This page documents our extensive research on how to establish our system as a new standard of treatment in the current and future therapeutics market, from the perspective of forming a startup based on our project. We used the example of applying our system to the chemotherapeutics market and using R bodies as a cancer treatment. We created comprehensive plans for future development with the aim of attracting investors, all of whom will want to know exactly what their money will be going towards and how our product can deliver returns.
Engaging with our entrepreneurial side for this special prize allowed us to have a whole different perspective on our project and where it could go next. We became acutely aware of potential challenges we could face in the market, but this only motivated us to do further research to prove that the benefits outweighed the risks and build a stronger case for our project.
Throughout the year, our team was able to secure funds for our research and other objectives planned throughout the year on the strength of our business case. So far, we have raised $11,000 from the Office of the NSW Chief Scientist & Engineer through the 2024 STEM Student Competition Sponsorship Program. We have also received $5000 each from the University of Sydney Faculty of Science, School of Life and Environmental Sciences and School of Chemistry.
1. Market Research and Analysis
Current chemotherapy limitations
in 2022, 20 million cancer cases were newly diagnosed and 9.7 million people died from the disease. By 2050, the number of cases are predicted to reach 35 million (American Cancer Society). The increasing incidence of cancer and cancer related deaths warrants the need for safer and more effective treatment.
Whilst chemotherapy has long remained the gold standard of treatment, it involves the indiscriminate killing of healthy cells in a patient. This can induce bone marrow suppression and gastrointestinal reactions, and generally compromises patient quality of life.
Another limitation in chemotherapeutic treatment is the ability of cancers to develop multidrug-resistant (MDR) mutations, compromising the effectiveness of the treatment. In fact, a study has shown that 90% of deaths of tumor patients were associated with drug resistance. In contrast, intracellular drug release is able to bypass the tumor cell ability to develop MDRs (Pavan, 2023; Cheng et al., 2021).
Therefore, in order to facilitate the development of targeted therapies, the drug delivery market is expanding and is expected to value over $300B by 2030 (Towards Healthcare, 2024).
Nanoparticle drug delivery
Since 1995, roughly 70 nanomedicines (consisting of a nanoparticle chassis with an integrated drug/biologic) have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (Halwani, 2022)
A majority of nanoparticle (NP) drug delivery chassis utilise organic nanomaterials like liposomes, as well as inorganic substances such as graphene and gold. Regarding anti-cancer drug delivery, the NP’s material and specific size are uniquely chosen according to the pathophysiology of the cancerous tumor.
The two current targeting mechanisms of NP systems are:
- Passive targeting: relying on the Enhanced Permeability and Retention (EPR) effect, so that at an optimal size, NPs can accumulate in tumor tissues which have an increased vascularization compared to normal tissues.
- Active targeting: NPs are coated with ligands that specifically bind to receptors that are overexpressed in cancerous tissue. For example, human epidermal receptor-2 (HER-2) in NP design is a currently common therapy for HER-2 positive breast and gastric cancer. (Kamaly et al., 2012)
A well-known NP drug delivery system is Doxil, a liposomal nanocarrier of the chemotherapeutic doxorubicin. Currently, Doxil is clinically used before surgeries to passively target breast cancer tumors, and generally, patients exhibit less nausea and vomiting compared to regular doxorubicin.
However, some limitations in current use of NP systems are (Papini et al., 2020):
- Inorganic NPs can be subjected to opsonization, where opsonins (antibodies) accumulate on the surface of the NP forming protein coronas.
- Toxicity associated with inorganic NPs can cause harm to cells. For example, it has been shown that cellular membranes and DNA suffer from free radicals (unstable atoms that damage cells).
- Animal studies have shown that the EPR effect impacts NPs differently in rodents compared to humans.
- These uncertainties and lack of human trials contribute to the relatively slow clinical translation and little use of NPs for drug delivery compared to the widespread NP research currently being conducted.
How our team have implemented NP drug delivery analysis into our work:
Our team has incorporated engineered solutions to circumvent some of these mentioned limitations. Our R body-based drug delivery system:
- Aims to utilize an active tumor targeting mechanism by conjugating ligands specific to the cancer cell type to the R body monomer.
- Will be coated in Polyethylene Glycol (PEG) to reduce toxicity, opsonization, and immune response.
Antibody-drug conjugates
Antibody-drug conjugates (ADCs) comprise a monoclonal antibody chemically linked to a cytotoxic drug, combining the advantages of highly specific targeting and highly potent killing effect (Fu et al., 2022). The antibody component often targets overexpressed antigens specifically expressed on cancer cells (e.g. HER2 for beast cancer or C20 for B-cell lymphoma), allowing the ADC to distinguish cancer cells from healthy cells and minimising off-target toxicity. Once the ADC binds to its target antigen, it is internalised and releases its payload intracellularly.
ADCs can also demonstrate a bystander effect, where the payload released in the tumour microenvironment can permeate tumour cells with low or even negative expression of the antigen targeted by the antibody, overcoming the issue of tumour heterogeneity. For example, HER2 is only overexpressed in less than 20% of breast cancers, but even among HER2-positive patients, approximately 30% exhibit intra-tumour heterogeneity in HER2 expression (Guo et al., 2024). Trastuzumab deruxtecan, an ADC, showed solid response rates in tumours with heterogeneous HER2 expression, and even in breast tumours with low HER2 expression, 30-40% showed responses.
Our proposed R body system differs from ADCs by the addition of the R body protein carrier in between the targeting molecule and the drug. We aim to conjugate a targeting molecule and drug payload to each R body monomer, achieving all of the benefits of ADCs including target specificity, cytotoxicity and bystander effect, but also improving on the mechanism of endosomal escape. ADCs require endosomal/lysosomal escape of the cytotoxic payload to have an anti-cancer effect (Tashima, 2022), but the mechanisms of payload escape are not well detailed in the literature. Using R bodies as a carrier provides a distinct mechanism for endosomal escape via the R body’s mechanical bursting effect upon acidification of the endosome, thereby enhancing the therapeutic effect of the payload.
2. Minimum Viable Product (MVP)
Our MVP includes:
- Purified R body pellets with chemically conjugated mNeonGreen and aldoxorubicin, confirming that ligands and drugs can be conjugated onto the polymer structure
- Internalisation of R bodies inside HEK293 cells, confirming that R bodies can successfully enter mammalian cells
- Purified R bodies with conjugated ligands which extend in response to changes in pH
These three characteristics demonstrate the ability of R bodies to act as a mechanically functional system which can carry drugs and ligands for targeted endosomal delivery. You can see our conjugation, internalisation and extension experiments on our Results page.
3. SWOT Analysis
After conducting research into the current state of the targeted drug delivery market, we developed a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis on our R body drug delivery system (Table 1). SWOT analysis provides an overview of the benefits of our medicine, which is essential for highlighting the clinical need for our medical solution. The analysis also introduces threats we may face during our manufacturing journey, which is critical for developing future contingency plans during the commercialisation process.
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Strengths:
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Weaknesses:
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Opportunities:
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Threats:
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4. PEST Analysis
PEST analysis assesses major external factors (Political, Economic, Social and Technological) that influence our operation in order to become more competitive in the market. Our product does not exist in a vacuum, and it is important to consider the context in which it exists as this can directly influence our efforts to bring it to market. Many of these insights were inspired by our stakeholder engagement, which you can also read about on our Human Practices page.
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5. Production Timeline
Below, our team has developed a production timeline for our start-up, detailing the approximate time required to build 100 units of our medicine (for a specific and known cancer cell line), as a start-up with 10 members/employees. The timeline approximates 40 days, and does not consider any post-manufacture validation experiments.
6. Future Expansion
Pre-clinical validation
As part of the commercialisation process, our team has developed an overview of some pharmacokinetic experiments to validate our medicinal product.
These experiments would provide the source of our pre-clinical data, to submit as a feasibility study for clinical trials. The presentation of pre-clinical data is a requirement for TGA conducted human clinical trials.
Experiment 1: Develop a physiologically-based pharmacokinetic (PBPK) model
Develop a physiologically-based pharmacokinetic (PBPK) model to predict:
- R body doxorubicin release rate
- Diffusion and accumulation profile of doxorubicin in tumor tissue
In doing so, the bioavailability, elimination half-life, clearance, and distribution of both the R body chassis and the released doxorubicin can be measured.
Experiment 2: Testing drug/biologic content in plasma
Test for doxorubicin and R body elimination and half-life rates by:
- Delivering a single dose of product to monkeys based on weight.
- Taking blood samples from monkeys at 10-minute intervals during the first hour, then every 30 minutes for the next 3 hours.
- Centrifuging samples to obtain plasma.
- Analysing drug concentrations in plasma.
Experiment 3: Bioavailability test
Compare oral vs intravenous administration of our product with the following steps:
- Fasting the test subjects (monkeys) for 24 hours.
- Delivering the R body-drug conjugate orally (single dose).
- Collecting blood samples every 30 minutes for 3 hours, then centrifuging to obtain plasma.
- Analyzing plasma profile for drug concentrations.
- Completing a washout period of the R body/drug from the animal’s system (24 hours).
- Delivering the R body-drug conjugate intravenously and repeating analysis.
- Comparing drug bioavailability for oral vs intravenous delivery.
Manufacturing and regulatory practices
A key component of pharmaceutical product commercialisation is the upholding of good manufacturing practice (GMP). Our team has aimed to incorporate necessary Therapeutic Goods Administration (TGA) on-site and documentation requirements into our start-up workflow and quality management.
Under TGA, our product would be a Higher Risk Product, which generally encompasses sterile and non-sterile medicines, and cellular therapies. Our start-up will apply for a GMP license, which includes registering a laboratory production facility and each team member for training.
Under the GMP, our start-up, being the initial main manufacturing source for our product, will:
- Have a quality management system in place to control all manufacturing activities.
- Provide information on how the laboratory equipment is maintained and controlled (e.g., phase microscope usage).
- Control manufacturing activities and experiments through the use of detailed procedures, in the form of an electronic lab notebook.
- Record manufacturing events using record-keeping practices (electronic lab notebook).
Other action items our start-up will initiate during post-market surveillance of our product, as required by the TGA (Therapeutic Goods Administration, 2023), include:
Developing a risk management plan: To identify and characterize known or potential safety concerns if our product and contingency plans to minimize risk. Assesses the risk-to-benefit ratio of our product for consumers with middle to late stages of cancer.
Developing an adverse reaction (AR) reporting system: To report harmful and unintended responses (no later than 15 days from occurrence) during clinical trials and when in market.
Ensuring pharmacovigilance audits: A pharmacovigilance system will help detect and investigate issues in consumer responses to our product in a timely manner. We will nominate a team member to act as a Qualified Person responsible for Pharmacovigilance Audit (QPPVA) undertakings. They will be responsible for communicating pharmacovigilance findings between us and the TGA. Pharmacovigilance training will be provided for all members in the team, educating them on ways to identify adverse events and how to mitigate them.
7. Commercialisation
The end goal of our start-up is to successfully commercialise our product, which will allow a wider population of patients to benefit from its therapeutic advantages. As a start-up composed of a team of undergraduate students, we knew we were naive to many of the real-world challenges of commercialisation. We sought insight from established researchers with commercialisation experience in our stakeholder interviews, but also contacted the Commercialisation Office at our university (which is responsible for commercialisation of university-owned intellectual property) for guidance about how commercialisation worked, and they very kindly agreed to answer our questions. We learned the following takeaways from our discussion with them:
- Researchers normally present the Office with an invention disclosure that details the potential applications of the research, and the market demand for it. We will need to demonstrate that endosomal escape is a highly relevant problem (i.e. that drugs are hard to get out of endosomal compartments), and that we are solving the problem in a way nothing else can.
- The Office then liaises with attorneys to determine if the research is patentable. Since further development of research requires lots of time and money, investors don't want to help if they aren't sure that the researchers have the exclusive rights to the idea, which would be formalised in a patent. The research must be novel (new, cutting-edge) and inventive (not obvious to other people or just a variation on a theme of previous research) because by filing a patent, the government is giving you monopoly on the whole idea. We need to prove that our idea solves a real-world problem that lots of people have, and do it better than anything that's been done before. This contributes towards a good intellectual property (IP) position.
- Startups and VCs look to acquire the idea if it's scalable within 10 years, but the rights can also be licensed to a company in the area of research if there's not as much potential for growth (e.g. if it's for a disease that doesn't affect as many people).
- It's important to look at what's been done before, especially since we're using existing plasmids/vectors. If people have already thought of the concept of using R bodies for drug delivery, a patent for the concept might be harder. We need to be clear on what's inventive about how we are using R bodies, because a patent might only protect a specific sequence we're using that's novel.
- No patent doesn't mean no commercialisation, but it does make it significantly harder to commercialise, especially in the highly competitive medical market.
- The more evidence we have to back up our claims (both of the inventiveness of the idea and its applications), the better. At minimum, we need data to prove it works (e.g. proof of concept with N=1). We will need robust evidence in various animals as well as bacterial cells in order to be confident about generalising to humans.
- Platform technology like ours needs a lead indication. Companies are rarely interested if you say it can do anything (e.g. us saying we can attach any drug), so it's good to use specific examples of how the research is better than anything else currently out there. We have addressed this issue by concentrating the majority of our Entrepreneurship (and engineering proof-of-concept) work on applying R bodies to delivery of aldoxorubicin, a cancer drug.
Patenting and invention disclosure
Our team is ultimately interested in the acquisition of a patent for our product, as this is often a prerequisite for commercialisation and collaboration and investment from companies. In our financial planning, we have considered costs of patent application fees and the cost of a patent attorney. Although patenting our project will require many more years of consolidation and research (especially in Australia where universities are hesitant to discuss patenting unless they can guarantee a return on investment), we are confident that something based on our research will be patentable in the future, and want to take proactive steps towards that.
The research we have conducted on our project throughout the year has allowed us to construct an Invention Disclosure, which is the first step towards commercialising intellectual property. The questions come from the New South Wales (NSW) Health invention disclosure form for Intellectual Property arising from Health Research
This is only a preliminary version of an Invention Disclosure as we would need many years more of research and validation experments, but it ties in to other work we had been doing for our project and more detail about the Invention Disclosure sections can be found elsewhere on our wiki:
- Relevant prior art is similar to the market research we have documented earlier in our Entrepreneurship work.
- More on problems, novel features and advantages of our system can be found on our wiki’s Description page.
- For more on proof-of-principle, refer to the Results page of our wiki.
- Commercial prospects are also detailed in "Our Solution" on the Description page, and the Strengths section of our SWOT analysis.
8. Stakeholder Engagement
Stakeholder interviews
Throughout our Entrepreneurship work, we continuously spoke to stakeholders and experts and gathered their input on the potential success of our product, how to improve it, and challenges we could face in the market. We specifically sought to interview academics who had experience with commercialisation, and oncologists who could recommend particular applications of our system (e.g. medical problems where intracellular delivery is a challenge), or hospitals where experimental treatments are easiest to push through. Full analysis of our stakeholder discussions can be found on our Human Practices page, but these are just some examples of key issues we learned about that were relevant to our Entrepreneurship goals:
- Antibody-drug conjugates as our main competitor in the chemotherapy market
- Demonstrating advantages over current standard (AAVs) in the gene therapy market
- Regulatory guidelines (characterisation data, manufacturing)
- Securing funding for further development and clinical trials
- Usability by community oncologists as well as those in well-resourced academic centres
StartUp Link speaker series
Our team was invited to present at a Speaker Series event for StartUp Link USYD, a student society which provides entrepreneurial-minded students with opportunities to learn about and gain insights into the world of start-ups. The theme of the event was ‘Sustaining Success and Future-Proofing’, and we were asked to discuss adapting to market changes, including the need to stay up-to-date with industry trends and market shifts, and the importance of collaborations with experts and stakeholders to gain insights into market dynamics. This was highly relevant to the work we had been doing for the Entrepreneurship special prize, so we jumped at the opportunity!
We knew this was a unique chance for our team to showcase the research we had been doing as a startup. We focused on the following things for the event:
- Communicating to people without a scientific background: StartUp Link specifically encouraged us to approach our presentation from a more general start-up and entrepreneurship perspective, and how our insights apply broadly across various industries, not just medical research. We also considered: how can we honestly and transparently inform potential consumers and the general public about what we are selling? What unique concerns do they have? How can we get them excited about something they know little about, and probably have apprehensions about?
- Talking to people from industry: what insights do other presenters and students have about challenges that are specific to industry (not just biotech)? We had received glimpses of these from our stakeholder interviews, but the perspective of someone who is purely in industry would be valuable, as the academics are not experts on entrepreneurship and often have to consult with industry experts themselves.
- Emphasising our image as a startup: What are we already doing that startups do, and what do we need to do in the future to build on our startup?
During our presentation, we discussed our product and how we adapted to a changing pharmaceutical market using market research and a Human Practices approach. We presented alongside two other speakers, who specialized in developing deep tech and fintech startups, as well as connecting growing businesses to larger companies for collaboration.
We explored how we approached market research, by breaking market research down into different aspects (e.g. clinical trials research, regulations, and emerging technologies), and keeping up to date on the news and literature on these topics. We also discussed our Human Practices approach, where we discuss and collaborate with stakeholders to gain a comprehensive overview of current limitations, opportunities, and competitors; collect feedback on our product; and address and acknowledge each party’s key concerns. Having laid out the variety of customers and stakeholders involved in bringing pharmaceuticals to market, we then presented examples of our discussions with Dr Hunt and Dr Kumar, showing their particular concerns as well as actionable insights we gained from speaking with them.
As our audience was largely from financial and technological backgrounds, they were interested in and learnt much from discussing a new market. Additionally, we learnt from their experience in entrepreneurship, such as different aspects of financial planning to consider, as well as tips for more efficient networking and branding to build trust with customers and potential collaborators and investors.
9. Financial Planning
As a form of financial planning, we created a breakdown of the Research and Development (R&D) costs required to manufacture 10g of our product onsite:
We have also have developed a hypothetical Operating Expenses (OPEX) financial projection. The projection assumes that our product: remains successful throughout phase I-III TGA clincial trials, patent acquisition, and that production is: scaled by a factor of 10 in 2025, doubled in 2026 and 2027, then remains consistent in 2028. This projection helped us as a team recignise the magnitued of revenue streams required for global production of our product, as an individual start-up.
10. Business Lean Model Canvas
Below is a business lean model canvas, which summarises the business model we have developed for our start-up.
You can read more about the problem, solution and unique value proposition on our Description wiki page.
References
A. A. Halwani, “Development of Pharmaceutical Nanomedicines: From the Bench to the Market,” Pharmaceutics, vol. 14, no. 1, p. 106, Jan. 2022, doi: https://doi.org/10.3390/pharmaceutics14010106.
American Cancer Society, “American Cancer Society,” Cancer.org. https://www.cancer.org/
E. Papini, R. Tavano, and Fabrizio Mancin, “Opsonins and Dysopsonins of Nanoparticles: Facts, Concepts, and Methodological Guidelines,” Frontiers in Immunology, vol. 11, Oct. 2020, doi: https://doi.org/10.3389/fimmu.2020.567365.
Fu, Z., Li, S., Han, S., Shi, C., & Zhang, Y. (2022). Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduction and Targeted Therapy, 7(1), 93–93. https://doi.org/10.1038/s41392-022-00947-7
Guo, Y., Shen, Z., Zhao, W., Lu, J., Song, Y., Shen, L., Lu, Y., Wu, M., Shi, Q., Zhuang, W., Qiu, Y., Sheng, J., Zhou, Z., Fang, L., Che, J., & Dong, X. (2024). Rational Identification of Novel Antibody‐Drug Conjugate with High Bystander Killing Effect against Heterogeneous Tumors. Advanced Science, 11(13), e2306309-n/a. https://doi.org/10.1002/advs.202306309
N. Pavan, “Drug resistance mechanisms in cancers: Execution of prosurvival strategies,” Journal of Biomedical Research/Journal of biomedical research, vol. 0, no. 0, Jan. 2023, doi: https://doi.org/10.7555/jbr.37.20230248.
Tashima T. (2022). Delivery of Drugs into Cancer Cells Using Antibody-Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect. Antibodies (Basel, Switzerland), 11(4), 78. https://doi.org/10.3390/antib11040078
Therapeutic Goods Administration, “Pharmacovigilance responsibilities of medicine sponsors Australian recommendations and requirements.” Available: https://www.tga.gov.au/sites/default/files/2023-08/pharmacovigilance-responsibilities-medicine-sponsors-2023.pdf
Towards Healthcare, “Advanced Drug Delivery Market Size Envisioned at USD 375.86 Billion by 2033,” Towardshealthcare.com, Feb. 15, 2024. https://www.towardshealthcare.com/insights/advanced-drug-delivery-market-sizing.
Z. Cheng, M. Li, R. Dey, and Y. Chen, “Nanomaterials for cancer therapy: current progress and perspectives,” Journal of Hematology & Oncology, vol. 14, no. 1, May 2021, doi: https://doi.org/10.1186/s13045-021-01096-0.