VDP-89 [Assessment]: ExcepGen Inc - RNA therapeutics for longevity

One-liner: Optimizing RNA Delivery for Longevity Therapeutics

Longevity Dealflow WG team

• Scientific & business evaluation: two longevity scientists, one biotech VC, two biotech entrepreneurs,
• Shepherd: Michael Baran
• Other squad members: Paolo Binetti
• Sourced by: Michael Baran

Project Lead

• Name: Thomas Folliard
• Email address: Thomas.folliard@excepgen.com

Simple Summary

ExcepGen is developing a new generation of vaccines and therapeutics with its RNAx platform. ExcepGen’s RNAx is delivered alongside primary RNA cargo. RNAx is translated by the cell to produce a regulator protein that modulates signals between the nucleus and the cytoplasm of cells in a tunable manner. By doing this, we keep cells in a low-stress state improving the effectiveness of the RNA cargo to produce significantly more protein leading to increased protection.

We are applying this technology to produce RNA vaccines for challenging antigens, such as universal flu antigens.

Problem

While industry-standard messenger (mRNA) was successful in producing a COVID-19 vaccine, this was partly possible because the Spike antigen is highly immunogenic. Other RNA vaccines that target more challenging viral antigens may require longer antigen expression and better immune engagement to be effective.

Self-amplifying RNA (saRNA) is a promising modality for eliciting broader immunogenicity and making better RNA-based vaccines, but it comes with a catch-22. On one hand: saRNA allows for greatly increased antigen expression, potentially requiring lower doses, increasing valences (number of encoded antigens), and providing better adaptive immune responses. On the other hand: its delivery and replication cause inflammatory intermediates and harmful innate signaling that counteract the potential benefits.

Solution

With ExcepGen technology, saRNA translation is protected from these cellular triggers.

We encode RNA to produce a regulator protein that makes cells amenable to RNA instructions, resulting in majorly increased cargo expression and prevention of unwanted innate signaling and inflammatory responses. The regulator works by dampening transport of signals between the nucleus and the cytoplasm. Others think this sounds like it would be detrimental to RNA translation and cell function. Counterintuitively, by dampening that “information highway” for the cell, we actually prevent stress signaling and innate immune signaling. The expected MOA is that stress signals are activated when certain cell signaling pathways rise above “normal” signal thresholds. By slowing down the flow of information, ExcepGen technology makes cells amenable to executing the instructions they have been given. We believe that this technology will open up a whole new world of RNA drugs across vaccines and oncology.

We have demonstrated that

1. saRNAx produces a 400% boost in cargo expression in vivo in mice compared to standard saRNA

2. saRNAx produces up to 2600% improvement in cargo expression in innate-immune-competent human BJ cells

3. saRNAx majorly reduces, and in some cases completely prevents, deleterious inflammatory cytokine release

Opportunity

Based on these exciting platform data, we are pursuing the holy grail of vaccines - a fully differentiated universal pan-flu vaccine that we believe can only be unlocked by saRNAx technology. This product is our primary focus for the vaccine space with additional pipeline products planned for vaccines, protein replacement, and gene-editing.

The competitive advantages over other research are:

• Core technology mechanism: We identified a counterintuitive, holistic way to make RNA perform better. Because our mechanism is counterintuitive, others in the space have not already been exploiting it.

• Synergistic technology: Our technology works across many RNA types so we can work with our own RNA modalities or those generated by Pharma partners (including linear and self-amplifying, modified and unmodified, etc.)

• IP Strategy: We have applied our technology broadly across RNA types and other nucleic acids to demonstrate our key benefits. We kept the company in stealth mode while developing our strong IP portfolio, which now gives us a strong foundation for technology partnerships in the RNA space.

• Nimbleness: We are a small team and we can iterate quickly. Our research process enables rapid in vitro and in vivo testing and refinement.

We know people need specifically what we are making because of the number of major mRNA companies looking to evaluate our technology for licensing.

IP Potential

We have already generated significant IP and we expect that we have strong IP coverage. We have a portfolio of patent applications submitted by Cooley LLP to protect our core technology and its applications.

Relevance for Longevity

Next-generation vaccines with better efficacy and broader protection are critical for increasing longevity. Severe viral infections have been associated immune dysfunction and chronic inflammation that match signatures of premature aging, an effect that can persist even after the pathogen has been cleared. Moreover, seasonal infections are a common cause of life shortening, frequently even in otherwise healthy individuals. The NIH’s National Institute on Aging has categorized flu as a very serious and life-threatening disease for elderly adults. The respiratory illness caused by viral influenza infection caused more than 12,000 deaths in older Americans over age 65 in 2018. Now in the endemic phase of Covid-19, the risk that aging populations face from viral infections has never been greater.

Team

The company founding team has deep technical expertise engineering reliability into biology for use in unreliable environments such as in microgravity and the rhizosphere. Educated at top universities, the co-founding team met at Oxford university and founded ExcepGen to engineer reliability into genetic medicines.

• Thomas Folliard (Chief Executive Officer)
• Barbara Mertins (Chief Technology Officer)
• Katherine Barcay (Chief Operating Officer)
• Imre Mager (Head of R&D)
• Jason Wojcechowskyj (Director of Vaccines)
• Pragya Mukherjee (Scientist)

Funding

ExcepGen is raising an equity round and has 100,000 USD allocated for the VitaDAO community

They currently apply the technology to vaccines. The proceeds would fund in vitro research, scientific operations, and an in vivo immunogenicity study.

Senior Review Digest

Qualitative assessment

All 5 reviewers recommend to advance this project for community feedback and provide the following evaluation summaries:

• “I really like this tech, lots of data and I saw other cancer data. The responses to my questions were acceptable–I would love a comparison to other tech but that’s not a big deal right now. Unlike many of our other assets, this is “advanced”, has lots of data, other partners, money raised, and could have a near term inflection point.”

• “I recommend funding this project by the VitaDAO community due to the huge potential of the platform for numerous applications across a variety of important therapeutic conditions or for prophylactic use. An equity investment is preferred to benefit from the potential of the platform rather than a specific project. The proposed flu vaccine project may address some questions related to immunogenicity and functionality of the platform for a pan-vaccine approach, but has at this stage limited relevance for VitaDAO and its mission.”

• “Technology with great potential in the use of Flu vaccine. The connection between the Flu vaccine and VitaDAO’s mission is strong considering the great impact flu has on especially the elderly population. The partnering potential of this technology is very big and I believe this could exit before clinical PoC has been achieved. The only downside is that we have not seen the true background of the 'special sauce', which was not shared with the VitaDAO reviewers. Nevertheless, I hope this program receives support from the VitaDAO community.”

• “Interesting technology that could be applied to mRNA vaccines with a large number of potential partners. With Pfizer on board as an investor, they may have a very clear and direct path toward a lucrative first partnership.”

• “Strong team, with strong investors and partners. Technology seems to work to increase protein expression many fold and to last much longer than mRNA could otherwise. Some concern about one trick pony, lack of MOAT.”

Quantitative Assessment

The reviewers have scored the proposal on different aspects including general conviction, on a scale of 1-5 (with 5 being the highest). Here are the average scores:

• Novelty & Impact: 4.2
• Feasibility & Data: 3.6
• Relevance: 3.4
• Science Team: 4.6
• Market Advantage: 4.2
• IP Potential: 4.8
• Conviction score: 4.2