One-liner : Fission Pharma is developing a protein-protein interaction inhibitor that cuts the link between chronic inflammation and mitochondrial dysfunction to treat multiple age-related diseases and extend human lifespan.
Revision Notes:
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This project was originally proposed as funding an external company with VDP-123 and rejected.
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It was then revised as a VitaDAO company building project worth $250k and proposed as VDP-143 on March 15th 2024, taking into account the feedback received on VDP-123. The Discourse poll had a positive outcome, with 16 votes in favor and 1 vote against
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The current update of the revision, dated April 5th 2024, includes a research plan expansion to be covered with $83 333 co-funding from Cerebrum DAO in exchange for a share of the resulting IP-NFT. It is motivated by the opportunity to significantly increase the probability of success at marginal cost as well as the interest of Cerebrum DAO to support this project
Longevity Dealflow WG Team
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Senior reviewers: the same reviewers as the previous proposal, including two entrepreneurs, an executive, a VC, and a professor, provided a review update.
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Shepherd: Paolo Binetti, Ryan Spangler
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Squad members: Eleanor Davies
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Sourced by: Paolo Binetti, Ryan Spangler
Project Team
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Principal Investigator: Luis Rios, PhD
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VitaDAO Entrepreneur In Residence/Project Manager: Anthony Schwartz, Ph.D.
Simple Summary
Fission Pharma is creating the first drug-like small molecule P110 mimetics. P110 is a mito-protective peptide originating from Stanford University [1]. The efficacy of P110 in treating neurodegenerative and cardiac disease is supported by 13 years of research, resulting in 20 scientific publications across 11 disease models and collaboration with 15 independent labs globally. P110 has highly generalized anti-degenerative activity, increasing lifespan in mouse models of neurodegeneration (HD [2-5], ALS [5-6], AD [5, 7, 8], PD [1], MS, stroke, and scrapie) and also a model of ischemic heart disease [9]. Dr. Luis Rios published the first small molecule P110 mimetics in 2023 [10] and showed comparable efficacy to P110 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. These compounds aim to be the first effective and generalized orally available and brain penetrant treatments for chronic inflammation and mitochondrial dysfunction, critical hallmarks of aging, and may do so without causing immunosuppression, the limiting factor in chronic inflammation treatment. The most tractable go-to-market strategy will be in a rare neurodegenerative disease (ALS) and they will expand to age-related degenerative indications such as AD and ischemic heart disease, the major limiting factors in human lifespan.
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. One of the primary consequences of inflammation is damage to mitochondria.
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, DNA, proteins, and ultimately tissues during chronic inflammation. DRP1 has a clear role in neurodegeneration [1-8], ischemia-reperfusion injury [9] (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 that becomes activated and interacts 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 [10].
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).
Figure 1: Pre-clinical proof of concept data for P110 and SC9. a-c, P110 increases lifespan in mouse models of Huntington’s Disease (zQ175 and R6/2) and ALS (SOD1). 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 in silico hits have higher binding scores and lower mass indicating increased ligand efficiency and potency.
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, pharma partnerships will be sought. Fission aims to address a total market exceeding $200B.
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).
Relevance to Longevity
Mitochondrial aging, inflammation, and secondary tissue degeneration are fundamental hallmarks of aging that have no effective treatments. Inflammation causes mitochondrial degeneration which prevents mitochondrial DNA exchange and generaties mutation causing ROS. Given that brains will be the most difficult organ to replace, and also the most difficult to deliver cell and gene therapies to, small molecule agents that prevent neurodegeneration are required to achieve longevity escape velocity for older adults living today. While more radical treatments are possible, less risky agents will be necessary to extend functional brain activity for the foreseeable future. However, even if other treatments are developed, whenever an inflammatory condition occurs, we will need effective anti-inflammatories to prevent age-accelerating damage to mitochondria and tissues. Preserving healthy metabolism during chronic inflammation is a novel anti-aging 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.
P110 addresses multiple hallmarks of aging (mitochondrial dysfunction and inflammation) and has demonstrated preclinical efficacy in diseases of aging that represent the limiting factors in human lifespan (ischemic heart disease and neurodegeneration). It increases lifespan in five mouse models of neurodegeneration (AD, PD, HD, ALS, and scrapie) showing broad anti-degenerative activity. The Alzheimer’s Drug Discovery foundation published a review in Cognitive Vitality on the potential of P110 in treating AD [8]. Other diseases of aging may also be treated that have yet to be investigated, however we anticipate the greatest benefit in high energy tissues that are heavily reliant on mitochondria such as the brain and muscles.
IP Roadmap
The project does not need to secure any background IP from previous research. The plan is to produce novel and defensible IP by the end of the project filing patents for 3 groups of NCEs with distinct PKPD and target indication space:
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First Group: Brain penetrant DRP1-FIS1 inhibitors, compositions and uses thereof.
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Second Group: Orally available but peripherally restricted DRP1-FIS1 inhibitors for peripheral indications, compositions and uses thereof.
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Third Group: Low penetrance DRP1-FIS1 inhibitors for gut and eye restricted delivery, compositions and uses thereof.
Experimental Plan
Below is the draft plan proposed for this project divided in four phases with go / no go milestone to trigger funding tranches (also shown) for each one of them:
December is considered a contingency buffer in case the project or the funding campaign for the follow-up take longer than expected.
Below is the draft plan for the follow-up until phase 1 clinical trial (not covered by this project, but provided for visibility into the next steps), including preliminary budget and milestones.:
The activities are described in detail below for phase 1, covered by this proposal, and phase 2, to be covered by the follow-up IPT funding.
Phase 1 (IP Building Round): In Silico Screen for DRP1-FIS1 inhibitors
We are screening the Enamine REAL library (48 billion compounds) that bind the DRP1-FIS1 protein-protein interaction groove. These hits are filtered for drug-like properties and problematic functional groups are removed with a series of filters (PAINS, Brenk, CYP inhibition, hERG, pg-p binding etc.). Hits are all synthesizable at a cost of ~$150 per compound for a total cost of $75K for a 500 compound screen.
Primary Screen (Selvita)
500 virtual hits are screened for anti-inflammatory activity and toxicity in freshly isolated human PBMCs at a cost of ~$50K per 500 compounds per screen. Analogues of hits are screened in a primary screen 2 to assess SAR.
Secondary Screen (Selvita)
Hits are screened for mito-protective effects in human neuronal cell-line with readouts being toxicity, EC50, mitochondrial ROS, and mitochondrial membrane potential.
Go/No Go Milestones Phase 1:
- Primary screen identifies hits compounds <10uM IC50 (Q4 2024)
- Hit to lead screen identifies hits compounds <1uM IC50 (Q1 2025)
- Lead candidates have mito-protective activity <1uM IC50( Q1 2025)
IP-NFT minted and IPT funding round launched.
Phase 2 (IPT Pre-Seed): Lead selection and In-vivo efficacy (not included in this proposal)
DMPK and Toxicity (Selvita)
Top 10 hits are screened for solubility, membrane permeability, liver metabolism, and hepatotoxicity. Results inform the hit to lead optimization design effort. IP is filed on high performing scaffolds.
In vitro efficacy in ALS, HD, and AD models (by Xin Qi at Case Western)
Disease modifying activity will be confirmed in lead candidates. AD, ALS, and HD patient iPSCs show a profound mitochondrial dysfunction due to mitochondrial and proteotoxic stress and this phenotype is corrected by P110 [3].
Figure 4: Human HD IPSCs treated with peptide P110 (Guo 2013). Lead candidates will be tested in HD, AD, and ALS iPSCs to confirm efficacy in correcting mitochondrial structure, MitoROS, and membrane potential (MMP).
Lead selection
The top 5 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 (by Xin Qi at Case Western)
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 and increased lifespan 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. The SOD1 mouse ALS model progresses faster and is also suitable. Both models will be run with the lead compound. WT aged mice can also be tested for benefits in mitochondrial function and life extension, however WT mice do not die of neurodegenerative disease or significant mitochondrial dysfunction like humans.
Go/No Go Milestones Phase 2:
- DMPK screen identifies drug-like properties in hits (solubility >10uM, caco-2 permeability >5 x 10(-6) cm/s, ex vivo liver metabolism half-life >1hr, ex vivo therapeutic index > 10 (Q2 2025)
- Lead molecule identified with serum half life >3hrs and BBB pentrance >0.5 (Q3 2025)
- Lead molecule active in human IPSC model and mouse models of neurodegeneration (ALS, HD, and AD).
IP Building Round Budget Breakdown
The total budget requested for this proposal is $333k, broken down as follows:
Financing and VitaDAO funding terms
IP Building Round: This phase focuses on identifying promising leads and filing provisional patents for NCEs (New Chemical Entities). The proposed amount is $333 333, consistent with the budget above, to be funded by:
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VitaDAO for $250 000
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Cerebrum DAO for $83 333.
The IP built by the team becomes an IP-NFT, whose ownership is split:
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60% VitaDAO
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20% Cerebrum DAO
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5% PI, Luis Rios
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5% Employee Option Pool
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5% EIR, Anthony Schwartz
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5% Deal squad
Pre-Seed Round (not included in this proposal): If milestones met for phase 1, would proceed to raise approximately $500k community-funded via an IPT mechanism. The objective is to progress from initial hits to lead compounds, positioning Fission for a subsequent seed round. Details would be determined in a future VDP proposal.
Team
Luis Rios, PhD- Co-Founder & CEO of Fission Pharma. Luis is leading the company by advancing the in silico discovery methods, building the team, 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. 3 years of experience in venture capital as a consultant at Longitude Capital, partner at Vine Ventures, and advisor at Healthspan Capital. Director of Drug Discovery at ImmuneAge Bio.
Anthony Schwartz, PhD- Co-Founder & COO of Fission Pharma. Co-inventor on multiple cancer and autoimmune drugs. 20 years experience, raised over $50 million & FDA approval. Professor - The Johns Hopkins University. Co-founded/launched 20+ companies. Former CEO - Interthyr Corp, Athencion Biotech, XTELL Corp
Akshat Nigam, PhD Candidate- Computational Chemist at Fission Pharma. Expert in AI and drug discovery. Inventor of Virtual Flow 2.0. PhD Candidate Stanford University. Worked with Insilico Medicine and Zapata AI on quantum computation. 9 publications in computation and
drug discovery.
Zack Lawrence- AI development partner and scientific advisory board member at Fission Pharma. Zack is the Founder & CEO of a Kyne Corp. AI and is an advisor on our in silico discovery strategy. He has expertise in AI, data science, and mathematics from Stanford University. Previously a partner at Vine Ventures.
Xin Qi, PhD- 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.
Justin Tso, MA- Fund-Raising Advisor for Fission Pharma. Justin 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.
Suman Pohkrel, PhD- Computational Chemistry Advisor for Fission Pharma. Virtual Screening and drug discovery expert from Bayer. Stanford Chemical and Systems Biology, PhD. Co-inventor of Drp1 and Fis1 targeted small molecules. Expert on Drp1 biology. Stanford Business School Ignite participant and founder of stealth technology company.
Nick Camp, PhD- Med Chem Advisor for Fission Pharma. Nick will advise on in silico hit screening, hit to lead optimization, analogue synthesis, and pharma acquisition strategy. He has >25 years of experience as a medicinal chemist. Retired as Group Leader and Research Advisor at Eli Lilly and advisor at WuXi.
Slide deck
VitaDAO-Fission Pharma Deck.pdf
Highlights
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P110 , a proof of concept peptide inhibitor for DRP1-FIS1 interaction, shows efficacy and no toxicity in many age-related disease models. 13 years of research, 11 disease models, and 20 publications on P110.
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The founder has developed SC9 , a P110-mimetic small molecule showing efficacy in vitro and in vivo.
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These compounds act via a novel mechanism of action and target site.
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VitaDAO will own composition of matter patents on compounds discovered.
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Pre-seed program with substantial scientific validation and IP-NFT offer.
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“Pipeline in a pill” with 3 major classes of compounds targeting different tissues.
Risks
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Novel mechanism of action that hasn’t been tested in humans (on-target tox)
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Poor models for brain aging (but good models of Huntington’s).
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Relevance for life extension not tested
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Competition
Bibliography
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Qi, X., et al. Novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci (2012).
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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).
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Disatnik, M.-H. et al. Potential biomarkers to follow the progression and treatment response of Huntington’s disease. Journal of Experimental Medicine (2016).
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Guo, X. et al. Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration. Journal of Clinical Investigation (2013).
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Joshi, A. U. et al. Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. NatNeurosci 22, 1635–1648 (2019).
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Joshi, A. U. et al. Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol Med (2018).
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Joshi, A. U.,et al. Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer’s disease. Oncotarget 9, 6128–6143 (2018).
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Tian L. et al. Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. J Mol. Med. (Berl). 95(4): 381–393 (2017)
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Rios, L., Pokhrel, S., et al. Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction. Nat Commun (2023).
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: 4.4
- Feasibility & Data: 4.2
- Commercial Potential & Impact: 4.2
- Novelty & Market Advantage: 4.2
- IP Defensibility: 4.2
- Relevance to Longevity: 4.2
- Deal Terms: 4.8
- General Conviction Score 4.2 (for reference, the average score of past funded projects is 3.7)
Note: while these scores refer to the original version of this proposal (VDP-143), we believe that they are mostly still applicable to the current revision.
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. With the new updates in company team and focused strategy for drug development convinced me more in a positive way. I have updated my scores and would be happy to endorse the company.
Reviewer 2
Yes, I would endorse it. Very feasible. The background science is solid and validated in mice disease models. The question is whether it will work in humans. They focus on a rare disease approach. Looks like a good first step.
Reviewer 3
Given the new additions to the team, the more straightforward path to IP, and the clear unmet need for ALS, I am more than happy to endorse this project. I am personally excited to see how the science plays out. The science is interesting. There could be applications to Longevity. The ask is reasonable.
Reviewer 4
Yes. Despite adding Anthony, this is still a risky project as it uses computational chemistry to screen for a new compound. However the risk/reward is worth it. Good survival data. Market is big for ALS, neurodegenerative diseases, etc. The terms are better now.
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.).
Note: while these endorsements refer to the original version of this proposal (VDP-143), we believe that they are mostly still applicable to the current revision.
Vote
- Agree
- Revisions Requested (Detail in Comments)
- Disagree
