One-liner: Fission Pharma is a pre-seed AI-driven drug discovery platform with a lead program developing a protein-protein interaction inhibitor that cuts the link between chronic inflammation and mitochondrial dysfunction.
Longevity Dealflow WG Team
-
Senior reviewers: two entrepreneurs, an executive, a VC, and a professor
-
Shepherd: Paolo Binetti
-
Squad members: Eleanor Davies, Rhys Anderson, Ryan Spangler, Tomer Landsberger
-
Sourced by: Paolo Binetti, Ryan Spangler
Project PI
- Luis Rios, PhD, CEO
Simple Summary
Fission Pharma is creating the first drug-like small molecule P110 mimetics. P110 is a peptide inhibitor of DRP1-FIS1 interaction originating from Stanford University [1]. The efficacy of P110 is supported by 13 years of research, resulting in 20 scientific publications [1–6] across 11 disease models and collaboration with 15 independent labs globally (full publication list in pitch deck). Dr. Luis Rios published the first small molecule P110 mimetics in 2023 [2] and showed that one of these compounds (SC9) has comparable efficacy in mouse models of ALS and sepsis. These inhibitors have a unique property, they inhibit the downstream pathological consequences of inflammation without inhibiting immune signals. Fission Pharma will develop the first drug-like lead compounds using an innovative AI-driven in silico discovery strategy. These compounds aim to be the first effective and generalized orally available and brain penetrant treatments for chronic inflammation, a critical hallmark of aging, and may do so without causing immunosuppression, the limiting factor in chronic inflammatory treatment. The in silico discovery platform can then be leveraged to discover ways to drug other difficult targets. Fission’s go to market strategy will be to initially focus on rare neurodegenerative diseases including ALS and HD and will then expand to other indications.
Problem
Pathological inflammation exemplifies antagonist pleiotropy in aging, where short-term survival adaptations, like an aggressive immune response in youth, incur longevity costs. Aging prompts hyperactive inflammation, accelerating age-related ailments. Mitigating inflammation is challenging due to immune signal complexity and secondary infection risk.
Cells employ dynamin-related protein 1 (DRP1) in a conserved metabolic stress response during inflammation, shifting mitochondria towards ROS production and glycolysis (the Warburg Effect), a process that damages mitochondria and tissues during chronic inflammation [7]. DRP1 has a clear role in neurodegeneration [8], ischemia-reperfusion injury (stroke and heart attack), septic multi-organ dysfunction, degenerative bowel disease, and many other pathologies (references in pitch deck). However, it remains an elusive target due to essential functions like mitophagy, necessitating selective inhibition of its role in inflammatory degeneration.
Solution
The solution lies in FIS1, a protein interacting with DRP1 exclusively during stress responses and not during normal function. Until 2023, the sole method to selectively inhibit DRP1-FIS1 mediated mitochondrial damage was the P110 peptide [1]. P110 showed strong target validation in many different human cells and animal models, with no apparent toxicity in up to 8-month mouse trials (Figure 1a-c). However, its peptide nature limited its pharmacokinetics. In 2023, SC9, a small molecule mimetic of P110, was discovered. SC9 demonstrates comparable efficacy and no tox with extended treatments (Figure 1d). Critically, in mice injected with LPS, it shows a large increase in survival (more than 3-fold) yet no significant difference in inflammatory cytokine levels (Figure 1e-g). However, SC9 faces similar pharmacokinetic limitations [2].
Fission Pharma has addressed these issues by refining our in silico discovery approach. We’ve discovered over 500 commercially available compounds with higher docking scores than SC9 and greatly improved drug-like properties (Figure 2). The next step involves using this data to train an AI model for efficient virtual screening of billions of compounds.
Figure 1: Pre-clinical proof of concept data for P110 and SC9. a-c, Genetic mouse model of Huntington’s Disease (zQ175 and R6/2) and ALS (SOD1) with P110 treatment. d, ALS SOD1 mouse model with SC9 treatment compared to top ALS candidates in the same mouse model. e, Inflammatory cytokine plasma levels after LPS injection and SC9 treatment shows that SC9 acts independently of cytokines. f-g, Respiratory distress and mouse survival after LPS injection and SC9 treatment shows that treatment blocks critical energetic failure.
Figure 2: Performance of original screening method used to discover SC9 compared to the Fission method. The original method used a surrogate model while the Fission method relies on GPU-accelerated empirical docking. a, BOILED-EGG plots show predicted bioavailability of hits. No hits from the original screen are predicted to have brain penetration while many Fission hits are. b, Fission hits have higher binding scores and lower mass indicating increased ligand efficiency and potency. c, Ligands can dock to an extended region of the DRP1-FIS1 binding groove, however only a specific pharmacophore centered around a small subset of the pocket was originally explored.
Opportunity
Fission Pharma will develop a diverse product pipeline, including CNS compounds, peripheral compounds, and tissue-restricted compounds making it an appealing licensing partner. Internally, we’ll focus on rare neurodegenerative diseases like ALS and HD. For larger indications, partnerships will be sought. Fission aims to address a total market exceeding $200B.
Post-Series A, we plan to expand into other hard-to-drug protein-protein interaction sites and will collaborate with ImmuneAGE Labs for longevity-focused incubation. These targets allow treatment to parse essential vs. pathological functions, reducing on-target toxicity, as seen with DRP1-FIS1 inhibitors.
While there are no direct competitors, NLRP3 inflammasome inhibitors are the most promising comparable. NLRP3 inhibitors were heavily invested in by VCs and big pharma and are being developed for a wide range of indications including neurodegeneration. Given the importance of NLRP3 in immune sensing and cytokine release, it is not clear whether these compounds will be suitable for long-term administration since they could lead to immunosuppression and an increased risk of infection. CP-456,773 (an NLRP3 inhibitor) demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS. By comparison, DRP1-FIS1 inhibitors have been shown to act independently of cytokines. Companies developing NLRP3 inhibitors include IFM Therapeutics (Acquired for $2.8B by BMS), Ventyx Bioscience (IPO $2.1B), Ventus Therapeutics (Post-Series C, $300M raised), BioAge Labs (Post-Series C, $265M raised), and NodThera (Post-Series B, $103M raised). The ALS drug Relyvrio by Amylyx (market cap of $1.3B.) is currently generating $400M annually while only slowing disease progression by ~25%.
Fission Pharma offers a balance of scientific validation and cost-efficiency, building on P110 and SC9 data. The original in silico method, though rudimentary, was effective in finding nM potent hits with in vivo efficacy. This validates that the in silico approach can work. Fission’s improved in silico methods will expand on this initial finding.
Relevance to Longevity
Preserving healthy metabolism during chronic inflammation is a novel strategy that could mitigate age-related mitochondrial dysfunction and inflammatory damage, without suppressing immune function. These therapeutics could also improve the efficacy of other rejuvenation strategies which may be held back by lack of energy required for rejuvenation processes.
IP Roadmap
First Group: Brain penetrant DRP1-FIS1 inhibitors, compositions and uses thereof.
· Patent application filing planned for 2024, before Case Western studies.
Second Group: Orally available but peripherally restricted DRP1-FIS1 inhibitors for peripheral indications, compositions and uses thereof.
· Patent application filing planned for 2025, just before IND-enabling studies.
Third Group: Low penetrance DRP1-FIS1 inhibitors for gut and eye restricted delivery, compositions and uses thereof.
· Patent application filing planned for 2025, just before IND-enabling studies.
In silico discovery method (trade secret).
· Using GPU-accelerated empirical docking to train a diffusion model and accurately screen for compounds at non-traditional binding sites (sites that are poorly represented in the training data sets used to train AI models).
Experimental Plan
AI-based In Silico Screen for DRP1-FIS1 inhibitors
We are constructing a custom AI-model that will allow us to screen 4.5 billion compounds that bind the DRP1-FIS1 protein-protein interaction groove. This will allow us to generate the highest accuracy hits with a manageable computational cost. This will demonstrate feasibility of the method and will be benchmarked to competing methods.
Primary Screen (Internal)
The Hela LRRK2 G2019S cells (and PD patient cells) show a profound mitochondrial dysfunction that is corrected by P110 [5]. LRRK2 mutation (most common cause of autosomal-dominant Parkinson disease) leads to mitochondrial dysfunction through interaction with DRP1 [9], making it an ideal reporter of compound activity. We will screen the top 500 commercially available hits from our in silico screen to identify the top 5 lead candidates. We can then expand into non-commercially available compounds (custom synthesis of novel optimized structures). Toxic compounds will be screened out.
Figure 3: LRRK2 G2019S Hela cells treated with P110 (1ÎĽM) for 20 hrs. membrane potential (TMRM), MitoROS (MitoSOX), and mitochondrial structure will be used to select P110-mimetic compounds.
Hit to lead optimization (Internal and Case Western)
We will use our AI-enabled hit optimization engine to screen for analogues of the top 5 hits from the primary screen generating 5 additional analogues. In addition, we will synthesize the top 5 non-commercially available scaffolds that could not be ordered off-the-shelf. These 15 lead candidates will be confirmed with the primary assay internally, IP will be initiated, and then they will be sent to Case Western for more detailed validation. A secondary assay that is unrelated to the first will ensure generalizability. HD patient iPSCs and Huntington mouse striatal cells also show a profound mitochondrial dysfunction due to proteotoxic stress and this phenotype is corrected by P1103.
Figure 4: Mouse striatal cells expressing normal (HdhQ7) and mtHtt protein (HdhQ111) treated with peptide P110 (1ÎĽM) for 3 days. Lead candidates will be confirmed with mitochondrial structure, MitoROS, and membrane potential (MMP) assays.
Lead Selection (Case Western)
The top 4 compounds will be selected with the help of Nick Camp, a veteran medicinal chemist. These compounds will be screened for toxicity and PKPD in mice. The compound with the most favorable pharmacokinetics will advance as our lead candidate.
In Vivo Efficacy Testing
Since WT aged mice do not display significant mitochondrial brain aging, genetic neurodegeneration models that progressively induce mitochondrial dysfunction are the only way to measure target engagement in mice. P110 has shown efficacy across many mouse neurodegeneration models (AD, PD, HD, ALS, MS, scrapie, and stoke). The R/2 Huntington’s Disease mouse model shows measurable mitochondrial dysfunction and a near complete remission with P110 and would make a suitable model to show target engagement in mice [3,4,6]. The SOD1 mouse ALS model progresses faster and is also suitable [10]. Both models will be run with the lead compound. WT aged mice will then be tested for benefits in mitochondrial function and life extension.
Budget
Financing and VitaDAO funding terms
Fission Pharma has been self-funded by Luis Rios to date and is presently in the process of securing a pre-seed funding round of $650k, divided in two steps:
-
Step 1 – $150k, covering the in-silico screen (see the experimental plan above):
- $50k are allocated to the VitaDAO community under a SAFE note with a 25% discount and a $6 million cap on the seed round valuation. This is contingent upon filling the rest of the round.
- The company is actively looking for the remaining $100k under the same terms
-
Step 2 - $500k, covering the rest of the experimental plan: Fission is looking for a lead investor, and has already concrete leads:
- late stage talks with IndieBio
- other confidential leads
Team
Core Business Development Team
-
Luis Rios, PhD- Founder & CEO of Fission Pharma. Luis is leading the company by advancing the in silico discovery methods, building the team and development pipeline, and fundraising. He is an ideal candidate to lead the company since he is the inventor of allosteric DRP1 inhibitor small molecules and has expertise in drug discovery, mitochondrial biology, and venture capital. 10 years of experience as a molecular scientist with a BA in Molecular and Cell Biology from UC Berkeley, 4 years of work at the Salk Institute, and a PhD in Chemical and Systems Biology from Stanford University. 2 years of experience in venture capital as a consultant at Longitude Capital, partner at Vine Ventures, advisor at Healthspan Capital, and entrepreneur in residence at the Centenarian Fund.
-
Co-founder- Pending funding for full-time hire. Ideal candidate selected.
-
Justin Tso, MA- Operations at Fission Pharma. Justin oversees funding opportunities, grant writing, deck building, and networking at events. He has venture experience as a venture fellow at RTW investments, Columbia Technology Ventures, and Nucleate. MA from Columbia University in Biotechnology. Bachelors in business administration from Emory University.
-
Ibrahim Elshamy, JD- Business, legal, and IP advisor for Fission Pharma. Ibrahim advises and audits all business transactions and is advising on IP strategy. He is an associate at Gunderson Dettmer and has a JD from Stanford University.
Virtual Screening Team
-
Niklas Rindtorff- Virtual screening partner for Fission Pharma and part of the scientific advisory board. He is running the GPU-accelerated empirical docking engine and building a learning loop for scaled in silico discovery. He is the Founder & CEO at LabDAO and has expertise in AI, in silico drug discovery, and data science. Physician scientist and previously Fulbright Fellow for drug screening.
-
Zack Lawrence- Fission Pharma AI development partner and scientific advisory board member. Zack is working on the scalable and trainable in silico diffusion model for allosteric sites. He is the Founder & CEO of a stealth AI company. He has expertise in AI, data science, and mathematics from Stanford University. Previously a partner at Vine Ventures.
Pre-Clinical Research Team
-
Xin Qi, PhD- Principal Investigator and SAB Member at Fission Pharma. Xin is a professor conducting drug discovery research at Case Western Reserve. She is the inventor of the allosteric DRP1 inhibitor peptide, P110 and is a world expert on DRP1 and neurodegeneration. She will be validating all hits with cutting edge methods and human patient cells.
-
Nick Camp, PhD- Med Chem Advisor for Fission Pharma. Nick will advise on in silico hit screening, hit to lead optimization, and analogue synthesis. He has >25 years of experience as a medicinal chemist. Retired as Group Leader and Research Advisor at Eli Lilly and advisor at WuXi.
Pitch
Slide deck: Sept2023_Pitchdeck_full.pdf - Google Drive
Pitch recording: https://drive.google.com/file/d/1U0ipUgeVzmZvTqV8ud2xAq-N_2Dx5062/view
Supplementary videos: Fission Pharma_Supp. Videos.pptx - Google Slides
Highlights
-
P110, a proof of concept peptide inhibitor for DRP1-FIS1 interaction, shows efficacy and no toxicity in many age-related diseases models. 13 years of research, 11 disease models, and 20 publications on P110.
-
The founder has developed SC9, a P110-mimetic small molecule showing efficacy in-vitro and in-vivo.
-
These compounds act via a novel mechanism of action and target site.
-
We will have composition of matter patents on compounds discovered.
-
Pre-seed offer that balances scientific validation and cost-of-equity for investors.
-
“Pipeline in a pill” with 3 major classes of compounds targeting different tissues.
-
Innovative in silico inhibitor discovery method for age-related disease platform.
Risks
-
Novel mechanism of action that hasn’t been tested in humans (on-target tox)
-
Poor models for brain aging (but good models of Huntington’s).
-
Relevance for life extension not tested
-
Competition
Bibliography:
-
Qi, X., et al. Novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci (2012).
-
Rios, L. et al. Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction. Nat Commun (2023).
-
Guo, X. et al. Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration. Journal of Clinical Investigation (2013).
-
Zhao, Y., Sun, X. & Qi, X. Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington’s disease. Biochem Biophys Res Commun (2018).
-
Su, Y.-C. & Qi, X. Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet (2013).
-
Disatnik, M.-H. et al. Potential biomarkers to follow the progression and treatment response of Huntington’s disease. Journal of Experimental Medicine (2016).
-
Eisner, V., Picard, M. & HajnĂłczky, G. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol (2018).
-
Sbai, O. et al. Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer’s disease? Front Mol Neurosci (2023).
-
Wang, X. et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet (2012).
-
Joshi, A. U. et al. Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol Med (2018).
Authors from the company team are highlighted in bold.
Senior Review Digest - Quantitative
Below is the average scores out of 5 per category from 5 reviewers, who all recommended that the project should be advanced for token-holders vote.
Average Scores
- Team Expertise: 3.0
- Feasibility & Data: 3.8
- Commercial Potential & Impact: 3.4
- Novelty & Market Advantage: 3.6
- IP Defensibility: 4.0
- Relevance to Longevity: 3.6
- Deal Terms: 3.8
- General Conviction Score 3.7 (for reference, the average score of past funded projects is 3.7)
Senior Review Digest - Qualitative
Each reviewer was asked whether they would endorse the project, below are their answers.
Reviewer 1
I would endorse the project because of its applications in several age-related diseases. Nevertheless, VitaDAO should take an active role in tracking the progress of the company and help in reaching the next milestones.
Reviewer 2
Yes, I would endorse it.
Reviewer 3
While I find the project too early regarding IP and development strategy and believe VitaDAO could invest in other projects with more defined drug development plans, I am happy to let the community vote.
Reviewer 4
No answer.
Reviewer 5
The project is in its infancy stage. If the company does not claim its relevance to longevity, I am more than happy to support the project once the team has clinical & commercial experts; if it is related to longevity, I would not support but will actively participate in it until data on longevity related conditions/diseases come out (i.e. premature ovarian failure, dementia, AD, etc.).
-
Agree
-
Revisions Requested (Detail in Comments)
-
Disagree
