Implementation
Implementation
Find out our next steps to bring cELPro to the market
Introduction
To be able to really implement cELPro in the future, many steps still need to be taken. First of all, the product itself needs to be optimized before we try to bring it to the market. Furthermore, clinical studies need to be done to assess the safety and effectiveness of cELPro. To keep the startup company alive, it is also important to think about funding and have a good businessplan that can be followed to ensure cELPro's success in the future. In the next section, you can read the steps our team intents to make in the future to implement cELPro in the real world.
Business model
Before a product can be brought to the market, the product and process need to be optimized. We have chosen to do this by using a LEAN business model canvas[1]. This method has been used by many other iGEM teams before and with this, we are following in the footsteps of the TU Eindhoven iGEM team of 2022. A good business model helps to verify the idea before investing a lot of time, effort and money into the product.
Click on the different parts of the business model canvas below to learn more about these segments.
Problem
Treatments are ineffective
Invasive
Many side effects
Existing alternatives
Anti-TNF antibodies
Corticosteroids
5-aminosalicylic acid
Solution
cELPro as a non-invasive, inexpensive treatment option.
Key metrics
Effectiveness
Revenue
Amount of patients treated with cELPro
Unique value Proposition
Specific
Non-invasive scalable
Affordable
Unfair advantage
Company secrets
Patents
Channels
Direct-to-consumer advertising
Physician detailing
Managed markets solutions
Customer segments
Pharmaceutical companies
Government
Patients
Cost structure
Legal and regulatory
Clinical trials
Consultancy
Material and facilities
Marketing
Salary
Revenue streams
Investors
Sales
Current treatments for IBD have many issues that we want to solve:
Side effects: Current alternative treatments only aim at relieving the symptoms of IBD and are not very specific. This causes patients to experience many side effects, which we learned from the conversations we had with doctors from the Erasmus Medical Centre and patients suffering from IBD.
Ineffective: Many patients do no respond well to their treatment. Anti-TNF antibodies do not work at all for 10-30 percent of patients, and 26-46 percent of patients lose response overtime[2].
Systemic: Current treatment options work systemically, which means that the medication travels throughout the whole body of the patient and is not targeted to a specific place. This causes side effects.
Invasive: Most patients need frequent hospital visits to have injections, which is not desirable. It puts strain on the patient as well as on the health care system.
cELPro is a pill that can be used to treat IBD locally with less side effects and in a non-invasive manner. Furthermore, we expect that we can produce it less expensive than current alternatives and that it will be a treatment that can be used for patients that have been out treated already.
The metrics to measure success will not stay the same over the years as the company develops. In the development stages the following metrics will be used:
Number of patients and willing to use the therapy: Patients and doctors need to be willing to use cELPro for it to have a chance of surviving in the long term. We already investigated this, and from about 195 responses only 10 percent of patients would not be happy to use cELPro. Their arguments were mostly based on the uncertain amount of side effects that first needs to be investigated. A few patients also responded that it sounds scary to ingest living organisms. This means that we need to gather more data about safety and educate doctors and patients more about why the therapy is safe.
At a later stage, when the therapy is fully developed, the following metrics will be used:
Effectiveness of the therapy: In the first years of the business, the most important metric to measure its success is the effectiveness of the technology. Having a treatment that is more effective and less invasive than others will ensure its success in the future.
Amount of patients who are treated with cELPro: When the product is on the market, a measure of its success will be the market share that we can obtain with cELPro.
Amount of revenue from sales: Lastly, when the business is fully developed, its success will be measured by the quarterly revenue from sales.
Specific: Local treatment at the site of the disease ensures that there will be no unnecessary side effects.
Non-invasive: A pill is an easy way to administer drugs that is more pleasant and cheaper than injections.
Scalable: Bacteria are easy to grow at small as well as low quantities which makes the solution scalable.
Affordable: Since there are no expensive materials involved and all the needed machinery is in the cells, the product can be made in an affordable way.
Since we will not try to apply for a patent in the beginning, making sure that our know-how stays within the company becomes more difficult. However, we think by making the knowledge we have a company secret until there is more intellectual property that we will keep our unfair advantage over other companies and stay ahead of them. Later on, we want to find IP to file for a patent.
Every company needs to think about how they will eventually communicate about their product to their customers. For pharmaceutical marketing, there are some special rules and methods.
The three main methods of pharmaceutical marketing are direct-to-consumer advertising, physician detailing, and managed markets solutions. These methods all have strict rules that may differ in different parts of the world[5]. Direct-to-consumer advertising involves for example television and radio that target the public in an effort to create awareness of the drug. Physician detailing is the practice of sending trained sales representatives to physicians’ offices to discuss the uses, benefits, and risks of a given drug. Finally, managed markets solutions involve talking with the parties paying to the therapy such as insurers and pharmacy managers in order to negotiate drugs to enter health insurance[6]. For cELPro, we want to focus on the latter two methods of marketing, but only after all clinical trials have been successful.
Many stakeholders are involved in our start-up company. Below we have defined our different types of customers.
Primary customers:
The primary customers of cELPro will be pharmaceutical companies. We aim to work together with them as investors on the treatment, since pharmaceutical companies have the know-how on how to develop a successful therapy. They will want to work with us since the pharmaceutical industry develops rapidly and they need to make sure to stay ahead of the rest of the market [7][8]. Because of this, they will be interested to work with us since there is also profit in it for them in the long term. We hope to partner up with one of the companies we mentioned earlier in the competitors section. They are the ones with a similar vision to us, and working for them will help cELPro as well as their own technologies to reach a higher level. They also have the manufacturing facilities needed to produce cELPro on a large scale. We have already tried to get in touch with them to partner up, however these attempts have not been successful until now.
Secondary customers:
Health insurance companies and the government: We have learned that health insurers and the government have two main interests. First of all, they focus on therapies that are effective. Second, to make it possible for a therapy to be included in basic healthcare, it should be affordable. We think cELPro can be both, and this is why we are optimistic about making sure that the therapy will be included in basic Dutch health insurance in the future.
Doctors and IBD patients:
Clinicians and patients will be the final users of the product. The most important factors for them to use the therapy are that the therapy is effective and carries less side effects to all other current options. To make sure all end users believe in our product, the TU Eindhoven team has included doctors from the Erasmus Medical Centre and patients suffering from IBD already from the beginning, as you can read in our Human Practices Page. Their feedback has been used to validate and further develop cELPro.
Early adopters:
Dutch doctors and patients who participate in clinical trials for the therapy. These will be the people who will be able to provide us the most feedback about our product when we are in the late development stages.
A start-up needs to make many investments to get production going. Apart from material costs, there are other expenses to be made. Below is a breakdown of the costs we expect to have in the first years.
Product development: Even though our team already has a lot of expertise, some parts are still missing, which is why certain parts need to be outsourced to other companies.
Legal and regulatory: Since we have no experience in the legal and regulatory field, we will outsource most of the work related to this. We will hire BG legal to help us with intellectual property, contracts and rules when it comes to marketing of medicines.
(pre-)Clinical trials: To conduct clinical trials, we will reach out to parties who do early clinical research. In the Netherlands, this is CHDR[7]. They conduct clinical trials. The estimated costs for this are high and come to about 50 million euros[8].
Consultancy: Since our team is relatively small and we do not have experience in all fields, we expect to need some more consultants along the way. Therefore, we aim to compensate for the lack of expertise and experience by hiring consultants. It is found that most MedTech consultant firms charge an average of 150 – 200 euros per hour[9][10]. Since we expect to hire two consultants for a technological and business point of view, for around 10 hours a week, we forecast 16,000 euros a month for consultancy.
Material and facilities: For the company cELPro to operate well, an office space and ML-I lab facility and equipment is needed. We were not able to find reliable estimations for the costs of this, so for now we estimate 100,000 euros.
Marketing expenses: Research has shown that a marketing budget for life science companies is usually somewhere around 8-13% of the revenue. For smaller businesses the amount is close to 8%[11]. However, since the first years will be focused on product development and the fact that there will be no revenue yet, it is not necessary to have such a large marketing budget from the beginning. Only minimal brand marketing activities need to be carried out and it is estimated that we already have the knowledge in-house and that this can be done for minimal costs.
Salary: The current team consists of 7 members, who will all be assigned a role. Crucial job titles for a medical start up are CEO, CSO, CFO, CDO, CMO, Legal Assistant & Office Administrator, Medical Laboratory Technician (MLT), and Clinical Study Manager[12]. One more role needs to be filled by a new team member who we will look for after the iGEM competition. In the first five years, the salaries of all job titles will be the same and be scaled to a salary similar to that of Ph. D students. This means, that the average salary costs for the company (including holiday allowance and insurance) are about 3300 euros per employee per month for the first five years[13]. However, as the company grows from 8 employees to more, overtime the costs for salary will increase.
Revenue will come from different streams. We make the division between non-operating and operating revenue.
Non-operating revenue: Investors
In the first 5 years, income will mostly come from investors since no sales of the product can be made yet. We will target interested companies to help finance our developments[14].
Operating revenue: Product sales
After all clinical trials, we expect to have a working therapy that we can start selling, form this point on, most revenue will come from these sales[14].
Besides a business model canvas, we have also done a SWOT analysis to clearly define our strengths, weaknesses, opportunities and threats. This overview gives us a clear idea of the things we need to look our for when the market develops. The most important points can be seen below.
Strengths
Weaknesses
Opportunities
Threats
In the sections below, you can read more about how we expect to improve cELPro and which steps we intend to take when it comes to the implementation of the therapy in the future.
During the conversations we had with relevant stakeholders such as the Erasmus MC, RIVM, and VIG that can be read on our Human Practices Page, some interesting questions and suggestions arose to further improve the design of cELPro after this year's project. The total input of these stakeholders can be read on the Human Practices page. The questions and suggestions for further research have the potential to make cELPro even safer and more effective.
Cell types
In the past year, the E. coli BL21 strain has been used for the development of cELPro. This strain is chosen for its ease of protein expression, due to its rapid growth and high expression rate[15]. However, the disadvantage of using E. coli is that through a process called conjugation, which lets bacteria exchange their genes with their neighbors, plasmids can be transmitted directly between bacteria[16]. This makes the use of a bacterial strain in the intestine less safe, since the antibiotic resistance gene can be transmitted to bacteria present in the microbiome of the consumers[17]. When this happens, the gene that codes for IL-10 is transmitted as well, which might cause uncontrolled production of the protein, which can lead to serious side effects. Fortunately, permanent gene incorporation of bacterial cells into mammalian cells is very rare[18]. For this to happen, a bacterial gene has to be transferred into a sperm or egg cell, which is not relevant for the current application of cELPro.
There are a few ways to prevent the transmittance of genes between bacteria described above. The first one is to make an mRNA-based therapy. The advantage of mRNA-based therapies is that there is no risk of gene integration into other cells[19]. Furthermore, mRNA degrades quickly, which will also prevent that production of IL-10 will be prolonged for too long in the gut.
Another option mentioned by Maikel Peppelenbosch is to use other cell types such as yeast as the host for the therapeutic. Yeast cells are used as hosts for pharmaceutical production since they are generally recognized as safe (GRAS)[20]. Yeast has already been used for decades for drug production making it a well-known and understandable host. Moreover, the risks to patients are also well-known. In addition, according to prof. dr. MP Peppelenbosch it is possible to build in introns in yeast. Prokaryotic cells, such as those in the microbiome, are not able to incorporate these genes. This eliminates the possibility of cross over to other bacteria. This makes the application safer for the consumer.
Biocontainment
Before further steps can be taken with cELPro some additional experiments need to be done regarding for example biocontainment. The most important one is to measure the lifespan of the engineered bacteria. This is a point that came up in multiple interviews we had that can be read on our Human Practices Page.
During the conversation with RIVM (National Institute for Public Health and the Environment), they stated that it can be harmful for the environment when our engineered bacteria get into the sewage system alive. To test whether the bacteria are already dead when they leave the human body the lifespan needs to be tested. We plan to do this with further CCK8 experiments (Experiments Section) and to do the live/dead staining of the bacteria after different timepoints.
At the moment, based on literature research, we expect that the lifespan of the bacteria is a few days. Researchers from a group in the United States made PEG-polymer based hydrogelated E. coli, these cells lived up to three days. This showed that engineering the bacteria to make them unable to divide decreases their lifespan.
However, if experiments show that the lifespan of the bacteria is too long, another bacterial host can be chosen as the host of cELPro. RIVM advised us to look into bacterial host that have shorter lifespan, such as Lactobacillales.
Competitors
During our project, we have talked to numerous people of which some have worked on similar ideas in the past. We also found some people who are still working on similar approaches to use bacteria in therapeutics. Before we can think of turning our idea into a start-up company and look for opportunities when it comes to intellectual property (IP), it is important to check what they are doing and to assess whether their developments will impact our technology and market in the future.
Professor Cheemeng Tan from UC Davis has formed hydrogels in bacteria with PEG polymers and is currently investigating applications for his idea. He has already shown that it is possible to infiltrate cancer cells with his bacteria by using the protein invasin[21]. Furthermore, he told us that he is currently looking into applications in the bowel. He also filed for a couple of patents, but nothing has been published about this yet. These patents might be something we need to be careful with in the future, however, we think our approach of forming a protein-based hydrogel is different enough and that this will not cause any issues with patents that have been filed for already.
Furthermore, we have found a couple of start-up companies who have a similar approach when it comes to IBD treatment, but are using different ways of engineering their bacteria. This will not cause any problems for us when it comes to our IP strategy, but it is important to be aware of them since they may bring a product to the market in the future which will affect the available market for us. These companies are Precigen and Synlogic. For our project we have also tried to get in touch with them to collaborate, but unfortunately their schedules were too busy to help us. When we keep working on cELPro after the iGEM competition, we will make sure to keep an eye on these companies and their developments.
IP
We have talked to IP experts from The Gate and BG legal, two companies who specialize in intellectual property and have many customers who are active in the medical field. During our meetings with them, we discussed our idea and the options when it comes to filing for a patent. In our conversation with Natasa from the Gate we found out that filing a patent requires more time and money (about 1 year and 4000 euros) than we had first anticipated. More about that conversation can be read in the timeline conversation on our Human Practices Page. Furthermore, if a patent is granted, it is useless when it is not maintained properly. Lastly, only the parts of our project that are under the patent application could be disclosed. However we wanted to keep working on our concept and keep making it better throughout the iGEM journey, and we want to share everything we did. This is why we came to the conclusion that a patent is not the right strategy for our team.
Even if we do not file for a patent, it is still possible to continue with our project after iGEM. We have discussed this in conversations with Bart van Grevenhof and Bart Koppelmans. More about this can be read on our Human Practices page and Attributions. Even though we are disclosing a lot of information on our wiki, the project remains complex and we think only our team has the know-how to develop it even further. This means that our team will be much faster in developing cELPro further. As soon as we find something new, we will turn it into a trade secret[22]. This is a form of IP where others can still file for a patent if they find it via their own path. So it might be risky, but we do not expect that other companies will pick up on our technique very soon, which gives us time to turn it into a business first. However to keep our knowledge a secret as long as possible, we will need to work with non-disclosure agreements .
Production process
In our meetings with RIVM, we have been told that it would be fairly easy to upscale our production in the lab that we are currently using. With only slight changes, such as buying larger vessels and incubators, we could already upscale to a few hundred litres cultures. We think this will be large enough production for the first few years of cELPro. More about the conversation can be read on our Human Practices Page.
Pill packaging
The engineered bacteria will be administered orally to the consumer in the form of a pill. For the bacteria to end up in the intestine alive, they first have to pass the acidic environment of the stomach. Although, in some conditions E. coli can survive in this environment, it is better to protect them since the importance for them to survive is very high. Paul and Alexander from BioConnection advised us to explore some pill coatings to make sure the bacteria are protected until they are in the bowel. More about the conversation can be read on our Human Practices Page. A very common and useful strategy for the delivery of oral drugs is enteric coating, which blocks drug release before entering the intestine[23]. The change in pH from the stomach to the small intestine will trigger the release of the drug since the enteric coating typically dissolves in water with a pH above 5.0 – 6.0[24]. The exact dissolution rate depends on the length and pKa of the poly-acid chain of the coating as well as the pH and ionic strength of the medium. A product that we have found that is suitable as the coating of our pill is Eudragit® RS.
Storage
In addition, to make sure the pills with the engineered bacteria can be stored for longer periods of time at the pharmacy or patient’s home, the bacteria will be freeze-dried. Freeze drying is a method to dry biological drugs that are unstable, delicate, or heat-sensitive at very low temperatures without damaging the physical structure of the biological. The reconstruction of freeze-dried products is quick and easy. The advantage of freeze drying is that it produces highly stable solid-state products that can be stored for a longer time. Moreover, this technique makes it possible to transport the product at room temperature. This would increase the chance for patients in third-world countries to also get the therapy since the costs would be lower.
Clinical trials are the primary way in which a new form of treatment gets evaluated on its effects on human health outcomes. They are carefully designed, reviewed and completed. Before a clinical trial is launched, pre-clinical trials and often animal studies are conducted to test safety and effectiveness. If these show good results, a clinical trial will be approved by the responsible agency in the country. In Europe, this is the European Medicine Agency (EMA)[25]. For cELPro, first the safety would be determined by pre-clinical trials and animal trials. Next, it will go through different phases of clinical trials in order to see if it also has potential in the human body. The phases are as follows[26]:
Phase 1: Test cELPro on a small group of around 20 to 80 people to judge its safety, including any side effects. Aside from that, it is important to test the safe dosage.
Phase 2: Include more participants (around 100 to 300) to help determine the effectiveness of the drug. This is meant to get preliminary data on whether cELPro works in patients with inflammatory bowel disease. Safety is still examined, including short-term side effects.
Phase 3: Gather additional information from several hundred to several thousand people about safety and effectiveness. This is a test on world level with different populations and dosages, also comparing the intervention with other drugs or treatment approaches. If the EMA agrees that the trial shows favorable results, approval of the drug will be given.
Phase 4: Takes place after the drug has been approved. The treatment’s effectiveness and safety are monitored in large, diverse populations.
We spoke to Peter Bertens of Vereniging Innovatieve Geneesmiddelen, which is a Dutch association that represents companies developing new medications and bringing them to the market. Details about the conversation can be read on our Human Practices Page. He told us about the multiple phases of clinical trials, and explained how safety is extremely important, too. In the case of cELPro, the most important part to be reviewed before it can be considered safe to use is what the lifespan of the ingested bacteria is. This will answer the two following questions:
1. How long will the bacteria stay alive inside the patient?
2. Will the bacteria have an effect on the environment?
It would be safest if the bacteria would die before they are out of the patient through their discharge. This way, they will not do any harm to the microbiome, and will not negatively affect the environment once they are out.
Aside from that, protecting the safety of clinical participants is done through review boards, informed consent, and monitoring committees[27]. The review board consists of doctors, scientists and members of the general public. They ensure that participants are not exposed to unnecessary risks, and review the study regularly and make sure that risks do not outweigh potential benefits. Study participants are provided with an informed consent document, which includes details about the study, such as the purpose, the length, procedures, who to contact, risks and benefits. Participants are free to withdraw from the study at any time. Additionally, clinical trials also have committees that monitor the safety throughout the study.
After cELPro enters the market, patients with inflammatory bowel disease (IBD) will be able to get a prescription for the medication from their general practitioner (GP). Despite the fact that patients will be the main end users of the cELPro, the GP is also seen as an end user.
Patients
Currently, IBD can be treated with numerous medications such as steroids, antibodies, and immunomodulators. Those treatments have different shortcomings. For example, the most advanced treatments only have a 50% success rate or lose effectiveness over time[28]. Moreover, Monique Devillers, IBD specialist at Erasmus MC, told us that most treatments have lots of side effects. More about this conversation can be read on our Human Practices Page. This is caused by the fact that treatments are administered locally, which also affects the immune system. From the patient survey and interviews, we found out that patients are willing to use cELPro over current treatments. What convinced them is that cELPro works locally, which eventually will cause fewer side effects since it does not harm the immune system.
Patients will need to go to their GP before they can start using cELPro. This decision is made to prevent people who do not have the right diagnosis from using the medication. Once they get approval from their GP to use the therapy, patients can get cELPro at their local pharmacy. The medication will be put in a pill which can be stored at room temperature. This makes storage easy compared to some current medications, such as a lancing device that needs to be stored in the fridge. When the patient gets a flare-up, they can take a pill. To find out more about the opinion of patients themselves, we conducted a survey amongst 195 patients. More about this can be read on Human Practices Page. From the patients, we received varying feedback on the pill intake routine. Some patients want more routine, e.g., taking the pill every day, while others like the idea that they do not have to use it that often. One of the patients we interviewed mentioned that this really depends on the severity of the symptoms. This is something to look into further to make the treatment as comfortable as possible for as many patients as possible.
General practitioner
As mentioned earlier, the general practitioner needs to prescribe cELPro to the patients before they can use it. In order to fully implement cELPro into the lives of patients, it is important that the GP truly believes that it is a safe and effective option. Therefore, GPs need to be informed extensively. This is why we also talked to Monique Devillers, a doctor who specialized in IBD. More about the conversation can be read on our Human Practices Page.
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