Binanox has a unique method of synthesis, which leads to the most optimal nanoparticles for PTT. We use synthetic biology to produce proteins in E. coli originating from metal-resistant bacteria. These metal-resistant bacteria have developed these proteins to survive in a metal-rich environment and negate the effect of the free metal ions by conversion to elemental form. By transforming them with the genes coding for these proteins, we increase the ability of E. coli bacteria to produce our spiky bimetallic nanoparticles (Fig. 2).

These spiky bimetallic nanoparticles are highly suitable for PTT. In PTT, a doctor administers metal nanoparticles to a cancer patient via injection. Once in the body, these particles specifically go to a tumor, where they accumulate. When the doctor irradiates the tumor with a laser, the metal nanoparticles become very hot. As a result, the cancer cells die at the site of irradiation. If you are interested, you can read more about PTT in the project description.

Our preferred exit strategy is Merger & Acquisition (M&A) after finalizing our proof of concept. This means we would merge with a similar company or be bought by a larger company.

A favorable strategy is to merge with a large pharmaceutical company that has already built experience participating in clinical trials, like Roche or Johnson & Johnson. These companies often exercise a combination of both pharmaceutical and biotech undertakings, indicating to have prior expertise operating biologically on a large scale.

Another option would be to merge with a company that is specialized in optics or the production of (NIR) lasers, such as Coherent, Inc. In that case, we have complementary skills and can come to the perfect treatment by combining our expertise. The nanoparticles won’t work as long as there is no laser included with the treatment. Whenever we have cooperated with a company specialized in optics and lasers, Binanox can provide lasers as well as a one-time purchase for every location that offers the treatment.

A triangular merge would presumably lead to the best combination of skills and expertise. Either way, we will draw up a contract in which we will discuss the consequences for both parties and to what extent Binanox will be involved. At a later time point in our developmental plans, another opportunity for Merger & Acquisition will perhaps present itself, since it is a general practice to execute an exit strategy via M&A after completing the clinical trials.

Patient needs

Examples of head and neck cancers are throat cancer, lip cancer, and nasal cancer. Patients with head and neck cancer are currently treated with surgery, radiation therapy, chemotherapy, immunotherapy, or a combination of treatments. For more information on how these treatments work, click here.

Surgery

Surgery for head and neck cancers can temporarily or permanently affect the patient’s ability to chew, swallow, or talk. The patient’s appearance might change after surgery, and the face and neck may be swollen. Therefore, treatment often also requires supportive services like physical and occupational therapy, speech and swallow therapy, and nutrition⁶. This increases the costs significantly and more importantly, this is all incredibly uncomfortable for the patient.

Chemotherapy

Aside from the common side effects, chemotherapy-induced nausea or vomiting, there are lots of other side effects caused by chemotherapy, like hair loss, numbness in fingers or toes, and sadness or depression.⁷ Most side effects disappear in the long term. However, there are some long-term side effects known as well, like cognitive difficulties, hearing problems, and reduced fertility^8,9,10.

Radiotherapy

Radiotherapy comes with similar side effects. Radiotherapy specifically applied for head and neck cancers, can lead to fatigue, hair loss, mouth problems, skin changes, taste changes, throat problems, and a less active thyroid gland¹¹.

Although side effects will improve slowly over time in many patients, others will experience long-term side effects of radiation therapy, including difficulty swallowing, speech impairment, and skin changes¹².

Immunotherapy

Immunotherapy is a relatively newly developed therapy. Unfortunately, this therapy is not perfect either. The treatment is, for example, unsuitable for the "immune suppression type" and the "immune exclusion type" of a tumor¹³. It could also lead to autoimmune diseases and even death¹³. Also, a variety of non-specific toxic side effects can occur after use in some patients, and even hyper-progressive disease may occur, accelerating the death of patients¹³. The effect of immunotherapy is moreover affected by many factors, which makes the survival rate and prognosis of patients uncertain¹³. And last of all, the treatment costs are very high¹³.

PTT

Therefore, these patients suffering from head and neck cancers are in strong need of more specific cancer therapy with reduced side effects. PTT is a promising solution as it is minimally invasive and potentially effective.

Based on a few desired characteristics, according to our literature research, we designed the perfect nanoparticles for PTT. These nanoparticles suitable for PTT have a bimetallic composition with a silver core and golden shell, sized between 20 and 150 nm. However, these ideal nanoparticles for PTT have not been made yet.

Additionally, the synthesis of nanoparticles is typically done using a variety of expensive and dangerous physical and chemical techniques. The application of chemical and physical procedures results in the absorption of some harmful compounds that may have negative effects on applications. Biologically synthesized nanoparticles are less dangerous and can be used widely in biomedical applications, according to a comparative study that found their cytotoxicity to be much lower than that of wet chemical nanoparticles¹⁴.

Comparing the green biosynthesis of bimetallic nanoparticles to physical and chemical approaches, which showed great biological activities, is a good, inexpensive, and non-toxic way¹⁵.

Biological production has several advantages compared to chemical synthesis:¹⁴

• Potential to produce nanoparticles on a large scale. For example, the ascorbic acid we used during our experiments for a comparable but chemical synthesis, poses several difficulties in scaling the production industrially¹⁶.
• No toxicity from hazardous chemical solvents during synthesis.
• Well-defined size and shape of nanoparticles
• Environmentally benign
• Promising to be cost-effective
• Natural traits of reducing and capping agents synchronize. While a capping agent is used to stabilize the nanoparticles, a reducing agent is utilized to create the nanoparticles. Since these are both present in our microbial factory, these agents can synchronize.

To summarize, there is a big need for a less invasive, but effective treatment for head and neck cancers, and our spiky bimetallic nanoparticles promise to be an answer to this.

Total Addressable Market

The total addressable market (TAM) is the maximum size of the opportunity for a particular product or solution. To determine Binanox’ Total Addressable Market, we thus assume that PTT therapy with Binanox’ nanoparticles will cover all currently used treatments for head and neck cancers. Therefore, Binanox’ annual TAM concerns the total number of new cases of head and neck cancers all over the world.

The market for medications to treat head and neck cancer was projected to reach US$1.51 billion in 2021¹⁷. Precedence Research predicts that the global market for head and neck cancer medications would reach US$ 2.99 billion by 2030 and increase at a compound annual growth rate of 7.9% between 2021 and 2030⁵.

In 2020, the global market for pharmaceuticals treating head and neck cancer was dominated by North America¹⁷. In North America, early detection of head and neck cancer has been made possible by improved access to healthcare and cutting-edge diagnostic tools¹⁷. Additionally, the prevalence of head and neck cancer has increased as a result of increased cigarette, alcohol, and smoking use¹⁷. The fastest-growing region is anticipated to be the Asia Pacific¹⁷. The growth of head and neck cancer market in the Asia Pacific is being driven by rising knowledge of the disease, rising healthcare spending, and rising use of health insurance in the region¹⁷.

Serviceable Available Market

In order to make a target market selection, we decided to base our decision on a SPA-canvas, in which size, potential, and access are compared for different continents (Tab. 1).

Table 1 | SPA-canvas for different continents.

Continent	Size absolute1	Size scaled 1-10 (1x)	Potential absolute18	Potential scaled (5x)	Access** (3x)	Score
Europe	117500	3	$2500	2	5	3,1
Northern America	66339	2	$8694	10	7	8,1
Asia	597230	10	$2300	1,5	3	2,9
Africa	69143	2	$1900	1	2	1,4
Latin America	54510	2	* $1900	1	2	1,4
Oceania	7462	1	$2600	2	5	2,9
* No treatment costs found for Latin America. Estimated to be the same as for Africa. ** Estimated on the basis of our conversation with experts.

Out of this SPA matrix, we can conclude that Europe and Northern America score the best on size, potential, and access. This means we could actually serve a share of this part of the TAM in the medium-long term. Assuming that Binanox’ therapy will be the standard treatment, our SAM will be = $293 million + $577 million = $870 million dollars yearly.

Serviceable Obtainable Market

Thanks to our conversations with experts from the Netherlands, we now know the Dutch pharmaceutical market the best. Since PTT is still in its early stages it is advantageous to develop this therapy where there is close cooperation between hospitals and academia, like in the Netherlands. The Netherlands also provide a very favorable entrepreneurial climate. The Leiden Bio Science Park, specifically, has technology, knowledge, and innovation we could take advantage of. Additionally, we can establish our distribution channels easily in the interior. That is why we will focus on the market for head and neck cancers in the Netherlands in the short term. Standard treatment with chemotherapy or radiotherapy costs 15,000 to 30,000 dollars per person on an annual basis in the Netherlands¹⁹ and there are about 3000 new cases every year²⁰. This suggests that our SOM will be 45 million to 90 million dollars each year.

Direct competitors

NanoSpectra seems to be our only direct existing competitor. NanoSpectra is based in Houston, Texas and was founded on intellectual property from Rice University and collaborative research with scientists at MD Anderson Cancer Center.

The company’s principal focus is the development of AuroLase® Therapy, which is a patented form of PTT, for the ablation of solid tumors. This therapy comes with a near-infrared laser source, a probe for delivering the laser energy near the tumor, and their patented class of nanoparticles, called AuroShell® particles. Just like Binanox’, these nanoparticles absorb near-infrared wavelengths of light that harmlessly penetrate human tissue.

AuroShell particles, which have a non-conducting silica core and a gold metal shell, are used to absorb the probe's near-infrared laser radiation. Since they are small in size and administered intravenously, they can collect inside tumors according to their leaky vasculature. According to NanoSpectra, the particles do not collect in healthy tissue, because they cannot enter the regular vasculature. Once the particles have gathered in the tumor, the tumor is treated with a near-infrared laser at wavelengths chosen to optimize light penetration into tissue. The AuroShells are designed to absorb this wavelength and convert the photonic laser's energy into heat strong enough to eradicate the tumor.

The AuroLase technique can be completed as an outpatient with substantially fewer side effects, allowing the patient to resume regular activities in days as opposed to weeks.

AuroShell particles are still investigational at this current time. The clinical trials that have been executed by Nanospectra are the following:²¹

• A terminated trial on lung tumors, 2016
• A completed trial on tumors of the head and neck, 2017
• An ongoing trial on prostate neoplasms, 2019
• A enrolling trial on prostate neoplasms, 2020

According to their website, Nanospectra focuses on the AuroLase Therapy for prostate disease. The company is currently conducting a multi-site clinical trial for prostate disease²².

As opposed to what you might think, the successes of NanoSpectra are actually really promising for Binanox. It doesn’t mean we are excluded from the PTT market at all. On the contrary, it shows that optimizing PTT by producing the most optimal nanoparticles is really worth working on.

Added to that, NanoSpectra focuses, unlike Binanox, on prostate cancer. The reason they shifted their focus from head and neck cancers to prostate cancer is unknown. Perhaps, the AuroShell nanoparticles are less suitable for head and neck cancers than they expected. Binanox’ nanoparticles, however, are promising to be THE optimal nanoparticles for PTT for head and neck cancers, because of the three main features, namely (i) bimetallic, (ii) urchin-like NPs, and (iii) employing particles within the size range of 20 and 150 nm, identified in the implementation page.

Nanospectra produces their nanoparticles chemically, which means they have to deal with the disadvantages of a chemical synthesis. Most important disadvantage is the risk of more adverse effects due to toxins coming from added chemicals. Other than that, their production process can be hazardous and lead to non-biodegradable and toxic waste. Also scaling up chemically is harder, which leads to lower cost-efficacy.

Another downfall we expect from NanoSpectra’s therapy is its unspecific way of targeting. According to a previous study, the amount of nanoparticles that can reach the tumor site for cancer treatment is much smaller than the amount of intravenous injection. Because of the clearing effect on the body, the drug does not have sufficient efficacy²³.

Read more about how we are planning to enrich the tumors with our nanoparticles right here.

Indirect competitors

Indirect competitors are competitors that don’t focus on PTT but on alternative cancer treatments that are on the market right now. The most common treatments are surgery, chemotherapy, radiotherapy, and immunotherapy. As explained earlier, these treatments don’t come without any harsh side effects. For example hair loss, mouth problems, loss of speech, and autoimmune diseases can occur.

F. Hoffmann-La Roche AG, Bristol-Myers Squibb Company, AbbVie, Inc., and Johnson & Johnson are a few significant companies in the market for cancer treatments. The cancer drug Revlimid, made by Bristol-Myers Squibb, comprises the largest share in the cancer therapeutics market in the year 2020. Revlimid is an oral cancer medication used to treat and manage multiple myeloma. This medication affects the patient's immune system in order to fight cancer cells. It is also often used in combination with daratumumab (Johnson and Johnson), which is also a form of immunotherapy²⁴.

As you might now know, immunotherapy is not applicable to every type of cancer. Only 15-20% of patients with head and neck cancers benefit from this therapy²⁵.

Other than that, it could lead to autoimmune diseases and even death. A diversity of non-specific toxic and side effects can occur, under which hyper progressive disease, accelerating the death of patients. The effect of immunotherapy is moreover affected by many factors, making survival rate and prognosis uncertain. And just as important, the treatment costs are very high. To compare, the average cost of immunotherapy in 2015 was $228,504 versus $140,970 for chemotherapy²⁶.

There is another big disadvantage to one of these therapies, that doesn’t directly affect the patient: the drugs used for chemotherapy may negatively affect the environment. These drugs stop the growth and division of cells. Released into the environment, they can affect the ecosystem through altered fertility and increased genetic defects²⁷.

Future competitors

Our future competitors are companies that are working on other novel cancer therapies. Examples of these novel therapies are personalized vaccines, CAR-T cell therapy, the use of CRISPR/Cas9, and medicines based on microbiome sciences. Continue reading to learn more about these therapies and their current state.

For making personalized vaccines, cancer mutations must be identified. Then, specific RNA in a vaccine can give instructions to create a particular cancer antigen that primes the immune system against the tumor. The vaccines do not directly modify human DNA, unlike gene editing. The tailored vaccines developed by BioNTech have shown promise in preliminary clinical trials ²⁸. However, the company still has to establish a manufacturing system that can reliably produce a different product every time. Also, for cancers with lower mutation loads other technologies, such as CAR-T therapy, might be more suitable for the patients.

Immune T-cells from the patient are used in CAR-T cell therapy, which are genetically modified to target a particular cancer antigen. Clinical trials using CAR-T have produced remarkable patient outcomes²⁹.

The technology has, however, also manifested some serious adverse consequences that resulted in patient fatalities. Organs can be harmed, and the patient may become permanently disabled or die when the target antigen is expressed on normal tissue. So far, the method has only been used to treat a few extremely uncommon types of hematologic malignancy. A new generation of CAR-T therapies that can target a wider variety of tumors is being developed by several players.

These updated and improved CAR-T cell therapy generations show promise. However, the clinical trials are still in their early stages and will require more time before commercialization.

CRISPR/Cas9 is a technique to modify DNA with high precision. In China, scientists are using CRISPR gene editing to remove a gene to evade an immune attack in humans³⁰. Another trial with a similar approach is currently running in the US³¹.

There are worries that we still don't fully understand the overall consequences of utilizing CRISPR in humans. But if these concerns are successfully addressed, the potential is substantial.

The French company Enterome develops medicines based on microbiome science. The human microbiome plays an important role in many aspects of our health, including cancer.

Tumor cells are often invisible to the immune system. In order to make the tumor visible to the immune system again, the microbiome’s ability to mimic tumor antigens can be used.

Based on these tumor-like chemicals, Enterome has developed a cancer vaccine that triggers potent immune reactions against the tumor. With this, the immune system can be reactivated and make tumors stand out. Although the cancer vaccine has shown promise in preclinical studies, it still has not been tested in human trials³².

These new technologies against cancer still have to prove their worth in clinical trials, especially for head and neck cancers. It will be several years until they are available, so they won’t be a direct threat to Binanox. We are excited about other companies’ innovations and we even see possibilities to cooperate and produce a merged therapy. This could have high potential since combining PTT with other cancer therapies seems to have beneficial effects³³.

Key partners

For the development of our company, we need several key partners. First of all, Luris, the Knowledge Exchange Office for Leiden University can help us with trademarking, registration, and further advice on intellectual property. unlock_, located at the Leiden Bio Science Park, is the only Life Sciences and Health-specific startup incubator in the Netherlands. Mr. Ellenbroek invited us to take part in the incubator program in the future. Then, clinical research organizations (CROs) are needed for the outsourcing of clinical trials. According to our experts, it is favorable to outsource these trials, since this is financially more advantageous. The Center for Human Drug Research (CHDR) is a full-service, early-stage contract research organization, located in Leiden, the Netherlands. They provide a full range of high-quality, data-intensive clinical pharmacology services to the (bio-)pharmaceutical industry. Their innovative methods and technologies, good facilities, and talented, motivated researchers will help us maximize our success. Also, we will need a biotech company, preferably working with E. coli, and a company specialized in optics or the production of lasers to cooperate with us. Other crucial key partners are EMA and RIVM for regulations and risk reduction. Both have to be persuaded of our nanoparticles’ safety and efficacy. Therefore, it is important to get in contact with them as soon as possible, in order to work according to Good Laboratory Practices. Additionally, we need to have lab space. This could be by cooperating with a company or by renting lab space at BioPartner, located at the BioScience Park. This company offers flexible office and laboratory facilities. For our raw materials, we will need multiple partners. However, a big partner will be SigmaAldrich, since they offer a large range of products for pharmaceutical development and manufacturing, And last but not least, a key partner will be a supplier of bioreactors. For example, Sartorius sells bioreactors that are sterile and can be modulated in size.

Key activities

Acquire Funding

The following steps are very costly, therefore it is crucial to acquire funding. Details about funding are described later.

Completing the proof of concept

What future steps need to be taken concerning the proof of concept, can be read here. After executing these steps we can show that we have promising safety and efficacy. This safety and efficacy should be as good or better than our competition, in order to continue as a business.

Register the company & possibly file a patent application

Whenever our proof of concept continues to be as promising as it is now, we should register our company and trademark. In the Netherlands, If you start your own company, you must register in the Trade Register of the Chamber of Commerce (KvK). This registration costs € 51.95 once. Additionally, when we have an optimized formulation or composition, patenting it would be an option.

Cooperating with pharma/biotech/laser company

As soon as we have the needed Proof of Concept, we can start cooperating with pharma, biotech, or laser companies, as discussed in the Exit Strategy. We can offer the company our expertise in our invention. We expect our chances of successful cooperation to be bigger, when we have thought thoroughly about the clinical trials in which we can take the most optimal costs/risk path, based on Question Based Development. Together with these companies, we can then invest in outsourcing the preclinical and clinical trials.

Testing through preclinical trials

During the preclinical trials, we will focus on dosage design, analytical and bioanalytical methods development and validation, metabolism and pharmacokinetics, toxicology, and GMP manufacture and documentation of drug products for use in clinical trials.

Testing through clinical trials

Clinical trials are performed to investigate the safety or efficacy of a medicine. For Binanox’ nanoparticles with human cancers as application, these studies must be carried out in human volunteers. Different medicine agencies, like EMA, FDA, and CHDTA, have different regulations for access to the pharmaceutical market. Since performing clinical trials is very costly, we aim to take all these regulations into consideration so that we don't lose any unexpected time or money for this.

Obtain EMA’s & the Dutch government’s approval

More of a point of time, instead of a time period, is getting EMA’s approval. According to EMA, following a positive recommendation from the Agency, the European Commission takes around two months to approve a medicine.

According to Dr. Frederix, clinical efficacy and a reimbursement file are both considered in an economic evaluation done during phase 3 clinical studies. In order to determine which improvements have been made and where this file compares the new therapy to current therapies. This is frequently very similar to what EMA demands. This material is given to the Zorginstituut in the Netherlands. There they evaluate the application and advise the minister about approval of the application, after which the minister has the final say.

When a new therapy is adopted in the Zorginstituut, it is re-evaluated once every couple of years depending on how expensive it is.

At this point in time, we could also try to get FDA’s approval. However, this is in no rush, which is why it is mentioned later on the timeline.

Marketing of our product

After finalizing the clinical trials and getting approval, the doctors should be convinced based on evidence. Marketing to doctors is allowed, so this involves lobbying doctors. The marketing of our

nanoparticles will be done via some of our Channels. The doctors will consequently have an influence on the golden standard for a certain disease, which is decided every two to five years. To be able to focus on the marketing of our product fully, new team members for sales should be hired.

Upscaling of the production process

In order to produce products on the scale of demand, upscaling is needed. For this, it is also important to establish agreements with manufacturers of raw products. You can read more about the upscaling on the implementation page.

Establish distribution channels

In the short term, production and end-users are nearby, so the distance of transportation is relatively small. However, supply chain companies with supply chain expertise and logistics capacities are still a need. Examples of such companies we can work with are MAERSK or DSV. Read more about distribution on the implementation page.

Key resources

Resources are indispensable in order to make our business a success. Probably the most important key resource is the experience, knowledge, and effort of our team, supervisors, and advisory board. Our supervisors and advisory board include experienced and valuable people with diverse backgrounds. With these aspects, we will be able to elaborate our Research & Development. Other than that, our unique method of synthesis is crucial for our business. Without this method we wouldn’t be able to answer the Patient’s Need, nor would we have any value propositions. To protect our unique method of synthesis, we will acquire proprietary DNA sequences optimized for nanoparticle production which you can read about in the paragraph intellectual property, down below. To further develop our product, we will validate our prototype with end users and redesign it. For this user experience expertise from patients or doctors is needed. Organizations providing grants are crucial for the funding of our business, or more specifically mostly for the clinical trials. Moreover, lab space and lab materials are essential for both R&D activities as well as commercial activities. In addition, Binanox is dependent on financial and reputational support from the university. Leiden University also offers intellectual property expertise, which will be of great help. Business development and sales expertise are needed during the marketing phase and can be offered by institutes like PLNT and unlock_. Lastly, for distribution, supply chain expertise is a necessity.

Value proposition

Binanox’ nanoparticles have a range of value propositions compared to other treatments, other nanoparticles, and other methods of synthesis. PTT is a therapy that is minimally invasive and potentially effective to treat head and neck cancers. The nanoparticles we plan to use for this treatment include, as described in the implementation page, all optimal features that lead to a higher safety/efficacy, compared to other nanoparticles. Also, our production process is greener and less hazardous than the chemical production of these nanoparticles, as you have read before in Patient Needs. With this biological synthesis, we have the ability to define the size, and shape of the nanoparticles. Moreover, no harsh chemicals will be used and only biodegradable and non-toxic waste is produced. As a result, no toxicity from hazardous chemicals occurs both during synthesis and during therapy. In addition, this method of synthesis has the potential to produce nanoparticles on a large scale and to be cost-effective.

Customer relationships

Customers are critical for a company. A long-term relationship with insurance companies and doctors is needed, in order to get our treatment insured. For this relationship, Binanox will offer personal assistance from medical representatives and our service desk. Other than that, there is a transactional relationship between end-users: the patients. This means there is no real relationship between the company and the patient.

Channels

The use of different channels is important for our company. Our communication, distribution, and sales channels describe how our company communicates and reaches our Customer Segments to deliver our Value Proposition. First of all, channels to promote the use of treatment with Binanox nanoparticles will be obtained. In the early stages, this would concern presentations at medical symposia. Also, doctors will be informed through pharmaceutical representatives. When registration of the device has occurred, we can start informing the general public on the news and popular scientific media. Another crucial channel is of course a distribution channel to make it possible for our nanoparticles to reach the location of treatment.

Customer segments

In order to make Binanox’ PTT the standard therapy in the Netherlands, the government and doctors need to be persuaded of the advantages of our therapy. This will be done via broadcasting and medical representatives. Since all Dutch pay insurance premiums to the insurance companies, these companies are our direct customers. However, our ultimate users of the products will be cancer patients.

According to our expert Anke Hövels, if a type of treatment cannot be taken at home in the Netherlands, it belongs to the hospital budget. The hospital, therefore, decides whether to provide the treatment or not. However, there is a limit to this budget. Even though there is no official set maximum, the general practice is that any treatment above €80,000 per quality-adjusted life year (QALY), will end up in a metaphorical black box. Here considerations will be made, and if it is decided that the therapy is worth it, the government will aid in financing the therapy.

Outside the Netherlands, the care system works differently. Healthcare is often more private and not even all patients are insured. This means that in the long term, when we have comprised the market outside the Netherlands as well, the cancer patients will be our direct customers. However, doctors and hospitals still have a great influence on what therapies they can offer, which makes these stakeholders the indirect customers.

Cost structure

The cost of R&D will be our main expense. This includes costs for completing the proof of concept, testing through preclinical trials, and testing through clinical trials. Other costs are registration costs and costs associated with upscaling. According to one of our experts, about 20% of the costs are generally lost for marketing purposes in the pharmaceutical industry. Lastly, Binanox will have costs concerning production. After upscaling we will need to buy large amounts of materials, for which we could negotiate a lower price per unit, leading to economies of scale.

Revenue streams

In the short term our revenue stream comes from Dutch insurance companies. In exchange, they will receive a brokerage fee that comes out of the monthly premium that the dutch pay for health insurance. In the medium long term, our revenue stream comes from patients from Europe and Northern America, which concerns an asset sale of our nanoparticles.

We talked with expert Lorenzo Bombardelli from Luris about the possibilities concerning intellectual property.

First of all, we could register our company Binanox by the Chamber of Commerce (KvK). This way we’ll be able to operate as a commercial entity.

For Binanox, a possibility would be to patent our nanoparticles. However, it is pretty hard to obtain a patent sufficiently broad to cover different types of nanoparticles and prevent competitors to market a product similar to ours.

In addition, if we were to patent our nanoparticles, we would also need to describe in details the sharpness, length and size of the particles. We would have to provide data for the patent claims. The description of the patent will be made public after 18 months Everyone, including our competition understand how the invention works and what is the scope of our patent protection. Based on our data, we could only patent particles of 50 nm and spikes of 5 nm with medium sharp spikes. What if someone takes note of our invention and makes nanoparticles with the same shape but 20 nm bigger? According to our research for the ideal nanoparticles these particles would still be effective, which is not covered by our patent, which means they could become a big competition for us.

Another option would be to patent the particle production method, which would include the necessary variables, like the range of pH, temperature, and concentrations of metal ions that lead to our nanoparticles. Also, it would include information about the genes we used to transform the E. coli bacteria with. What if another company for example uses the pH that falls just outside of this range, but works as good? Or what if another company finds a gene that works just as well? And how could we find out what a potential competitor is infringing? It is practically impossible to check how other companies produce their product.

However, since the use of microbes to produce metallic nanoparticles is a relatively new field, our development could profit from a first-mover advantage: Being the first to market in a new product category gives it an advantage over its rivals. It would be unfortunate to not make use of this advantage and make our unique technology our property. However, the best option for our company would be to choose the trade secret as a protection method for our technology.

The best option for our company would be to choose the trade secret as a protection method for our technology. We could raise funds to sponsor proof of concept experiments to improve the production methods for nanoparticles and also test efficacy and safety in animal models. We could achieve this by partnering as discussed in the exit strategy. We envision that the development process will generate new IP worth patenting and increase the value of our company. Once we have a robust production method and possibly a patented formulation/composition we will consider licensing it out to larger companies that will take care of testing our particles in clinical trials.

Cost analysis

The final costs of commercializing our nanoparticles are highly dependent on the specifics of our R&D and manufacturing. This is why it is difficult to give an accurate estimate of the development of our business. The average costs of phase I and II of clinical trials are $3,4 and $8,6 million dollars respectively³⁵. The median estimated cost of oncology-specific pivotal trials was $31.7 million³⁶. However, the costs to develop one cancer drug are way higher: approximately $648 million³⁷. Nanospectra, our direct competitor, has raised $10.6M³⁸. However, they have not finished their multi-site pivotal trial yet, so this amount of money is for sure not their seed round. When observing the amount of money described above, we can best estimate the total costs to the average costs of developing a cancer drug, which is $648 million. This concerns R&D only, which means that costs for marketing and upscaling should be added to this. With the help of our experts, we have estimated this on an additional $200 million.

Funding

Even though these costs are high, the majority will only be required in later stages, when we have already executed our exit strategy: Merger & Acquisition. Binanox is likely to produce an orphan drug. Accordingly, the European Commission designated a medication for the treatment of patients with squamous cell carcinoma of the head and neck as an orphan medicine in 2011³⁹.

Because of this, we could get additional aid from EMA and other institutions, during our entire development.

In our discovery phase, the phase from iGEM to proof of concept, we will get the majority of our funding from family, friends, and fools (FFF), crowdfunding, grants, and from university support. However, strategic big pharma investors are often keen to learn about new technologies and tap into innovations early. These big pharma investors can play an important role during the entire development timeline. When our nanoparticles are in the preclinical phase we are dependent on grants, crowdfunding, and business angels. While in the clinical trial phase, we will be reliant on venture capitalists and Initial public offering (IPO). For the clinical trial phase III, we will be more reliant on private equity.

A potential source of funding is the MIT regulation. This regulation aims to stimulate innovation within small and medium-sized enterprises (SMEs), that are in line with the innovation objectives of the Dutch top sectors. The Ministry of Economic Affairs and Climate and the Dutch provinces make an annual budget available for the MIT regulation. Binanox could apply for MIT R&D collaboration: this is a project consisting of industrial research or experimental development carried out by at least two SMEs, who renew or develop at the joint expense and risk. For MIT R&D collaboration, the subsidy amounts to a maximum of 35% of the eligible costs up to a maximum amount of €350,000 per MIT R&D collaboration project.

Enterprise Leiden Fund Pre-seed, or ELF Pre-seed, is an early phase loan that can help us to further develop and finance our idea. Luris is in charge of allocating the loan. We have already had contact with Luris, which might increase our chances of getting this loan.

The Dutch Organization for Scientific Research (NWO) is a significant source of funding for research in the Netherlands. The take-off initiative of NWO is a funding instrument available to all scientific fields. This encourages activity and entrepreneurship within Dutch knowledge institutions. For a feasibility study, researchers within Take-off can request financing of €20,000 to a maximum of €40,000. This loan can be used to perform a feasibility study of the commercial application of innovative ideas and the start of activity on the basis of knowledge innovations from knowledge institutions. With take-off early stage routes, startups that have just been initiated by researchers or entrepreneurs can request a loan of €50,000 to a maximum of €250,000.

UNIIQ combines the expertise and networks of three top Dutch universities and a regional development agency, where, on the one hand, universities introduce the necessary technological knowledge, and on the other hand, InnovationQuarter brings market knowledge, as well as an extensive network of private investors.

Last but not least, venture capital funds may invest to raise money. Healthy Ideas, Healthy Returns (HIHR) is one of the potential ways to meet investors. Around one hundred investors, spin-offs, and TTOs are connected through this network in the Benelux. By presenting our project at HIHR, we might make relationships that are helpful for securing additional funding in the future.

A big investor in the Netherlands is Forbion, which is a leading venture capital firm that works closely with entrepreneurs to build life sciences companies.

The foundation Mibiton enables young entrepreneurs in the Life Sciences to finance expensive equipment or facilities. The fund Mibiton Share offers young Life Sciences companies and knowledge institutions the opportunity to invest in equipment or facilities together. At least two contract partners use the equipment or facilities. The maximum investment is € 650,00.

Biogeneration Ventures (BVG), another venture capital firm, offers early-stage funding for European life sciences companies. According to their website, BGV has built relationships with Leiden University, which makes getting funding for Binanox more feasible⁴⁰.

Our expert Adam Cohen has introduced us to Question Based Development (QBD). To pay for the huge expenses of innovative research and development, pharmaceutical businesses must rely on a small number of really profitable drugs⁴¹. It pays to stop failing experiments as soon as feasible in order to keep medication development expenditures to a minimum. QBD can aid in this early termination, by answering five questions during the clinical trials. Under each question, sub-questions we came up with during our QBD session with Adam Cohen, are shown.

1. Does the biologically active compound/active metabolites get to the site of action?

• Can the nanoparticles get into the bloodstream?
• What are the factors that influence this?
• How quickly do the nanoparticles get cleared?
• What is the tumor/tissue ratio?
• What is the tumor/blood ratio?
• Does the mode of clearance differ between animals and humans?

2. Does the compound cause its intended pharmacological or functional effects?

• What is the effect on the tumor without NIR radiation?
• What is the affinity of the antibody of the nanoparticle with other tumors?
• What is the effect of NIR light?

3. Does the compound have beneficial effects on the disease or its pathophysiology?

• How toxic are the nanoparticles for the tumor cells?

4. What is the therapeutic window of the new drug?

• What are the effects on tumor growth?
• How do the nanoparticles interact with existing therapies?

5. How do the sources of variability in drug response in the target population affect the development of the product?

• How do different types of tumors react to the nanoparticles?

The goal of the question-based methodology is to make the main problem in drug development programs explicit rather than implicit. By thinking of sub-questions like the above, and then the suitable biomarker, validation status, trial to answer the question, costs, and probability of failure, all the important questions are asked and effectively addressed. After this, a regulatory body can confidently approve a market. QBD makes the assumption that it is possible to estimate the costs of response and the likelihood that it can be provided adequately. Every combination of probabilities, costs, and market value will have a unique optimal priority order.

The ideal development method, which differs for each medicine, is determined by a special combination of costs and the probability of effectively answering the issue. Additionally, it highlights the development's bottlenecks and significantly aids in the early termination of failures. Contrary to traditional Net Present Value calculations, the question-based approach incorporates the value of both knowledge about methodology and additional early evaluation studies because the probability of successfully answering the questions is determined by both the potential of the compound and the availability of methods to demonstrate the effects.

We have a very passionate team that consists of people with various backgrounds in the biology field. Our members include both bachelor and master students, which are biology students, life science and technology students, molecular genetics and biotechnology students, biopharmaceutical science students, and even a mathematics student. Additionally, our team has a lot of different nationalities, including people from Indonesia, Luxembourg, Russia, Tanzania, and the Netherlands. These different backgrounds help to tackle challenges since we are able to look at things from different perspectives.

Moreover, we are really thankful to have support from our supervisors and advisory board. Our supervisors are people with a lot of experience, knowledge, and skills, and have helped us before with coming up with solutions for some difficult problems.

Not to forget, is the support of the university. Leiden University has built a lot of credibilities, experience, and a good reputation over the years. This ensures that we are one step ahead compared to other startups. We may also receive support from Luris, the Knowledge Exchange Office of the University. Luris gives advice on how to protect inventions, negotiates with interested companies, helps to find partners interested in the invention, and maintains long-term relationships with these companies.

With these people, we are convinced we could make Binanox into a successful start-up.

Understanding stakeholders is crucial, both for integrated human practices and for the future of our project as a business. Therefore, we visualized the interest and power of our stakeholders in Figure 8, with help of iGEMers guide to the future, the result of a four-year collaboration of iGEM teams. For example, competitive NP producers have concerns about the development of our nanoparticles, since this can worsen their position in the market. However, they have the power to influence our position negatively as well, by strengthening their own products’ value proposition. Cancer patients, however, don’t have a lot of power to influence the development of the treatment with Binanox’ nanoparticles, at most by giving their personal preference for another treatment, but they are naturally very interested in this promising treatment. EMA has lots of power to influence our project, simply by rejecting or accepting the use of the nanoparticles in a treatment. Their interest can be considered negative since EMA is an institute that will have lots of concerns, which can be seen in its many regulations and demands.

Fig. 8 | Stakeholder map. Power means that the stakeholder has the power to influence your project, positively and negatively. Interest also includes concerns or the degree of criticality, which is on the negative side of the y-axis and can be organized from greater to lesser.