Renaissance of interest in medicines modulating ECS: Rising to the challenge

Steve McConchie, CEO at Aptus Clinical shares his analysis on cannabinoid medicines, with Andy Yates of Artelo Biosciences, in Pharmafile.

The body’s endocannabinoid system (ECS) consists of receptors and chemical messengers located in the central and peripheral nervous system, forming a biochemical communication network throughout the body that regulates a variety of physiological and cognitive processes.

Drugs that modify the activity of endocannabinoids such as cannabinoid receptor agonists and antagonists, agents modifying cannabinoid transport, or those inhibiting their biosynthesis/metabolism have the capacity to treat neurodegenerative, cardiovascular and inflammatory disorders, obesity/metabolic syndrome, cachexia and chemotherapy-induced nausea, and vomiting. In pain management, cannabinoid receptor activation or endocannabinoid upregulation has the potential to overcome opioid addiction by providing a less-addictive substitute drug, with fewer side effects, for chronic pain.
ECS modulation, largely targeting the primary receptors, CB1 and CB2, has been accomplished through three broad treatment approaches: naturally occurring plant-derived chemicals (cannabinoids), small molecules that target the receptors of the ECS (synthetic cannabinoids), and endocannabinoid modulators that seek to regulate endocannabinoids, the cannabinoids produced in the body.

Overview of cannabinoid medicines
Of the common types of cannabinoids found naturally in the cannabis sativa plant, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have primarily been investigated. These have demonstrated broad efficacy and have complimentary and differing mechanisms of action.

While this research activity is welcomed and some emerging products are being researched and manufactured to a high standard, some products are entering the market with poor scientific evidence for efficacy and safety. For example, over-the-counter food supplements tend to have limited oversight and their relative efficacy is often difficult to interpret because of differences in product composition, dose, and administration regimes. Some countries, including the UK, have rescheduled cannabis-based medicinal products (CBMPs) to allow their use in limited circumstances. Thus, herbal cannabis mixtures and isolated cannabinoid preparations can potentially be prescribed as special medicines in these markets, despite not having undergone a formal licensing process.

Some manufacturers of the isolated cannabinoids have chosen to develop their products to pharmaceutical grade. These follow a classical regulatory development pathway, with in-depth review and, ultimately, approval.

Cannabinoid products

Several companies are currently engaged in such development programmes, and four compounds have so far been approved as licensed treatments by either European or US regulators:
1. Sativex (nabiximols): extracted from the cannabis sativa plant, Sativex is formulated as an oromucosal spray for the treatment of multiple sclerosis (MS)-related spasticity and cancer-related pain
2. Nabilone: a synthetic cannabinoid that mimics THC. It has therapeutic use as an antiemetic and adjunct analgesic for neuropathic pain − it is licensed for chemotherapy-induced nausea and vomiting
3. Dronabinol: a bioidentical synthetic version of THC. Dronabinol is licensed for chemotherapy-induced nausea and vomiting, and anorexia associated with HIV
4. Epidiolex (CBD): a proprietary oral solution of highly purified plant-derived CBD. It is approved for two severe, orphan, early-onset, treatment-resistant epilepsy syndromes
None of these compounds have so far generated significant sales by pharmaceutical standards, partly because the support shown by the general public for them is not fully shared by the medical profession, regulatory, and payer bodies. This is largely driven by small data sets, lack of clinical experience, and cost-effectiveness arguments − a picture replicated across global markets. Cannabis is not part of typical treatment regimes, training on its use is not mainstream, and opportunities for direct experience is limited by so few approved drugs, which helps explain the reluctance to embrace this new health innovation.

Regulators have also created barriers to enter the pharma market. Sativex, for example, is not approved in the US, and although approved for use in the UK, it was only recently endorsed on 19 November by
the National Institute for Health and Care Excellence (NICE), the government body that provides national guidance. Epidiolex is selling well in the US, but was similarly rejected on first round by NICE, although
it has subsequently been approved. Dronabinol and nabilone have generated reasonable sales, but they are not supported by a significant package of clinical trial, quality of life, or real-world evidence data,
which may inhibit broader use. In development

The number of cannabis-based drug candidates entering Phase 1-3 development is increasing. Of these, Arena Pharmaceuticals and Corbus Therapeutics
are developing synthetic cannabinoids, while endocannabinoid modulators are being evaluated by Janssen and Pfizer. Zynerba Pharmaceuticals and GW Pharmaceuticals are developing naturally occurring
cannabinoids. Artelo Biosciences is the only company that is currently developing a diverse portfolio of drug candidates in each of the three therapeutic approaches, designed to target cannabinoid receptors
and inhibit endocannabinoid transport. Artelo Biosciences’ pipeline includes a high-potency G protein-coupled CB1 and CB2 receptor agonist (anorexia in cancer), a proprietary cocrystal of CBD (post-traumatic
stress disorder, inflammatory bowel disease, stroke, rare diseases), and a fatty acid-binding protein-5 inhibitor (cancer, inflammation, and pain).

Variation in global markets

The extent to which markets permit the medical use of cannabis or cannabinoids largely depends on their legal and regulatory instruments. Cannabis and CBD are readily available in parts of the world, sometimes legally and sometimes not, and can be obtained with or without a prescription. Some apply frameworks such as expanded-use or exceptional use access programmes to allow patients to be treated with specific preparations while also protecting against illicit drug use. North America was the first region to launch access schemes, and other countries, such as the Netherlands, Germany, and Israel, are among those
most advanced in their advocacy of, and legislation for, medical use cannabis.

Over thirty countries have so far implemented some form of regulatory change in this field over the past decade, and WHO has proposed that cannabis should be rescheduled within international law because of growing evidence of its medicinal applications. Nevertheless, despite this movement, differences in adoption rates and highly variable regulatory structures have created a unique medical, commercial, and legal conundrum for pharma developers trying to navigate these complexities across global markets.

Challenges in cannabinoid development

Perhaps surprisingly, scientists still know very little about how cannabinoids are absorbed and metabolised in the body, which is fundamental to establishing different indications. This is further complicated by whether a single chemical entity, a combination of products, or an extract from a plant containing potentially hundreds of compounds. Legal and regulatory restrictions to guard against illicit use have historically prevented mainstream science and pharma industry research for decades. Attempts by several governments to relax these regulations have led to a renaissance among high-quality growers/manufactures, pharma, and biotechnology companies who recognise the therapeutic potential of cannabis-based medicines to treat a range of conditions and are keen to invest in their development.

Regulatory
Perhaps the most significant challenge concerns the legal classification that cannabinoids fall under. This is especially true in countries where they are categorised as requiring the highest level of control.
These ‘Schedule 1’ controlled drugs require licences to possess, supply, and manufacture, resulting in excessively stringent patient recruitment criteria and severe restrictions placed on manufacture,
supply, and pre-clinical and clinical evaluation. Development becomes time consuming, expensive, and logistically difficult for manufacturers who do not hold the required controlled substance licence.

Even in markets where cannabis-based medicines have been reclassified as ‘Schedule 2’, as in the UK following a legislative change in November 2018, there remain some very significant barriers. The decision to allow CBMPs to be legally prescribed in the UK by a specialist doctor in limited circumstances was taken extremely quickly. As a consequence, the market is still largely unprepared and immature, with poor institutional penetration, variable quality standards, and subject to a regulatory and payer framework that was designed for traditional treatments.

In conventional drug development, research efforts by industry are motivated by the assurance that their clinical assets will be protected by intellectual property (IP), data exclusivity, or orphan disease designation. Typical IP protections do not apply to phytocannabinoids, where products are formed from common plant or flower extracts or encapsulated isolates, which creates a bias towards orphan indications to maximise market exclusivity periods. Therefore, regulatory reform is required if we are to build a stronger evidence base to guide clinical decision making. Otherwise, manufacturers will continue to have little incentive to fund robust Phase 1-3 clinical development programmes, clinicians will continue to feel ill-informed and unprotected by legislation that is widely open to interpretation, and patients will continue to be deprived of
potential benefit.

Given the prospect of costly protracted recruitment, regulatory uncertainty, and little realistic chance of a return on investment in the short term, it is perhaps unsurprising that governments are expressing an interest in finding optimal ways to facilitate regulatory changes to encourage R&D.

Prescribing
Another area that requires consideration is the prescribing pathway for non-licensed cannabis-based products. For example, in the UK, while these products have been rescheduled, they can only be prescribed
by a very narrow sector of specialist clinicians. By restricting prescribing to such a small number of difficult-to-access specialists, most patients fail to obtain legitimate prescriptions. A further restriction
on prescribing is placed by both medical professional bodies and payer structures, of which both continue to express scepticism due to a lack of data. This is not such a problem in private pay markets or where
CBMP are reimbursed by insurance or national schemes.

Addressing the challenges
Although there has been a shift in the willingness by hospitals and academic institutions to engage in clinical research in this field, there remains a reliance on industry to fund classic Phase 1-3 trials,
either using molecules protected by IP or in developing rare diseases that afford protection. The barriers discussed above must be removed if pharma companies are to be persuaded to invest more broadly
in this field, especially as many of the indications where CBMPs show promise are in low growth areas. Easing restrictions on trial protocols would be a potential means of increasing patient access to cannabis based medicines. To satisfy regulators, companies are currently often forced to design trial protocols that exclude prior illicit use of cannabis, even though this renders significant patient numbers ineligible.

One potential solution would be for companies to develop simple CBMPs without solid IP protection that is ‘development light’. This approach requires a company to initiate a range of specific investigator led
studies, including pharmacokinetic and pharmacodynamic studies, drug-drug interaction testing and chemistry, manufacturing, and control quality assurance. These, together with a wide-ranging real world
evidence study programme, could support a more regulated use or even approval of cannabinoids and avoid many of the risks and costs to pharma companies of the traditional phased-research approach.

Regulators also need to address the legislative restrictions imposed on researchers if we are to gain a detailed understanding of the mechanisms, absorption, and metabolism of cannabinoids, and make informed
decisions on their dosing and indications. The lack of reliable data in this area means that some clinical trials may fail not because cannabinoids do not help, but because the dosage or indication was inappropriate. While the appetite for deregulating and lowering controls for plant-derived cannabinoids should be regarded as a positive, the tightening of restrictions on previously non-controlled synthetic cannabinoids
and modulators of the ECS (i.e., the New Psychoactive Substances Act in the UK) has made research in this area more difficult, particularly in the pre-clinical phase of research into CB1-activating compounds.

As many licensed cannabinoid medicines have faced challenges in achieving regulatory and payer acceptance, much more focus should be spent by companies on their regulatory and cost-effectiveness strategy at an earlier stage of development to ensure the data package is robust in these areas.

R&D in cannabinoid medicines is a more complex and challenging area than some more conventional targets, and there are advantages to be gained by working with companies and organisations in legal jurisdictions that have successfully worked with cannabinoid medicines previously as they will have encountered and overcome many of the additional hurdles that will be faced.

Future prospects
Investigation of the use of cannabis based medicines in a diverse range of indications continues, and it is likely that over the next 5-10 years, improvements in patient outcomes and quality of life will be demonstrated across a spectrum of diseases. Now that some laws are changing around the globe for cannabinoid medicines, it is important that stakeholders are given the opportunity to help shape the design and implementation of new regulatory systems, which overcomes the current challenges and are able to deliver on what could be a transformation in the care of patients with chronic conditions. It is important that as countries look to incorporate these new medical approaches into their regulatory systems, they learn from the experiences of those countries that are already well established. Many of the changes to legislation have followed high-profile public action groups seeking referenda and patient-centred media campaigns. While these have been instrumental in eliciting change, a consequence has been widespread confusion and misinformation, which has created unrealistic expectations among the public for what products are available and their likely clinical benefit. A lack of good information from trusted sources, limited knowledge, and poor awareness of trial results among clinicians, restrictive local policies, and prescribing guidelines disempowering general physicians and pharmacists have all contributed to a state of confusion in many countries.

As new research results are being released on a monthly basis and the field of study is expanding, there is a clear ongoing need for these data to be interpreted for clinicians. Interested groups, such as the
Committee for Medicinal Cannabis in the UK, have already committed to closely examining this growing evidence base and reporting promptly on its implications. It should be remembered that while plant-based cannabis-based medicinal compounds will undoubtedly find increasing usage and acceptance within healthcare systems, it will still be the mainstay of ‘business-as-usual’ pharma development of novel  cannabinoids and novel formulations of cannabinoids that are likely to provide access to these drugs for the majority of patients through conventional regulatory approval in major markets. It is incumbent on trial sponsors and ethics committees to ensure good quality clinical research is conducted to help provide certainty on how these medicines react in healthy and diseased bodies.

In particular, detailed research on the biological actions and transportation within the body of cannabis compounds, as well as the effectiveness of different delivery avenues and dose-response curves in
diverse populations, are urgently required to help understand the complex biochemistry of cannabinoids.

An expanded, high-quality pool of clinical evidence in a range of indications will enable national and international guidelines to be developed that would provide certainty and reassurance to the medical community. Several countries are now recognising the need to make funds available to accelerate this purpose, and in the UK, the government has sought to help satisfy regulatory decision makers, clinicians, and clinical commissioning groups who procure services by undertaking an expedited review of the clinical evidence and promptly develop detailed national guidance.

Read this article in Pharmafile here: https://edition.pagesuite-professional.co.uk/html5/reader/production/default.aspx?pubname=&pubid=ae30e764-f51e-4e4c-822a-f41c938499ae

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