Evaluates opportunities to deepen and broaden testing of PD-001 as a broad-spectrum oral antiviral

Toronto, Ontario -April 1, 2022 – PharmaDrug Inc. (CSE: PHRX) (OTCQB: LMLLF) (“PharmaDrug” or the “Company“), a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs, is pleased to provide an update on multiple activities currently underway which support the Company’s ‘pipeline-in-a-pill’ approach in the development of PD-001, its patented, orally bioavailable version of cepharanthine for the treatment of cancer and infectious disease.

Following submission of its Type B pre-IND meeting request and briefing package to the U.S. Food and Drug Administration (FDA), the Company received a written response regarding its clinical development plan for PD-001, as a potential oral antiviral pill for COVID-19 and variants of concern. PharmaDrug believes the feedback provides a path to agreements on IND-enabling studies, the design of a Phase 1/2 clinical study, and the overall clinical development plan to move PD-001 forward as an oral treatment for COVID-19. By extension, the FDA guidance also provided important insights on advancing PD-001 as a potential treatment for oncology indications as part of the Company’s ongoing strategy of targeting prostate and esophageal cancers. The Company remains focused on completing the remaining IND-enabling studies to support its planned clinical studies.

Based on positive feedback from the FDA on the Company’s proposed Chemistry and Manufacturing Control (CMC) program, PharmaDrug has initiated cGMP production at Southwest Research Institute (SwRI) of a quantity of PD-001 that is expected to be sufficient to support development activities through to the end of phase II assessment. Since the Company’s press release on January 26^th, 2022, bulk active pharmaceutical ingredient (API) has been received by SwRI and the drug substance, cepharanthine-2HCL, is being manufactured. Completion date is expected to be Q2, 2022. Following full characterization of the drug substance for critical quality attributes the drug product manufacturing (enteric coating of the drug substance) will commence. The material produced under these tasks will support IND-enabling activities, such as stability, safety, toxicology, pharmacokinetic and non-clinical efficacy studies, required by the FDA prior to proceeding to human clinical studies. Work completed thus far on the parent molecule, cepharanthine by PharmaDrug and others, potentially de-risks and expedites several aspects of these studies.

Daniel Cohen, CEO and Chairman of PharmaDrug commented, “We are excited to be efficiently moving our PD-001 program towards a clinical trial. The critical path from a timeline perspective is driven by the GMP production of our drug product and the associated non-clinical testing that will be performed on the product. In the meantime, we have identified 3 distinct indications that we believe are of merit for a cepharanthine clinical trial; esophageal cancer, prostate cancer and Covid. Our current lead indication continues to be esophageal cancer, based on the ODD status we received from the FDA, the efficacy data and the current unmet need in esophageal cancer. We plan to continue to add to the breadth of all 3 programs as we execute the activities necessary to bring PD-001 to the clinic.”

PD-001 For Prostate Cancer

The Company is focused on advancing the clinical development of an improved and patented enteric-coated oral formulation of cepharanthine (PD-001) to treat responsive cancers and COVID-19. Compared to generic cepharanthine, PD-001 has been shown in rodent and non-rodent models to possess markedly improved oral bioavailability (more easily absorbed). These findings support the development of an orally administered formulation, and in so doing, removes the undesirable requirement for frequent intravenous dosing to maintain therapeutic levels of drug in circulation.

In 2021 the Company initiated a series of cancer screening studies aimed at uncovering therapeutic opportunities for cepharanthine when used alone or in combination with standard of care (SoC) chemotherapy drugs. Results from these in vitro studies revealed that the combination of cepharanthine and cabazitaxel, a SoC used for castration-resistant, metastatic prostate cancers, provided unexpectedly synergistic reduction in prostate tumor cell survival. The Company previously reported that a once-per-day oral regimen of PD-001, in combination with cabazitaxel provided statistically significant benefit at the scheduled end of dosing (day 21) in its recently completed prostate efficacy study. Specifically, PD-001 delivered at doses of 3, 9, or 27 mg/kg/day combined with cabazitaxel (3mg/kg/Q3D) provided up to a 64% tumor growth inhibition compared to 37% noted for treatment with cabazitaxel alone. Based on these results, the addition of PD-001 to the SoC, cabazitaxel was found to improve tumor growth inhibition by 73% compared to cabazitaxel-alone.

Since releasing interim results from this study (March 9^th, 2022), the Company has been provided a final study report. Currently, the Company’s intellectual property counsel is working on a provisional patent submission that aims to provide new evidence to support and potentially expand its claim set around the use of PD-001 and cabazitaxel to treat prostate cancer. Agents such as PD-001 which show synergistic benefit when combined with taxanes for the treatment of prostate cancer are sorely needed. The Company plans to provide an update on the final in vivo study outcome soon.

PD-001 For Esophageal Cancer

In addition to its ongoing investigations of PD-001 for prostate cancer, the Company plans to fully leverage the streamlined path to approval which comes by way of a recently granted FDA Orphan Drug Designation for PD-001 for the treatment of esophageal cancer. To that end, PharmaDrug has now initiated an IND-enabling study to evaluate efficacy and tolerability of orally administered PD-001 in an esophageal cancer model. For this study, PD-001 will be administered alone and in combination with a SoC chemotherapy drug and tumor growth will be monitored. Results of this study are expected in Q2, 2022.

Collectively the Company’s panning approach of going from very broad to very specific cancer types which are highly responsive to PD-001 has yielded two high impact hits and has laid a strong foundation for continued development in the oncology space. For reference to previous press releases which detail PharmaDrug’s ongoing efforts in oncology please see the Company’s press releases dated March 9, Feb 1, 2022 and Nov 18, Oct 15, July 28, 2021.

Cepharanthine for Cancer: Mechanism of Action

PharmaDrug’s cancer program is based on cepharanthine’s known anti-cancer activities. Cepharanthine has been shown in multiple preclinical efficacy models to inhibit cancer cell proliferation, induce cancer cell apoptosis (death) and restore cancer cell sensitivity to multiple unrelated classes of chemotherapy. Multidrug resistance continues to represent a considerable clinical challenge. As such, preclinical cancer studies aimed at elucidating the mechanisms that underly chemoresistance; including the critical role drug efflux pumps play in this phenomenon by reducing the intracellular concentration of chemotherapeutic drugs, are of particular interest to PharmaDrug. Cepharanthine has been shown in preclinical studies to potently reverse chemoresistance by downregulating expression of ABCB1, the transcript of which codes for multidrug resistance protein 1, (MDR1, aka P- glycoprotein). Importantly, several prior in vitro and in vivo studies have shown that cepharanthine-mediated reductions in ABCB1 expression restores cancer cell sensitivity to a range of chemotherapeutics including taxanes, vinca alkaloids and platinum-based drugs^1-4.

PD-001 For Infectious Disease, Including COVID-19

To date, several third party validated library screens of approved and investigational drugs have identified cepharanthine as a forerunner candidate molecule in the treatment SARS-CoV-2, the virus that causes COVID-19^5-7. In fact, cepharanthine has now been shown to be highly effective at blocking cell death following exposure to multiple different coronaviruses, including COVID-19, lab-attenuated SARS-CoV (original SARS) and the virus that causes Middle East respiratory syndrome (MERS)^5-7.

In November 2021 an independent research group examined the potential of cepharanthine to limit the cytopathic effects of the South African COVID-19 variant, B.1.3514. It was found that cepharanthine was at least 6-times more active against the South African variant strain than original SARS-CoV-2, and that cepharanthine was the most effective of all the drugs used in the in vitro screen that was perfomed⁸. Although the Omicron variant shares several features in common with the previous South African variant, B.1.351, it remains to be determined how well cepharanthine will perform at treating this emerging threat. Intriguingly, the same authors noted that cepharanthine also displayed significant potency with favorable selectivity index for other RNA viruses including Zika and Ebola⁸. Despite the promising findings for cepharanthine noted above, translation into clinical application has thus far been hampered by the need for the generic formulation of the drug to be delivered by intravenous due to its intrinsically poor oral bioavailability.

As such, it is believed that the Company’s novel oral formulation of cepharanthine, PD-001 would be an ideal candidate to evaluate as a potential treatment for mild to moderate COVID-19. By leveraging its exclusive rights to U.S. Patent: 10,576,077, titled “Pharmaceutical Salt forms of Cepharanthine and Tetrandrine”, PharmaDrug intends to develop and commercialize PD-001 as an oral antiviral treatment for patients with mild to moderate SARS-CoV-2 infection.

How Cepharanthine May Work to Block Coronavirus Entry

In a recent peer reviewed manuscript cepharanthine was shown to display greater antiviral potency against SARS-CoV-2 than existing clinical development candidates remdesivir, lopinavir, favipiravir, nelfinavir and chloroquine⁵. Researchers identified a putative binding site on the surface of SARS-CoV-2 spike protein known to facilitate viral docking with the human ACE2 receptor. Consistent with this mechanism of action, application of cepharanthine to cells exposed to SARS-CoV-2 fully blocked viral internalization and subsequent production of viral particles 24 hours post infection.⁵

The Company is not making any express or implied claims that its product has the ability to eliminate, cure or contain the Covid-19 (or SARS-2 Coronavirus) at this time.

About PD-001 (Enteric-coated Oral Cepharanthine)

Cepharanthine is a natural product and an approved drug used for more than 70 years in Japan to successfully treat a variety of acute and chronic diseases. In clinical research, Cepharanthine has been shown to exhibit multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic effects^9,10. However, historically cepharanthine’s low oral bioavailability has represented a major obstacle to realizing its full clinical potential.

About PharmaDrug Inc.

PharmaDrug is a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs. PharmaDrug owns 100% of Pharmadrug Production GmbH (“Pharmadrug Production”), a German medical cannabis distributor, with a Schedule I European Union narcotics license and German EuGMP certification allowing for the importation and distribution of medical cannabis to pharmacies in Germany and throughout the European Union. PharmaDrug owns 100% of Sairiyo Therapeutics (“Sairiyo”), a biotech company that specializes in researching and reformulating established natural medicines with a goal of bringing them through clinical trials and the associated regulatory approval process in the US and Europe. Sairiyo is currently developing its patented reformulation of cepharanthine, a drug that has shown substantial third party validated potential for the treatment of infectious disease and rare cancers. Sairiyo is also conducting R&D in the psychedelics space for the treatment of non-neuropsychiatric conditions. The Company also owns 100% of Super Smart, a company building a vertically integrated retail business with the goal to elevate the use of functional mushrooms, and psilocybin mushrooms where federally legal, as natural based medicines.

For further information, please contact:

Daniel Cohen, Chairman and CEO
dcohen@pharmadrug.co
(647) 202-124

Caution Regarding Forward-Looking Information:

THE CANADIAN SECURITIES EXCHANGE HAS NOT REVIEWED NOR DOES IT ACCEPT RESPONSIBILITY FOR THE ADEQUACY OR ACCURACY OF THIS RELEASE.

This press release contains “forward-looking information” within the meaning of applicable securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. Generally, forward-looking information may be identified by the use of forward-looking terminology such as “plans”, “expects” or “does not expect”, “proposed”, “is expected”, “budgets”, “scheduled”, “estimates”, “forecasts”, “intends”, “anticipates” or “does not anticipate”, or “believes”, or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. In particular, this press release contains forward-looking information in relation to: the development and commercialization of cepharanthine including regulatory approval thereof and the associated studies; the ability to produce PD-001 in a quantity sufficient to support development activities and the timing thereof. This forward-looking information reflects the Company’s current beliefs and is based on information currently available to the Company and on assumptions the Company believes are reasonable. These assumptions include, but are not limited to the ability of the Company to successfully execute on its plans for the Company and its affiliated entities; the ability to obtain required regulatory approvals and the Company’s continued response and ability to navigate the COVID-19 pandemic being consistent with, or better than, its ability and response to date.

Forward-looking information is subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of the Company to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; the actual results of the Company’s future operations; competition; changes in legislation affecting the Company; the ability to obtain and maintain required permits and approvals, the timing and availability of external financing on acceptable terms; lack of qualified, skilled labour or loss of key individuals; risks related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to try to limit the pandemic, including travel restrictions, border closures, non-essential business closures, service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, economic activity, financing, supply chains and sales channels, and a deterioration of general economic conditions; and a deterioration of financial markets that could limit the Company’s ability to obtain external financing.

A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in the Company’s disclosure documents on the SEDAR website at www.sedar.com. Although the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Accordingly, readers should not place undue reliance on forward-looking information. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated.

The Company’s securities have not been registered under the U.S. Securities Act of 1933, as amended (the “U.S. Securities Act”), or applicable state securities laws, and may not be offered or sold to, or for the account or benefit of, persons in the United States or “U.S. Persons”, as such term is defined in Regulations under the U.S. Securities Act, absent registration or an applicable exemption from such registration requirements. This press release shall not constitute an offer to sell or the solicitation of an offer to buy nor shall there be any sale of the securities in the United States or any jurisdiction in which such offer, solicitation or sale would be unlawful.

Forward-looking information contained in this press release is expressly qualified by this cautionary statement. The forward-looking information contained in this press release represents the expectations of the Company as of the date of this press release and, accordingly, are subject to change after such date. However, the Company expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law.

References:

1. Saito T, Hikita M, Kohno K, Tanimura H, Miyahara M, Kobayashi M. Enhanced expression of the multidrug resistance gene in vindesine-resistant human esophageal cancer cells. Oncology. 1994 Sep-Oct;51(5):440-5. doi: 10.1159/000227380. PMID: 8052486.
2. Zhou P, Zhang R, Wang Y, Xu D, Zhang L, Qin J, Su G, Feng Y, Chen H, You S, Rui W, Liu H, Chen S, Chen H, Wang Y. Cepharanthine hydrochloride reverses the mdr1 (P-glycoprotein)-mediated esophageal squamous cell carcinoma cell cisplatin resistance through JNK and p53 signals. Oncotarget. 2017 Nov 27;8(67):111144-111160. doi: 10.18632/oncotarget.22676. Erratum in: Oncotarget. 2021 Jan 05;12(1):61-62. PMID: 29340044; PMCID: PMC5762312.
3. Huang CZ, Wang YF, Zhang Y, Peng YM, Liu YX, Ma F, Jiang JH, Wang QD. Cepharanthine hydrochloride reverses P glycoprotein-mediated multidrug resistance in human ovarian carcinoma A2780/Taxol cells by inhibiting the PI3K/Akt signaling pathway. Oncol Rep. 2017 Oct;38(4):2558-2564. doi: 10.3892/or.2017.5879. Epub 2017 Aug 4. PMID: 28791369.
4. Zahedi P, De Souza R, Huynh L, Piquette-Miller M, Allen C. Combination drug delivery strategy for the treatment of multidrug resistant ovarian cancer. Mol Pharm. 2011 Feb 7;8(1):260-9. doi: 10.1021/mp100323z. Epub 2010 Dec 17. PMID: 21166459.
5. Ohashi H, Watashi K, Saso W, Shionoya K, Iwanami S, Hirokawa T, Shirai T, Kanaya S, Ito Y, Kim KS, Nomura T, Suzuki T, Nishioka K, Ando S, Ejima K, Koizumi Y, Tanaka T, Aoki S, Kuramochi K, Suzuki T, Hashiguchi T, Maenaka K, Matano T, Muramatsu M, Saijo M, Aihara K, Iwami S, Takeda M, McKeating JA, Wakita T. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment. iScience. 2021 Apr 23;24(4):102367. doi: 10.1016/j.isci.2021.102367. Epub 2021 Mar 26. PMID: 33817567; PMCID: PMC7997640.
6. Chen CZ, Xu M, Pradhan M, Gorshkov K, Petersen JD, Straus MR, Zhu W, Shinn P, Guo H, Shen M, Klumpp-Thomas C, Michael SG, Zimmerberg J, Zheng W, Whittaker GR. Identifying SARS-CoV-2 Entry Inhibitors through Drug Repurposing Screens of SARS-S and MERS-S Pseudotyped Particles. ACS Pharmacol Transl Sci. 2020 Oct 19;3(6):1165-1175. doi: 10.1021/acsptsci.0c00112. PMID: 33330839; PMCID: PMC7586456.
7. Fan HH, Wang LQ, Liu WL, An XP, Liu ZD, He XQ, Song LH, Tong YG. Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model. Chin Med J (Engl). 2020 May 5;133(9):1051-1056. doi: 10.1097/CM9.0000000000000797. PMID: 32149769; PMCID: PMC7147283.
8. Zhang S, Huang W, Ren L, Ju X, Gong M, Rao J, Sun L, Li P, Ding Q, Wang J, Zhang QC. Comparison of viral RNA-host protein interactomes across pathogenic RNA viruses informs rapid antiviral drug discovery for SARS-CoV-2. Cell Res. 2021 Nov 4:1-15. doi: 10.1038/s41422-021-00581-y. Epub ahead of print. PMID: 34737357; PMCID: PMC8566969.
9. Bailly C. Cepharanthine: An update of its mode of action, pharmacological properties and medical applications. Phytomedicine. 2019 Sep;62:152956. doi: 10.1016/j.phymed.2019.152956. Epub 2019 May 10. PMID: 31132753; PMCID: PMC7126782.
10. Rogosnitzky M, Danks R. Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions. Pharmacol Rep. 2011;63(2):337-47. doi: 10.1016/s1734-1140(11)70500-x. PMID: 21602589.

PharmaDrug Announces Filing of US Provisional Patent for Cepharanthine to Treat Prostate Cancer

Patent claims on synergistic application of cepharanthine, cabazitaxel and other taxane family members used in combination to treat primary, metastatic and chemotherapy-resistant prostate cancer

Expands on Company’s ‘pipeline in a pill’ strategy with cepharanthine in treating rare cancers

Toronto, Ontario – February 1, 2022 – PharmaDrug Inc. (CSE: PHRX) (OTCQB: LMLLF) (“PharmaDrug” or the “Company“), a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs, is pleased to announce that the Company has filed a US provisional patent application which details the novel synergistic combination of cepharanthine (PD-001) and cabazitaxel on prostate cancer growth inhibition and also sets forth claims related to the use of PD-001, cabazitaxel and/or other taxane family members used in combination to treat primary, metastatic and chemotherapy-resistant prostate cancer.

In 2021, the Company initiated a series of cancer screening studies aimed at uncovering therapeutic opportunities for cepharanthine when used alone or in combination with standard of care (SoC) chemotherapy drugs. Results from these studies revealed that prostate cancer was particularly responsive to cepharanthine, second only to esophageal cancer. Specifically, the top dose of cepharanthine examined inhibited growth of the prostate cancer cell line, 22Rv1 by 99.95% compared to the maximal growth inhibition noted for cisplatin of 95.46% and SoC, cabazitaxel of 96.63%. While the potency of cepharanthine on prostate cancer was notable in the context of other common chemotherapeutic agents, here the Company reports that the combination of cepharanthine plus cabazitaxel provided unexpectedly synergistic reduction in prostate tumor cell survival. A provisional US patent has now been filed to protect these findings and the Company plans to strategically build out and extend patent protection for PD-001 in the oncology space. Consistent with this, the Company has initiated in vivo prostate cancer model studies to examine the synergistic relationship between cepharanthine and cabazitaxel more closely. PharmaDrug will have one year post filing (January 26^th, 2023) to provide additional supportive data and to potentially modify its existing claim set based on new findings. During this time the Company plans to also continue with IND-enabling studies directed towards the use of cepharanthine for esophageal cancer; an indication that the Company’s PD-001 previously received orphan drug designation for.

Daniel Cohen, CEO and Chairman of PharmaDrug, commented, “We are extremely excited to continue to broaden the use case for PD-001 as a treatment for various cancers. While esophageal cancer continues to be our main focus with a goal to move towards an FDA clinical trial, we believe that cepharanthine will ultimately show a wider potential use in the treatment of cancers, specifically in combination with the current standard of care. We will continue to explore cepharanthine’s potential therapeutic relationship with existing standard of care chemotherapies.”

About PD-001 (Enteric-coated Oral Cepharanthine)

Cepharanthine is a natural product and an approved drug used for more than 70 years in Japan to successfully treat a variety of acute and chronic diseases. In clinical research, Cepharanthine has been shown to exhibit multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic effects^1,2. However, historically cepharanthine’s low oral bioavailability has represented a major obstacle to realizing its full clinical potential.

The Company is focused on advancing the clinical development of an improved and patented enteric-coated oral formulation of cepharanthine (PD-001) to treat responsive cancers and COVID-19. Compared to generic cepharanthine, PD-001 has been shown in rodent and non-rodent models to possess markedly superior oral bioavailability (more easily absorbed). These findings support the development of an orally administered formulation, and in so doing, removes the undesirable requirement for frequent intravenous dosing.

PD-001 for Cancer

PharmaDrug’s cancer program is based on cepharanthine’s known anti-cancer activities. Cepharanthine has been shown in multiple preclinical efficacy models to inhibit cancer cell proliferation, induce cancer cell apoptosis (death) and restore cancer cell sensitivity to multiple unrelated classes of chemotherapy. Multidrug resistance continues to represent a considerable clinical challenge. As such, preclinical cancer studies aimed at elucidating the mechanisms that underly chemoresistance; including the critical role drug efflux pumps play in this phenomenon by reducing the intracellular concentration of chemotherapeutic drugs, are of particular interest to PharmaDrug. Cepharanthine has been shown in preclinical studies to potently reverse chemoresistance by downregulating expression of ABCB1, the transcript of which codes for multidrug resistance protein 1, (MDR1, aka P- glycoprotein). Importantly, several prior in vitro and in vivo studies have shown that cepharanthine-mediated reductions in ABCB1 expression restores cancer cell sensitivity to a range of chemotherapeutics including taxanes, vinca alkaloids and platinum-based drugs^3-6. Collectively the two in vitro screening studies already completed by the Company, and those in vivo studies currently underway aim to identify and provide focus to novel opportunities in oncology by revealing optimal cancer cell types as a monotherapy and/or drug combinations and situations where PD-001 can prevent, lessen, or reverse chemoresistance, and provide additive or synergistic benefit to existing standard of care treatments. For reference to previous press releases related to PharmaDrug’s ongoing efforts in the oncology space please see previous press releases Nov 18, Oct 15, July 28, 2021. In addition to its ongoing investigations of PD-001 for prostate cancer, the Company plans to fully leverage the streamlined path to approval which comes by way of a recently granted FDA Orphan Drug Designation PD-001 for the treatment of esophageal cancer.

Potential of PD-001 to Treat Prostate Cancer

According to the American Cancer Society, in 2021 there were approximately 248,530 new cases of prostate cancer and about 34,130 deaths from prostate cancer in the United States, and it is the second leading cause of cancer death in American men. Metastatic prostate cancer is commonly treated using androgen deprivation therapy (ADT), including surgical or medical castration, but metastatic castration-resistant prostate cancer (mCRPC) commonly emerges⁷. The taxanes docetaxel and cabazitaxel are approved for the treatment of mCRPC, however resistance to taxanes is known to develop over time. Agents such as PD-001 which show synergistic benefit when combined with taxanes for the treatment of prostate cancer are sorely needed. The Company’s forthcoming in vivo studies are specifically designed to address the potential of PD-001 to overcome taxane-based chemoresistance in vivo.

About PharmaDrug Inc.

PharmaDrug is a specialty pharmaceutical company focused on the research, development and commercialization of controlled-substances and natural medicines such as psychedelics, cannabis and naturally-derived approved drugs. PharmaDrug owns 100% of Pharmadrug Production GmbH, a German medical cannabis distributor, with a Schedule I European Union narcotics license and German EuGMP certification allowing for the importation and distribution of medical cannabis to pharmacies in Germany and throughout the European Union. PharmaDrug owns 100% Sairiyo Therapeutics (“Sairiyo”), a biotech company that specializes in researching and reformulating established natural medicines with a goal of bringing them through clinical trials and the associated regulatory approval process in the US and Europe. Sairiyo is currently developing its patented reformulation of cepharanthine, a drug that has shown substantial third party validated potential for the treatment of Covid-19 and rare cancers. Sairiyo is also conducting R&D in the psychedelics space for the treatment of non-neuropsychiatric conditions. The Company also owns 100% of Super Smart, a company building a vertically integrated retail business with the goal to elevate the use of functional mushrooms, and psilocybin mushrooms where federally legal, as natural based medicines.

For further information, please contact:

Daniel Cohen, Chairman and CEO
dcohen@pharmadrug.co
(647) 202-1824

Caution Regarding Forward-Looking Information:

THE CANADIAN SECURITIES EXCHANGE HAS NOT REVIEWED NOR DOES IT ACCEPT RESPONSIBILITY FOR THE ADEQUACY OR ACCURACY OF THIS RELEASE.

This press release contains “forward-looking information” within the meaning of applicable securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. Generally, forward-looking information may be identified by the use of forward-looking terminology such as “plans”, “expects” or “does not expect”, “proposed”, “is expected”, “budgets”, “scheduled”, “estimates”, “forecasts”, “intends”, “anticipates” or “does not anticipate”, or “believes”, or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. In particular, this press release contains forward-looking information in relation to: the development and commercialization of cepharanthine, the results of the Company’s research and development in the psychedelics space and the development of the Supersmart business . This forward-looking information reflects the Company’s current beliefs and is based on information currently available to the Company and on assumptions the Company believes are reasonable. These assumptions include, but are not limited to the ability of the Company to successfully execute on its plans for the Company and its affiliated entities; the ability to obtain required regulatory approvals and the Company’s continued response and ability to navigate the COVID-19 pandemic being consistent with, or better than, its ability and response to date.

Forward-looking information is subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of the Company to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; the actual results of the Company’s future operations; competition; changes in legislation affecting the Company; the ability to obtain and maintain required permits and approvals, the timing and availability of external financing on acceptable terms; lack of qualified, skilled labour or loss of key individuals; risks related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to try to limit the pandemic, including travel restrictions, border closures, non-essential business closures, service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, economic activity, financing, supply chains and sales channels, and a deterioration of general economic conditions; and a deterioration of financial markets that could limit the Company’s ability to obtain external financing.

A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in the Company’s disclosure documents on the SEDAR website at www.sedar.com. Although the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Accordingly, readers should not place undue reliance on forward-looking information. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated.

The Company’s securities have not been registered under the U.S. Securities Act of 1933, as amended (the “U.S. Securities Act”), or applicable state securities laws, and may not be offered or sold to, or for the account or benefit of, persons in the United States or “U.S. Persons”, as such term is defined in Regulations under the U.S. Securities Act, absent registration or an applicable exemption from such registration requirements. This press release shall not constitute an offer to sell or the solicitation of an offer to buy nor shall there be any sale of the securities in the United States or any jurisdiction in which such offer, solicitation or sale would be unlawful.

Forward-looking information contained in this press release is expressly qualified by this cautionary statement. The forward-looking information contained in this press release represents the expectations of the Company as of the date of this press release and, accordingly, are subject to change after such date. However, the Company expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law.

References:

1. Bailly C. Cepharanthine: An update of its mode of action, pharmacological properties and medical applications. Phytomedicine. 2019 Sep;62:152956. doi: 10.1016/j.phymed.2019.152956. Epub 2019 May 10. PMID: 31132753; PMCID: PMC7126782.
2. Rogosnitzky M, Danks R. Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions. Pharmacol Rep. 2011;63(2):337-47. doi: 10.1016/s1734-1140(11)70500-x. PMID: 21602589.
3. Saito T, Hikita M, Kohno K, Tanimura H, Miyahara M, Kobayashi M. Enhanced expression of the multidrug resistance gene in vindesine-resistant human esophageal cancer cells. Oncology. 1994 Sep-Oct;51(5):440-5. doi: 10.1159/000227380. PMID: 8052486.
4. Zhou P, Zhang R, Wang Y, Xu D, Zhang L, Qin J, Su G, Feng Y, Chen H, You S, Rui W, Liu H, Chen S, Chen H, Wang Y. Cepharanthine hydrochloride reverses the mdr1 (P-glycoprotein)-mediated esophageal squamous cell carcinoma cell cisplatin resistance through JNK and p53 signals. Oncotarget. 2017 Nov 27;8(67):111144-111160. doi: 10.18632/oncotarget.22676. Erratum in: Oncotarget. 2021 Jan 05;12(1):61-62. PMID: 29340044; PMCID: PMC5762312.
5. Huang CZ, Wang YF, Zhang Y, Peng YM, Liu YX, Ma F, Jiang JH, Wang QD. Cepharanthine hydrochloride reverses P glycoprotein-mediated multidrug resistance in human ovarian carcinoma A2780/Taxol cells by inhibiting the PI3K/Akt signaling pathway. Oncol Rep. 2017 Oct;38(4):2558-2564. doi: 10.3892/or.2017.5879. Epub 2017 Aug 4. PMID: 28791369.
6. Zahedi P, De Souza R, Huynh L, Piquette-Miller M, Allen C. Combination drug delivery strategy for the treatment of multidrug resistant ovarian cancer. Mol Pharm. 2011 Feb 7;8(1):260-9. doi: 10.1021/mp100323z. Epub 2010 Dec 17. PMID: 21166459.
7. Komura K, Sweeney CJ, Inamoto T, Ibuki N, Azuma H, Kantoff PW. Current treatment strategies for advanced prostate cancer. Int J Urol. 2018;25(3):220-231. doi:10.1111/iju.13512