Cannabis Officially Enters the Craft Beer Craze

It should come as no surprise that cannabis has finally found its way into the the craft beer craze that has dominated world alcoholic beverage markets for the past decade or so.  Last week, LGC Capital, Cresco Pharma and Baltic Beer Company announced a joint venture company called CLV Frontier Brands with the goal of developing a full beverage portfolio using proprietary cannabis terpene blends and hemp ingredients.

According to reports, CLV plans on crafting four premium beers (that contain different terpene blends and other “innovative ingredients”) with a global release of the first batch of beer in Spring 2018.  While Humboldt Brewery and a partnership between Lagunitas Brewing and Absolute/Xtracts  already brew Hemp Ale with toasted hemp seeds and an IPA with terpenes respectively,  CLV joint venture represents the first aggressive effort to bring cannabis and hemp-based  craft beers  to the global stage.  CLV plans on building a pilot brewing facility in Tallinn, Estonia and has identified potential distribution partners in Europe, East Asia, Central and Latin America, Africa and Canada/Australia and New Zealand.

Noticeably absent from the distribution list of potential partners is the US.  Although terpenes, non-psychoactive cannabinoids that give different cannabis strains distinctive odors and flavors are generally recognized as safe (GRAS) by the US Food and Drug Administration (FDA) and classified as food additives, cannabis is a schedule 1 drug and anything derived from it is illegal at the federal level in the US.  Consequently, because  the beers will be brewed overseas and require shipping to the US they will not be legally available in the US (even in states where cannabis has been legalized) because interstate shipping is regulated by the federal government.  That said, I suspect that some of CLV’s products may make it into the heads of cannabis craft beer enthusiasts!

Currently Approved Cannabis-based Pharmaceuticals and Some in the Pipeline

Because of historical negative perceptions and ongoing legal concerns, only a few cannabis-based pharmaceuticals are currently licensed for clinical use. In the United States and Europe the synthetic Δ-9-THC drugs nabilone (Cesmet®) and dronabinol (Marinol®) and dronabinol (Marinol®) are approved for treatment and prevention of chemotherapy-induced nausea and vomiting (CINV; 1).  Another synthetic Δ-9-THC product, Syndros (dronabinol oral solution) received approval in 2016 for the treatment of anorexia associated with weight loss in patients with AIDS and for cancer patients with CINV who failed to adequately respond to conventional antiemetic treatments.

GW Pharmaceuticals’ Sativex®, an extract containing THC and CBD, is approved in 27 countries Europe and elsewhere for the treatment of spasticity associated with multiple sclerosis and, in Canada, is also approved as an adjunctive treatment for cancer pain (1) The CB1 cannabis receptor agonist rimonabant (Acomplia®) was approved for use in Europe to treat obesity but was discontinued because of serious adverse effects (2)

While the approved cannabis-based pharmaceutical list is quite short, there are several compounds and extracts that are currently being evaluated in human clinical trials for regulatory approval. Sativex®, which received FDA fast track designation, has completed Phase 3 clinical testing and an application for approval has been filed at FDA. Another GW Pharmaceuticals product called Epidiolex® received FDA orphan drug status and is currently in mid to late stage clinical testing as a treatment for orphan pediatric epilepsy including Dravet Syndrome and Lennox Gastaut syndrome

Other companies, including Arena Pharmaceuticals, are attempting to develop cannabis-based drugs and mimetics that treat pain by binding to certain types of cannabis receptors found throughout the body (3). Removing cannabis’ psychotropic effects and preserving its pain-relieving benefits is the major objective for this new class of pharmaceuticals.  Although these drugs are still in early stages of development, using them rather than addictive opioids to manage chronic pain would be an important step in combating the US opioid epidemic.

Although the future of cannabis-based pharmaceuticals in the US  is brighter than it has been over the past 50 years, there are still some major hurdles and obstacles that must be overcome. To gain some insight into some of these, please read 2015 testimony to Congress given by Douglas C. Throckmorton, M.D. Deputy Director for Regulatory Programs Center for Drug Evaluation and Research Food and Drug Administration.

Moreover, the approval process for cannabis-based pharmaceuticals has an additional layer of complexity as compared with conventional pharmaceuticals.  Because cannabis and its products are classified as Schedule 1 drugs according to the US Drug Enforcement Agency (DEA), a product that garners FDA approval must also be reviewed by DEA for scheduling recommendations. To that end, FDA usually provides DEA with a scientific and medical evaluation to help with scheduling.  Scheduling classification is important because it affects the controls necessary for prescribing, supplying, or storing the product.  At present cannabis’ Schedule 1 status means that it and any products derived from it have no medicinal value or benefit and consequently are illegal in the US.  Nevertheless, it is extremely likely that any newly approved cannabis-based pharmaceuticals  will be rescheduled as Schedule II or Schedule III drugs as was  FDA’s previous experience with nabilone, dronabinol and Syndros.  That said, permanently removing  cannabis and its products form the Schedule 1 list would  undoubtedly help to speed development and subsequent regulatory approval of potentially life-altering cannabis-based pharmaceuticals.

References

  1. Ladin, DA, Soliman E, Griffin L and Van Dross, R. Preclinical and clinical assessment of cannabinoids as anti-cancer agents. Front Pharmacol. Oct. 2016; 7: 361 DOI: 10.3389/fphar.2016.00361
  2. Fijal, K, Filip M. Clinical/therapeutic approaches for cannabinoid ligands in central and peripheral nervous system diseases: mini review. Clin Neuropharmacol 2016; 39:94-101.
  3. Mintz CS, Fabrizio AJ, Nison E. Cannabis-Derived Pharmaceuticals. J. Comm. Biotechnol. 2015; 21:16-30.

 

Does a Regulatory Pathway for Cannabis-Derived Prescription Pharmaceuticals Exist in the US?

All new prescription drugs introduced to the US market must be evaluated by a “tried and true” regulatory approval process established by the Federal Food, Drug, and Cosmetic (FDC) Act of 1938 (1).  The United States Food and Drug Administration (FDA) is the federal agency that oversees new prescription drug approvals.  Of course, over the years, changes have been made to the approval process to accommodate the scientific, medical and technology advances that have been made in the biotechnology, pharmaceutical and medical devices industries.

While the approval process is somewhat arcane and difficult to navigate at times, the end result is always the same. That is, approved drugs are biochemically uniform, stable, safe and effective.  Further, new drugs must posses a practical and suitable delivery system and be manufactured according to current Good Manufacturing Practices (CGMP; 2)

And, probably surprising to some, the same pathway that is used to approve new pharmaceutical and biotechnology drugs can be used to garner regulatory approval for cannabis-based  prescription drugs.  At present there are several cannabis companies, most notably, GW Pharma, that are using the pathway to get approval for their products.  However, the progress of these approvals has been greatly slowed by the fact that cannabis is federally scheduled as a Schedule 1 drug and is illegal (3). Sadly, this adds another layer of complexity to the federally-mandated regulatory approval process.

To overcome this wrinkle, 27 states including the District of Columbia (DC) have made medical marijuana legal (4).  This means that medical marijuana products sold to the public in states where it is legal do not have to go through the rigorous regulatory approval process to assure drug uniformity, quality, efficacy and safety.  Put simply, there is no regulatory oversight and the quality, safety and effectiveness of medicinal cannabis products cannot be confirmed nor guaranteed.  Ironically, this is the environment that led to the approval of the 1938 Federal Food Drug and Cosmetic Act to ensure that prescription drugs are safe and effective.

The best solution to this conundrum is to reschedule cannabis so that it is no longer illegal at the federal level. This will require medical cannabis companies to follow the new prescription drug regulatory process (that ensures product quality, efficacy and safety) before their products can be sold to US consumers.  While this may increase the time  for medical cannabis products to hit the market, it will guarantee the safety and therapeutic benefits of cannabis products for patients who suffer from diseases that cannot be controlled by conventional prescription drugs.

References 

  1. https://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm Accessed August 24, 2017
  2. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211 Accessed August 24, 2017
  3. https://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm498077.pdf  Accessed August 24, 2017
  4. https://en.wikipedia.org/wiki/Medical_cannabis_in_the_United_States  Accessed August 24, 2017

Editorial: Are Cannabis-derived Pharmaceuticals a Possibility in the US?

Surveys conducted in the 1990s (1) and 2000s (2) found that between 30% and 54% of internists and oncologists were in offering cannabis as a therapeutic option for their patients. Yet, despite this, the willingness of many physicians to prescribe medical cannabis for their patients has been less than enthusiastic. Many physicians are concerned about the legality of making medical cannabis recommendations or writing prescriptions regardless of state laws that make medical cannabis legal (3).

Because cannabis and its products are illegal at the Federal level, many physicians believe that they may find themselves in legal jeopardy even though medical cannabis is legal in the states where they practice medicine.  Further, because medical cannabis has not be test or evaluated like other medicinal products, physicians have little or no scientific data to convince them that anecdotal claims about the there therapeutic benefits of cannabis are true. Finally, physicians make recommendations to patients about specific prescription drugs because they are educated about the safety and efficacy of those products.  In the absence of this vital information, physicians will not write prescriptions.

The existing confusion about the legality/criminality of cannabis-derived products has also had an effect on the behavior of insurers and third party payers. To that point, medical cannabis is not on the formularies of almost all insurers in states where medical cannabis is legal and, because of this, they do not reimburse patients for out-of-pocket medical cannabis costs.  While payers currently do not reimburse patients for the use of medical cannabis, it is possible that insurers may reimburse patients who use US Food and Drug administration (FDA)-approved cannabis products but continue to not reimburse patients who use unapproved medical cannabis treatments. Regardless of the outcome, medical cannabis costs continue to rise and its access and use by patients who might benefit from it may be in jeopardy unless payers place it on their formularies.

Because of the legal patchwork for Cannabis that has evolved over time in the US, it is likely that cannabis-derived pharmaceuticals may only be available in the states that have legalized their use. This would force companies developing cannabis-derived pharmaceuticals to duplicate commercial operations in states where medical cannabis is legal and underwrite multiple product launches in individual states because interstate transport of these products is currently illegal. This would be extremely costly (driving up product price) and also decrease patient access to these products to address unmet medical needs. To that point, most companies developing cannabis-derived pharmaceuticals believe that rescheduling of these products from Schedule I drugs to Schedule 2 or 3 would obviate most of these concerns and allow the US Cannabis market to grow to its full potential.  Alternatively, FDA may reschedule cannabis-derived pharmaceuticals on a case-by-case basis upon approval of individual products.

Finally, because Cannabis-derived pharmaceuticals represent a new class of therapeutics, patient and healthcare provider education will be vital to successfully commercialize these products. Put simply, if physicians don’t understand cannabis-derived pharmaceuticals, and they are not convinced they are safe and effective, then, they are not   going to write prescriptions for their patients. Therefore medical cannabis and cannabis-derived pharmaceutical companies must invest in public outreach activities as well as continuing medical education workshops and courses for healthcare professionals to ensure product success.

Despite all of these challenges, there is growing popular demand for cannabis-derived pharmaceuticals in the US. And, it is likely that inclusion of these products in the American pharmacopoeia will begin to address growing unmet medical needs in the US healthcare system and improve patient access to possibly life-changing therapeutic treatments.

References

  1. Doblin RE, Kleiman MA. Marijuana as antiemetic medicine: a survey of oncologists’ experiences and attitudes. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 1991; 9:1314-1319. 
  2. Charuvastra A, Friedmann PD, Stein MD. Physician attitudes regarding the prescription of medical marijuana. Journal of Addictive Diseases 2005; 24: 87-93.
  3. Bowles DW, O’Bryant CL, Camidge DR, Jimeno A. The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology 2012l; 83:1-10.

Commercializing Cannabis-Derived Pharmaceuticals: Manufacturing, Quality and Healthcare Challenges

While overcoming the legal and regulatory challenges for commercializing cannabis- derived pharmaceuticals is essential, there are a variety of technical, manufacturing and healthcare obstacles that must be addressed before this class of molecules can be successful.

First, substantial financial investment must be made in infrastructure and production facilities to breed and grow different cannabis strains to obtain appropriate chemical compositions and extracts to treat specific therapeutic indications (1). Industry experts contend that this investment must include research on strain construction, cannabinoid concentrations at different stages of plant growth/harvest times and yield improvements. Interestingly, crop failure (not having a redundancy of supply) is a serious issue that all commercial entities in the medical cannabis industry must address and contend with to meet commercial demand.

Second, plant growth (use of insecticides, herbicides etc), extraction processes, and product formulation of cannabis-derived pharmaceuticals must be conducted according to Current Good Manufacturing Practices (CGMP) and rigorous quality standards (1). After all, the primary reason for seeking regulatory approval for these drugs is to demonstrate to patients and healthcare providers that cannabis-derived pharmaceuticals have been thoroughly reviewed, are well characterized and determined to be safe and effective. Implementation of pharmaceutical CGMPs (2) will ensure cannabis-derived pharmaceutical product safety, efficacy and quality over time.

Third, the route of delivery and dosing regimens for cannabis-based pharmaceuticals for specific indications will be vitally important. While smoking/vaporizing cannabis is currently the most obvious method to deliver desired therapeutic effects, it may not be the most effective to maximize its therapeutic benefits for different indications and individual patients (3). Over the past few years, there has been a growing interest in exploring oral, oromucosal, topical and sustained release delivery of cannabis-derived pharmaceutical depending upon the therapeutic indication of interest.

Fourth, efforts must be initiated to get Cannabis-derived pharmaceuticals on the drug formularies of state government insurers and third party insurance companies. At present, medical marijuana costs are usually not reimbursable by conventional health insurance companies (4) and out-of-pocket expenditures can be costly especially for those individuals who suffer from long term, chronic clinical indications like cancer, multiple sclerosis and epilepsy. However, if Cannabis-derived pharmaceuticals are approved by the US Food and Drug Administration (and are rescheduled) it is likely that these drugs will be covered by government and third party healthcare payers (5).

Finally, safeguards must be put into place to ensure protection against misuse, fraud and abuse of Cannabis-derived pharmaceuticals by healthcare providers and patients. The development of novel metered dose devices to deliver these products will help to limit misuse and abuse.

References

  1.  https://daggacouple.co.za/wp-content/uploads/2014/07/Economies_Scale_Production_Cannabis_Oct-22-20131.pdf Accessed July 18, 2017
  2. https://www.fda.gov/food/guidanceregulation/cgmp/  Accessed July 18, 2017
  3. https://www.medicaljane.com/category/cannabis-classroom/consuming-cannabis/   Accessed July 18, 2017
  4. http://www.cheatsheet.com/money-career/why-your-health-insurance-wont-cover-medical-marijuana.html/?a=viewall  Accessed July 18, 2017
  5. http://www.medicalmarijuanainc.com/medical-marijuana-covered-health-insurance/ Accessed July 18, 2017

 

Commercializing Cannabis-Derived Pharmaceuticals: Legal and Regulatory Challenges

The current regulatory and legal landscape for cannabis and cannabis-derived products is extremely difficult and fraught with numerous challenges. For example, in the US, cannabis and products derived from it (including hemp) are federally classified as Schedule I drugs according to the US Controlled Substances Act (1). This means that cannabis and its products have been deemed to have “no currently accepted medical use in treatment in the US” (heroin and LSD are also schedule I drugs), are harmful and consequently, are illegal (2).

Not surprisingly, its Schedule 1 classification has seriously hindered cannabis research in the US and made it extremely challenging for drug companies developing cannabis-derived pharmaceutical products (3). However, over the past decade or so, 29 states including the District of Columbia have enacted legislation that permits some form of cannabis consumption for medical purposes (4). Yet, despite this, cannabis and products derived from it remain illegal at the federal level and during interstate transport (even between states where medical marijuana has been legalized) is illegal and criminally punishable (2).

The confusion regarding cannabis use at the state and federal levels has given rise to two distinct types of companies that are attempting to commercialize cannabis (and products derived from it) for medicinal purposes. The first of these are commonly referred to as medical marijuana or medical cannabis companies. Typically, products from these companies are botanical extracts or actual plant materials derived from specific cannabis strains with anecdotally-reported medicinal properties that can be topically applied, ingested, smoked or vaporized. Patients require a “prescription” (card) from a state-licensed physician to obtain medical marijuana and it can only be used in states that permit consumption of cannabis for medical purposes. It is important to note, that while a prescription is required for medical cannabis use, these products do not require human clinical testing for safety, tolerability and efficacy (like other prescription drugs) prior to their sale in states where medical marijuana is legal.

In contrast with medical marijuana companies, biopharmaceutical companies including GW Pharma, Zynerba, Insys, Kannalife, Aphios and others (Table 1) are committed to developing cannabis-derived pharmaceuticals using conventional US Food and Drug Administration regulatory approval pathways. UK-based GW Pharma is the clear leader in cannabis-derived pharmaceutical space—its flagship product Sativex®, a plant extract, has been approved as a treatment for cancer-related pain and MS spasticity in 27 countries outside the US (5).

While the business case for developing pharmaceutical cannabis-derived pharmaceuticals is a sound one, the time and cost necessary for regulatory approval will be much greater than that for commercializing medical marijuana. At present, the United State Food and Drug Administration (FDA) has signaled a willingness to review new drug applications for cannabis-based pharmaceuticals (6). However, the agency has yet to issue definitive guidance for regulatory approval of these products and to date has not approved any application for cannabis-based products (6). Nevertheless, garnering FDA regulatory approval for cannabis–derived pharmaceuticals may offer several competitive advantages over numerous medical marijuana products that currently dominate the US market.

First, the average cost per patient of Sativex® to treat MS spasticity in countries where it has been approved has been estimated to be roughly $16,000 (6). Several studies indicate  (7, 8) that the high price of Sativex® will make it unlikely to be considered cost effective by regulators in countries with government-mandated national formularies like the UK, Ireland and Australia. However, this should not be an impediment in the US market because the federal government does not set drug prices and third-party payers dictate formulary placement and set drug reimbursement rates.

Second, unlike medical marijuana (which as previously state is a Schedule 1 drug), FDA approved cannabis-based pharmaceuticals like dronabinol and nabilone have been classified or reclassified as Schedule 2 (opioids) or Schedule 3 (codeine) drugs (5, 9). Federal regulators are likely to apply the same scheduling criteria to the next generation of FDA-approved cannabis-derived pharmaceuticals like Sativex® and others. Rescheduling will effectively allow these products to compete with medical marijuana because unlike medical marijuana—which is legal in only 29 states and cannot be transported across state borders—approved cannabis-derived pharmaceuticals can be legally prescribed, sold and used in all 50 states and US territories.

Finally, and perhaps most importantly, physicians may be inclined to prescribe FDA-approved cannabis drugs as compared with medical marijuana because they have been evaluated in human clinical trials and officially deemed to be safe and effective treatments for specific therapeutic indications.. In marked contrast, medical marijuana can be prescribed and sold in states where it is legal without going through any formal drug review process. While this is unlikely to interfere with possible therapeutic benefits offered by medical cannabis questions concerning product safety, effectiveness and reproducibility about these products are likely to continue to  arise until industry best practices are implemented and standardized.

References

  1. https://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm  Accessed July 17, 2017
  2. https://www.dea.gov/druginfo/ds.shtml  Accessed July 17, 2017
  3. https://www.brookings.edu/wp-content/uploads/2016/06/Ending-the-US-governments-war-on-medical-marijuana-research.pdf  Accessed July 17, 2017
  4. http://medicalmarijuana.procon.org/view.resource.php?resourceID=000881 Accessed July 17, 2017
  5. https://www.gwpharm.com/products-pipeline/sativex  Accessed July 17, 2017
  6. https://www.fda.gov/newsevents/publichealthfocus/ucm421163.htm  Accessed July 17, 2017
  7. Pharmacoeconomic NCF. Cost-effectiveness of Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®) as add-on treatment, for symptom improvement in patients with moderate to severe spasticity due to MS who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. 2014. http://www.ncpe.ie/wp-content/uploads/2013/01/Summary-v1.pdf.
  8. Lu L, Pearce H, Roome C, Shearer J, Lang IA, Stein K. Cost effectiveness of oromucosal cannabis-based medicine (Sativex(R)) for spasticity in multiple sclerosis. PharmacoEconomics. Dec 1 2012;30(12):1157-1171.
  9. https://www.deadiversion.usdoj.gov/fed_regs/rules/1998/fr1105.htm  Accessed July 17, 2017

Is Cannabidiol (CBD) An Effective Treatment for Epilepsy?

Stories of the ability of Cannabis  to alleviate seizures have been around for about 150 years (1).  Early randomized, placebo-controlled clinical studies conducted between 1978-1990 involving 48 patients with epilepsy found that daily treatment with 200-300 mg of cannabidiol (CBD) for up to 4 months was safe and well tolerated (2). However the small number of patients and short trial duration were not sufficient to draw any conclusions about CBD’s efficacy (1, 2)

Over the past decade, there have been reports that cannabis extracts with high concentrations of CBD may be effective anticonvulsants for children suffering from severe forms of uncontrollable epilepsy known as Dravet Syndrome and Lennox-Gastaut Syndrome (1, 3).  At present there are 9 ongoing or completed US clinical trials that evaluated the effects of CBD on epilepsy, treatment-resistant epilepsy, Dravet Syndrome (DS) and Lennox Gastaut Syndrome (LGS)

A Table that lists the ongoing clinical trials that are evaluating CBD as a treatment for epilepsy, DS, LGS and treatment-resistant forms of epilepsy can be found here.

Industry leaders in this field include GW Pharma and a relatively new entrant called INSYS Therapeutics Inc.  Of interest, in 2014, GW pharma’s Epidiolex, a liquid formulation of highly purified Cannabis-derived CBD was granted Orphan Drug Designation by the US  Food and Drug Administration (FDA ) as a treatment for Dravet and Lennox-Gastaut syndromes and other pediatric epilepsy syndromes.

More recently, a Phase 3, double blind, placebo-controlled study conducted with 120 children and young adults with Dravet syndrome and drug resistant seizures revealed that treatment with CBD (20 mg per kilogram of body weight) per day reduced the median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (4).  Further, the percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with CBD and 27% with placebo (4). The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (4).

Finally, adverse events that occurred more frequently in the CBD group as compared with the placebo group included diarrhea, vomiting, fatigue, sleepiness and abnormal liver function test results (4).

Similar results were observed in a randomized, double-blind, placebo-controlled trial CBD clinical trial conducted with 156 patients with Lennox-Gastaut Syndrome (5).

The results from these studies suggest that highly purified preparations of CBD may be effective in controlling patients who suffer from DS, LGS and other treatment resistant forms of epilepsy.  However, additional studies must be conducted with CBD with the goal of reducing the high frequency of adverse events associated with long term CBD treatment.

References

  1. Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia 2014; 55:783-786.
  2. Gloss D, Vickrey B. Cannabinoids for epilepsy. The Cochrane Database of Systematic Reviews 2014; 3:1-23
  3. Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia .2014: 55:787-790.
  4. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L et al. Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome. N Engl J Med 2017; 376:2011-2020
  5. Thiele, EA, Mazurkewicz-Beldzinska M, Denbadis, S, Marsh et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut Syndrome (LGS): Results of a multi-center, randomized double-blind placebo-controlled Trial (GWPCARE4) American Epilepsy Society Annual Meeting. 2016. ( 1423_AES_Poster_LGS_)