The U.S. Food and Drug Administration (FDA) has authorized Tetra Bio-Pharma, a biopharmaceutical company focusing on cannabinoid-based drug discovery and development, to resume the Plenitude trial (NCT04042545), the company‚Äôs interventional phase II clinical trial for its investigational therapeutic QIXLEEF‚ĄĘ (PPP001).
QIXLEEF is being developed for the treatment of uncontrolled pain in advanced cancer patients. Uncontrolled pain significantly ‚Äď and adversely ‚Äď impacts function and affects health related quality of life (hrQoL) during cancer treatment and survivorship. Overall, it reduces a patient‚Äôs potential tolerance of cancer therapy and may cause them to discontinue their cancer treatments. Over the last decade, a number of studies have shown that improved pain management results in improved survival.
Cannabis has historically been used as a healing herb and mild-altering plant and a wealth of anecdotal and preclinical data in a number of acute, chronic, neuropathic and cancer pain models, has demonstrated sufficient evidence supporting favorable (palliative) outcomes in the treatment of chemotherapy-induced nausea and vomiting and cancer-related pain, with evidence of advantageous neurological interactions. 
However, some of the clinical evidence for efficacy of cannabinoids has, as argued by some scientist, been ‚Äėlost in translation.‚Äô This is, in part, caused by a high variability of medicinal marijuana, lack of a validated scientific approach and insufficient or no standardization in clinical trial design and construction, inconsistent drug formulation and pharmacodynamics. 
In addition, the scientific community, governmental regulators and the patient, need to reach consensus on safety, quality control and efficacy.
To change the paradigm, Tetra Bio-Pharma is pioneering rigorous clinical research initiatives employing the traditional methods of medicinal cannabis use within scientifically designed medical studies, yielding validated safety and efficacy data.
Their approach follows the same time-honored process that any pharmaceutical agent must attain to receive regulatory approval ‚Äď a validated proof of biochemical uniformity and stability along with safety and efficacy as proven by randomized clinical trials (RCT). But, in the case of cannabinoids, a practical and suitable delivery system designed to minimizes patient risk, including intoxication and serious adverse events is also required.
Tetra‚Äôs goal is to develop and advance a pipeline of biopharmaceutical agents containing standardized cannabinoid-derived products and other medicinal plant-based elements that meets the standards of regulators, medical societies, physicians and insurance companies. This includes conducting clinical studies with a number of strategic partners and the development of an advanced delivery system to optimize patient care.
The Plenitude trial, one of Tetra‚Äôs clinical study was allowed to proceed after the FDA reviewed the company‚Äôs quality file, including mycotoxin quality information. After ensuring the safety assessments were adequate to protect patients, the FDA authorized the company to resume the trial.
As part of their quality approach, Tetra Bio-Pharma developed and validated several screening tools and assays designed to map out and quantify known mycotoxins (T2 toxin, ochratoxin A, vomitoxin, penicillic acid, etc.) growing on a crop and bulk plant supplies. a In addition, the company assayed all raw materials as well as finished products and required suppliers of bulk plant materials to subject to a stringent monitoring program.
Following the FDA‚Äôs decisions, Tetra Bio-Pharma resumed the Plenitude trial program, initiate study enrollment as quickly as possible.
‚ÄúWe ‚Ä¶ have been able to provide the FDA with a comprehensive information package which has led to the FDA‚Äôs authorization and Tetra‚Äôs initiation of our Plenitude trial,‚ÄĚ noted Guy Chamberland, MSc, Ph.D, Chief Executive Officer and CEO and Chief Regulatory Officer of Tetra Bio-Pharma
‚ÄúWe will be working in the coming weeks to (re-) launch the trial as quickly as possible,‚ÄĚ he added.
The Plenitude study is a 4-week double-blind, randomized, placebo-controlled, parallel group design trial to evaluate the safety and efficacy of inhaled PPP001 on uncontrolled cancer pain in 78 adult patients with symptoms related to advanced incurable cancer and uncontrolled pain related to cancer. After the¬† the double-blind part the trial continues with an open label period of 2 years.
As part of the trial, participating patients will be asked to measure uncontrolled cancer pain will using a patient self rating questionnaire, using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire.
The company anticipates results from the Plenitude clinical trial will be part of the drug approval for QIXLEEF.
In connection with launching this clinical trial, Tetra is accelerating plans to sign a commercial partner in the United States for the distribution and sale of QIXLEEF.
The company is working closely with its partners to ensure clinical and commercial readiness. As part of this process, the company has signed a research collaboration agreement with Sue A. Sisley, MD., a former clinical assistant professor at the University of Arizona College of Medicine.
As an Arizona-based physician Sisley practices internal medicine and psychiatry and is the leading international advocate for the benefits of whole-plant based cannabis therapies and a recognized expert in post-traumatic stress disorder (PTSD).
Tetra started working with Sisley, who‚Äôs cannabis clinic, Scottsdale Research Institute in Scottsdale, Arizona, United States, holds a Schedule 1 license for inhaling cannabis from the US Drug Enforcement Agency (DEA), several months ago. With the this is a single site study authorized, Sisley and Tetra‚Äôs clinical research team intend to amend the DEA license to add the Plenitude trial to allow for Sisley‚Äôs clinical site to run the trial.
Tetra expects that this amendment will be completed within a few weeks.
‚ÄúWe are very fortunate to collaborate with Sisley and believe she will play an important role in educating physicians on the therapeutic potential of vaporized dried flower bud. Sisley‚Äôs expertise and advocacy will be key for any partner distributing QIXLEEF in the United States or globally,‚ÄĚ Chamberland noted.
‚ÄúAdditionally, we believe Sisley will be instrumental in helping with trial enrollment and patient analysis,‚ÄĚ he added.
First generation cannabinoid therapeutic
QIXLEEF is Tetra‚Äôs the company‚Äôs first-generation cannabinoid therapeutic in development for treating advanced cancer patients with uncontrolled pain. The company believes a subset of the advanced cancer patient population prefers to consume cannabis in the traditional way, using dried flower bud as a therapeutic drug.
In early 2019, Tetra uncovered an impurity in the dried flower bud cannabis and worked diligently to find solutions to develop a pharmaceutical grade cannabis drug free of any traces of the impurity.
Through its ongoing research, the company has also developed a second-generation medicinal product, Caumz‚ĄĘ (PPP011), which is currently in development for patients with advanced cancer pain. Once the company gains approval for Caumz‚ĄĘ in patients with advanced cancer pain, it will continue clinical development program in parallel and seek approval in breakthrough pain and fibromyalgia.
As part of an expedited review of Caumz‚ĄĘ by the FDA ‚Äú[‚Ä¶] we have taken the care to address all of the regulatory requirements in our Type B meeting with the FDA and look forward to providing additional clarity as we receive confirmation from the FDA on our final development plan,‚ÄĚ Chamberland said.
‚ÄúI am extraordinarily proud of our Research & Development and Quality and Compliance teams. We have worked diligently to get FDA authorization for the trial and revive QIXLEEF, and we have also been able to leverage the investment in our research to bring two generations of inhaled cannabinoid and cannabis drugs to patients,‚ÄĚ he added.
Unrelated to the FDA‚Äôs approval for the rivival of the QIXLEEF trial, Canadian Tetra Natural Health, a wholly owned subsidiary of Tetra Bio-Pharma has submitted two over-the-counter (OTC) DIN applications to Health Canada for drugs treating hemorrhoids the temporary relief of aches and pains of muscles and joints associated with backache, lumbago, strains, bruises, sprains and arthritic or rheumatic pain, pain of tendons and ligaments.
Tetra has created an OTC product line containing beta-caryophyllene b to bring self-care therapies that act on the CB2 receptor directly to pharmacies and patients. The company intends to commercially launch these OTC pain medications in the $ 19 billion OTC market .
‚Äú[We have] always had a focus on bringing evidence-based therapies to patients, and this OTC drug line is part of that vision.‚ÄĚ Chamberland said.
Tetra continues to expect its commercial OTC launch in Canada in pharmacy retail outlets in early 2020, and is in commercial agreement discussions with various companies for the sale and distribution of these products. Tetra also plans to launch its OTC product line containing beta-caryophyllene in the United States market in 2020.
In preparation for a U.S. launch, Tetra is in discussions with a contract manufacturer to set up the manufacturing and to obtain a National Drug Code (NDC) number from the U.S. Food and Drug Administration (FDA) for each drug, which is required for all OTC drugs sold in the U.S.
a The company implemented Quantitative PCR (qPCR), also known as real-time PCR, to screen to detect mycotoxin encoding genes.
b Beta-caryophyllene, a ‚Äúdietary cannabinoid,‚ÄĚ is common component of food that has GRAS (Generally Recognized as Safe) status and is approved by the U.S. Food and Drug Administration (FDA) for food use.
For more information
‚Äď The Onco‚ÄôZine Brief on PRX: Cannabinoid-based Drug Discovery and Development Designed to Benefit Cancer Patients [Listen on PRX][Download]
‚Äď OpEd/Editorial: Chamberland G. Can Cannabinoids have a Curative Impact on Glioblastoma? Onco‚ÄôZine. April 1, 2019. Online. Last accessed November 26, 2019.
‚Äď Safety and Efficacy of Inhaled Cannabis For the Uncontrolled Pain Releif in Patients With Advanced Cancer (Plenitude) ‚Äď NCT04042545
‚Äď Safety and Efficacy of Inhaled Cannabis (Synthetic THC/CBD) for Improving Quality of Life in Advanced Cancer Patients (Serenity) ‚Äď NCT04001010
‚Äď Cannabis Oil and Radiation Therapy for the Management of Pain ‚Äď NCT03763851
‚Äď Inhaled Cannabis Versus Fentanyl Buccal Tablets for Management of Breakthrough Pain in Cancer Patients ‚Äď NCT03564548
‚Äď Safety and Efficacy of Smoked Cannabis for Improving Quality of Life in Advanced Cancer Patients ‚Äď NCT03339622
‚Äď Safety and Efficacy of Medical Cannabis Oil in the Treatment of Patients With Chronic Pain ‚Äď NCT03337503
 L√∂tsch J, Weyer-Menkhoff I, Tegeder I. Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings. Eur J Pain. 2018;22(3):471‚Äď484. doi:10.1002/ejp.1148
 Turgeman I, Bar-Sela G. Cannabis Use in Palliative Oncology: A Review of the Evidence for Popular Indications. Isr Med Assoc J. 2017;19(2):85‚Äď88.
 Turgeman I, Bar-Sela G. Cannabis for cancer ‚Äď illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology. Expert Opin Investig Drugs. 2019;28(3):285‚Äď296. doi:10.1080/13543784.2019.1561859
 Russo EB. Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues. Front Pharmacol. 2016;7:309. Published 2016 Sep 14. doi:10.3389/fphar.2016.00309
 Over-the-Counter Pain Medication Market will Exhibit a Steady 4.0% CAGR through 2028: Future Market Insights. February 20, 2019
 U.S. Topical Pain Relief Market Outlook ‚Äď 2025. Sayali Shinde , Onkar Sumant. Allied Market Research. June 2019. Global Topical Pain Relief Market. Allied Market Research. April 2019.