VDP-87 [Assessment] Zoe Biosciences

[Paolo]

One liner: An early-stage therapeutic biotech with two programs each centered on targets that are well validated both for longevity and aging-related diseases.

Longevity Dealflow WG Team

Reviewers: 2 scientists, two biotech venture capitalists and 2 business experts

Shepherd: Ryan Spangler

Other squad members: Rhys Anderson, Paolo Binetti, Maria Marinova, Mantas Matjusaitis

Sourced by: Ryan Spangler

Project lead: Scott Gies (CEO) and Douglas Vaughan MD (CSO)

Simple Summary

Zoe Biosciences is an early-stage pre-clinical biotech developing breakthrough therapeutics for age-related diseases and aging itself focusing on drug targets that are well validated both for longevity and aging-related diseases, high-leverage (pleiotropic), and low-hanging. They currently have a pipeline with two assets, both with the potential to extend human healthspan. The first program is PAI-1 biologic inhibitors with high target selectivity and affinity, relevant for diseases including elevated FGF23 syndromes and metabolic disorders. The second program is APJ small-molecule agonists for similar age-related indications. The two assets can also be advanced in combination.

Opportunity

PAI-1

The PAI-1 (plasminogen activator inhibitor-1) program is built upon human, genetic evidence in a Swiss Amish population in northeastern Indiana. Dr. Vaughan, Zoe’s CSO, has worked with this community since 2015 when he discovered community members with a rare, loss-of-function mutation for the gene that codes for PAI-1, the main inhibitor of the fibrinolytic system. Carriers of this mutation exhibit delayed biological aging and a lower prevalence of chronic disease, informing Zoe on the effects of lifelong PAI-1 inhibition (see figure below).

A lifelong reduction of PAI-1 in Amish with a heterozygous loss-of-function mutation protects against chronic disease and prolongs human lifespan

At present, the lead indications include metabolic disorders (prediabetes and polycystic ovary syndrome), elevated FGF23 syndromes (advance chronic kidney disease, oncogenic osteomalacia, and familial hypophosphatemic rickets), and cardiovascular disorders. Additionally, Dr. Vaughan’s studies with the Indiana Swiss Amish community will refine indication and endpoint selection.)

Various attempts at targeting PAI-1 in the past confirm its clinical relevance. All the past failed attempts, as well as ongoing ones with low affinity, are based on small molecules. Leveraging the founders’ strong understanding of PAI-1 biology and novel approaches suggested in literature, Zoe chose a biological approach for superior affinity (see figure below).

APJ

APJ is expressed across many cell types and organs and plays a multitude of physiological and pathological roles related to aging, notably those mentioned above. Other, specific roles include regulation of blood pressure, cardiac contractility, metabolic balance, angiogenesis, cell proliferation, apoptosis, inflammation, anxiety, depression, and water homeostasis. Aging decreases expression of apelin and APJ (apelin is an agonist at the APJ receptor).

The Zoe team chose APJ for two reasons: 1. there is broad evidence for its beneficial impact on aging-related pathology and 2. apelin/APJ and PAI-1 synergistically antagonize each other. Via nitric oxide, PAI-1 blocks the beneficial effects of apelin, whereas apelin reduces the deleterious effects of PAI-1 (see below). This makes it an ideal target for a PAI-1-focused platform with a host of indication options unique to it.

PMID: 21358420

Solution

PAI-1

Our lead antibody was raised against human PAI-1 and is reactive towards human, mouse, and rat PAI-1. It has a high affinity KD (0.2 nM) and converts active PAI-1 to substrate PAI-1, which has been confirmed in vitro and in vivo. The antibody is undergoing early preclinical/POC testing. Additionally, we will use these early tests to finalize indication selection. Zoe has PAI-1 nanobodies it is advancing as well.

APJ

Zoe has a lead small molecule Good PK and efficacy in rodent models with no off-target or toxicological effects in preclinical models (non-GLP).

Relevance for longevity

On top of genetic validation of healthspan extension (see above), PAI-1 addresses all nine of the Hallmarks of Aging (see figure below):

Plan and IP roadmap

With this funding round, Zoe plans to advance both assets to be in the position to raise series A to conduct IND-enabling work. According to the current top level development plan the IND for the PAI-1 antibody is planned for late early 2025, for the APJ agonist the IND is scheduled for late 2024 - early 2025 (see figures below).

PAI-1

With this seed round, Zoe plans to accomplish the following: lead selection, lead optimization, and preclinical results to support indication selection and a series A. Zoe has an exclusive option on a panel of PAI-1 murine monoclonal antibodies and antibodies developed by Dr. Paul Declerck at KU Leuven in Belgium (Zoe’s scientific advisor & a long-time collaborator of Dr. Vaughan’s).

If Zoe chooses to advance the antibody as the lead (the most likely scenario), the plan is to humanize & optimize (e.g. for subcutaneous delivery) the antibody and then file for fresh IP. In order to do so, Zoe has an agreement with Twist Bioscience. The work will be broken up into the following phases:

• Project Order Initiation
• Framework Selection
• Screening Completion
• Project Completion

This round will lead to fresh NCE IP.

APJ

Zoe has an exclusive licensing option with Sanford Burnham Prebys for Dr. Layton Smith’s APJ agonists. There is a lead compound and a backup.

With seed round financing, Zoe plans to run preclinical studies to finalize indication selection and formalize the license (see preclinical models above – sarcopenia/cachexia is a lead indication for the APJ program at the moment). This in vivo work will set up Zoe’s APJ program for Series A financing and IND-enabling studies.

Financing and VitaDAO funding terms

Zoe has raised pre-seed funding from two longevity venture capital, Longevitytech Fund and Healthspan Capital.5

In the current seed round, Zoe is seeking $1.5M. VitaDAO would fund 100 k€ with equity terms.

Team

• Scott Gies, CEO and Founder: Scott is the CEO of Zoe Biosciences and a former Advisor to Sergey Young’s Longevity Vision Fund. Scott’s mission is to advance biology that helps alleviate suffering. To that end, he helped build the Flow Research Collective, a company studying the neuroscience of peak performance, as the Head of Business Development & Strategic Partnerships, and worked on the scientific diligence team at OS Fund, a deep tech-focused VC firm. Scott’s research experience spans epigenetics/genetics work studying tandem repeats (Sharp Lab at Mount Sinai), cognition research in octopuses (Tse Lab at Dartmouth), in silico autism research (In Silico Biosciences), and marine biology conservation work in Madagascar. He graduated from Dartmouth College with a degree in neuroscience.

• Douglas Vaughan, CSO and Founder: Dr. Vaughan is the Chairman of the Department of Medicine and the Irving S. Cutter Professor of Medicine at Northwestern University Feinberg School of Medicine and the Physician in Chief of Northwestern Memorial Hospital. His lab has been at the forefront of basic and preclinical investigations that have helped define the molecular physiology of PAI-1 and its role in arteriosclerosis, metabolism, senescence, and aging. Dr. Vaughan is also the Founding Director of the Potocsnak Longevity Institute at Northwestern, a multidisciplinary institute looking to expand human healthspan.

• Advisors

1. Paul Declerck, PhD, PharmD: expert in PAI-1 antibody & nanobody development

2. Layton Smith, PhD: expert in apelin biology

3. Benjamin Singer, MD: Expert in epigenetics

4. Vibeke Strand, MD: expert in regulatory strategy & clinical research

Slide Deck

Use this link: Slide Deck

Publications

Sillen, M.; Declerck,P.J. A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?. Int. J. Mol. Sci. 2021, 22, 2721. https://doi.org/10.3390/ ijms22052721

Vaughan DE, Rai R, Khan SS, Eren M, Ghosh AK. Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):1446-1452. doi: 10.1161/ATVBAHA.117.309451. Epub 2017 Jun 1. PMID: 28572158; PMCID: PMC5846199.

Czekay, Ralf-Peter et al. “PAI-1: An Integrator of Cell Signaling and Migration.” International journal of cell biology vol. 2011 (2011): 562481. doi:10.1155/2011/562481 4. Yahata, Takashi et al. “TGF-β-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche.” Blood vol. 130,21 (2017): 2283-2294. doi:10.1182/blood-2017-02-767384

Elzi, David J., et al. “Plasminogen activator inhibitor 1-insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence.” Proceedings of the National Academy of Sciences 109.30 (2012): 12052-12057.

Lu, Ake T et al. “DNA methylation GrimAge strongly predicts lifespan and healthspan.” Aging vol. 11,2 (2019): 303-327. doi:10.18632/aging.101684

Catarinella, Giorgia et al. “Targeting SERPINE1 Reverses Cellular Features of Hutchinson-Gilford Progeria Syndrome.” BioRxiv, 5 Nov. 2021, https://doi.org/10.1101/2021.11.05.467259.

Khan Sadiya et al. A null mutation in SERPINE1 protects against biological aging in humans. Sci Adv. 2017 Nov 15;3(11):eaao1617. doi: 10.1126/sciadv.aao1617. PMID: 29152572; PMCID: PMC5687852.

Ye, Yao, et al. “Role of plasminogen activator inhibitor type 1 in pathologies of female reproductive diseases.” International journal of molecular sciences 18.8 (2017): 1651. 17. Liu, R-M., et al. “Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer’s disease.” Neurobiology of aging 32.6 (2011): 1079-1089.

Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., … & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617.

Senior expert evaluation digest

This proposal has been evaluated by two scientists, two biotech venture capitalists, and two business experts, please find below a digest of their evaluation:

Qualitative evaluation

PAI-1 is genetically validated in humans, and their CSO has done high quality research on it. APJ is validated in the sense BioAge is working on the same target. Both MOAs are applicable to both age-related disease and longevity, with the potential to treat many disease indications and potentially prevent aging in general. PAI-1 and apelin synergistically antagonize each other, which would potentially offer a combined treatment approach at later stages of development. The company has a strong IP portfolio with exclusive licenses for multiple PAI-1 monoclonal antibodies (mAbs) and APJ agonists. There are competitors and previous failures targeting PAI-1 with small molecules. Zoe has promising efficacy studies in mice with a murine antibody. It remains an uncertainty if a chronic mAb treatment at an affordable price will be a viable approach. Creating a systemic PAI-1 inhibitor could bring unforeseen consequences considering PAI-1 has diverse functions on different tissues. There are many directions this project can go: need to zero in on best indication.

Quantitative evaluation: 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: 3.5

• Feasibility & Data: 3.7

• Relevance: 4

• Science Team: 4.5

• Market Advantage: 2.7

• IP Potential: 3.2

• Conviction score: 3.3

Highlights

• PAI-1 is genetically validated in humans. Seems to be an important target. APJ is strategically validated in the sense BioAge is working on the same target.

• Promising efficacy studies in mice with a murine antibody

• Head scientist is very knowledgeable.

• Mechanisms of action applicable to both longevity and age related disease, such as cardiovascular, metabolic, musculoskeletal, and hearing loss, as well as to FGF-23 syndrome, an orphan genetic disorder, and Polycystic ovary syndrome, another unmet need

• Have good in vivo data demonstrating improved insulin sensitivity

• Strong IP portfolio - exclusive licenses for multiple PAI-1 mAbs and APJ agonist and IP pending around therapeutic applications for PAI-1

• PAI-1 and apelin synergistically antagonize each other. This would potentially offer a combined treatment approach at later stages of development. Or, in case one product fails, the other could still create substantial value for Zoe and investors.

• The PAI-1 mab strategy could be better than other companies that have aimed to inhibit PAI-1 with limited success to date.

Risks

• The biggest challenge will be finding the right first indication to go after. The company should zero in on best indication and focus its work on what is needed to raise a phase A leading to IND-enabling studies.

• PAI-1 has been abandoned by other players. The APJ drug that BioAge has was abandoned by Amgen.

• APJ is a niche target from what I see in the literature.

• PAI-1 interacts with FGF21 which has struggled to-date in other efforts with CV toxicity

• The team size appears quite small for the planned programs and timelines, although this is also motivated by the company’s choice to subcontract to CROs.

• It remains an uncertainty if a chronic treatment strategy with (likely) large amounts of antibody needed for adequate inhibition of endogenous PAI-1 at an affordable price will in the end be a viable approach.

• Difficult regulatory path for antibody-based drugs without immediate life-threatening danger, although PSK9 inhibitors are paving the way.

• PAI-1 and apelin synergistically antagonize each other, a potential cannibalism of projects should be avoided e.g. by clear differentiation of indication areas.

• Agree

• Revisions Requested (Details in Comments)

• Disagree