ENERGEM is committed to combating the increasing incidence of myopia across the globe. By innovating the way we approach treatment, we're working to make 7-methylxanthine (7-MX) not only more affordable but also more effective through a patented sustained-release pill form. Our vision is to introduce the world's first FDA-approved oral treatment for myopia, ensuring that the gift of clear sight is within everyone's reach.

Driven by urbanization, increasingly sedentary lifestyles, and growing screen time demands, the world is facing a myopia epidemic.

Myopia, better known as near-sightedness, is the excessive elongation of the eye which causes objects that are viewed at a distance to be blurred via the refractive image formed by the cornea and the lens to fall in front of the photoreceptors of the retina [1]. As a consequence of shifts in age demographics and lifestyle patterns, the incidence rate of this eye condition is skyrocketing. Myopia rates have increased by 66% over the past 30 years in the United States, and now affects 41.6% of the population [2]. More than 13 million Americans are affected by high myopia alone. Despite this prevalence, more than one in three Americans are still unaware of their treatment options.

This issue is particularly important in East and Southeast Asia, where approximately 95% of the population needs visual aids. About 90% of young adults are myopic, a remarkable increase from only 15% three decades ago [2]. The increase in the number of years of education a person undergoes is accompanied by more near-work, time using a screen, and reduced time outdoors, which are each strongly correlated with myopic incidence [3].

Beyond its immediate consequences, nearsightedness is a gateway to serious eye conditions such as cataracts and glaucoma. Those with high myopia are 3 to 5 times more likely to develop nuclear glaucoma and have a 30% higher risk of developing posterior subcapsular glaucoma [4].

Recognizing the gravity of the issue, the World Health Organization has listed myopia as one of the top five health priorities. The foundation predicts that by 2050, half of the world’s population, or about 5 billion people, will be nearsighted. Given these alarming statistics, there is an immediate need for effective solutions to manage and prevent myopia. Urgent attention is needed to raise public awareness and develop new therapies to address this growing health problem.

Cornell iGEM proudly introduces ENERGEM, a cutting-edge process of transforming cheap caffeine into high-value 7-methylxanthines. ENERGEM is committed to combating the increasing incidence of myopia across the globe. By utilizing the power of synthetic biology, we're working to make 7-methylxanthine (7-MX) not only more affordable but also a novel treatment for myopia.

Our vision is to introduce the world's first FDA-approved oral treatment for myopia, ensuring that the gift of clear sight is within everyone's reach.

ENERGEM consists of numerous hardware and software components:

Engineered E. Coli for Optimal Production: ENERGEM's foundational technology relies on the genetic engineering of E. coli. These bacteria have been precisely modified to produce the caffeine-metabolizing enzymes NdmA and NdmB. This bio-based approach to production ensures a more sustainable and efficient yield of methylxanthines, specifically 7-methylxanthine and paraxanthine, which are pivotal in addressing myopia.

Advanced Bioreactor Design: ENERGEM's foundational technology relies on the genetic engineering of E. coli. These bacteria have been precisely modified to produce the caffeine-metabolizing enzymes NdmA and NdmB. This bio-based approach to production ensures a more sustainable and efficient yield of methylxanthines, specifically 7-methylxanthine and paraxanthine, which are pivotal in addressing myopia.

Enzyme Encapsulation: A significant feature of ENERGEM's process is the enzyme encapsulation technique. We immobilize our meticulously engineered enzymes within sodium alginate beads. This process ensures the enzymes' longevity and optimal functionality within the bioreactor, promoting consistent yields across cycles.

While 7-Methylxanthine itself is not a patentable compound due its natural occurrence, our innovative approach to its production offers multiple avenues for intellectual property protection, the cornerstone of any product’s commercial success.

Cornell iGEM is set to file a provisional patent with the USPTO for our enhanced 7-methylxanthine production method, utilizing a single, optimized E.Coli strain. Inspired by Dr. Summer’s multi-strain approach, our single-strain technique offers balanced enzyme outputs, streamlining production and bolstering cost-efficiency. Paired with our proprietary reactor, this positions us uniquely for a significant process patent, primed for industrial scale-up. Our patent filing will grant us a “patent pending” status and a 12-month window to further refine our processes before submitting a full patent application. The provisional patent has significant commercial potential as can be sold or leveraged for other partnerships.

Following filing a provisional patent, Cornell iGEM will file an international patent application with the USPTO to apply via the Patent Cooperation Treaty to secure “patent pending” status across 152 countries. This application will act as an option contract and will allow our team to begin the foreign filing process while securing an additional 12-30 months from our US provisional patent filing date to make further refinements to our patent application [5].

We are committed to reaching peak enzymatic performance for our 7-methylxanthine before filing for a non-provisional patent. Through later rounds of fundraising and partnership, our team will acquire access to CRISPR technology which will help us to achieve an optimal strain performance. We will patent this particular strain. Until then, details regarding previous iterations of strains done with epPCR will remain confidential, classified as trade secrets to protect our intellectual property.

At the core of ENERGEM is our proprietary isothermal biochemical synthesis reactor (IBCS). The reactor presents a unique methodological approach to producing biomolecules which will be the cornerstone of our company’s future and upcoming product pipeline. Unlike traditional methods, the IBCS reactor is designed to handle various biochemical pathways and synthesize small biologically active molecules constantly so long as the necessary enzymes are encapsulated using our alginate bead encapsulation strategy. Therefore, we have a strong potential patent claim on a unique continuous process to produce small molecules of interest.

Finally, the future of our ENERGEM product line hinges on producing a patentable application of 7-methylxanthine for myopia treatment. Dr. Nita Mehta, professor of ophthalmology at Stony Brook Medicine, pointed out to our team that 7-methylxanthine is metabolized quickly. To mitigate this rapid metastasis, Dr. Mehta recommended our team investigate a sustained-release oral delivery method. Under the guidance of our scientific advisor partner from the Dyson Institute, we would seek to develop this technology as it would grant our product patent protection. Our team will simultaneously consider patenting other delivery methods such as intravitreal injections based on efficacy, cost, and targeted drug delivery.

Given that our ideal patients are children with myopia, a majority of our studies will be pediatric. This makes our product eligible for an additional 6 months of patent protection under Section 505A (Pediatric Exclusivity) of the Federal Food, Drug, and Cosmetic Act [6].

The pharmaceutical industry's value chain consists of five main stages: drug discovery, drug development, production/manufacturing, distribution, and sales & marketing. Currently, Cornell iGEM's focus is refining 7-methylxanthine production for a new myopia treatment, placing ENERGEM in the "drug development phase."

Cornell iGEM has specific assets for research and biomanufacturing. To effectively traverse the entire value chain, especially areas outside our direct expertise, we recognize the importance of strategic partnerships. Collaborations with industry specialists and organizations will provide the expertise and resources needed to propel ENERGEM through its developmental stages and into the market.

To transition into a startup, we're seeking entry into Cornell's Praxis Center for Venture Development and Weill Cornell Bioventures e-Lab incubators. These programs offer advanced facilities, equipment, and expert advice. They also provide guidance in securing SBIR-STTR grants, which will fund equipment like CRISPR, which is essential for our patentable strain development. Through BioVentures E-Lab, we'll collaborate with the Margaret M Dyson Vision Institute, a 12,000 sq. ft. research hub boasting top-tier ophthalmologists and researchers. This partnership grants us superior facilities, clinical trial resources, and invaluable expertise, enhancing our understanding of 7-methylxanthine and potential delivery methods. With grants streamlining our operations, we will onboard a Principal Investigator from the Dyson institute to serve as a scientific advisor and oversee our preclinical study efforts.

As Cornell iGEM transitions into evaluating ENERGEM’s therapeutic potential and a sustained-release delivery’s viability, we will conduct meticulous pre-clinical trial studies that build upon Trier et al’s results. Due to our partnership and future enrollment in the Praxis and Bioventures e-Lab accelerator, we will receive access to resources that would otherwise demand large investments, such as advanced lab equipment, animal access and care, in vitro, vivo, silico models, and etc. However, our team’s focus is on improving our manufacturing process, so we would not directly participate in the pre-clinical trials of our product.

Instead, the safety and efficacy of our 7-methylxanthine product will be scrutinized under the direction of our scientific advisor and principal investigator at the Dyson Institute. Recognizing the intensive and specialized nature of pre-clinical trials, we will streamline the process by partnering with EyeCRO, to examine the efficacy of novel test agents and therapeutic modalities. EyeCRO has over 20 years of experience serving 400 clients and offers state-of-the-art technologies such as optokinetic tracking, electroretinography, and optical coherence tomography. EyeCRO is accredited by the AAALAC, certifying its commitment to conducting ethical animal studies. EyeCRO is the ideal partner to identify our product’s efficacy, toxicity, pharmacokinetic, safety, and suggested dosage information.

As we conclude the pre-clinical studies, our company will enter Series-A funding which will facilitate funding for the clinical trials phase.

Backed by Series A and B funding, Cornell iGEM will transition to conducting clinical trials for our sustained release form of our 7-methylxanthines. Our clinical trial strategy will be defined through our partnerships with key organizations and specialists to ensure proper vetting of our product.

Cornell iGEM will partner with ICON to coordinate these clinical trials. ICON is a global, full service CRO with a track record of success that includes overseeing more than 16 significant studies spanning nearly 6,000 patients across 633 sites. ICON’s specialty in patient recruitment will help us succeed in a therapeutic area that is hyper-competitive for patients and suffers from patient unfamiliarity with new products.

Our team has consulted with Dr. Luca Zatrenau, Chief of the Retina Division of Rochester Regional Health, on the execution of a successful clinical trial for ENERGEM. Our team will establish our primary study site at their ophthalmology flagship Riedman Health Center. We will work with Dr. Zaternau, Rochester Regional Health Directors and ICON to identify a suitable Principal Investigator to oversee our clinical trials. By utilizing Rochester Regional Health’s extensive network of pediatric ophthalmologists and staff, we will have access to ample study physicians, research pharmacists, and research nurses. While our phase I trial can be operated out of the Riedman Health Center, we will employ ICON’s site selection services to identify other collaborators to expand our studies as the phases progress.

Upon completion of Phase III of our Clinical trials, we will finalize a New Drug Application for the FDA.

Through our participation in the Entrepreneurship Community at Cornell University, Cornell iGEM has access to the Entrepreneurship Law Clinic. While our company is in its initial stages, the ELC will assist our team in drafting and negotiating contracts and patent applications. Once our company matures and requires appropriate legal counsel to abide by FDA regulations, potential mergers and acquisitions, and meticulous patent applications and extensions, we will consult with WilmerHale, an international law firm that has an established relationship with Cornell University and companies that originate from it.

A crucial step towards ensuring patient access for our product is to foster a robust relationship with insurance providers and vision centers, ensuring that ENERGEM is included in insurance coverage plans and formularies. A key aspect of this initiative involves engaging with Pharmacy Benefit Managers (PBMs), the intermediaries who decide the list of drugs an insurer covers. By understanding and aligning with the criteria set forth by PBMs and insurance companies, we aim to secure a place for ENERGEM on insurance formularies, which would significantly enhance its affordability for consumers.

Vision center partnerships are a key component of our market penetration strategy for ENERGEM. Through educational seminars, workshops, and a plethora of informative resources, we aim to impart a thorough understanding of the benefits and effectiveness of ENERGEM to vision center staff. Establishing referral programs will further incentivize vision centers to recommend ENERGEM, creating a mutually beneficial partnership. In tandem, we plan to initiate discount programs where vision centers can offer ENERGEM at a reduced price, promoting its affordability and accessibility. Joint marketing campaigns will serve to underscore the shared goal of improving eye health, showcasing the collaborative efforts between our company and vision centers. A crucial part of this partnership involves setting up customer feedback loops to gain consumer insights for continuous improvement, and integrating our supply chain with the inventory management systems of vision centers to ensure a consistent and timely supply of our product.

Furthermore, we plan to engage with authorized insurance brokers to provide an avenue for assisting consumers in enrolling in insurance plans that cover ENERGEM. We also envisage exploring opportunities for the inclusion of ENERGEM in government health plans like Medicare and Medicaid. Continuous communication with insurance providers, healthcare providers, and vision centers will help in providing regular updates on any new clinical findings or consumer feedback regarding ENERGEM, bolstering its coverage and acceptance.

Today, myopia affects more than 2.6 billion people worldwide [14]. Children are the most vulnerable population to myopic incidence. The National Institutes of Health report a myopia prevalence of 36% among US children, translating into an estimated affected population of 19,512,708 children between the ages of 5 and 17 [11]. The costs associated with myopia are substantial. Annually, the direct costs for contact lenses alone range between $198.30 and $378.10, while spectacles and refractive surgeries are priced around $342.50 and $19.10, respectively [9]. Other more specialized treatments like Ortho-K and MiSight can cost between $1,000 to $4,000 per year [10]​.

Geographic factors and access to health insurance play an important role in determining the access to and the marketing focus of our drug, as 41% of myopia children reside in urban areas while 15.7% are in rural areas [11]. In rural counties, approximately 12.3% of residents lack health insurance coverage compared to only 10.1% of residents in mostly urban counties [12] . Novel therapeutic agents are found to be covered by a median of 61% of insurance plans at 1 year post-FDA approval, and this coverage increased to 79% at 3 years post-approval [13]. Although health insurers typically cover ophthalmic treatments, insurers focus on covering the costs of treatment that are medically necessary. Dr. Maria Liu, Chief of the UC Berkeley Myopia Clinic, expressed great excitement in ENERGEM as a tool for myopia control and prevention. Dr. Liu mentioned that the oral treatment delivery would make patients much less apprehensive about myopic treatment. Dr. Luca Zatrenau, Retina Chief of Rochester Regional Health, similarly concurred by telling our team that ENERGEM’s caffeine-based nature, compared to a complex synthetic product, would make parents significantly less apprehensive in letting their children take the drug. Dr. Nita Mehta from Stony Brook showed us that ENERGEM would work well in conjunction with other treatments such as atropine or contact lenses. Their glowing recommendations, and an overall embrace by the eye care professional community, would push many insurance plans to cover this drug.

Taking into account that approximately 87.7% to 89.9% of children are covered by health insurance, this brings our service available market to approximately 17,112,644 to 17,541,924 patients. Parents, who are the decision-makers for their children’s drug treatments, “prefer safety, convenience, clarity, [and] affordability” [17] when seeking alternative effective myopia controls. 52.4% of parents surveyed indicated that they would have preferred a safer and convenient option than ortho-k lenses for their children. 3.1% of children with myopia, approximately or 530,491-543,799 patients use ortho-k lenses [20]. Additionally, approximately 33% of children from ages 6-17 with myopia (5,648,155 to 5,796,079 patients) use glasses or contacts, but it is reported that 11-16% [19] rarely wear their glasses or contacts for a variety of reasons, resulting in a range of 621,296 to 927,372 patients that would be interested in an oral treatment for myopia. Finally, each year there are 1.5 to 3 million new diagnoses of myopia [18]. Assuming that the drug treatment is launched and our marketing campaign yields conservative results (8% engagement), there is a potential base of 120,000 to 240,000 patients that would be interested in our treatment.

These factors produce a serviceable obtainable market of parents unsatisfied with Ortho-k lenses (277,943-285,017), patients unsatisfied with their glasses or contacts (621,296 to 927,372) and new informed patients being diagnosed with myopia (120,000-240,000) of approximately: 1,019,239 to 1,452,389 patients. By taking the average and assuming that 61% of patients are eligible for insurance coverage of our product, we can estimate that our first year serviceable obtainable market to be around 753,846 patients.

ENERGEM's marketing focus is on healthcare providers, especially ophthalmologists and optometrists. Our central message underscores that the 7-MX-drug, derived from non-toxic caffeine compounds, presents a safer and more efficient alternative to atropine-based and other invasive treatments. By gaining the trust of these professionals, we hope to tap into their patient base, leveraging an established doctor-patient trust dynamic, to boost consumer buying behavior by 56% within the first 12-months of launch [16]. Even more importantly, 78.8% of parents follow the recommendations of eye care practitioners, further underscoring the importance of having the support of this community [47].

Our content strategy will be two fold:

We'll conduct research to understand healthcare providers' reservations about current atropine treatments for myopia, and subsequently curate educational content like whitepapers, blog posts, and an Educational Video Series elucidating the risks of atropine and the advantages of using ENERGEM for 7-MX drug production.

To engage our target audience, we will not only attend and sponsor key ophthalmology and optometry conferences but enhance our presence by hosting dedicated workshops, training sessions, and Interactive Learning Modules providing professionals hands-on experience with ENERGEM-produced drugs. Furthermore, our engagement will extend online through SEO-Optimized Content, Social Media Campaigns, and a regular Newsletter, fostering a community where professionals can exchange insights aboutENERGEM-produced 7-MX drugs. Industry Collaborations with thought leaders will also be sought to co-create content or obtain endorsements for ENERGEM, thereby enriching our content strategy and broadening the reach and trust in ENERGEM.

The current direct competitors within the market are divided among three groups, LASIK surgery, glasses/contact lenses, and prescription eye drops.

While LASIK Eye Surgery may represent the most successful treatment option to restore patients to 20/20 vision, LASIK is typically not covered by health insurance and has a wildly fluctuating price that ranges from $1,000 to $4,000 per eye. For many patients, LASIK will remain an expensive dream.

Orthokeratology, or ortho-k contact lenses, temporarily reshape the cornea to correct refractive errors by applying hydraulic pressure, allowing for clearer daytime vision without glasses or traditional lenses [17]. Despite a market size exceeding $600 million in 2021 and a 6.5% CAGR, these lenses, FDA-approved since 2002, face challenges. The adaptation period can span 1-3 weeks, causing discomfort, with over 31% of patients experiencing irritation, leading 50% to discontinue due to an intolerable foreign body sensation [18]. More gravely, extended wear led to Microbial Keratitis in 3 out of 50 patients, resulting in permanent scars. Balancing wear-time is crucial; overuse risks infection, while underuse compromises comfort and efficacy. Targeting a younger demographic, adherence becomes problematic. Consequently, many optometrists reserve ortho-k as a last resort due to these limitations [19].

Other contact lens treatment options are multifocal soft contact lenses, like MiSight® 1 day contact lenses. These lenses are the only FDA approved daily contact lenses (or treatment in general) with the ability to inhibit Myopia, however, they are not for everyone. Astigmatism is another refractive error condition that occurs when the cornea or lens are shaped irregularly. Since this condition affects 1 in 3 people, there tends to be significant overlap between myopic patients and those with astigmatism [21]. MiSight can be detrimental to children with moderate astigmatism [21]. Since Ill-fitting lenses can cause misalignment of vision zones since all of them are standard for all patients, ophthalmologists refrain from recommending these lenses to patients with moderate to severe astigmatism. ENERGEM does not affect those with astigmatism due to the lack of side effects of orally administered 7-methylxanthine, providing an option that is suitable and safe for all myopic patients [19].

While atropine eye-drops [19] are capable of slowing the progression of myopia by up to 76% in the first two years, the high required concentration causes a plethora of side-effects such as photophobia, blurred vision, and allergic reactions. Low dosage atropine eye drops were found to be no better than a placebo at slowing down myopia. Furthermore, discontinuation of treatment led to an astounding rebound of 300% increase in myopia progression rate, presenting a high-risk high-reward strategy for patients that leave many too uncomfortable to take the gamble. Atropine Eye Drops are not FDA approved.

As a biomanufacturing company, we adhere strictly to the FDA’s regulations that govern the production and use of pharmaceutical materials to minimize risk to our product, process, and stakeholders. As our primary market, we will establish rigorous compliance with the Food and Drug Administration’s standards for drug approval and Current Good Manufacturing Practice (cGMP). Once we’ve established a foothold in the North American markets, we will seek compliance with the Chinese National Medical Products Administration and the European Medicines Agency abroad.

In the initial phase, the focus will be on gathering all existing data related to 7-MX application with a particular focus on the dosages used in Trier et al’s study as benchmarks. This will form the basis for preparing justification for further clinical studies on 7-MX. Parallely, we will focus our efforts on optimizing the manufacturing process to ensure that the yield and purity of the 7-MX batches remain consistent over time. This consistency is crucial as it lays the foundation for further regulatory steps.

As mandated by the FDA, new controlled studies will be designed to meet the required standards. These studies will aim at ascertaining both the safety and efficacy of 7-MX. This includes establishing toxicity profiles and pharmacological activities through rigorous in-vitro and animal studies. The outcomes of these studies are critical for transitioning to the clinical testing phase.

Upon successful completion of animal tests and verification of 7-MX’s safety and efficacy, the transition to human clinical trials begins. This is significant as ENERGEM will attain a new legal standing under the Federal Food, Drug, and Cosmetics act. At this stage, we will file an Investigational New Drug (IND) application in order to allow our 7-MX to transport across state lines. This application will encompass data from animal pharmacology, toxicology studies, manufacturing details, clinical protocols, and relevant investigator information. This documentation will serve as a formal proposal to the FDA for the commencement of clinical trials on humans.

Clinical trials will be structured into three distinct phases to meticulously evaluate the safety, dosage parameters, effectiveness, and comparative efficacy of 7-MX against existing treatments in the market.

• Phase I, involving 20-80 participants, primarily focuses on gauging the safety and identifying the appropriate dosage parameters of 7-MX.
• Phase II extends to a few dozen to 300 participants, with the objective of evaluating the effectiveness of 7-MX and closely monitoring any side effects.
• Phase III, encompassing hundreds to several thousand participants, will compare 7-MX's treatment efficacy to existing treatments available in the market.

The insights gathered from these trials are crucial for the next step, which is drug approval.

Upon the successful conclusion of all clinical trial phases, all data will be meticulously compiled and collated. Concurrently, manufacturing protocols for large-scale production will be documented in detail. The New Drug Application (NDA) will then be filed with the FDA, which is a formal proposal for the approval of 7-MX for sale and marketing in the U.S. The NDA encapsulates all the data gathered during the animal studies and human clinical trials. It aims to provide comprehensive information to permit FDA reviewers to determine the safety and effectiveness of 7-MX, the appropriateness of the proposed labeling, and the adequacy of the manufacturing methods and controls used to maintain the drug's quality [20]​.

Following the approval and market introduction of 7-MX, a rigorous monitoring mechanism will be instituted to track any adverse reactions or long-term effects not observed during clinical trials. This post-launch surveillance is integral to ensuring the continued safety and effectiveness of 7-MX in the broader population.

The outlined regulatory pathway demonstrates a structured and meticulous approach towards ensuring that 7-MX not only meets the requisite regulatory standards but is also deemed safe and effective for the intended use. Throughout this process, close collaboration with the FDA and other regulatory bodies is imperative to navigate the complex regulatory landscape successfully.

Throughout the drug approval process and after we secure approval, Cornell iGEM will oversee the biomanufacturing of ENERGEM and all future biomolecules, in close adherence with the FDA’s regulatory framework. Our manufacturing processes will follow closely the FDA’s Current Good Manufacturing Practice (CGMP) regulations, as outlined in 21 CFR Part 210 and 21 CFR Part 211. These regulations outline the minimum standards for the manufacturing, processing, packing, and holding of drugs including biologics like 7-MX produced using engineering E.coli [21]​.These regulations ensure that the drug product is safe for use, possesses the claimed ingredients and strength, and is free from contamination. Key aspects of CGMP include maintaining clean and hygienic manufacturing areas, conducting thorough quality control testing, and establishing robust quality management systems.

The FDA encourages the adoption of advanced manufacturing [49] technologies to improve drug quality and address medicine shortages. Our IBCS bioreactor design and enzyme encapsulation technique are engineered to align with these CGMP standards. Our enzyme encapsulation technique within a fixed-bed reactor meets the CGMP requisites for process control and consistency.

As we scale production, managing byproducts like formaldehyde, which is generated in small amounts during the caffeine metastasis pathway, becomes increasingly important. Although at current production levels, formaldehyde is not considered a significant threat, the scaled production scales that we plan for at post-approval will pose concern. We plan to introduce additional processing steps to neutralize or remove formaldehyde and other potentially harmful byproducts to ensure compliance with environmental and safety regulations. These steps will include but not be limited to, deploying specific catalysts to break down formaldehyde and employing filtration systems to remove any residual toxic substances. Moreover, continuous monitoring and regular testing will be instituted to detect and manage the levels of such byproducts, ensuring they remain within the acceptable limits as defined by regulatory authorities.

Ensuring the microbiological [50] quality of 7-MX is crucial, particularly given its production through engineered E. coli. CGMP regulations mandate a rigorous microbiological testing regimen to remove the presence of potentially harmful microorganisms, which align closely with Cornell iGEM’s stringent process control and testing protocols. We will purify and verify the purity of 7-MX from the bioreactor outflow using High-Performance Liquid Chromatography (HPLC).

The FDA's biotechnology inspections will allow us to validate our compliance with CGMP and other pertinent regulations. By preparing and passing these inspections through internal audits and inspections, we guarantee that Cornell iGEM will be able to manufacture enough product safely to meet the expected post-approval demand.

The success of ENERGEM’s mission hinges on a robust and agile supply chain. Our aim is to ensure a seamless flow from the procurement of raw materials to the delivery of 7-methylxanthine to our partners.

Our procurement strategy is two-pronged. Initially, we'll forge partnerships with local coffee shops to procure caffeine-rich waste like coffee grounds. This approach not only provides us with a steady supply of raw materials but also underscores our commitment to environmental sustainability by utilizing waste products. However, to ensure consistency in supply and quality, we will also source raw caffeine from reputable suppliers. We'll employ rigorous quality control measures to test all incoming materials for residual caffeine and other parameters to ensure they meet our stringent standards before entering the production phase.

Our production will be done in-house. A meticulously planned production schedule coupled with real-time monitoring systems will ensure that production milestones are met efficiently while adhering to the highest quality standards.

Our distribution strategy is customer-centric with a focus on ensuring that ENERGEM’s treatment reaches patients seamlessly and efficiently. As a pharmaceutical company, we will be selling our product directly to patients, thus bypassing the traditional channels. Our distribution will be orchestrated through a multi-channel approach, including online sales via our website, partnerships with healthcare providers, and direct sales through our dedicated sales force. We will also explore partnerships with reputable online pharmacies to broaden our distribution reach. To ensure a smooth distribution process, we will invest in an advanced logistics management system. This system will automate order processing, tracking, and delivery scheduling to ensure timely delivery to our customers.

A crucial aspect of our supply chain is the proper storage of 7-methylxanthine to maintain its efficacy and quality. Our storage facilities will be designed to meet the stringent regulatory standards set by the FDA and other relevant bodies, and will be equipped with climate-controlled systems to ensure the optimal storage conditions for 7-methylxanthine. According to several sources, the typical storage conditions for pharmaceuticals include a temperature range of 15°C – 25°C (59°F – 77°F), although some facilities may allow for temperatures up to 30°C depending on the specific requirements of the pharmaceutical product and the climate in the region​ [22,23,24,25]. The relative humidity in the storage facilities should be kept below 60% to prevent any moisture-related issues that could affect the quality of the product [22]. We will employ state-of-the-art HVAC systems to precisely control the temperature and humidity in our storage facilities, aligning with the guidelines provided by the USP 797 and USP 800 Compliance standards for Pharmacy HVAC Systems​2​. Moreover, our facilities will have robust inventory management systems to ensure real-time tracking of stock levels, batch control, and expiration date management. The storage containers for 7-methylxanthine will be kept tightly closed in a dry and well-ventilated place, and under inert gas to maintain its stability as per the recommendations for this compound [25,26]​. This meticulous approach to storage will ensure that only top-quality products reach our customers and comply with all regulatory requirements.

ENERGEM’s primary risk is competition from established chemical production and pharmaceutical companies, which already have a solid foothold in the market and are backed by robust financial resources and an extensive customer base. Similarly, the competition with alternative therapeutic options for myopia is significant. The market is saturated with various interventions ranging from optical corrections like glasses and contact lenses to pharmaceutical solutions such as atropine eye drops and surgical interventions like laser eye surgery.

The novelty of ENERGEM's oral therapeutic for myopia presents another risk. The market's unfamiliarity with oral treatments for myopia could potentially hinder the adoption rate of ENERGEM. Furthermore, ENERGEM consists of 7-MX in an oral tablet form. Securing intellectual property is critical to ENERGEM’s commercial success as a drug. Being unable to secure a patent for the process of creating 7-MX or the process of creating biomolecules with our IBCS reactor, would hinder our company’s commercial viability.

Market price volatility of chemical inputs for production is a risk that could unpredictably escalate production costs. Lastly, securing adequate financing is an important risk.Without a stable influx of capital, Cornell iGEM’s operations from research and development to marketing could face significant hurdles. The challenge to attract investors amidst a competitive marketplace and ensure they see the value and potential return on investment that ENERGEM is clear cut.

ENERGEM has outlined several steps to handle the identified risks. To fend off competition from established chemical production companies, we plan to engage legal consultants, through the Entrepreneurship Law Clinic at Cornell and WilmerHale, early on to explore intellectual property protections. Through filing a provisional patent soon and a nonprovisional patent in the near future, we plan to initiate preclinical trials as quickly as possible to gather data that supports the efficacy and safety of our product, which is crucial to enter the market.

To effectively compete against alternative myopia treatments, a comprehensive marketing campaign will be executed, emphasizing the unique benefits of the 7-MX treatment. The campaign will leverage evidence from clinical trials or Proof of Concept (POC) studies to illustrate that our treatment is not only cost-effective but also more accessible due to its oral administration. The novelty of an oral therapeutic for myopia will be highlighted as a modern, convenient, and non-invasive treatment option. This marketing strategy aims to alleviate any consumer apprehensions towards trying this new method of drug administration and to position ENERGEM as a favorable alternative in the market.

To ensure we have enough financing for our project, we plan to connect with angel investors and venture capital firms, leveraging the Cornell Entrepreneurship ecosystem. By showcasing the diverse talents of the Cornell iGEM team, we aim to attract a broad range of investors. The Cornell Startup Organization has already connected us with potential angel investors in the healthcare industry and is connecting us with important investment organizations with a presence on Cornell’s campus such as the Dorm Room Fund, Big Red Ventures, Red Bear Angels, Rough Draft Ventures, and the SBIR/STTR Assistance Program.

To insulate ENERGEM from the volatile prices of essential inputs in the drug production process, we intend to capitalize on the networks of our pharmaceutical partners and the extended Cornell alumni base. By establishing solid relationships with reliable suppliers and wholesalers, we aim to secure a steady supply of necessary materials at predictable prices. This strategic relationship-building not only provides a buffer against market fluctuations but also supports a smooth, uninterrupted production process. Our approach prioritizes both cost-effectiveness and operational efficiency, ensuring that the production of 7-MX remains on schedule and within budget.

Each of these steps is geared towards directly addressing the identified risks, to ensure the smooth progression of ENERGEM from its developmental phase to a successful market entry and sustained growth.

Our revenue-cost analysis includes a breakdown of expected costs and expected revenue streams.

The cost analysis for the production of 7-methylxanthine (7-mx) entails a variety of materials, each playing a crucial role. Gene Fragments, essential for engineering the E. coli strains, are relatively cost-effective at $0.15 per run. Reagents, being the backbone of the chemical reactions, are the most significant cost factor at $10.41 per run. Histag Columns, priced at $0.46 per run, are indispensable for purifying the proteins, while Glassware, at $0.30 per run, ensures safe handling and reaction processes. Oligonucleotides, at $1.3 per run, serve as the primer for DNA amplification, a core part of the genetic engineering process. The encapsulation of enzymes within beads and the operation of the IBCS reactor are facilitated by items like Beads, Motor, and Arduino, totaling $0.10 per run. Data logging and monitoring, enabled by an SD card at $0.0049 per run, ensure quality control, and the Press Machine at $1.19 per run is pivotal for forming tablets, the final product. High-Performance Liquid Chromatography (HPLC), which costs $1.51 per run, is the crucial step in the purification process as it allows us to separate pure 7-methylxanthine from the bioreactor outflow and transform it into our oral treatment form. This meticulous allocation of resources culminates in a total cost of $15.41 per run, translating to $108.04 per gram of 7-mx produced, $324.14 for a monthly supply, and $3943.71 for an annual supply, laying a solid foundation for pricing and revenue strategies.

The breakdown of costs associated with reagents sheds light on the financial allocation for essential materials in the production process. Each reagent serves a unique purpose: q5 high fidelity Mastermix and Gibson Assembly Mastermix, costing $1.72 and $1.14 per run respectively, are crucial for DNA assembly; Gel loading dye and dNTPs, priced at $0.8 and $4.6 per run, are fundamental for DNA visualization and synthesis. Other essential reagents include Imidazole, MES Buffer, and PCR and DNA Cleanup kit, contributing to protein purification and DNA cleanup. Costs associated with LBA Powder, Manganese Chloride, Caffeine, Petri Dishes, and Gel extraction Kit are imperative for various stages of the production process, cumulatively amounting to $10.41 per run.

Table 4 underlines the production rates of 7-MX by ENERGEM. A reaction rate of 0.743 mmol/l/hr was achieved, with a 71.35% recovery rate by mass. This process yielded 142.699g of 7-mx. The estimated production rate stands at 0.1718 mmol/l/hr, within a run time of 0.231 hours per run. These metrics reflect the efficiency and effectiveness of the production process, crucial for planning and scaling operations.

Expected costs begin with 1) proof-of-concept development, 2) machinery and maintenance, 3) chemicals for synthesis, 4) research and development, 5) laboratory space, 6) labor. 1) costs include all initial chemical inputs and the IBCS which totals to $2,661, 2) costs are scale-dependent, 3) is volume-dependent but is projected to be $108.04 per gram of 7-MX, 4) assuming an average rent price of $3,000 per month per 2,000 sqft laboratory space, our initial cost will be $36,000 per year for laboratory space and is expected to scale up rapidly thereafter, 5) labor costs include wages for scientists, laboratory technicians, and support staff - with average wages amounting to $30 per hour. Given that a 20 person team will be suitable to launch, labor costs will total to $8.64mm per year and increase thereafter with a headcount increase.

Costs of clinical trials average to around $36mm [32] for an ophthalmology drug, which is inclusive of Phase 1-3 clinical trials, labor, recruitment, consultation, and legal fees.

Costs of customer acquisition include 1) advertisement to drug wholesale distributors, 2) advertisement to consumers, and 3) advertising to research groups at universities and institutions. 1) advertisement streams include direct contact and healthcare conference presence which is projected to cost a combines $15,000 per year, 2) includes social media advertising campaigns, television advertisement, and other internet content that totals to over $150,000 per year, 3) costs involve direct engagement and attending university and affiliate events, totaling to another $15,000 per year.

Costs of shipment and distribution include 1) drug packaging, 2) freight and air shipping, and 3) insurance on delivery. 1) costs ~30% of our product’s retail price, 2) costs to ship small packages in bulk are ~$5 per unit, so we assume total cost per year to exceed $500,000, 3) we project insurance costs to be negotiated to cover bulk orders, which we approximate to be in between 1.25%-1.5% of any total shipment value.

Additional costs to consider include legal consultation, management consultation, and intellectual property costs. Although these costs are highly variable, we project they will exceed $200,000 per year.

Expected revenue streams include sale of 7-MX based myopia drug units to wholesale distributors who then sell to hospitals, medical providers, and pharmacies. Our cost to produce one gram of 7-MX is $108.04 and we project the cost to decrease as production is optimized and materials are purchased in bulk. Each capsule of our treatment includes 100mg, which totals to a cost of $10.08 per capsule. Assuming a ~100% markup on costs, which reflects industry average profit margins expected of a biomanufacturer and pharmaceutical company [51], for our sale price per unit, our price per capsule is $20.16. Our projected treatment course includes 1 capsule per day for 6 years given that most children start using ortho-k lenses at 6-8 years old and stop at ~14 years of age. Therefore, the average annual price of treatment for an uninsured patient is projected to be $7887.42 per person. With a target of 753,846 patients in the United States our revenue is expected to be $5.9bn before expansion. Given our low cost of treatment, we expect to penetrate the market rapidly and expand into other markets and revenue streams quickly. In addition, 61% of Insurers cover a drug 1 year after FDA approval, climbing to 79% after 3 years. This will also contribute to boosted sales post-FDA-approval [13]. In addition to the expected growth rate of myopia patients, we project exceeding $8.9bn in revenue 3 years after release

In the future, revenue streams may expand to include 1) adaptation of 7-MX to new indications in ophthalmology or beyond, 2) sale of 7-MX in bulk directly to clients, and 3) licensing out the IP for the 7-MX production process or the IP for the myopia drug development process and collecting royalties from both.

Our investments in the first stage of ENERGEMs [33] life cycle include two types of capital expenditures and labor investment.

The first investment Cornell iGEM considers to be vital is investment in machinery and chemical inputs to our production process. This includes spending on the goods themselves, maintenance, and operational expertise. The second investment type includes laboratory space, enabling production to scale and order fulfillment rate to increase, thus bolstering revenues. The third investment category includes labor expertise in machine operations, chemical synthesis, scientific research, drug application, drug delivery method experts, and more. This labor base is crucial to expansion efforts and is dependent upon the two investments listed above.

Financing options are key considerations while looking to grow ENERGEM. From the conventional methods of debt or equity financing, it is cheaper to acquire financing from debt investors, but due to the early stage of our startup and the significant risk associated with investing in a pre-seed biotechnology company, it will be difficult to acquire such financing. Thus, equity investors are more likely to invest in the business as they are better adapted to risk. Equity investors can come in the form of VCs or angel investors, both of which would be beneficial to have as investors. These parties would assist in operational and growth decisions, as well as help resolve any issues that impact our bottom line. Such partnerships have potential to be advantageous, connecting us with clients, partners, and consultants. Beyond equity financing, grants and donations have been our most successful method of financing thus far. These financing methods have enabled us to work toward proof of concept, and after this occurs, only limited options within these two financing categories will exist. Thus, Cornell iGEM is actively seeking to engage with equity investors that take the form of either Venture Capital or Angel Investors.

To ensure that our company is exposed to healthy cash flow, Cornell iGEM seeks to only make investments and spending in categories that positively impact our revenue. While in such an early stage, it is important that we ensure our assets and purchases do not exceed the cash we have on hand through equity investors, grants, and donations. In addition, by choosing to avoid debt investors, we can ensure that continuous investment into our firm from outside parties is dependent on cash flow generation, a criteria investors will look for to validate their investments.

With ENERGEMs’ feasibility having been evaluated above, we observe that the first several years post-POC will be fully funded via investors who see potential in our long term revenue generation. Thus, although it is likely we will lose money until we expect to release our drug in 2035, our long term strategy projects that cash generation will happen shortly after, enabling us to deliver to investors and attract additional investment to fund our scaling strategy.

Our primary goal is for ENERGEM to become a leading myopia control treatment. Our growth will be predicated on a few factors: customer willingness to try an oral treatment for myopia and our ability to gain market share. Given the lack of myopia treatment solutions, lenses have emerged as the most popular treatment - a remedy rather than a solution. This would allow us to gain significant market share, since the market is far from saturated, with plenty of room for innovation. To strengthen our position in this market, we will look to establish connections with wholesale distributors who have sales pipelines to hospitals, pharmacies, and other institutions. By expanding our set of connected wholesale distributors, we hope to gain exposure to more clients and partners who may want to help in optimization of our drug production process or leverage their platforms to expand customer share.

Cornell IGEM will explore product expansion as a route to expanding revenue. Product expansion can take 3 forms: 1) adaptation of 7-MX to new indications in ophthalmology or beyond, 2) licensing out the IP for the 7-MX production process or the IP for the myopia drug development process and collecting royalties from both 3) small molecule production. If our efforts to secure a patent for the continuous process of manufacturing biomolecules with our IBCS reactor proves successful, we hope to leverage the process into exploring other molecules both inside and outside the methylxanthine pathway. If ENERGEM proves successful, our next production target would be Paraxanthine which has a retail value of $1,450 per gram [52]. In addition to this strategy, Cornell iGEM plans to expand its assets through acquisition of more laboratory space, labor, and machinery to scale up the business and increase output. Exploring these additional revenue streams and growth opportunities can yield exponential growth that can help ENERGEM approach a sustainable and successful future.

ENERGEM looks to continuously improve and expand the process of 7-methylxanthine and other biomolecule production over the next two decades. The product aims to infiltrate the myopia treatment market via mass production of 7-methylxanthines with our IBCS reactor system. With an effective market campaign it is possible for ENERGEM to maximize market opportunities via strategic partnerships and sustainable growth targets. By 2040, we hope to have non provisional patents for our production method, during which we will continue to improve our product technology and start sourcing pharmaceutical companies to partner with. Through these partnerships, Cornell IGEM would be able to drive down the cost of other xanthine-based drugs such as Dyphylline, Aminophylline, and Theophylline. Many respiratory drugs require methylxanthines and, with our more efficient and effective process, we can bring the cost for consumers down while retaining a high profit margin.

Our short-term goals include finalizing our proof of concept, exploring the optimization of this process, and ensuring safety and maximum output is prioritized. Thereafter, our goal is to expand into the therapeutic space by leveraging our optimized 7-MX production and knowledge of the myopia market. We aim to engage in clinical trials afterwards in which we will test the drug profile. Long term, we seek to generate revenue through selling our drug, our intellectual property, and producing other commercially viable biomolecules.

Many startups evolve into corporations, and thus, the exit may occur at any point in the company's life cycle. However, to guide an informed and advantageous exit, a strategy is needed from the start to best identify at what stage may be the best time to exit. Two critical things to consider in a strategy include how to maximize profit and how to ensure the long term success of the company under another manager’s control. To address the first, this can occur through a sell-out or an initial public offering. In either case, it is important that ENERGEM engages with a management consult or investment bank to determine which strategy is most profitable in the given market conditions. In regards to the second, ENERGEM seeks to provide long term value to myopia patients through a safe and affordable therapeutic solution. Thus, when considering an exit, we will evaluate the motivations of our stakeholders to assess whether they align with patient impact or strictly profit. In the case of the former, we will look to engage in a sale, and in the case of the second, long-term engagement will be necessary to ensure that the company continues to positively impact myopia patients and that products are not compromised by the motivation for margin expansion.

Read more about ENERGEM's Business Model Here

References