CDP-14: [Funding] Fission Pharma

One liner: Fission Pharma is developing a protein-protein interaction inhibitor drug that cuts the link between chronic inflammation and mitochondrial dysfunction to treat multiple age-related and neurodegenerative diseases to extend human lifespan. Referenced from VitaDAO VDP-143

Revision Notes:

• This project was originally proposed to fund a spinout company operated by VitaDAO. Cerebrum DAO would cover $83 333 co-funding, in exchange for a 20% share of the resulting IP-NFT. The resulting financing amount would have totalled $333,333 USD.
• Following discussions with VitaDAO and the Fission Principal Investigator, Cerebrum DAO will solely operate the spin-out and development process.
• This proposal outlines the conditions of the revised funding agreement for this project.

Cerebrum DAO Deal Team

Senior reviewers: the same reviewers as the previous proposal. Two entrepreneurs, an executive, a VC, and a professor, provided a review update. Project Team: Maryna Polyakova, Brian Magierski, Eleanor Davies, Peter Groenen Sourced by: VitaDAO, Maryna Polyakova, Brian Magierski

Project Team

Principal Investigator: Luis Rios, PhD Translational Neuroscience Advisor: Peter Groenen, PhD Project Team: Maryna Polyakova MD/PhD, Eleanor Davies

Summary Deal Analysis

(For the detailed summary of the Fission proposal, please refer to VDP-143 referenced above.)

Fission Pharma is developing a first-in-class brain-penetrant small molecule analog of P110, a DRP1-FIS1 interaction inhibitor. 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 generalised 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 identified a P110-binding site to a switch I-adjacent grove (SWAG) on the DRP1 protein and discovered three molecules mimicking P110 activity in 2023 [10] demonstrating a comparable efficacy of these molecules to P110 in mouse models of sepsis. These inhibitors have a unique property in that they inhibit the downstream pathophysiological consequences of inflammation without inhibiting physiological immune signals. These compounds aim to provide a route to a first in class, effective, orally available and brain penetrant treatment for chronic inflammation and mitochondrial dysfunction, without causing immunosuppression, a limiting factor in chronic inflammation treatment. The most tractable go-to-market strategy will be in a rare neurodegenerative disease (such as ALS) with the life cycle strategy of expansion into age-related degenerative indications such as, but not limited to AD and ischemic heart disease.

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 each a distinct PKPD and target indication space:

• First Group: Brain penetrant DRP1-FIS1 inhibitors, compositions and uses thereof.
• Second Group: Orally available and BBB restricted DRP1-FIS1 inhibitors for systemic indications, compositions and uses thereof.
• 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 milestones to trigger funding tranches (also shown) for each one of them:

Hit secondary confirmation and hit-to-lead optimization will be conducted after the IPT round.

Phase 1 (IP Building Round): In Silico Screen for DRP1-FIS1 inhibitors We are screening the Enamine REAL library (48 billion structures) for potential hits 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 and Brenk filters). The library design was biassed toward drugs with BBB penetrant compound-like properties. Primary Screen (Pharmaron) The 1000 virtual hits are selected for chemical synthesis and subsequently screened for mito-protective effects in Hela cells with readouts being cellular toxicity, IC50, mitochondrial ROS, and DRP1 translocation to the mitochondria. Go/No Go Milestones Phase 1:

1. Assay parameters optimized for screening 1000 compounds with sufficient statistical power (2 months)
2. Primary screen identifies hit compounds <10uM IC50 (3 months) IP-NFT minted and IPT funding round launched.

Future Plans:

Phase 2 (IPT Pre-Seed): Lead selection and In-vivo efficacy (not included in this proposal)

Potency optimization Analogs of the top hits are screened to maximize potency using the primary screen assay.

Secondary Screen Hits are screened for mito-protective effects in human neuronal cell-line with readouts being in vitro toxicity, IC50, mitochondrial ROS, and mitochondrial membrane potential. This assay confirms that efficacy seen in the primary screen translates to a neuronal model.

**In vitro DMPK ** Top 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 Disease modifying activity will be confirmed for 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 series selection The top compounds will be selected with the help of Nick Camp, a veteran medicinal chemist. Compounds are further optimized until a lead compound is selected for IND enabling studies.

IP Building Round Budget Breakdown

The total budget requested for this proposal has been revised to $200,000 broken down as follows:

Financing and Cerebrum DAO Funding Terms

The Cerebrum DAO Translational Neuroscience Working Group has recommended funding $200,000, consistent with the budget above, to the project to accomplish Milestones 1 and 2 within Phase I. The funding should be transferred in tranches, based on milestone completion. Upon success, the Fission Pharma company will mint an Intellectual Property Non-Fungible Token (IP-NFT) and launch an IPT crowdfunding round to support the remainder of the study. This will advance the project from PRL 2 (validated hypothesis in animal studies) to PRL 4 (Initial hits identified, leads are effective in the secondary screen in neurons). Funding will be contingent on the following conditions:

• Successful accomplishment of Milestones 1-2 within Phase I: (IP Building Round): focusing on identifying promising hits.
• Pre-Seed Round (not included in this proposal): If milestones met for Phase 1, we will proceed to raise approximately $500k via the IPT community-funding mechanism. The objective is to progress from initial hits to lead compounds, positioning Fission for a subsequent Seed round. Details will be determined in a future CDP proposal.

As a part of the agreement, Cerebrum will incorporate and manage the Fission Pharma Operating Company (NewCo) which will manage the day-to-day operations. Ownership of the NewCo will be structured as follows:

• Cerebrum DAO: 85% in Preferred Stock
• PI, Dr. Luis Rios: 15% in Restricted Common Stock Proforma IPT ownership:
• Cerebrum DAO: 75%
• PI, Dr. Luis Rios: 15%
• Project Manager and Board Members: 5%
• Project Team: 5%

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Please visit the following link to view the full proposal, as the proposal content exceeds Discord Forum's character limit: https://docs.google.com/document/d/1RTOW6sNVZEBmXSHv1uGRK82PhqwTFRwcg9YKW_z87MQ/edit?usp=sharing