Entrepreneurship

Phase 1: Research

Project development

Going back to the very beginning of our project, our first steps were assessing the problem and choosing our approach, with the aim of tackling autoimmune pernicious anaemia.

Brainstorming

Coming up with a project idea requires the consideration of the whole context, which included a business plan and preparing a market approach in order to potentially sell our product. One of the first ideas we had was the proposal to market our mutated recombinant IF as a drug. In this drug, our IF would be in complex with vitamin B12 and the delivery method is a pill that is taken orally. IF itself has been characterised as a potential drug carrier [1], therefore increasing the chances that our delivery method is feasible.

Market analysis

In large surveys in the United States and the United Kingdom, approximately 6% of the population aged 60 years or older are vitamin B12 deficient. The rate is much higher in underdeveloped and developing countries in Africa, and some parts of South-East Asia [2]. Increasing prevalence of malnutrition among children across the globe is expected to result in the growth of the market for treatment of vitamin B12 deficiency.

The global vitamin B12 market is projected to grow at a compound annual growth rate of 7.2% from USD 292.6 million in 2019 to USD 409.7 million in 2027 [3]. The demand is driven by the crucial functions of vitamin B12 in maintaining functions of many enzymes and the central nervous system [4]. Another critical reason is the prevention of megaloblastic anaemia. Furthermore, since we are considering selling our product as a drug, we investigated the market for protein drugs.

The market size of protein drugs is projected to grow 8.25% through 2022 to 2029, reaching nearly USD 461.86 Billion [5]. New protein therapies have been developed after the first synthetic protein drug, which was human insulin [6]. This market analysis seems promising for the future of our drug.

We found one potential competitor, Xeragenx, a business that makes recombinant human IF from plants. They are mainly targeting vitamin B12 deficiency by making diagnostic home tests for vitamin B12 deficiency but also propose to use IF coupled with vitamin B12 as a nutritional supplement and drug delivery method [7].

Cost analysis

Developing a drug is expensive, and estimating the cost of producing our protein in the future is difficult based on the information that we have gathered during our experiments. The main factor that influences our production cost is scale, which means that our proof of concept production phase is likely to be significantly more expensive than larger scale production in the future. Therefore, we looked at a large company producing a recombinant intrinsic factor, Sinobiological. Their list price is $2000 per milligram [8], which should serve as an adequate estimate for our production cost. Of course, an alternative to in-house production is to partner with Sinobiological. For this reason, we reached out to them and they agreed to sponsor us by sending us discounted products, while also showing interest in potentially collaborating in the future.

In addition to the production cost of a recombinant intrinsic factor, we need the amount that would be required for one dose. However, the required dosage is unknown to us and would need to be estimated in further studies, since it depends on many factors. Posology is commonly studied during phase I clinical trials [9]. In short, we cannot estimate the cost of our drug, since the appropriate dose is unknown. As a very rough initial estimate, if a dose requires approximately one milligram of recombinant mutated intrinsic factor, then a dose would cost in the hundreds to thousands of US dollars.

Stakeholders analysis

In order to deliver our product to the market we also conducted a stakeholders analysis taking into account the interest and the power of the stakeholders that will affect our approach. Since a large part of the project requires grants and funding, it is important to investigate the potential stakeholders in advance. Stakeholders who might play a smaller role in this stage of the project are patients, who will become more important in the later stages of our project when our drug is finally in the market.

Panel discussion

We contacted several people researching the same field in order to help us improve our marketing and business approach. We were interested in listening to the opinion of experts for the possibility of selling our mutant IF with vitamin B12 as a pill. This would guide us to think more about the pros and cons of our product and improve our idea. In order to implement our idea, we also wanted to take a look at the fundings that we could receive to bring our idea into life. The main recommendation from the experts was that we needed to clarify the market for our product and that we mainly needed to show proof of concept. Experts present in the panel discussion included people from KI Innovations, AstraZeneca, Merck Innovation Hub, KTH and SciLifeLab.

Feedback from stakeholders & experts

KI innovation

KI Innovations runs Karolinska Institutet's innovation office and an incubator programme. It is committed to transforming inventions and innovations from research into services and products, creating value for patients and society.

At the beginning of the project, we take the commercialisation of the project into consideration. We had an in-depth communication with the business coach of KI Innovations, Patrik. He has extensive experience in transforming ideas into businesses. With his help, we set the project ideas and completed the draft of the business plan, which included a team introduction, core technology, products, and a financial plan. KI innovations helped us connect with KI Development, an early-stage investment institution focused on drug research and development. Patents represent another important issue, which KI Innovations suggested that we ask KTH Innovation for help as they have good partners in parenting. We further received a grant for project development from KI Innovations.

Karolinska Development

Karolinska Development AB is an investment company focused on identifying medical innovation and investing in the creation and growth of companies developing these assets into differentiated products that will make a difference to patients’ lives and providing an attractive return on investment. It has established a portfolio of 10 companies targeting opportunities in innovative treatment for life-threatening or serious debilitating diseases.

We had a meeting with Linda, who is the investment manager of Karolinska Development AB. We presented our business plan in detail, and received suggestions. These included establishment of different departments, and selection of particular sub-team leaders as co-founders with other team members holding shares. We should further consider the patent for our technology and potentially approach consultant companies for assistance for the application. Linda also recommended applying for funding from sources such as our universities, the Swedish government, and some foundations. Once our drug reaches the preclinical stages, we can again approach Karolinska Development for investment.

KTH Innovation

At this phase in the project, we had concerns about the regulations that would apply to our product, and what we would need to focus on in order to plan ahead for eventual clinical trials. To get feedback on this aspect, we turned to one of our other universities through KTH Innovation, which acts as the supporting body for new solutions coming from KTH students and researchers. KTH Innovation has expertise in patent and intellectual property law, and we obtained valuable guidance. Mainly, we were advised to focus on the technical readiness of our solution, and as our project evolved, to then focus on regulations and approval. However, KTH Innovations also suggested investing in market research, to ascertain the market demand for our project, and the scope of its impact.

While we agreed with the importance of making our project work in a technical sense, we were still concerned with how our project would be received by regulatory bodies. However, market research became a priority, which led us to get in touch with clinicians, who would get to say whether they could see a use for our product in the field.

Doctors

Chinese Doctors

In order to understand the current incidence, risks, current diagnosis and treatment of pernicious anaemia in China, we interviewed Dr. Qian from the Department of Haematology, Nantong University Affiliated Hospital and Dr. Hou, from the Department of Haematology, The Second Affiliated Hospital of Nanjing Medical University. From their point of view, pernicious anaemia is a rare disease. However, there may also be missed diagnosis, because the diagnosis process of pernicious anaemia is complicated, and the symptoms are easily confused with other diseases. The treatment of pernicious anaemia with positive intrinsic factor antibody is currently mainly intramuscular injection of vitamin B12. While they believed PA to be a relatively rare disease in China, they confirmed current treatments as intramuscular vitamin B injections, and thought it would be useful to have a pill alternative.

Physician at BUMM

While the vast majority of pernicious anaemia cases are found in the population aged above 60, we wanted to confirm this with the experience of a physician. We got the opportunity to talk to Haitham Aldaher, a physician based in Stockholm with more than a decade of experience working with teenagers and children. He had never encountered patients with pernicious anaemia in his career, while vitamin B12 deficiency was a relatively common occurrence among his patient groups. Since this confirmed our research thus far, we asked about our solution and what we could do to make it better.

In his opinion, a cheap diagnostics tool would be the most valuable for any disease, not only PA. SNP, protein and antibody arrays are great diagnostics tools that can target multiple diseases at once, but their main drawback is cost. For that reason, they only get used if the doctor suspects that the patient has a serious enough condition to warrant the cost. After realising the need for a more cost-effective diagnostics tool, we invested some time to devise a concept for a test that could accompany our solution.

When it came to the treatment option, our idea of a pill was well received thanks to the ease of use, as long as its cost could be kept down in order to maximise its use when deemed appropriate, not only in the most dire cases.

Phase 2: Application

Regulations

Any potential treatment must go through strict regulatory inspection before use can be approved.

EMA

As our project started in Stockholm, Sweden, any medical device needs to be authorised through the European Medicines Agency (EMA), which is an agency of the European Union. Sweden also has a national medicines agency called Läkemedelsverket, which is a part of the EMA [10]. In the EU, most applications for marketing authorisation go through a central process that starts with an application sent to the EMA. For clinical trials, a national decision is taken and applies to the EMA’s member nations. For a marketing authorisation, a “host nation” for the application is requested by the applicant, but all EMA nations are part of evaluating the marketing authorisation [11]. EU law and regulations being very complex, we sought to get a grasp of what our future application would entail in a more practical sense. We were able to interview Lorenzo Montrazio, who has 15 years of experience from working at the EMA, through the Italian medicines agency Agenzia Italiana del farmaco (AIFA).

The first question we had was what it would require for us to perform clinical trials and subsequently get market authorisation for our protein drug. Lorenzo was able to give us a clear figure: 10 000 EUR for each patient and 5 000 patients. This would put us in the ballpark of 50 million euros in order to get approval. Lorenzo pointed out that in most cases the drug would be sold to a larger company which has sufficient resources, before entering the authorisation process.

Other than the financial requirements, which seemed far from achievable at this stage, we asked about what we could do now to facilitate any future approval processes. Lorenzo advised us to again focus on the technology, just like KTH Innovation advised us, but told that the EMA offers scientific advice that we could request before we send in our application for market authorisation. This would increase our chances of performing as thorough studies as possible, and reduce potential requests for more analysis or data further along the application process, which can prove costly [12].

Bioethics

Our aim is to be best prepared for a successful launch of our product and while ethical questions would traditionally be associated with safety and security, we thought that they are an important part of the core business concept. In order to assure that our business follows guidelines and references relating to human rights, we discussed our project with Lee Hibbard from the Council of Europe (CoE) Bioethics group [13]. What we are able to apply to our business model is the importance of securing patient data and any human data that we produce during our research. According to Lee Private healthcare companies that store data can be seen as a threat, especially if they are able to sell data further, which is why we would need to make sure that this is impossible. Fortunately, we should only need to access sensitive patient data during clinical trials, which would take place in partnership with a hospital, meaning that their guidelines would be followed.

We further considered any potential human rights violations, particularly in the context of GDPR policy [14][15][16]. We concluded that ethical questions are essential for society but also for our success, and that our business plan does not collide with ethical practices or Human rights protection.

Stakeholders

Consulting company

Key2Compliance is a consulting company with focus on the life science industry providing complete solutions in all aspects of regulatory compliance. We were not sure whether our final product is a nutrition supplement or a drug. Thus, we decided to interview Åsa Möllby, Director of Quality Assurance of Key2Compliance.

Firstly, she analysed the advantages and disadvantages of supplements and drugs. To develop a drug, it would take almost 10 years and millions of Swedish krona (SEK). On the contrary, to develop a supplement, it would take less time and money. SNotably, vitamin B12 is currently considered a supplement in Europe. However, our project contains a mutated transport protein, and so might no longer be considered a supplement, and thus be subject to further regulations.

Phase 3: Future plan

Drug versus supplement?

Having gathered the suggestions and opinions from the experts in the business field we needed to take into consideration the pros and cons of selling our product in the market. In order to patent our idea and sell our mutant intrinsic factor with vitamin B12 as a drug, specific requirements need to be fulfilled. The product has to be patentable (pharmaceutical drug), new, inventive, useful, and does not have prior use. These all are fulfilled by our product. After accepting the patent, the drug, depending on the category that it belongs to, will obtain certain years for exclusivity, and protection against generic drug competition.

In the case that the drug is considered as an over-the-counter monograph, then the FDA has pre-determined that the drug is safe and effective. In other cases, both pre-clinical trials and clinical trials consisting of four phases are necessary to continue with the drug approval. Once we have FDA approval, the drug requires market autorisation. Another option, as previously mentioned, is to classify our product as a supplement, together with vitamin B12. According to the FDA, the term dietary supplement should include one or more of the following: a vitamin, a mineral ,a herb or botanical, a substance that can be used as a supplement for a diet [17]. In our case, vitamin B12 and the mutant IF can be considered in some ways supplements. As we saw in our market analysis, the market for protein drugs is much larger compared to that of vitamin B12.

Our solution as a template

Once our project has run its course, we would have a protein drug in our hands that hopefully treats the rare autoimmune disease pernicious anaemia. Furthermore, by producing this drug, we have gone through the engineering cycle extensively, providing us with a full development plan for similar products. For example insulin autoantibodies could be a potential target for our solution [18].

Our autoantibody-evading protein development plan can be divided into two parts: software and screening.

With our software, any amino acid sequence can be mutated at given epitopes, and the mutant sequences as well as the primers for creating these mutants would be given as an output.

Once the mutants are created, antibody screening takes place and putative mutants that evade autoimmunity can be selected.

Both of the above mentioned parts can also be provided as services to external customers, who would be other businesses or researchers (Business to Business). Furthermore, owning expertise in both parts would also allow us to provide a complete service for producing mutant proteins from a protein target identified by researchers for instance, which could be the activity of a company in and of itself.

Scale-up plan: protein production

In order to plan for the future, we have detailed the necessary steps that would need to be undertaken to reach the commercial launch of a protein drug based on BiG-IF. In the figure below, a scale-up plan is described, showing the processes that take place from drug discovery to evaluation of market authorisation.

We have engaged with Sinobiological as a potential partner during the discovery stage, and moving forward we would contact other contract development and manufacturing organisations (CDMOs) to provide us with proteins that fit our requirements for the coming processes.

Business plan

A summary of our entrepreneurship journey is presented in the form of a milestone plan in the figure below. The figure shows the chronological progression of our solution, from an iGEM project, on to clinical trials and establishing a medium-sized company. Our company would start off at a very small scale in order to gather relevant preclinical data, while preparing for either selling the intellectual property or partnering with a company able to invest in clinical trials.

SWOT analysis

While establishing our business, it is crucial to be aware of where we stand and how we can improve during the development of our business. In order to summarise our standing, we have come up with a SWOT analysis in the figure below, which prescribes the strengths, weaknesses, opportunities and threats of our solution.

References