ARPA-H-SOL-26-165_COSMOS_ISO_Amendment 01.pdf

ARPA-H-SOL-26-165, COSMOS

INNOVATIVE SOLUTIONS OPENING

FOR

COMPREHENSIVE ORGAN SYSTEM MODELING IN OUTER

SPACE

COSMOS

HEALTH SCIENCE FUTURES (HSF)

ARPA-H-SOL-26-165

Amendment 01: 17 September 2026

16 September 2026

Table of Contents

1 Solicitation Summary Information

2 INTRODUCTION TO COSMOS

2.1 Background

2.1.1 Executive Summary

2.1.2 Current State of R&D in Low Earth Orbit:

2.2 Age-related Disease:

2.2.1 Microphysiological Systems / Organs on Chips:

2.2.2 Regenerative Medicine:

2.2.3 Pharmaceutical Drug Screening:

2.3 COSMOS Overview

3 COSMOS DETAILS

3.1 COSMOS Structure and Timeline

3.2 Phase I Details

3.2.1 Phase I Launch Schedule

3.2.2 Phase I Results Showcase

3.2.3 Phase I Commercialization Requirements

3.3 Phase II Details

3.3.1 Phase II: Establishing Rapid Drug Screening for Age-Related Diseases

3.3.2 Phase II Launch Cadence

3.3.3 Phase II Results Showcase

3.3.4 Drug Candidate Selection

3.3.5 Phase II Commercialization Requirements

3.4 Performer Reporting, Evaluation and Progress Monitoring

3.4.1 Required Meetings

3.5 Required Commercial Biopharmaceutical Partnernerships Engagement

4 MANDATORY EXPERIMENTAL DESIGN

4.1 Phase I Experimental Design

4.1.1 Experimental Age Brackets

4.1.2 Terrestrial Study

4.1.3 LEO Twin Study

4.1.4 Commercial Service Providers (CSP)

4.1.5 Phase I Design Requirements

4.1.6 Mandatory Microphysiological Systems / Organs on Chips & Organoid Parameters

4.1.7 In Silico Aging Model

4.2 Phase II Experimental Design

4.3 MPS-based Disease Model

5 COSMOS METRICS

5.1 Phase I Metrics

5.2 Phase II Metrics

6 COSMOS Team Requirements

7 COSMOS Data & Data Management

8 ELIGIBILITY INFORMATION

8.1 Eligible Proposers

8.2 Prohibition of performer participation from Federally Funded Research and Development Centers (FFRDCs) and other Government Entities

8.2.1 Current professional support

8.2.2 Non-U.S. Entities

8.3 System for Award Management (SAM)

9 PROPOSAL REQUIREMENTS

9.1 Proposal Volume I

9.2 Proposal Volume II

9.2.1 Cost Proposal Excel File

9.2.2 Cost and Pricing Data Support

9.3 Task Description Document (TDD)

9.4 Milestone and Payment Table Model

9.5 Attachment B COSMOS Eligibility and Conformance Sheet

9.6 Attachment C COSMOS Schedule

10 SUBMISSION PROCESS

10.1 Submission process Overview

10.2 Full proposal submissions

10.3 Submission Information

PROPRIETARY INFORMATION

11 Document Descriptions

12 SUBMISSION REVIEW AND EVALUATION PROCESSES

12.1 Conforming submissions

12.2 Proposal review process

12.3 Evaluation Criteria for proposals

12.3.1 Criteria 1: Overall Scientific and Technical Merit

12.3.2 Criteria 2: Proposer’s Capabilities and/or Related Experience

12.3.3 Criteria 3: Assessment of Cost Reasonableness

13 SELECTABLE OR NON-SELECTABLE DESIGNATION

13.1 Selectable

13.2 Non-Selectable

13.2.1 Non-Selectable Criterion 1 Solutions

13.3 Review and Evaluation Timelines

13.4 Handling competition sensitive information

13.5 Evaluation and Award Disclaimers

14 POLICY REQUIREMENTS AND MISCELLANEOUS OTHER INFORMATION

14.1 Controlled unclassified information (CUI) on Non-Federal Information Systems

14.2 Organizational Conflicts of Interest (OCI)

14.2.1 Agency Supplemental OCI Policy

14.3 Intellectual Property

14.4 Data and Data Management

14.5 Research Security Disclosures

14.6 Human Subjects Research

14.7 Electronic Invoicing and Payments

14.8 Genomic Data Sharing

14.9 Procurement of Synthetic nucleic acids or benchtop synthesizers

14.10 Dangerous Gain-Of-Function Research

ATTACHMENTS

ATTACHMENT A: Proposal Model Documents (3 total)

ATT A.1: Volume 1 Model (Technical and Management Proposal)

ATT A.2: Task Description Document Model [MS Word] (component of Volume 1)

ATT A.3: Milestone and Payment Table

ATTACHMENT B: COSMOS Eligibility and Conformance Certification Sheet

ATTACHMENT C: COSMOS Schedule

ATTACHMENT D: COSMOS Cost Proposal Template

ATTACHMENT E: COSMOS Administrative and National Policy Requirements

1 SOLICITATION SUMMARY INFORMATION

FEDERAL AGENCY: Advanced Research Projects Agency for Health (ARPA-H)

TITLE: Comprehensive Organ System Modeling in Outer Space (COSMOS)

ANNOUNCEMENT TYPE: Innovative Solutions Opening (ISO)

ISO SOLICITATION NUMBER: ARPA-H-SOL-26-165

ISO CONTACT: COSMOS@ARPA-H.GOV

ANTICIPATED AWARDS: Multiple Other Transaction (OTs) Agreements

DATES: (All times listed are Eastern Time)

Questions & Answers (Q&A) due date: October 1, 2026, 5pm ET Full Proposals due date: October 7, 2026, 2pm ET ISO closing date: October 7, 2026, 2pm ET

WHERE TO SUBMIT:

Proposals: https://solutions.arpa-h.gov/Submit-Proposal/ Questions: https://solutions.arpa-h.gov/Ask-A-Question/

Registration is required to submit documents via the ARPA-H Solutions site.

ISO PURPOSE:

ARPA-H seeks proposals from all eligible entities (see Section 8, Eligibility Information) to accomplish the COSMOS goals as described in this solicitation package. Ultimately, ARPA-H intends to negotiate multiple OT Agreements with Proposers whose proposals are most advantageous to the government.

mailto:cosmos@arpa-h.gov https://solutions.arpa-h.gov/Submit-Proposal/ https://solutions.arpa-h.gov/Ask-A-Question/

2 INTRODUCTION TO COSMOS

2.1 BACKGROUND

2.1.1 Executive Summary

Regenerative therapeutics, those that return healthy function to damaged or otherwise compromised tissues, are an aspirational goal at present. Currently, there are no targeted therapeutics to mitigate or reverse diseases of age in the heart, brain, uterus or kidney. Current approaches frequently require 10 to 15 years to move from discovery to approved therapy. This is in part because existing preclinical models do not adequately capture the biology of human aging- the central driver of many of these diseases.

Cellular senescence, where cells no longer divide but maintain most other processes, combined with direct damage may represent important components of aging.

Microgravity in low Earth orbit (LEO) is believed to accelerate aging (or potentially senescence) over weeks rather than years, offering a unique research opportunity to investigate aging. However, that acceleration of aging has never been substantiated or experimentally validated. To meaningfully perform biotechnology and biomedical R&D in LEO, it is essential that we first understand whether accelerated aging takes place in LEO to justify the investment. Moreover, above a certain aging rate threshold, biomedical R&D in LEO may in fact be cheaper and faster than R&D on Earth, decreasing the time and costs currently hindering the drug development pipeline.

Comprehensive Organ System Modeling in Outer Space (COSMOS) centers on quantifying the Tissue Aging Rate in Space (TARIS) relative to the Tissue Aging Rate on Earth (TAROE) for human tissues affiliated with diseases that have the highest morbidity and mortality across multiple adult age groups. COSMOS will establish if there is an accelerated aging rate in LEO flight across four critical tissues—brain, cardiac, uterine, and kidney—using microphysiological systems (organs-on-chips) and organoids.

COSMOS will definitively prove or disprove if exposure to microgravity in LEO truly accelerates tissue aging across these four tissue types and across representative adult age brackets. Provided TARIS exceeds TAROE at a rate that exceeds the on Earth breakeven cost for new drug R&D, COSMOS will create a first-in-class platform for fully autonomous, high-throughput drug screening in LEO that would be more cost effective and faster than new drug R&D on Earth.

2.1.2 Current State of R&D in Low Earth Orbit:

Space based research has, until recently, been limited by the issue of reliable, repeatable access. The International Space Station (ISS) and the ISS National Lab have provided a platform for scientific research for decades, enabling proof-of-concept demonstrations of numerous space-based methods and biologic phenomena. The ISS will be decommissioned in ~2030, adding time pressure to the already limited availability of experimental locker space and ascent/descent payloads. A number of new entrants into the commercial space industry, also known as Commercial LEO Destinations or CLDs, are building a thriving, private sector market that promises to allow for a high cadence of LEO flights with plentiful R&D space on board, reducing experimental costs and risk over time while opening the opportunity for further biotechnology R&D in space. These CLDs will range from fully crewed to fully autonomous, providing optionality and healthy market competition. With commercial space entities and commercial LEO destinations, it is now feasible to plan and execute experiments at the scale that can generate robust evidence in LEO and compel large biopharma entities to consider entering the arena.

2.2 AGE-RELATED DISEASE:

Age-related diseases—including neurodegenerative, cardiovascular, chronic kidney, and female reproductive conditions—are overwhelming our current healthcare and drug development systems, with no regenerative cures in sight. The following tissue types are affiliated with the highest morbidity and mortality rates Nationwide and deserve particular focus in the quest for regenerative therapies:

Brain. Neurodegenerative diseases (ND) including Alzheimer’s, Parkinson’s and other dementias affect an estimated 8-11 million Americans (~200,000 deaths) and cost more than $435 billion dollars when considering direct and indirect costs1.

Heart. Cardiovascular diseases (CVD) including stroke, heart disease and arterial pathologies affect an estimated 127 million Americans (~843,000 deaths) and cost more than $400B in direct and indirect costs1.

Uterus. The uterus goes through a series of poorly understood changes across a lifespan. Organ-specific pathologies such as fibroids, the effects of polyendocrine metabolic ovarian syndrome, and abnormal bleeding conditions. Though difficult to define, estimates on healthcare and quality of life costs associated with non-fertility related reproductive ailments ballpark $17- 35B annually with attributable deaths greater than 30,000 per year2.

Kidney. “Kidney disease” includes chronic kidney disease (often caused by diabetes, hypertension, and obesity), nephritis, nephrosis and other medium to long-term kidney conditions affect ~35 million Americans. Though the annual death rate is relatively lower than CVD (~55,000), the annual cost of Medicare-based dialysis alone is greater than $6.7 billion annually3.

1 Centers for Disease Control (CDC) and Prevention. (2026c). About chronic diseases.

https://www.cdc.gov/chronic-disease/about/index.html CDC. (2006). Dementia and its implications for public health. Preventing Chronic Disease, 3(2). https://www.cdc.gov/pcd/issues/2006/apr/05_0167.html 2 Centers for Disease Control (CDC) and Prevention. (1987). Hysterectomies in the United States, 1965–84 (Series 13, No. 92). National Center for Health Statistics. https://www.cdc.gov/nchs/data/series/sr_13/sr13_092.pdf; CDC.

(2025b, June 10). Cervical cancer statistics; CDC (2025c, August 15). Health and economic benefits of cervical cancer interventions https://www.cdc.gov/nccdphp/priorities/cervical-cancer.html. Nature Reviews Endocrinology, 18(5), 290–308. https://www.nature.com/articles/s41574-021-00629-4; Frontiers in Cell and Developmental Biology, 9. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.633180/full https://www.cdc.gov/cervical-cancer/statistics/index.html; De Corte, P., Klinghardt, M., von Stockum, S., & Heinemann, K. (2025). Time to diagnose endometriosis: Current status, challenges and regional characteristics—A systematic literature review. BJOG: An International Journal of Obstetrics and Gynaecology, 132(2), 118–130. https://pubmed.ncbi.nlm.nih.gov/39373298/ 3 Hassan, M.B. et al; Chronic kidney disease and cardiovascular risk: Pathophysiology and interventional approaches – systematic review. Medicine, 104(49), e46189. https://doi.org/10.1097/MD.0000000000046189;

National Institute of Diabetes and Digestive and Kidney Diseases. (n.d.). Kidney disease statistics for the United States. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease; United States Renal Data https://www.cdc.gov/pcd/issues/2006/apr/05_0167.html

2.2.1 Microphysiological Systems / Organs on Chips:

An organ-on-a-chip is a small microphysiological system (MPS) that recreates key functions of a specific organ using living cells. MPSs are three-dimensional microfluidic devices that incorporate living human cells to replicate the structural, mechanical, and biochemical conditions of specific tissues and organs in vitro. These controlled environments can mimic dynamic fluid flow, shear stress, and biochemical gradients more closely approximate in vivo conditions than conventional two-dimensional cell culture.

Due to their biological complexity and scale, robust microfluidic support is required to keep MPSs healthy. Engineering microfluidics for support of MPSs in LEO has been achieved on small scales (up to 16 MPSs), and many of the optimizations made for terrestrial studies are adaptable to LEO. Commercial service providers (CSP), in fact, now offer fully autonomous lab units compatible with commercial launch cargo parameters. In addition to the engineering advances needed, MPS technology continues to be refined, and MPSs of greater complexity featuring multiple organ systems working together are routinely produced. The field has developed to the point where the semi-mass or mass production of many MPSs is achievable on a predictable timeline. Leveraging the maturation of MPSs as a biological proxy for human tissues, they present a potential path to modeling aging in human tissues.

2.2.2 Regenerative Medicine:

Regenerative medicine refers to the science of repairing, replacing, or restoring the biological function of damaged tissues and organs. Currently, approaches include cellular therapies, biomaterials, gene editing, and tissue engineering. Rather than managing symptoms, its core aim is to address the underlying structural and functional deficits that arise from disease or injury. While regenerative medicine is agnostic to the reason that restoration is needed, it is not agnostic to the mechanisms of functional decay. "Aging" is biologically defined by a collection of changes to cells and tissues that include genomic instability, telomere attrition, epigenetic alterations, protein dysfunction (from translation through correct turnover), mitochondrial dysfunction, cellular senescence, and stem cell exhaustion.

Individually (or more frequently in combinations) these changes degrade cell function and converge to impair the body's intrinsic capacity for tissue repair and homeostasis.

Age-related disease reflects, in part, a failure of endogenous repair mechanisms, and regenerative strategies offer a framework for restoring those mechanisms at the cellular and tissue levels. The loss of maintenance and renewal creates conditions favorable to chronic diseases such as neurodegeneration, cardiovascular diseases, and metabolic

System. (2024). Healthcare expenditures for persons with CKD. Annual Data Report. https://usrds-adr.niddk.nih.gov/2024/chronic-kidney-disease/6-healthcare-expenditures-for-persons-with-ckd; National Institute of Diabetes and Digestive and Kidney Diseases. (n.d.). United States Renal Data System.

https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/usrds syndromes. By design, regenerative therapies would encompass therapeutics that could intervene in multiple degradative cascades from the molecular to systemic scale.

There are at least two paths to humans living longer healthier lives: finding ways to treat the changes caused by aging or preventing those changes in the first place. It is unclear which path may be more effective. The road to an answer starts with reliable and reproducible models of human aging.

2.2.3 Pharmaceutical Drug Screening:

Traditional drug candidate screening requires a broad assessment of potential therapeutics across a library of assets, lead asset selection and optimization, and validation within an animal model of disease. The preclinical stage alone can take more than 5 years, assuming relevant in vivo models have even been established. Adding to that potential time, the translation through small animal, large animal, and non-human primate models each offers an opportunity for failure. Recent FDA guidance (New Approach Methodologies (2026), Roadmap to Reducing Animal Testing in Preclinical Safety Studies (2025)) has incentivized a more streamlined process that relies heavily upon robust, in vitro tissue models of disease that would limit both animal and human testing. High fidelity, naturally aged models made from human cells could both shorten the lead development and pre-clinical timelines. The potential advantages of LEO remain unrealized, as no TARIS has been definitively established and no current platform exists for autonomous LEO-based pharmaceuticals, and, therefore, the value proposition for private industry remains unproven. Opening a LEO-based bioeconomy rests on demonstrating the utility, feasibility, and extensibility of a LEO-based pharmaceuticals platform which inspires pharmaceutical manufacturers to co-invest.

2.3 COSMOS OVERVIEW

Comprehensive Organ System Modeling in Outer Space (COSMOS) centers on quantifying Tissue Aging Rate in Space (TARIS) relative to Tissue Aging Rate on Earth (TAROE) for human tissues affiliated with diseases that have the highest morbidity and mortality across multiple adult age groups impacting four critical tissues—brain, heart, uterus, and kidney—using microphysiological systems (organs-on-chips) and organoids. Accelerating the drug discovery process via COSMOS will mean more treatments in the development pipeline can be screened faster and more cost effectively than on Earth, expediting both the pathway to patients and decreasing downstream pharmaceutical costs.

COSMOS will definitively prove or disprove if exposure to microgravity in LEO truly accelerates tissue aging across these four tissue types and across representative adult age brackets. Provided TARIS exceeds TAROE at a rate that exceeds the breakeven cost on Earth for new drug R&D, COSMOS will then create a first-in-class platform for fully autonomous, high-throughput drug screening in LEO that would be more cost effective and faster than new drug R&D on Earth.

COSMOS will not only accelerate the creation of best-in-class MPSs across the largest donor pool in history for tissues affiliated with the leading causes of death but will also use that MPS platform for biopharmaceutical R&D at a scale never seen before. In turn, COSMOS will generate downstream pharmaceutical and private space interest and investment that can create a sustainable pathway for drug testing and, ultimately, development and clinical trials in space.

3 COSMOS DETAILS

3.1 COSMOS STRUCTURE AND TIMELINE

COSMOS includes two sequential phases. See Attachment C: COSMOS Schedule for more granular details of the schedule.

• Phase I is 27 months and includes establishing and validating an MPS system based on a selected target organ with the objective of definitively establishing the TARIS and TAROE in four tissues (heart, brain, uterus, and kidney) across a range of representative ages that cover all adult populations.

• PH II is 15 months. Phase II performers will use the MPSs or organoids (tissue and age range) in which the TARIS substantially exceeds TAROE to develop models of age-related pathology. These models will be used to justify LEO R&D for targeted, pro-regenerative drug testing on validated and unvalidated therapeutic assets in partnership with commercial biopharmaceutical partner(s) (CBPs). The objective is to demonstrate that MPSs can offer an in vitro high fidelity test bed for regenerative medicines that either directly counteract age-related tissue changes or prevent those tissue changes even as tissue ages.

3.2 PHASE I DETAILS

During Phase I, proposers shall establish and validate an MPS system based on their selected target organ (each proposer can only select one organ). The MPS design, cell types, and interactions must recapitulate structures and functions that change with age.

Phase I experiments consist of a terrestrial MPS set and a LEO MPS set. There will be two scheduled spaceflights for performers to fly their MPSs: one at month 19 and one at month 23. Each flight will remain in LEO for 4 total weeks but requires that fifty percent of

Figure 1 COSMOS schedule; for granular schedule see Attachment C

MPS tissues are preserved at 2 weeks in LEO, and the remainder at 4 weeks in LEO, prior to descent.

All experimentation in LEO will be fully autonomous, requiring no human input or interaction from launch through splashdown. All twinned LEO experiments performed on Earth will also be autonomous. This must be accounted for in each proposer’s experimental design and plans. A Hardware Validation Launch will occur at Month 12 Ffter Contract (MAC) but will not involve MPSs or organoids as it is intended to ensure all non-biology logistics are in lockstep prior to the month 19 launch.

Each team must present a plan to develop MPSs at the scale required for the terrestrial arm, and a plan to develop no fewer than 384 single-donor MPSs that will mature in parallel (matched 192 LEO: 192 Terrestrial) and be delivered as a LEO payload by the established launch dates(s) for the LEO Twin Study (See Figure 2: Phase I Experimental Design requirements). The ‘twin’ in this instance refers to a set of MPSs derived from the same donor (n=384), constructed under the same protocols and conditions, and housed in autonomous laboratory housings. One of the sets will remain on earth (n=192), the other will launch and achieve flight for a specified amount of time (n=192). All MPSs will be preserved using identical technology and then analyzed for LEO-associated variances.

3.2.1 Phase I Launch Schedule

Phase I includes two (2) space launches tentatively scheduled for months 19 and 23.

Both hardware for housing MPS systems and launch vehicles will be provided by ARPA- H selected Commercial Service Providers.

3.2.2 Phase I Results Showcase

Phase I culminates in a 3-month window where the ARPA-H team will convene a research forum (date to be determined, 25-27 MAC) where performer teams will share the completed results of their Phase I efforts including TARIS: TAROE modeling.

3.2.3 Phase I Commercialization Requirements

See Section 3.5

3.3 PHASE II DETAILS

Success in Phase II requires that each team have an established partnership (e.g., signed contractual agreement) with a commercial biopharmaceutical partner (CBP) that has drugs of interest applicable to the selected organ type and age brackets in which

TARIS>TAROE.

3.3.1 Phase II: Establishing Rapid Drug Screening for Age-Related Diseases

Phase II performers will use the MPSs or organoids (tissue and age range) in which the TARIS substantially exceeds TAROE to develop models of age-related pathology. These models will be used to justify LEO R&D for targeted, pro-regenerative drug testing on validated and unvalidated therapeutic assets in partnership with CBP(s).

3.3.2 Phase II Launch Cadence

Phase II includes two (2) space launches tentatively scheduled for months 39 and 41.

No less than 50% of MPS and drug combinations described in Table 1 (Section 4.2) must be launch capable simultaneously (e.g., 50% of the selected MPSs need to launch on the first launch and the remaining 50% need to fly on the second launch).

3.3.3 Phase II Results Showcase

The format and schedule of the end of program meeting will be established during Phase II, but the general intention is an all-COSMOS showcase of results of the second phase.

3.3.4 Drug Candidate Selection

Drug libraries licensed or acquired should have relevance to any biological variances discovered in the LEO Twin Study data of Phase I. Ideal libraries or candidates would target tissue/organ processes, mechanisms, or phenotypes known to contribute to pathology.

3.3.5 Phase II Commercialization Requirements

See Section 3.5

The following experimental design, technical, personnel, scale, and timing requirements must be met by a successful performer team.

3.4 PERFORMER REPORTING, EVALUATION AND PROGRESS MONITORING

To ensure success, each COSMOS phase will include regular performance evaluations, including (but not limited to) monthly, semi-annual, and annual progress reports.

Specifics regarding deliverables will be stipulated in any award made under this solicitation.

In addition to the technical requirements associated with each phase, COSMOS also includes additional metrics designed to guide and monitor each Performer’s progress towards biopharma partnerships and regulatory buy-in for sustained, post-program biopharma and biotechnology work in LEO (e.g., in vitro clinical trials, drug development, and continued drug screening).

Performer progress evaluation will be an ongoing process over the duration of COSMOS.

Written deliverables, meetings, schedule and financial management, and achievement of milestones are some of the information that is integrated into progress evaluation. The ARPA-H model requires active performer management and a high degree of involvement by the PM and their technical team. Performers should expect regular interactions with the ARPA-H team. Further details will be available in any awards made under this solicitation.

3.4.1 Required Meetings

• Kickoff Meeting (Include in travel budget) - ARPA-H will convene a kickoff meeting at the beginning of COSMOS, after contract award. Details will be forthcoming, but the meeting is likely to be held at a TBD CONUS space launch facility.

• Scientific Reviews (Include in travel budget) – Semi-annual all-performer (technical and CSP) meetings with locations TBD to discuss progress, hurdles, key findings, etc.

Current tentative schedule is for months 7,14, 21 (Phase I) and 34 (Phase II). Further details and a template for deliverables will be provided at kick-off.

• Site visits - At the discretion of the GOV team with the expectation key personnel are present at their prime location. ARPA-H will travel to you at a cadence TBD.

• MPS/Organoid and CSP Hardware/Flight Team Meetings: Regular touchpoints between MPS/Organoid teams and Commercial Service Partner Engineering teams are required. It is understood that the physical support of MPS for flight is complex and will require iteration and testing. Immediately following award, Performer teams must initiate material transfer agreements and data-sharing agreements to allow full cooperation on the design, build, and testing of autonomous experimental MPS support hardware and MPS design teams.

• Ad Hoc Meetings: At the program manager’s discretion, additional meetings will be requested with Performer teams. These requests will be made in writing, listing the team members requested to attend.

3.5 REQUIRED COMMERCIAL BIOPHARMACEUTICAL PARTNERNERSHIPS

ENGAGEMENT

• Phase I: By the end of Phase 1, each team must establish a signed, contractual commercial public-private partnership (PPP) with AT LEAST one Fortune 100 biopharmaceutical company to leverage the COSMOS platform for regenerative therapeutic R&D for all tissues where TARIS>TAROE to include: drug screening, in vitro clinical testing, etc. Selected partner must have:

• Each team’s partner(s) must: 1) have ³3 drug candidates that are either approved for age-related disease in the selected tissue type or target aging-relevant molecular pathways in clinical testing and/or 2) have a panel of known and novel drug candidates relevant to the target tissue type. Drugs selected for screening must be relevant to aging and the target tissue and must include drugs with known mechanisms of action and/or drug candidates/leads.

• Proposers must also propose the design, development plan, and substantiating evidence for MPSs of disease in only the ages and tissues demonstrating TARIS>TAROE. Those MPS-based models of disease will be what the CBP will use to screen validated and unvalidated therapeutics of interest in Phase II.

• For each tissue and age group where TARIS>TAROE, the CBP must demonstrate how that rate translates to the discount on the downstream therapeutic MSRP. For instance, if 35-year-old uterine tissue demonstrates TARIS is 5x TAROE, the CBP must clearly demonstrate how that 5x accelerated rate will be recognized by patients benefiting from novel regenerative therapeutics.

Phase II: Technical teams (MPS/Organoids) will establish a commercial public-private partnership (PPP) with a Fortune 100 pharmaceutical company to leverage the

COSMOS platform for translational, regenerative therapeutic applications to include:

drug screening, in vitro clinical testing, etc.

• Proposers and their CBP(s) shall use the MPSs in which the TARIS substantially exceeds TAROE to utilize LEO R&D for targeted, pro-regenerative drug testing in validated and unvalidated therapeutic assets. De minimis, proposer teams must secure access to a drug library relevant to the cell types, functions, and variance associated with the “accelerated aging” models developed in Phase I.

• Performer teams are expected to coordinate with the selected CBP to develop MPS models of disease relevant to the drugs being screened in LEO. Selected CBP must have three approved drugs which target aging-related pathways proof of concept of the COSMOS as well as a panel of experimental therapeutics for LEO-based drug screening.

• Phase II success includes the creation of a PPP pipeline to utilize the COSMOS platform.

4 MANDATORY EXPERIMENTAL DESIGN

Each performer team will produce the required number of MPS and organoids from the designated number of donors in each Phase. Each Phase has specific design requirements that are laid out on the following tables. Phase I details are in Section 4.1; Phase II details in Section 4.2.

4.1 PHASE I EXPERIMENTAL DESIGN

The parameters outlined in the infographic, text, and tables below are mandatory. Please ensure your final proposal package includes all the relevant experiments, justifications, and design requirements outlined in Tables 1-3 and sections 4.1 and 4.2.

Figure 2: COSMOS Phase I Design Parameters – note these numbers address the entire period of performance; metric tables in Section 4.1.5

4.1.1 Experimental Age Brackets

All Phase I experiments must include cell/tissue donors in the following restricted age brackets: 30 years ± 2 years, 45 years ± 2 years, 60 years ± 2 years. These age brackets have been selected based on emerging evidence that our bodies age in a non-linear pattern, where a large change across the system occurs at relatively predictable timepoints (Liu et al, Nature 2024). An emerging model of aging is that there are non-linear accelerations in age in the mid-30’s, mid-40’s and mid-60s. Around age 30, most adults are past developmental maturation but have not generally hit the first major nonlinear aging shift seen in later adulthood. This makes it a useful reference/baseline state for adult biology.

The mid-40s are the first major adult aging inflection point. In women, this window also often overlaps with perimenopausal transition biology, which can strongly affect metabolism, inflammation, vascular risk, bone, and immune regulation. Midlife is when cardiovascular aging becomes more biologically apparent, with rising arterial stiffness, endothelial dysfunction, vascular inflammation, and subclinical atherosclerotic burden. The late transition point, the mid-60s, is when many aging hallmarks become more integrated at the organism level: immune remodeling, senescence burden, endocrine change, vascular stiffening, and reduced resilience.

4.1.2 Terrestrial Study

This arm of the study will act as a temporal and technical ‘ground’ for the LEO Twin study. The object is to run technical duplicates (2) for each donor for each relevant time point. For example, for kidney MPS from a 30 (+/-2 years) year-old, a total number of 4 MPSs are required. This must be replicated for each required age bracket. The experimental timepoints can be determined by the performer, though the proposer should offer justification as to why timepoints were selected. This study does not require the use of the CSP-provided microfluidics housing.

4.1.3 LEO Twin Study

All MPSs for the LEO Twin study (both terrestrial and flight twin) will be housed for the experimental duration in a fully autonomous functional unit provided by a commercial service provider (to be determined by ARPA-H and relayed to selected performers). This arm of the study will determine if there is detectable variance between MPS on earth (at 2 and 4 weeks) and those in flight for the same time points (at 2 and 4 weeks). Each organ will be recapitulated in quadruplicate with 2 for flight and 2 on earth.

4.1.4 Commercial Service Providers (CSP)

The government will select and announce two commercial service providers who will work in collaboration with each performer team and will be responsible for flight hardware and logistics. These CSPs will be determined by the Government, and it is expected that selected performers will only work with and use the designated CSPs within COSMOS.

CSP-Hardware will provide experimental housing (with power, imaging, sample preservation, and microfluidic support) compatible with the CSP-Flight LEO platform.

At the time of award, performer teams will immediately institute the required agreements with the CSP partners to allow for co-engineering, testing and integration of MPS systems and flight hardware. The ARPA-H technical team will work with performers to determine how many MPS from each team will launch on each launch.

4.1.5 Phase I Design Requirements

The following tables (Tables 1, 2, 3) outline the Experimental parameters, MPS requirements, and Computational modeling (Baseline, TARIS/TAROE) requirements.

Table 1: Phase I Mandatory Experimental Parameters

Per Team Experimental Design

1 Tissue of Interest per team

Brain OR Heart OR Uterus OR Kidney

NOTE: Do NOT propose to more than one organ group per proposal

Donor Ages 30+/- 2 yrs, 45+/- 2 yrs, AND 65 yrs+/- 2 yrs

Experimental Timepoints

Terrestrial: Performer determined; justify why these timepoint(s) were selected, how they will contribute to the TARIS model and support the maximum potential data extraction from the MPS and organoid

LEO Twin: MPS fixation will occur at 2 weeks flight time and 4 weeks flight time

Experimental design

The experimental design of LEO and terrestrial components of the MPS twin study must be identical to facilitate direct comparison of aging rates.

Terrestrial-only study must adhere to the twin study set up as much as practicable but will not require housing in CSP hardware

Tissue donors

• 32 healthy individuals for the LEO/Terrestrial MPS twin study

• ≥50 healthy individuals for the supplemental terrestrial-only study for each age group Teams must ensure that the selected donors have sufficiently large tissue samples to generate the appropriate number of MPSs: ≥2 MPS/tissue sample for the terrestrial-only study and ≥4 MPS/tissue sample for the twin study

Terrestrial MPS total

[51 healthy donors] x [3 age group] x [technical duplicates] x [2 experimental time points] = 612 MPS for Phase I

NOTE: NO fewer than 75% of the total numbers of the experimental units must be MPS; the use of organoids in some percentage is encouraged to act as a ‘fail safe’ for the MPS cohort

Terrestrial Organoids

A subset of 51 donors, distributed across age groups should contribute to ~500 organoids

LEO Twin MPS (Per team)

[32 donors] x [3 age groups] x [experimental duplicates (1 LEO:1 Terrestrial)] x [2 experimental time points] = 384 MPS for Phase I

NOTE: NO fewer than 75% of the total numbers of the experimental units must be MPS; the use of organoids in some percentage is encouraged to act as a ‘fail safe’ for the MPS cohort

LEO Twin Organoids

Subset of 32 donors distributed across age groups should contribute to 217 organoids

Co- Engineering progress

Commercial service providers for flight hardware and experimental support systems will be selected by the Government under separate solicitation.

Technical performers are expected to schedule regular meetings with hardware providers to support co-engineering of MPS support systems

Twin LEO MPS Design Lock

Design of MPS organ and required fluidics support must be design locked no later than 10 MAC

Co- Engineering Design Lock

MPS and support housing designs must be locked not later than 10 MAC

Phase I Exit Criteria

Only the tissue types and donor ages in which TARIS exceeds TAROE (such that it justifies further investment) will move into COSMOS Phase II

4.1.6 Mandatory Microphysiological Systems / Organs on Chips & Organoid Parameters

Table 2: MPS/Organoid Required Parameters

Item Requirements

MPS

requirements

• All MPSs must be derived from primary human cells, iPSC, or tissue samples from healthy donors. Proposers selecting iPSC must justify why that organ specifically requires iPSC over primary cells

• MPSs must recapitulate key features of the tissue/organ of interest as demonstrated by an analysis of the 3D microarchitecture, cell lineage identity and composition

• MPS cells, structure and maturation conditions must be selected to support the detection of age-related changes over time

MPS Model Fid elity

• MPSs recapitulating organs with specific basement or other critical, functional membranes must have robust physiologically relevant basement membranes

• Proposers must offer justification for how both tissue age and tissue physiology is represented in the MPS

Organoids A fraction of the experimental samples (≤25%, TBD by launch capacity) must be comprised of organoids

Donor Heterogeneity

To the maximum extent possible given time and budget, donor heterogeneity (outside of the age requirement) should follow American population demographics:

• Sex: 50% female (for non-uterine tissues)

• Race/Ethnicity: 56% Non-Hispanic (NH) White, 20.5% Hispanic or Latino of any race; 13.5% NH Black; 6.9% NH Asian; 4.9% multiracial (≥2 races); 2.1% American Indian & Alaskan Native; 0.3% Native Hawaiian/Pacific Islander

MPS In Flight Monitoring Requirements

MPSs must be optically clear to allow for real-time imaging/ monitoring of the viability of each MPS; further monitoring and testing integration should be described to satisfy the data targets requirement

NOTE: For LEO Twins, final testing, monitoring, -omics, and extraction processes will be determined and refined in partnership with the commercial service provider for hardware

Preservation MPS will be preserved at experimental timepoints (2 and 4 weeks of flight) by the method required to perform the multiomic analyses selected by the performer

Experimental Assessments

≥2 broad, quantitative and unbiased multi-omics approaches that allow a holistic analysis of tissue/organ function and integrity must be selected to assess LEO Twin samples

MPS chip & microfluidics design lock

LEO Twin Study MPS format and protocol must be locked no later than Month 10 in consultation with the Hardware Commercial Service Partner

Data Targets

≥2 broad, quantitative and unbiased multi-omics approaches that allow a holistic assessment of normal vs. pathological organ function must be selected

Any available non-destructive orthogonal approaches for real time data capture prior to MPS preservation should be integrated and that data captured (up to the limit of the autonomous housings for the LEO Study arm)

Approaches selected to monitor variance / potential aging for each organ must allow monitoring of ≥2 biomarkers for each of the following: 1) established and potential tissue agnostic and tissue-specific biomarkers of aging, 2) age-related biological pathways (e.g. stress, senescence, inflammation), and 3) tissue agnostic and tissue specific biomarkers of tissue integrity

Data Analysis Performers must complete all data analysis within three months of landing

4.1.7 In Silico Aging Model

To establish if there is variance between healthy tissues on the ground and identical tissues in flight, proposers must offer a rational data capture and modeling strategy.

Table 3: In Silico Aging Model

Item Requirements

In Silico Aging Model

Performers will create an in silico model of aging as a pre-flight baseline for their tissue/organ using extant and open-source data

• This model should serve as the grounding for MPS-derived data from the terrestrial experimental set, as well as for the future integration and comparison of data form the LEO twin set

• Performers must: establish the data sources to be used, training and test data, integrated assumptions in the model build, describe the model and establish how it will be used to inform the TARIS/TAROE analyses

• Performers may leverage extant models of aging for their specific organ provided they can justify the model selected, and clearly detail how new data will be added, or the model will be modified with TAROE and TARIS data

• Using the in silico model of aging in the specific organ type, each team should put forth a list of prospective biopharma partners with relevant drug libraries for their organ

Final In Silico Aging Model

TARIS and TAROE data from month 19 and month 23 flights will be used to refine the In Silico Aging Model in the selected organ. This flight-optimized In Silico Aging Model will be presented at a specific date TBD between 22-24 MAC. Refined final models and results should seek to prove or disprove the “accelerated aging in space” hypothesis across each age bracket and tissue type.

4.2 PHASE II EXPERIMENTAL DESIGN

Each performer team selected for Phase II will generate testable disease model(s) using the organ and age bracket(s) (up to 2 brackets per performer team) that showed the greatest TARIS:TAROE ratio. The design parameters for Phase II are listed in Table 4.

4.3 MPS-BASED DISEASE MODEL

Each performer team selected for Phase II will generate testable disease model(s) using the organ and age bracket(s) (up to 2 brackets per performer team) that showed the greatest TARIS:TAROE ratio. Technical details for Phase II MPS-based disease models are not required at time of proposal submission, however a generalized technical plan for no more than 2 models per organ team is required in the proposal. Model designs and specifics are not part of this current proposal beyond budgeting for the potential of 1-2 disease models per team. Technical description and justification of the MPS-based disease model will be finalized in the final quarter of Phase I (18 MAC). It is expected that disease models would be developed with specific pharmaceutical partner(s) in mind.

Table 4: Phase II Mandatory Experimental Design

Item Requirements

Figure 3: COSMOS Phase II

MPS-based disease model

The model must accurately represent the organ and its functions AND reproduce organ biology related to the drug library selected for Phase II

Pharmaceutical Library Requirement

Drugs selected for screening must be relevant to aging and the target tissue and must include both drugs with known mechanisms of action, a validated control drug, and drug candidates

Pharmaceutical Testing Design

Performers will develop a prospective drug testing strategy based on the hardware CSP parameters and biopharma requirements. This will be a COSMOS deliverable due at 6 MAC.

MPS Disease Model Scale Production

Selected performers must be capable of scaling MPS production for a single organ. Final number to be determined by selected Phase II commercial service providers

Co-Engineering Design Lock

MPS and support housing designs must be locked not later than

35 MAC.

MPS cell sourcing

• Performers must utilize donors from the age brackets showing the greatest TARIS:TAROE in collaboration with their commercial partners

• Teams must ensure that the selected donors have sufficiently large tissue samples to generate the appropriate number of MPSs

Co-Engineering progress

Commercial service providers for flight hardware and experimental support systems will be selected by the Government under separate solicitation. Technical performers are expected to schedule regular meetings with hardware providers to support co-engineering of MPS support systems

LEO Launches Phase II features 2 launches on a commercial service provider’s hardware and flight vehicle; launches tentatively scheduled in months 37 and 39

5 COSMOS METRICS

To evaluate how effectively a proposed solution will achieve the stated objectives, the government hereby promulgates the following metrics that may serve as the basis for determination of satisfactory progress to warrant continued funding.

Although the COSMOS metrics are specified below, Proposers should note that the government has identified these goals with the intention of bounding the scope of effort while affording maximum flexibility, creativity, and innovation of proposed solutions to the stated problem. Proposals should cite the quantitative and qualitative success criteria that the effort will achieve by each Phase’s milestone and intermediary metric measurement.

5.1 PHASE I METRICS

Table 5 Phase I Success Metrics

Metrics Specifications

Phase I Deliverables

• Quantification of Tissue Aging Rate in Space (TARIS) using microphysiological systems (MPSs) (and potentially organoids as well) for target organ

• Licensable data set comprising the Terrestrial Arm data and LEO Twin Data

• Commercial CSP Hardware integration plan with MPSs for timely spaceflight

• Baseline In Silico Aging Model pre-flight

• Final In Silico Aging Model of tissue changes in LEO

• Signed, contractual partnership and licensing agreement with AT LEAST one CBP that has drugs of interest that are applicable to the organ type with the greatest

TARIS:TAROE

Commercial Biopharmaceutical Partnership (CBP)

• By the end of phase 1, each team must establish a signed, contractual commercial public-private partnership (PPP) with AT LEAST one Fortune 100 biopharmaceutical company to leverage the COSMOS platform for translational, regenerative therapeutic R&D for all tissues where TARIS>TAROE to include: drug screening, in vitro clinical testing, etc. Selected CBP must have:

• ≥3 drug candidates that are either approved for age-related disease in the selected tissue type or target aging-relevant molecular pathways in clinical testing,

• Have a panel of known and novel drug candidates relevant to the target tissue type.

• Drug Screening: Drugs selected for screening must be relevant to aging and the target tissue and must include drugs with known mechanisms of action and drug candidates

Demonstrate TARIS >

TAROE

Present data and evidence that there is or is not an accelerated, detectable variance between identical tissues from normo-versus microgravity

TARIS Model of Aging

In the event of a detectable variance between terrestrial and LEO-flown MPS, performers will leverage the alpha model and the data collected in Phase I to formulate a model of aging or age-like effects induced by flight in LEO

Phase II Disease Model and Scaling Plan

Credible plan to develop relevant disease model(s) within the selected organ based on state of the art, scale MPS production to occupy a to-be-determined number of payloads on a commercial service provider’s autonomous LEO platform

5.2 PHASE II METRICS

Table 6 Phase II Success Metrics

Metrics Specifications

Phase II Deliverables

• Credible, reproducible disease model(s) of tissues where TARIS > TAROE from Phase I successfully used in coordination with commercial partner(s) for novel drug screening

• Demonstration of proof-of-concept high throughput drug testing using microgravity-leveraged MPS models of aging to identify drugs that can prevent and/or reverse age-related tissue dysfunction and/or disease

• Commercial CSP Hardware integration with MPSs for timely spaceflight

Commercial Biopharmaceutical Partnership

• Proposers and their commercial biopharma partner(s) (CBPs) shall use the MPSs in which the TARIS substantially exceeds TAROE to utilize LEO R&D for targeted, pro-regenerative drug testing for at least three validated and unvalidated therapeutic assets. De minimis, proposer teams must secure access to a drug library relevant to the cell types, functions, and variance associated with the “accelerated aging” models developed in Phase I.

• Successful collaboration with a CBP with three approved drugs which target aging-related pathways proof of concept of the COSMOS as well as a panel of experimental therapeutics for LEO-based drug screening.

• For each tissue and age group showing TARIS>TAROE, the CBP must demonstrate how that rate translates to the discount on the downstream therapeutic MSRP. For instance, if 35-year-old uterine tissue demonstrates TARIS is 5x TAROE, the CBP must clearly demonstrate how that 5x accelerated rate will be recognized by patients benefiting from novel regenerative therapeutics.

• Evidence of post-program investment from at least one of the team’s CBP for continued use of the COSMOS platform in the commercial sector following contract conclusion

6 COSMOS TEAM REQUIREMENTS

Teams must present a plan to have a qualified team of expert advisors with adequate levels of effort and subject matter expertise to ensure the success of the effort.

Successful proposers and performer teams will be comprised of, at minimum, the following experts and specialists. Unless sufficiently justified otherwise, the government’s assumption is that the Project Manager is full-time, and the other key personnel (KP) will be proposed for at least a minimum of a 0.5 full-time equivalent and cannot be the same person. KPs require Research Security Review (RSR). See Section 14.5 for RSR details.

Table 7 Required Personnel

Title Description

Project Manager

(KP)

Project manager must have a demonstrated history of managing large, complex, high budget, ARPA (or ARPA-like) research programs. Subject matter expertise is strongly preferred to ensure proper, reliable integration of multiple data streams into polished results and reporting deliverables

Principal Investigator (KP)

The experimental design and technical lead responsible for the overall design of the project.

Engineer(s) Emphasis and extended experience in microfluidics support of MPS

Organ Specialist

(KP)

Expert in structure, function, physiology…