Biosynthesis Platform for Pharmaceutical-Grade Cannabinoids

InMed is developing a biosynthesis platform to manufacture pharmaceutical-grade, cost-effective cannabinoids. Plant extraction is not feasible to meet long-term pharmaceutical demand of cannabinoid therapeutics, particularly rare cannabinoids.

Alternative methods needed to manufacture cost-effective, pharmaceutical-grade cannabinoids

Manufacturing pharmaceutical-grade cannabinoids remains a challenge, especially for those that are found in only trace amounts in the cannabis plant. The more than 100 rare cannabinoids may hold very important medical benefits, but they make up, in total, less than 1% of the plant, making them economically impractical to extract and purify for pharmaceutical use. To provide a reliable source of pure, competitively priced, pharmaceutical-grade cannabinoids that are bio-identical to the compounds found in nature, alternative methods from plant extraction need to be developed.

Biosynthesis and chemical synthesis are two different approaches to synthetic manufacturing of cannabinoids. Both approaches have the same goal, which is to produce high-purity cannabinoids in a cost-effective manner. Either synthetic process may provide a reliable, consistent, scalable and compliant process versus the variability and complexity associated with the extraction and purification of the rare cannabinoids from the plant.

InMed’s biosynthesis approach a potentially disruptive technology

InMed is developing a proprietary, robust, microbial-based biosynthesis process for producing selected rare cannabinoids in a cost-effective manner for use in pharmaceutical products. The cannabinoids produced from our process are bio-identical to the naturally occurring cannabinoids in the cannabis plant. Our process is designed to offer superior yield, control, consistency and quality of rare cannabinoids when compared to alternative methods.

Through InMed’s R&D activities, we have identified two manufacturing approaches demonstrating the potential to produce cannabinoids to meet the long-term commercial requirements of our drug products and potentially to supply other pharmaceutical companies. In the current and rapidly emerging cannabinoid pharmaceutical sector, InMed’s biosynthesis approaches to produce pharmaceutical-grade and bio-identical cannabinoids are potentially disruptive.

There are several key advantages of manufacturing cannabinoids through a biosynthetic process:

  • Access to minor cannabinoids that are currently not economically feasible to extract from plant sources and develop into drug candidates;
  • Cost-saving relative to the existing agricultural methods (plant-grow-harvest-extract-purify);
  • Increased yield of the rare cannabinoid(s) with optimized fermentation, purification, consistency and quality control
  • Scalable process to allow efficient and cost-effective supply as market demand increases; and,
  • Process produces bio-identical cannabinoids to those found in nature.
Biosynthetic approaches provide long-term sustainable option

While cannabinoids may hold medically-important properties to treat a number of diseases, the current traditional method to obtain cannabinoids – grow, harvest, extract and purify – is not feasible for long-term pharmaceutical demand. The costs associated with the large carbon footprint of greenhouses or exterior fields combined with the security requirements, use of pesticides, fertilizers and variability in growth and expression of the target compound at a highly consistent level in the plant make the biosynthetic approach a more economically sound and socially responsible strategy, from our perspective. A key goal is to produce cannabinoids identical to those produced naturally in the plant.

Biosynthesis is used in manufacturing many pharmaceuticals, such as insulin

Biosynthesis is the process of genetically modifying an organism to produce a compound that it otherwise would not normally make. Currently, biosynthesis processes are used in multiple industrial applications, including use of bacteria or yeast-based systems for the production of pharmaceutical products, including human insulin, vitamins and antibiotics.

How InMed’s biosynthesis technology works

Microorganisms do not naturally produce cannabinoids. However, utilizing genome engineering to modify their metabolism, InMed has systematically introduced the cannabis plant’s metabolic pathways into bacteria, and has developed what it believes to be the first-of-its-kind production of downstream cannabinoids in these hosts.

InMed has identified the specific gene sequences from the cannabis plant that encode the instructions to make specific enzymes that enable cannabinoid assembly and subsequently transfer these genes into the bacterium E. coli. This intervention converts the bacterium into a manufacturing engine that produces large quantities of the target compound on demand.

This development provides an opportunity for industrial-scale manufacturing of naturally occurring cannabinoids, and we believe that this will offer a significant improvement over existing manufacturing platforms such as direct extraction from cannabis plants.

Direct extraction of minor/rare cannabinoids is quite cumbersome, time-consuming and low yielding. The use of microorganisms for manufacturing cannabinoids eliminates the process of planting, growing, harvesting, extracting and purifying. There are also economic and environmental savings such as substantially reduced resource requirements (water, electricity, manpower, large volume of solvents etc.). Furthermore, the growing/harvest process has several hard-to-remove impurities (e.g., pesticides), potentially presenting significant safety issues. As with all crops, yield fluctuations present an additional risk. Only a few of the 100+ cannabinoids can be extracted from the plant in sufficient quantities to make that process economically viable.

Biosynthesis of cannabinoids

Cannabinoids are prenylated polyketides that are derived from fatty acid and terpenoid precursors. The biosynthesis of these molecules involves four metabolic pathways, two of which originate from central carbon metabolism. The first pathway (“terpenoid pathway”) culminates with the synthesis of geranyl pyrophosphate (“GPP”), and neryl pyrophosphate (“NPP”). These molecules are terpenoid building blocks, or precursors.

The second cannabinoid biosynthetic pathway, the “polyketide pathway”, is a truncated version of a polyketide biosynthetic pathway and results in the second requisite precursor, either: olivetolic acid (“OA”) and/or divarinic acid (“DVA”). The polyketide precursors subsequently combine with the terpenoid precursors in the third pathway, which comprises a single, specialized gateway enzyme, to yield the gateway cannabinoids. For instance, OA combines with GPP to yield the gateway cannabinoid cannabigerolic acid (“CBGA”).

Synthesis of the gateway cannabinoid CBGA is the most prevalent pathway in the cannabis plant, leading to numerous cannabinoids including high levels of both THC and CBD. InMed’s technology can mimic the natural synthesis of cannabinoids using an E. coli fermentation process.

The gateway cannabinoids are subsequently modified in the fourth pathway to yield cannabinoids such as tetrahydrocannabinolic acid (“THCA”) and cannabidiolic acid (“CBDA”). We refer to this fourth pathway as the downstream pathway and it involves the transformation of the acid form of the cannabinoids into the non-acid form via enzymes called “synthases”. Other combinations of the various precursors result in different gateway cannabinoids which, in turn, leads to diversification into the 100+ cannabinoids.

InMed’s proprietary validated biosynthetic pathway is more productive than terpenoid pathways

We have successfully constructed the terpenoid biosynthetic pathway and the gateway pathway for synthesis of CBGA and the downstream pathways for synthesis of THCA and CBDA. Our proprietary pathway is significantly more productive than previously patented terpenoid pathways, and we have confirmed the biosynthesis of the cannabinoids using validated HPLC methodologies and 1H-NMR instrumentation.

We have constructed a series of E. coli strains that express variations and/or subsets of the entire biosynthetic pathway and have tested production in lab-scale fermentation tanks. Next steps in the biosynthesis program are to:

  • Continue efforts to further diversify the number of cannabinoids produced using InMed’s system
  • Scale-up the biosynthesis process to larger vessels, where protocols will be developed to optimize manufacturing parameters to increase production yield
  • Develop a down-stream purification process with CDMOs to isolate selected cannabinoid with high purity

Options for InMed’s Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP) product manufacturing include either (1) building a dedicated biosynthesis facility or (2) transferring our process/know-how to a contract manufacturing organization with existing infrastructure to produce for us the preclinical, clinical and commercial scale supply of our product candidates.

In addition to providing a source of raw materials (active pharmaceutical ingredients, or “API”) for InMed’s therapeutic products, our biosynthesis program may play a significant role as a source of raw materials to other pharmaceutical companies, as well to a number of other industries outside of the pharmaceutical segment (e.g. cosmetics, nutraceuticals, etc.).

The role of THC and CBD continues to expand at an exceptional rate in the recreational, nutraceutical and medical spaces, where biosynthesis may prove to be an economical alternative to plant-sourced products. According to an October 2016 report issued by the Hemp Business Journal, the total consumer market for CBD alone is expected to surpass $2.1 billion by 2020, up from only $90 million in 2015. Estimates for the medical use of marijuana (delivering THC and CBD from the plant via smoking) have been estimated to be $12 billion in 2016 by Visiongain Ltd. and is expected to surpass $55 billion by 2025, according to a 2017 report by Grandview Research, Inc.