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Gravity Fund

The ExcepGen Investment Thesis

mRNA technology uses a copy of a molecule called messenger RNA to produce a directed immune response. The technology delivers molecules of antigen-encoding mRNA into immune cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen (such as a virus) or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.

First, some history on the mRNA technology platform. In late 1987, Robert Malone performed a landmark experiment. He mixed strands of messenger RNA with droplets of fat. Human cells bathed in this mixture, absorbed the mRNA, and began producing proteins from it. If cells could create proteins from mRNA delivered into them, he wrote on 11 January 1988, it might be possible to “treat RNA as a drug”. Although, the ability to build mRNA had been around since the 1960s, this was the first time anyone had used fatty droplets (lipid nanoparticles or LNPs) to facilitate mRNA’s passage into the cells of a living organism. Malone’s experiments were a major breakthrough towards development of mRNA technology as we know it today.

But the path to success was not direct. For many years after Malone’s experiments, which themselves had drawn on the work of other mRNA researchers dating back to the 1960s, mRNA technology was seen as too unstable and expensive to be used as a drug or a vaccine. Dozens of academic labs and companies worked on the idea, struggling with finding the right formula of fats and nucleic acids — the building blocks of mRNA vaccines and therapeutics.

In the 1990s and for most of the early 2000s, nearly every vaccine company that considered working on mRNA opted to invest its resources elsewhere. The conventional wisdom held that mRNA was too prone to degradation, and its production too expensive.

mRNA technology had a more favorable reception in oncology circles, albeit as a therapeutic agent, rather than to prevent disease. Beginning with the work of gene therapist David Curiel, several academic scientists and start-up companies explored whether mRNA could be used to combat cancer. This work inspired the founders of the German firms CureVac and BioNTech — two of the largest mRNA companies in existence today — to begin work on mRNA.

This new generation of mRNA therapeutics set off massive inflammatory reactions when they were injected into mice. In 2005, it was discovered that rearranging the chemical bonds on one of mRNA’s nucleotides, uridine, to create an analogue called pseudouridine, seemed to stop the body identifying the mRNA as a foe, thus somewhat mitigating the inflammatory cellular stress response. Moderna and BioNTech, the originators of the first mRNA vaccines for COVID-19 both utilized this modified mRNA in their products.

Another advancement occurred in 2012 with the development of a mixture of four fatty molecules: three contribute to structure and stability; the fourth, called an ionizable lipid, is key to the LNP mixture’s success. This substance is positively charged under laboratory conditions, which limits the toxic effects on the body. What’s more, the four-lipid cocktail allows the product to be stored for longer on the pharmacy shelf and to maintain its stability inside the body. This mixture can now be found in the COVID-19 vaccines from BioNTech and CureVac. Moderna’s LNP concoction is not much different.

Concurrently, a new way to mix and manufacture these nanoparticles had been devised. It involved using a ‘T-connector’ apparatus, which combines fats (dissolved in alcohol) with nucleic acids (dissolved in an acidic buffer). When streams of the two solutions merged, the components spontaneously formed densely packed LNPs. Once all the pieces came together, drug developers realized that they finally had an mRNA development and manufacturing process that they could scale. Every mRNA company now uses some variation of this LNP delivery platform and manufacturing system.

A new industry was born when several big pharmaceutical companies entered the mRNA field on the heels of those breakthroughs. In 2008 both Novartis and Shire established mRNA research. BioNTech launched that year, and other start-ups soon entered the fray, bolstered by a 2012 decision by the US Defense Advanced Research Projects Agency to start funding industry researchers to study RNA vaccines and drugs. Moderna was one of the companies that built on this work and, by 2015, it had raised more than $1 billion on the promise of harnessing mRNA to induce cells in the body to make their own medicines — thereby fixing diseases caused by missing or defective proteins. When that plan faltered, Moderna, led by chief executive Stéphane Bancel, chose to prioritize a less ambitious target: making vaccines.

By the beginning of 2020, Moderna had advanced nine mRNA vaccine candidates for infectious diseases into humans for testing. None was a slam-dunk success. Just one had progressed to a larger-phase trial. But when COVID-19 struck, Moderna was quick off the mark, creating a prototype vaccine within days of the virus’s genome sequence becoming available online. The company then collaborated with the US National Institute of Allergy and Infectious Diseases (NIAID) to conduct mouse studies and launch human trials, all within less than ten weeks. BioNTech, too, took an all-hands-on-deck approach. In March 2020, it partnered with New York-based drug company Pfizer, and clinical trials then moved at a record pace, going from first-in-human testing to emergency approval in less than eight months. Both authorized vaccines use modified mRNA formulated in LNPs. Both vaccines showed initial promise but ran into the same hurdles that Moderna experienced with its first nine mRNA vaccine candidates, namely the expression of the viral antigen cargo was not robust enough to produce a durable immune response. This is a result of an inflammatory cellular stress response that lingered, despite the 2012 LNP mixture breakthrough. This technical challenge remains and plagues every mRNA vaccine and therapeutic spanning nearly every disease state (infectious disease, cancer, etc.).

mRNA technology has attracted more capital from the pharmaceutical industry than nearly any other platform technology before it, and the cellular stress response challenge stands in the way of the pharmaceutical industry monetizing those mRNA investments to date.

Enter ExcepGen. ExcepGen introduces its proprietary technology into the LNP mRNA cocktail, producing broad based cellular stress response inhibition. Inhibition of the cellular stress response allows the cell to solely focus on efficient antigen production and removes antigen production inhibition mechanisms.

ExcepGen’s mRNAx platform works by re-engineering viral proteins to slow the transport of signals between the nucleus and cytoplasm. mRNAx produces a protein that modulates nucleocytoplasmic transport. This mechanism prevents pathways that interfere with RNA. As a result, the translation of the primary mRNA cargo is prioritized and massively boosted, because cell stress signaling is prevented.

ExcepGen is the first technology to holistically overcome the residual cellular stress response challenge and the ExcepGen IP portfolio is built to cover the modulation of nucleocytoplasmic transport to improve cargo expression from nucleic acid. This should give ExcepGen broad based IP protection. The ExcepGen technology works with mRNA, saRNA and other RNA modalities.

Given the nearly 100x improvement in antigen expression the implications of the ExcepGen technology in infections disease and cancer are profound. In infectious disease, the ExcepGen team believes they can unlock universal antigens (which were previously poorly immunogenic) in order to create broadly protective (i.e. against multiple viral variants) and durable vaccines. A long-standing goal of not only mRNA vaccine development, but vaccine development since the inception of vaccines.

ExcepGen builds on a platform biotech business model and engages in partnerships with biopharma for development of clinical assets. ExcepGen has received collaboration and licensing offers but walked away to pursue more favorable terms by starting with Material Transfer Agreements (MTAs) to further validate its technology. For these MTAs, ExcepGen shifts the overwhelming majority of the project costs onto the pharma partner by agreeing that each side bears its own costs. For ExcepGen, this is about $5K per MTA. All the rest of the costs are incurred by the pharma partner. This allows ExcepGen to get a foothold with pharma partners while generating the data necessary to negotiate, with leverage, large co-development deals.

ExcepGen currently has MTAs in place several top mRNA players. This cohort of initial MTA partnerships spans the top mRNA companies in the world. ExcepGen’s partnership pipeline is expanding rapidly beyond these opportunities. ExcepGen utilizes investment banking advisors for partnership and licensing deals to augment its internal efforts to initiate partnership conversations and negotiate partnership terms. Post MTA partnerships will follow traditional co-development models including upfront payments, milestone payments and backend royalties.

THE MARKET

The size of mRNA therapeutics market was valued at $39.40 billion in 2022 and is projected to reach $45.40 billion by 2030, with a compound annual growth rate (CAGR) of 1.5% during the forecast period from 2023 to 2030.

This market is fueled by the rising prevalence of chronic diseases like cancer, heart disease, respiratory, CKD, and rare diseases like propionic acidemia, methylmalonic acidemia, glycogen disease, phenylketonuria, and metabolic and immune disorders. For instance, according to Globocan, in December 2020, there were 19.3 million new cases of cancer worldwide and 10 million cancer-related deaths were reported. Furthermore, the popularization of mRNA vaccines; the development of personalized therapeutics for cancer; and a strong pipeline of new products increase the demand for mRNA vaccines and therapeutics, thus propelling the industry growth during the projection period.

Continued heavy investment by big pharma for the development and production of mRNA vaccines and therapeutics is likely to support industry growth throughout the projected timeframe.

CONCLUSION

We believe that the rapidly accelerating partnership interest from some of the largest mRNA companies in the world is indicative of the emerging recognition that ExcepGen solves the most significant remaining hurdle hindering mRNA clinical progress.

Removal of that technological hurdle gives any one of ExcepGen’s pharma partners a significant leg up in the mRNA category. Most, if not all, of the large pharma companies have invested billions of dollars into mRNA technology development. ExcepGen’s technology allows those companies to achieve significantly better clinical outcomes and begin monetizing their investments in mRNA technology. It’s difficult to utilize other mRNA comps to capture that dynamic, a solid traditional mRNA acquisition comp is Sanofi’s $3.2B acquisition of Translate Bio. Such an outcome would result in a 75x return for Gravity fund (accounting for dilution).

Due to the potential ‘winner takes all’ dynamic that the ExcepGen unlocks in the mRNA sector, we believe there exists significant upside beyond the Translate Bio comp.