Proposed Implementation
Introduction
Here at Symemco Therapeutics we have researched the logistics of implementing our project beyond iGEM. We have considered our proposed end users and our potential first customer, other applications of our project and additional potential revenue sources. In addition we explored the patenting and licensing agreements that needed to bring a new drug to the market, and how we could scale up production from what we are currently doing in the lab. Finally, we analysed a range of risks and challenges encompassing our project and implementing it after the competition. This research laid a foundation to our entrepreneurial vision, which can be found on our entrepreneurship page.
Proposed End Users
We have grouped our proposed end users into the following groups:
In the UK, there were 128,400 people with mild dementia and 236,900 people with moderate dementia in 2020, and the total number of people with dementia (mild, moderate and severe) is estimated to reach 1 million by 2025 (Wittenberg et al., 2019). According to the World Health Organisation (2021), Alzheimer’s disease is the most prevalent form of dementia and is estimated to account for approximately 60 to 70% of dementia cases. Pterostilbene has been shown to inhibit ATP hydrolysis in the NLRP3/caspase-1 neuroinflammatory pathway found in mild to moderate cases of AD in preclinical trials (Li Q et al., 2018), (Wang et al., 2020), thus patients diagnosed at mild to moderate AD will be our first potential proposed end users.
Most cases of AD are late onset and the prevalence of AD increases as age increases. According to the National Institute of Ageing (2019), after the age of 65 the number of people with Alzheimer's doubles every 5 years and over the age of 85 around a third of people are thought to have AD. Therefore the age range our product will initially be targeted towards is 65 years and over.
In the initial stages, we intend to roll out our Alzheimer’s therapeutic within the UK where Symemco Therapeutics is based, and where we envision our product to create the largest impact more near term. In the UK, the National Health Service (NHS) is the largest provider of healthcare and it is a publicly funded system of Trusts that span the whole of the UK providing healthcare based on need, not a patient's ability to pay. Therefore, we aim to make our drug accessible to the NHS so it can be provided to AD patients receiving public healthcare treatment. This involves market authorisation from both the MHRA and European Medicines Agency (ESA) then further health technology appraisal through NICE where the clinical effectiveness of the drug is assessed alongside the proposed cost of the drug (The King’s Fund, 2020).
Other Users
The doctors within the NHS and other private healthcare providers are key decision makers in prescribing our drug to their patients.
There is proven need for treatments for age related diseases outlined in the NHS long term plan (2019). Chapter 2 of the plan states that more NHS action is required on prevention and health inequalities due to the growing and ageing population, increasing the number of people needing NHS care and the intensity of care they require. Additionally, the same source contains a section with regards to supporting people living in care homes, aiming to reduce the number of emergency admissions to hospital by improving the level of care and meeting needs that are not currently being met.
By supplying clinicians with our therapeutic, they can prescribe a drug knowing this meets the criteria summarised in the NHS Long Term Plan 2019. Clinicians that work in the private healthcare sector are also regulated by the Care Quality Commission (CQC), exactly the same as the NHS, meaning they will have to meet the same standards of care offered on the NHS, thus by meeting the expectations of the regulatory bodies needed to sell our drug to the NHS we will also be able to branch out to private healthcare providers.
Larger companies that are suppliers of Alzheimer's therapeutics are a potential user that would supply our therapeutic to healthcare providers.
Eisai Ltd, is a current supplier of some AD therapeutics including a donepezil tablet called Aricept 5mg tablets. As a larger company who is already selling to the NHS as a reputable supplier, there is a possibility for Symemco Therapeutics to form a partnership with Eisai Ltd to ensure the distribution of our drug to relevant healthcare providers. Strategic partnerships with large pharmaceutical companies can also provide us with the alliance needed to further develop research and development and assist with late-stage commercialisation costs (Brown, 2021).
Within the UK there are many Alzheimer’s charities, including Alzheimer’s Research UK, Alzheimer's Society and Age UK. These charities are involved in funding research, providing support to patients, caregivers and families and raising awareness surrounding AD.
Alzheimer’s Research UK is responsible for funding 491 researchers in 2021, investing more than £171 million into projects from 1998 (Alzheimer’s Research UK, 2021). Forming a partnership with this charity could provide funding for the next stages of our treatment and continued research into the field of Alzheimer’s, aligning with our goals to turn our research into a therapeutic drug.
Additionally, charities such as Age UK and Alzheimer's Society have a strong relationship with patients and carers, offering a range of emotional and financial support. These charities have extensive knowledge of the needs of patients and carers. Partnering with charities like those previously mentioned allows us to develop our product to caregivers and patients unique needs, therefore making our product more accessible to our end users.
First Potential Customers
Our initial focus is to successfully complete clinical trials in order to build partnerships with healthcare providers and hospitals in the UK. After these stages we intend to market our novel AD therapeutic to our first potential customers. Following our TAM, SAM and SOM analysis and investigations into potential end users, we have identified that the first potential customers of our pterostilbene based AD therapeutic from Symemco Therapeutics will be patients diagnosed with mild to moderate AD, aged 65 years old and above, within the UK, specifically targeting age related disease specialised facilities in and around the London area, local to where Symemco Therapeutic is based.
Value Propositions:
After addressing our proposed end users, we decided to outline what we intend to deliver to our range of stakeholders through value propositions. These are outlined in Figure 1 below.
More details regarding our potential customers and value propositions can be found in the market segmentation section of our business plan found on our entrepreneurship page.
Additional Applications
Potential use of E. coli as additional revenue stream:
Alongside selling our therapeutic to various healthcare providers, there is the potential to sell our patented biosynthesis pathway of pterostilbene in E. coli, for companies to develop for their own needs. For example, by changing certain aspects of the pathway, other pterostilbene derivatives or compounds present in the pathway can be obtained and used to treat a range of other diseases. This is advantageous to the therapeutics industry because its use and further modification will contribute to drug development research. If new therapies can be produced by our modified E. coli, they will add to the range of therapeutics on the market used to treat Alzhiemer’s disease and/or other diseases. This potential for additional therapeutic development leads to addressing the range of unmet medical needs that exist. Not only is selling our biosynthesis pathway beneficial to different disease markets and meeting unmet medical needs, but also has the potential to act as a revenue stream during our drug development process. The revenue generated can contribute to our research and development through licensing agreements with companies surrounding our patented E. coli.
Pterostilbene Applications
In literature, pterostilbene has been used as treatment in vivo and in vitro for various diseases including, but not limited to: dementias, cardiovascular diseases and cancer (McCormack and McFadden, 2013). We are currently investigating the anti-inflammatory application of pterostilbene in Alzheimer's disease, and we plan to explore the use of pterostilbene in other neurodegenerative diseases in the future. In particular, we have considered the use of pterostilbene in the treatment of Parkinson’s Disease, which has been reviewed in literature, and results suggest there is potential for the polyphenol to have neuroprotective effects (Arbo, 2020). Additionally, as pterostilbene has been shown to be a potent neuromodulator in improving cognitive function, (Chang et al., 2012) another potential application includes symptomatic treatment for diseases associated with cognitive decline, including other dementias, not just AD.
Studies on the use of pterostilbene in the treatment of cardiovascular disease have shown that pterostilbene has antioxidant properties which can prevent ischaemic cell apoptosis (McCormack and McFadden, 2013). These same antioxidant properties have been shown to inhibit breast cancer in vitro and in vivo by altering cellular oxidative activity, a process which is thought to play a role in cell death (McCormack and McFadden, 2013).
The multiple potential applications of pterostilbene in the treatment of a range of diseases provides a wide avenue of application options beyond our initial scope of AD treatment, all with the potential to address current unmet medical needs.
Long Term Implementations
Production of Pterostilbene in the Long Term
When considering the long term implementation of Symemco Therapeutics, there are aspects of our current project we have to adapt to accommodate the scaling, of which we have split into the following 3 sections.
Once we have concluded the current stage of our project, we expect to determine the bioavailability and blood-brain-barrier permeability of pterostilbene in humans. This ensures we can determine early on in the drug development pipeline more precise data to back up what our foundational research has suggested before moving onto pre-clinical trials and clinical trials.
Future tests we intend to carry out in the development of our therapeutic include in vitro experiments that look into the difference in the formation of the NLRP3 inflammasome complex in microglia, in the presence and absence of our pterostilbene produced from our E. coli. This experiment aims to confirm the literature used in the development of our project and validate the use of pterostilbene as a therapeutic for AD. Another aspect we intend to test is the therapeutic efficiency of pterostilbene. This will be executed using a BV-2 cell line and ELISA assay to show the therapeutic effect of pterostilbene on microglial interleukin secretion in IL-B and IL-18 on NLRP3/caspase-1 pathway. Results from this will be used to justify clinical trials and provide more details in regards to how we will treat AD.
We also intend to explore the challenge of specificity raised by Dr Joao Amorim, using either lipid nanoparticles or liposomes to transport our pterostilbene directly to microglia in the brain to avoid unwanted interactions with other parts of the body that are therapeutic is not intended to target. However, in a meeting with Dr. Ana-Rodriguez Mateos, whose work focuses on polyphenols and their cardiovascular health benefits, we discussed pterostilbene benefits outside of our target of AD and she suggested this was not something we necessarily needed to change as additional benefits could in turn help with our target. More details regarding these discussions can be found on our human practices page. Subsequently, we intend to thoroughly research whether we should aim to make pterostilbene more specific or not by contacting further researchers and developing protocols for our own experiments and modelling to investigate how the off target benefits could potentially enhance our therapeutic.
Alongside the development of the pterostilbene therapeutic we also intend to carry out investigations into a range of routes of administration to suit as many customers as possible, this is inline with our company values of accessibility. So far we have evaluated the current methods of delivery and future considerations include ensuring we thoroughly research the regulatory body approval for drugs in prospective countries we aspire to roll out our therapeutic to, so that we can make our therapeutic available to the global market.
Implementing our therapeutic into the AD market will involve upscaling our manufacturing process. This involves forming partnerships with distributors and suppliers, and potentially acquiring our own space and employing a larger team to manufacture the pterostilbene suitable for the market.
Currently, the costs of components for our laboratory work have been obtained from Sigma Aldrich, a global, reputable supplier of services and solutions for the life science sector. As we require more components and a sustainable supply chain we aim to form partnerships with suppliers such as Sigma Aldrich with the hope to reduce our initial materials cost, especially through ordering in larger quantities. Further down the line we intend to form partnerships with global suppliers and distributors to assist in delivery of our therapeutic to the global market, some of these companies include Eisai ltd and Sigma Therapeutics plc. Partnerships with suppliers of E. coli, such as the National Collection of Type Cultures, provide a reliable source of bulk quantities of the bacteria, whilst also being cost effective in comparison with smaller suppliers and ordering smaller quantities. As our product continues to develop it is likely we will find more direct suppliers to make certain that costs of developing our product are kept to a minimum.
To further accommodate the upscaling of our manufacturing, it would be beneficial to acquire our own workspace and hire more people. Having a singular site of production ensures costs are kept to a minimum and helps to mitigate issues with transportation of materials between sites. All details and processes would be undertaken at the same place which could also reduce the time taken to complete the manufacturing of pterostilbene. This also reduces costs associated with transporting materials between multiple sites, as no external company or transport system would have to be put in place with our laboratories being situated in close proximity. Our intended business structure and employment plans can be found in the business plan on our entrepreneurship page, which includes a current cost analysis of staffing and scaling.
Patent Strategy
In the UK, the Intellectual Property Office (IPO) is the official regulatory body responsible for intellectual property rights (Intellectual Property Office, 2022). Commercialising our product and gaining rights over our intellectual property provides us with an advantage in the biotechnology industry to maintain market share and market position (Michael Price Associates Ltd, 2022).
On average, it takes up to 5 years to have our patent granted successfully, as per our discussion with patent attorney Dr Sara Holland. Per IPO painting guidelines, we will make sure the work we patent will be out of the public domain (Michael Price Associates Ltd, 2022).
Due to the nature of iGEM being open source, filing for a patent is not appropriate within our iGEM timeline, as information about our product is public domain. We aim to file a patent for our improved invention, corresponding to our future goal of expanding to other neurodegenerative diseases after October 2022, when the competition is complete.
We intend to patent our biosynthesis pathway, which uses a Malonyl-coA inhibition system to increase its production. The biosynthesis pathway includes four enzymes - vVROMT, RGTAL, vVSTS and AT4CL that have been mutated according to sequences researched by Yan et al.,(2021). We intend to patent an operon system that expresses our four mutated enzymes to produce pterostilbene, a method that has not previously been used. We have also designed an sRNA system to inhibit Malonyl-coA consumption to increase final pterostilbene production titre, which will also be a part of our future patenting strategy.
More details with regards to our patent strategy and our licensing agreement can be found within our Business Plan on our entrepreneurship page.
Safety Considerations
Risk Mitigations
As we are developing a therapeutic for AD, a neurodegenerative disease, there are several aspects of our project that can be challenging, and the risks must be highlighted and assessed. Below we have listed the main risks we have addressed. A more detailed risk assessment has been completed for our project at this stage, which can be found in our business plan.
Side Effects:
As with any drug, part of the development pipeline involves ensuring side effects caused by the drug are kept to a minimum. Side effects must be evaluated so that we meet all guidelines and expectations set by the regulatory bodies, including the Medicines and Healthcare products Regulatory Agency (MHRA), and The United States Food and Drug Administration (FDA) when entering the US market.
Through literature research we discovered that LDL cholesterol has been shown to increase in human trials using pterostilbene for therapeutic use. According to Brenner C., and Boileau A. C. (2018), administration of pterostilbene (100mg/day and 250mg/day) with and without nicotinamide riboside caused statistically significant increases of LDL. Additionally, Riche et al. (2014) suggests that pterostilbene lowers blood pressure, though the mechanism behind this action is still poorly understood and its clinical significance is unclear.
These issues are significant enough to address, but the lack of supporting evidence suggests it is not enough of a concern to dismiss using pterostilbene at this early stage of our project design. As described in our rationale, this compound holds a lot of promise in therapeutics, though further exploration needs to transpire. To address this, we understand we must carry out clinical research and continually be transparent with our results surrounding the effects of pterostilbene in humans, ensuring side effects of our therapeutic are minimised in line with regulations set by the regulatory bodies previously mentioned.
Using E. coli:
E. coli is often used as a host in the biotechnology industry due to its rapid growth, high product yield and straightforward scalability (Baeshan, 2015). However, there are external awareness factors that should be considered when choosing to work with E. coli. Public perception of bacterias, including E. coli, may not always be positive. Although there are harmful strains of E. coli, such as the Shiga toxin-producing E. coli (STEC), most strains of E. coli are in fact harmless to humans (World Health Organisation, 2018). It is essential for the progression and public acceptance of our novel biosynthesis methods for producing pterostilbene that we inform and promote the use of non harmful strains of E. coli in therapeutics and the implications of genetically engineering the bacteria. As part of our marketing efforts, we must also endeavour to continually raise awareness surrounding synthetic biology in order for the industry to develop, benefiting our own research and the therapeutic industry as a whole.
Supply Chain
During the initial stages and in the scaling of a company, there is the opportunity for issues to arise in the supply chain. This can be due to a number of reasons, including, errors in communications, limitations with raw materials, machinery faults, staffing issues, and costs. Currently, the COVID-19 pandemic has had a major effect on many global supply chains, where lockdowns have led to a reduced number of labour workers meaning a reduction in manufacturing on a widespread scale.
Moreover, geopolitics can further disrupt the global supply chains with the Russia-Ukraine war being a prime current example of effects on rail and air freight transportation (JP Morgan, 2022). Although this is not a major current issue for Symemco Therapeutics, when designing our packaging and distribution of our product we will need to consider these factors.
Issues that are more specific to us currently include the delivery of genes and components necessary for our experiments. To limit supply chain issues in all stages of our project, research needs to be conducted into the materials we require and multiple suppliers must be evaluated to avoid relying on one producer to supply Symemco Therapeutics with a particular element of our project and ensure we are choosing the best option available to us.
Patient Selection:
We have identified our target patient group as over 65 year olds, diagnosed with mild to moderate AD. This group was determined using previous literature on the effects of pterostilbene and our understanding of AD pathophysiology. It is crucial that we run human clinical trials to support our predictions and make changes where necessary, to ensure our drug is being used correctly and maximising its beneficial effects. As our research and project develops we can then gain an understanding of changes that need to be made to ensure our product can be more accessible to other patient groups and potentially other neurodegenerative diseases.
Other Challenges
In addition to the risks mentioned above, we have also identified areas that could be challenging that need to be addressed throughout the development of Symemco Therapeutics. The challenges we have identified are detailed below.
Use of pterostilbene as a therapeutic
In vitro and in vivo studies showed promising outcomes in regards to polyphenols, specifically pterostilbene on neurodegenerative diseases. Through discussions with scientists who have been working in relation to polyphenols and disease, we discovered that many of pterostilbene's molecular targets remain unknown. Details of these discussions can be found on our human practices page. Although its mechanism in anti-inflammation is known, which is the context we are using pterostilbene in, the actions on other molecular targets and receptors in the body must also be researched to gain a full understanding of its effects in humans before our therapeutic reaches clinical stages.
In a meeting with Dr. Amorim, we were advised to improve the specificity of pterostilbene for future use and consider the context of how pterostilbene would be used. This includes the possibility of our therapeutic being used for other neurodegenerative diseases, which is a long term goal of Symemco Therapeutics. All of these considerations must be taken into account in the development of our pterostilbene based therapeutic, alongside meeting the regulatory bodies guidelines in bringing a new compound to the market.
Classification of a new drug
Medicines and Healthcare products Regulatory Agency (MHRA) (2020) defines medicinal product as a substance or combination of substances presented as having properties for treating or preventing disease in human beings or substances which may be used in, or administered to, humans, with the intention to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis. Meanwhile, food supplements exert none of these mentioned effects, and can only have a nutritional or physiological benefit.
Pterostilbene is currently registered as a food supplement, not a medicinal product. When a product changes its classification from a food supplement to a medicinal product, there are certain objectives it needs to satisfy. Commissioned consumer research needs to be conducted to understand how the supplement is used currently and whether it is used for medicinal purposes (Medicines and Healthcare products Regulatory Agency, 2018). Furthermore, the level at which the substance exerts a pharmacological effect on the human body needs to be reviewed. Licensed medicinal products have to meet safety, quality and efficacy standards to protect public health (Medicines and Healthcare products Regulatory Agency, 2018). These are considerations to be made to firmly establish our pterostilbene as a medicinal product and separate it from a food supplement. As of now, we are marketing our product as an efficient way to produce a compound with therapeutic effects for AD as it targets neuroinflammation, an underlying pathology, therefore should be able to meet the classification requirements of a medicinal product.
Methods of Delivery:
Further along our drug development pipeline, when producing our therapeutic we must consider the potential method of delivery and their associated safety elements. As a company that intends to be as accessible as possible we hope to have many options available to patients to suit a range of needs. The risks and benefits associated with each delivery method are detailed in Figure 2 below. As Symemco Therapeutics progresses, we hope to use this foundation research to finalise the options we would like to implement in terms of methods of delivery.
Environmental Impact
The environment is of huge importance to us at Symemco Therapeutics and we aim to use the most environmentally-beneficial methods of production and materials to ensure our carbon footprint is minimal. By engineering a synthetic metabolic pathway for the production of pterostilbene, we hope to make this naturally derived polyphenol sustainably manufactured on a large scale, and an alternative to current manufacturing methods which involve extracting and purifying pterostilbene from blueberries, which for therapeutic use would be unsustainable due to the large quantities of natural sources required to produce the desired concentrations. We intend for future packaging materials to be sustainably sourced, and reusable and recyclable where possible. Through development and reviews of our lab protocols we plan to continually find areas to reduce our environmental impact as our project progresses.
Alzheimer’s diagnostics and treatment
A challenge relevant to Alzheimers specifically is the developing understanding of the pathophysiology of AD, and the limitations with current diagnosis methods. AD is not fully understood, many complex changes in the brain are thought to occur that influence the progression of AD. This impedes the progression of both the diagnosis and treatment of AD, as in order to specifically target and identify AD, and produce a disease-modifying therapeutic, is it essential that the pathophysiology is understood in detail. Limitations experienced in diagnosing patients with AD directly impacts those that can receive treatment, it would be beneficial to form a partnership with a diagnostics company so that knowledge can be shared so a comprehensive diagnostic and treatment plan for AD patients can be established.
Additionally, as research is still evolving, it is important to stay up to date with what is going on in the scientific community. This is particularly relevant considering the recent discovery of faked data surrounding the role of beta-amyloid plaques in AD progression (Lowe, 2022), and the potential impact it could have in the field of AD therapeutics. This also highlights the importance of remaining transparent about research conducted at Symemco Therapeutics, for the interest of all working towards the shared goal of treating AD. Thus far, we have ensured that we are using credible and recent evidence to base our product from and we will gather our own evidence to solidify this literature.
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