25-SOL-125_PROSPR ISO_AMEND2_23 MAY.pdf

Innovative Solutions Opening (ISO)

PROactive Solutions for Preserving Resilience (PROSPR)

Proactive Health Office (PHO)

ARPA-H-SOL-25-125

April 4, 20251

Amendment 1 - April 22, 2025 Amendment 2 - May 23, 2025

1 The final ISO is binding and supersedes the DRAFT ISO posted on December 12, 2024. Any changes to the final ISO will be made via formal amendments.

ARPA-H-SOL-25-125, PROSPR

1 INNOVATIVE SOLUTIONS OPENING (ISO) SUMMARY INFORMATION

1.1 ISO Purpose

1.2 ISO Questions and Answers

1.3 Proposers’ Day

2 PROGRAM INFORMATION

2.1 BACKGROUND

2.2 PROSPR PROGRAM DESCRIPTION AND SCOPE

2.3 TECHNICAL APPROACH AND STRUCTURE

2.3.1 APPROACH BY TECHNICAL AREA (TA)

2.3.2 DELIVERABLES AND TRANSITION ACTIVITIES

2.3.3 PROGRAM STRUCTURE

2.3.4 PROGRAM METRICS AND TIMELINE

2.3.5 PROSPR DATA SHARING PLAN

3 ELIGIBILITY INFORMATION

3.1 Eligible Applicants

3.2 System for Award Management (SAM)

4 SUBMISSION AND EVALUATION PROCESS

4.1 Solution Summary Submission Requirement and Guidance

4.2 Solution Summary and Proposal Submission Information

4.3 Solution Summary and proposal Submission Deadlines

4.4 Proprietary Information

5 REVIEW AND EVALUATION OF FULL PROPOSALS

5.1 Conforming Proposal Submissions

5.2 Proposal Evaluation Criteria

5.2.1 Overall Scientific and Technical Merit

5.2.2 Proposer’s capabilities and/or related experience

5.2.3 Budget Analysis

5.3 EVALUATION AND SELECTION PROCESS

5.4 Handling Of Selection Sensitive Information

5.5 Evaluation and Award General Guidelines

6 GENERAL REQUIREMENTS AND INFORMATION

6.1 PROPOSING TEAMS

6.2 HEALTH DATA PROTECTION AND PRIVACY

6.3 SCIENTIFICALLY APPROPRIATE REPRESENTATION IN CLINICAL STUDY

POPULATIONS

7 ADMINISTRATIVE AND NATIONAL POLICY REQUIREMENTS

7.1 Organizational Conflicts Of Interest (OCI)

7.2 Agency Supplemental OCI Policy

7.3 Intellectual Property

7.4 Animal Subject Research

7.5 Human Subjects Research

7.6 Electronic Invoicing and Payments

7.7 Government-Furnished Property/Equipment/Information

7.8 Associate Performer Agreement

APPENDIX A: Associate Performer Agreement (APA) Information

APPENDIX B: Solution Summary Format and Instructions

APPENDIX C: Full Proposal Format and Instructions

ATTACHMENT 1: Model PROSPR Other Transaction Agreement (OT)

1 INNOVATIVE SOLUTIONS OPENING (ISO) SUMMARY INFORMATION

Federal Agency: Advanced Research Projects Agency for Health (ARPA-H), Proactive Health Office (PHO)

Program Title: PROactive Solutions for Preserving Resilience (PROSPR)

Announcement Type: Solicitation

ISO Solicitation Number: ARPA-H-SOL-25-125

Dates (all times listed are Eastern Time):

o Solution Summary Due Date for TA 1/2 Solutions : April 25, 2025 at 2 PM : June 5, 2025 at 2 PM o Full Proposal Due Date:

Anticipated awards: Multiple Other Transaction Agreements (OTs)

Agency Contact: All inquiries shall be sent to PROSPR@ARPA-H.GOV

*See ISO Sections 3 and 4 for additional information about Solution Summary and Full Proposal Submissions (e.g., to be eligible to submit a Full Proposal, a Proposer must have submitted a timely Solution Summary and received feedback from the government).

1.1 ISO Purpose

ARPA-H seeks proposals from all eligible entities (see Section 3, Eligibility Information) to accomplish the PROSPR program 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.

1.2 ISO Questions and Answers

All questions regarding this ISO must be submitted to PROSPR@arpa-h.gov. ARPA-H will post Q&As to the PROSPR program website on an on-going basis and will not respond to questions directly. All questions must be submitted in English and must include the name, e-mail address, and telephone number of a point of contact. Proposers submitting questions to individual government team members (e.g., Program Manager) should not expect a response. ARPA-H will attempt to answer questions in a timely manner; however, questions submitted after the Q&A due date may not be answered. Further, duplicative questions may be combined and rephrased to streamline responses.

1.3 Proposers’ Day

ARPA-H invites proposers to view the Proposers’ Day video posted to SAM.gov and the

1 ARPA-H has reopened the Solution Submission Portal exclusively for TA3 solutions. ARPA-H encourages the submission of new TA3 Solution Summaries, as well as revised Solution Summaries from previous TA3 proposers seeking to update their earlier submissions. Please note that new and/or revised submissions for TA1 and TA2 solutions will not be accepted at this time.

mailto:POSEIDON@ARPA-H.GOV mailto:PROSPR@arpa-h.gov

PROSPR Program page.

2 PROGRAM INFORMATION

2.1 BACKGROUND

Despite major advances in scientific discovery and clinical interventions that have added years to life expectancy, there has not been a corresponding increase in healthspan, the number of years spent in good health. Instead, the prevalence of chronic diseases in American adults has dramatically increased, particularly worsening with age. In the United States and elsewhere, medicines and scientific research are heavily focused on reactionary, post-symptomatic illness treatment, despite overwhelming evidence that early interventions are far more effective, and many diseases are preventable.

The Proactive Health Office (PHO) at ARPA-H is seeking solutions to extend the healthspan for Americans, with a focus on interventions aimed at early disease prevention. The PHO believes that population-level improvements in access to and adoption of disease prevention and wellness-promoting behaviors, novel early-detection methods, and prophylactic interventions could drastically improve Americans’ health throughout their lives, and that system-level innovations are required for effective proactive health delivery.

In the United States, age-related chronic diseases come with an annual healthcare cost burden of nearly $1 trillion. The healthcare costs for the aging population is projected to increase by 75% if nothing is done to prevent the progressive loss of physical functioning during aging, according to a Pew Research Center Study, which will place an immense strain on our healthcare and economic resources. Currently, no preventive treatments exist for the general health decline that inevitably occurs during aging and geriatric medicine remains focused on post- symptomatic treatments.

Four major factors limiting progress in healthspan extension have been identified:

1. Health decline during aging is accepted as normal.

Aging is the most significant risk factor for a variety of diseases and yet age-associated health decline is not researched nor treated like other risk factors, such as hypertension or pre-diabetes. A major contributor to the acceptance of fatigue, muscle weakness, reduced memory, worsening hearing and vision, and many other non-disease symptoms as a “normal” part of aging, is likely because we lack therapeutic options to prevent these general health declines.

However, considering that some individuals maintain excellent health far longer than others, it is clear aging does not automatically necessitate poor health and accumulation of disease but rather extending healthspan for the majority should be possible. In fact, animal studies with parabiosis, exercise, and caloric restriction demonstrate that a youthful healthy state can be maintained in older ages.

2. Geriatric medicine focuses on post-symptomatic disease treatments.

Because the early decline in health during aging is not the focus of geriatric medicine, much of the progress in healthspan research has been incidental, following specific disease targeting.

This roundabout fortuitous approach slows larger-scale advancements. Aging is now known to involve systemic changes such as increased inflammation and metabolic dysfunction, which often precede age-related diseases. Drugs like Rapamycin, Ozempic, and Metformin have https://www.pewresearch.org/short-reads/2024/01/09/us-centenarian-population-is-projected-to-quadruple-over-the-next-30-years/#%3A%7E%3Atext%3DThere%20are%20currently%20roughly%2062%2Cestimated%2023%25%20of%20the%20population shown pleiotropic effects, though most studies are limited to individuals with various diseases.

Our lack of attention to the aging community before significant ailments arise contributes to a limited understanding and lack of therapeutic options for the health declines that begin for many in their 40s.

3. Clinical trials are too costly and time-consuming for age-induced health outcomes.

Clinical trials are not feasible for most researchers and biotech companies despite a growing interest in therapeutics that facilitate healthy aging. For this reason, scientists are forced to conduct studies with shorter outcomes, such as those in age-related diseases after the onset of symptoms. A clinical trial with healthspan changes as the outcome could take 20-50 years, as this is time required for a typical 35-year-old to develop recognized clinical endpoints such as mortality or accumulation of disease. Considering the average clinical trial for diseases costs about $2 billion to conduct, a healthspan study could cost well over $6 billion.

4. Lack of validated surrogates for healthspan.

The major limiting factor that contributes to the cost and time requirements for human clinical trials on healthspan is the designated clinical endpoint. For some diseases, a surrogate biomarker can be demonstrated to accurately predict the clinical endpoint and can be approved by the FDA as a validated surrogate clinical endpoint. If we had a validated surrogate endpoint for long-term, age-induced outcomes, we could dramatically reduce the time and cost required for these trials. One way to measure age-induced general health is through intrinsic capacity (IC), a score generated by assessing a wide-range of physical and mental abilities. IC progressively declines with age, transitioning from peak physical health and highly functioning systems in young adulthood to a frail state or diseased state until death. Low IC has recently been demonstrated to roughly correlate with an increased risk of future chronic disease development.

Blood-derived biomarkers, particularly those associated with inflammation and metabolism, have shown promising correlations with IC in older adults. However, IC studies are in their infancy, being performed in small scale, short duration studies and have not been used to generate a 20-year mortality or morbidity prediction. Further, the generalizability of current IC research is limited by low population diversity and minimal data from adults younger than

60. Now that initial studies have demonstrated the potential of IC to predict health outcomes, standardization and refinement of IC measures and analysis on a larger scale are necessary to enable their implementation in clinical and healthcare settings.

While these challenges are significant, there is progress being made in each area that will serve as the basis for exponential growth through the PROSPR program.

2.2 PROSPR PROGRAM DESCRIPTION AND SCOPE

PROSPR is a 5-year program aims to develop interventions that extend healthspan by 20 years by targeting the underlying causes of age-induced health loss and thereby prevent the onset of multiple age-related diseases simultaneously.

To facilitate the study and testing of healthspan interventions, PROSPR will first reduce the time and cost investments that currently prevent a thriving healthspan therapeutics industry from developing. By directly demonstrating that human age-induced health outcomes can be predicted by biochemical and physiological measures in a single composite intrinsic capacity (IC) score, PROSPR will remove the need for 20-year clinical efficacy trials. By focusing second-generation interventions on those that target early health loss, PROSPR aims to preserve health in aging individuals before chronic diseases can develop. This will transform geriatric medicine into a personalized, comprehensive, preventive care model.

2.3 TECHNICAL APPROACH AND STRUCTURE

The PROSPR program has established detailed objectives for each Technical Area (TA) in Table

1. Table 2 lists deliverables for each TA and quantifiable and qualitative program metrics for each TA in Tables 3-5. Performers will be required to provide status reports during meetings with the Program Manager (PM), including detailed technical progress, financial updates, and any necessary data to validate alignment with technical milestones These reports, reviewed alongside the metrics and milestones outlined below, will be used to evaluate the progress of performer teams and their success within each phase. Performers will be required to coordinate within their team and with other performers, as directed by the PROSPR PM, the Administrative Officer (AO), and as specified in the agreed upon contract. This coordination will include the use of Agreements and Performance Assessments and general program interactions, which will be detailed in the model OT.

2.3.1 APPROACH BY TECHNICAL AREA (TA)

The three PROSPR TAs are listed below. TA1 and TA2 each have two tracks, while TA3 is a single track. All tracks and TAs are designed to run concurrently, with an expectation of ongoing collaboration and integration across teams, as outlined in the Program Structure section. Each proposal can address any number or combination of tracks, including only a single track. ARPA- H may choose to fund only a portion of any proposal. All performers are expected to collaborate with each other throughout the life of the program and will therefore have Associate Performer Agreement (APA) language included in their respective award; see Appendix A.

Technical Area 1 (TA1): PROSPR intrinsic capacity score (see Table 3 for metrics)-60 months

• TA1 Phase I (12 months) includes developing IC score (v1.0) and IC assessment technology (v1.0) and preparing for a clinical observational study to measure IC score.

• TA1 Phase II (12 months) includes refinement of IC score (v1.1) and IC assessment technology (v1.1) using data from the clinical observational study.

• TA1 Phase III (12 months) includes conducting a lifestyle intervention study to test the intervenability of IC score (v1.2) and detection capacity of the IC technology (v1.2).

• TA1 Phase IV (12 months) includes refining IC score (v2.0) and IC assessment technology (v2.0) using data from lifestyle intervention study.

• TA1 Phase V (12 months) focuses on deployment and commercialization.

TA1 is comprised of two interconnected tracks, Track 1a and Track1b.

Track 1a (PROSPR IC score) Track 1a performers will define a single score (PROSPR IC) comprised of human physiological and biochemical components, that predicts 20-year health outcomes.

In year 1, performers will harmonize existing human datasets (see metrics for details) to identify the weighted contribution of each IC component to a composite PROSPR IC score. Two PROSPR IC scores will be generated independently, one with components weighted for contribution to female IC and one for males, as we anticipate the contribution of certain components will vary significantly by sex. Performers can include any number of physiological and biochemical components in their initial testing but must at least include all five components of WHO-defined IC and DNA methylation. Please also note that we prefer components which do not require invasive methods of sample collection. Components should be included or excluded in the final composite PROSPR IC score based on their contribution to the accuracy of the composite score to predict 20-year health outcomes. TA1 will label the PROSPR IC score as an improved version of intrinsic capacity to leverage the existing ICD-11 (Internal Classification of Disease-11) code, accelerating its clinical use.

In year 2, Track 1a performers will validate and improve the accuracy of the PROSPR IC score using data provided by the decentralized or hybrid study conducted by Track 2b performers (see below).

In years 3 and 4, Track 1a performers will validate the intervenability of the PROSPR IC using data provided by the multi-modal lifestyle intervention clinical trial conducted by Track 1b performers (see below). Additionally, Track 1a performers will collaborate closely with Track 1b to guide technology development based on the components of the PROSPR IC score identified during the data harmonization in year 1. They will continue to guide refinements in later phases as the score improves.

Track 1a performers will compile the data from other PROSPR performers that use PROSPR IC in clinical trials. Throughout the duration of the program, performers will discuss the data with other performers and the FDA and prepare submission packages for the FDA, for surrogate endpoint designation of PROSPR IC and biochemical surrogates.

Note: Track 1a performers are responsible for conducting targeted analyses on biospecimen samples collected from PROSPR study participants (see below) to validate TA2 Track 2a-identified biomarkers throughout the program.

Track 1b (PROSPR IC assessment technology)

In year 1, track 1b performers will work closely with Track 1a performers to incorporate insights gained from the components of PROSPR IC score from Track 1a to develop in-home PROSPR IC assessment technology. PROSPR envisions a digital health platform (app) that connects with common existing health monitoring devices and wearables to assess different components of the PROSPR IC score. The platform will include methods for minimally-invasive collection of biological samples as necessary, such as blood spots or saliva, for DNA methylation and other biochemical analyses. This platform must also provide educational information in easy-to-understand language to promote health ownership.

In year 2, performers will test the technology’s accuracy and user-friendliness to measure PROSPR IC in a one-year decentralized or hybrid PROSPR study. Proposals will be accepted from performers seeking to extend already existing large-scale longitudinal studies of human measures, provided they add the PROSPR TA1 track 1b study requirements (see Table 3).

Participants will report monthly PROSPR IC score with the in-home PROSPR IC assessment technology, while clinicians conduct the same assessments during clinic visits at baseline, six months, and at the end of the study. Each participant must be assigned a coach to virtually assist with the technology, facilitate regular engagement, and provide feedback to the performers.

Starting with version 1.0, the PROSPR IC score will undergo iterative updates, progressing to version 2.0 by the end of the program. Each version will incorporate refinements and improvements based on data collected from participants in the PROSPR study, enhancing the predictive accuracy of the score over the course of the study.

Feedback on IC assessment technology accuracy, usability, and user-friendliness from participants in the TA1 track 1b PROSPR study will be continuously integrated into the refinement of the IC assessment technology. Starting with version 1.0, the technology will evolve through iterative updates, including milestones such as version 1.1 and 1.2, leading to version

2.0 by the end of the TA1 track 1b study. Each version will incorporate refinements and improvements based on participant feedback, ensuring the technology is progressively optimized throughout the study. If a technology demonstrates sufficient accuracy and technical progress at this stage, the PM may nominate the team to work with the agency’s commercialization team, the Project Accelerator Transition Innovation Office (PATIO). The team would similarly iterate on its product design and business model with a goal of <$100 per consumer assessment at a realistic production volume by the end of the program.

In year 3, Track 1b performers will recruit a subset of participants from the TA1 track 1b PROSPR study into a 1-year in-home lifestyle intervention study with continued PROSPR IC monitoring facilitated by a coach and using the PROSPR IC assessment technology. The lifestyle intervention will end in year 4, and performers will continue to collect participants’ PROSPR IC with PROSPR IC assessment technology to determine if health improvements are sustained or return to baseline.

The lifestyle intervention must include at least four of the following lifestyle management options for participants, weighted for their needs established during the PROSPR study: diet, exercise, stress, social engagement, sleep, poor habit management, mental health, or others.

After the one-year PROSPR lifestyle intervention study, participants will continue to report their PROSPR IC score for an additional year without the coach to determine whether the PROSPR IC score remains improved, returns to baseline, or follows another trajectory.

In year 5, Track 1b nominated performers will work with ARPA-H PATIO and its partners to commercialize the in-home PROSPR IC score assessment technology, validating progress toward the affordability objective and optimizing deployment within the health system workflow.

Performers will also discuss approval of the PROSPR IC assessment technology with the FDA for clinical and in-home use of the IC assessment for patient IC measurement. Further, track 1b performers will work with payers to develop a strategy for covering the consumer costs and propose a plan for in-home screening and monitoring outside the FDA-regulated clinical diagnosis pathway.

Note: Annual discussions with the FDA are a requirement for TA1 (track 1a and 1b) performers to advance to the next phase of the program. The FDA encourages early engagement so that they may provide guidance on where additional data may be needed for validation. TA1 performers must provide an update on their progress with these FDA interactions to the PROSPR PM as part of the quarterly status meetings.

Note: Track 2b performers are responsible for providing biospecimen samples collected from PROSPR study participants to Track 1a to support the validation of TA2-identified biomarkers throughout the program.

Technical Area 2 (TA2): Repurposing FDA-approved interventions for healthspan extension (see Table 4 for metrics)-60 months

• TA2 Phase I (12 months) includes identifying intervenable biomarkers and preparing for a phase 3 decentralized clinical trial for drug repurposing.

• TA2 phase II (6 months) includes finalizing clinical trial study requirements and sharing identified biomarkers.

• TA2 Phase III (12 months) focuses on conducting the phase 3 decentralized clinical trial.

• TA2 phase IV (12 months) continues data collection and monitoring.

• TA2 phase V (18 months) concludes phase 3 trial and involves engaging with the FDA for regulatory approval.

TA2 is comprised of two interconnected tracks, track 2a and track 2b.

Track 2a (Biochemical markers)

Performers will collect clinical data and blood samples from existing clinical trials where a therapeutic intervention has demonstrated broad health improvements to identify biochemical markers (genes, metabolites, proteins, etc.) consistently responsive across interventions. These biomarkers will be shared with TA1 performers for potential inclusion in the composite PROSPR IC score. We encourage performers to consider trials of the following treatments: rapamycin, metformin, GLP-1, acyclovir, naltrexone, and somatostatin. Performers must have letters from trialists agreeing to share the stored blood samples for omics analysis. Track 2a will conduct comprehensive omics analyses on these blood samples to identify biochemical changes during an 18-month funding period. Throughout the funding period, Track 2a will collaborate closely with TA1 Track 1a and 1b performers to integrate identified biochemical markers into the TA1 track 1a-developed PROSPR IC score and TA track 1b-developed PROSPR study design. The biochemical markers identified by Track 2a will be tested by Track 2b in a Phase 3 clinical trial using FDA-approved drugs to determine whether the biomarkers are responsive to these interventions.

Track 2b (FDA-approved drugs)

TA2 track 2b performers will identify up to two FDA-approved drugs with strong safety data and evidence of multimorbidity reduction in humans or evidence of healthspan, frailty, or lifespan improvement in preclinical animal models, and conduct a 3-year, phase 3 randomized clinical trial, conducted in a decentralized manner (DCT). The trial will test the drug’s efficacy for improving PROSPR IC, the biomarkers identified in phase 1 of TA2, and health outcomes in 60-year-old participants. Track 2b performers will work with the FDA on decentralized clinical trial design and validated surrogate endpoints for healthspan. Track 2b performers will also share IC data with TA1 performers during the clinical trial to allow TA1 to determine whether PROSPR IC is responsive to pharmacological interventions in humans.

Note: Track 2b performers are responsible for sharing IC data and the findings of their targeted analyses of intervenable biochemical markers (identified by Track 2a) from clinical trial study participants with TA1-Track 1a performers. This enables TA1-Track 1a performers to compile the data and prepare submission packages to the FDA for the validated surrogate endpoint designation of PROSPR IC and biochemical surrogates.

Technical Area 3 (TA3): Second-generation interventions (see Table5 for metrics)-60 months

• TA3 Phase I (18 months) includes preclinical validation using aged animal models.

• TA3 Phase II (18 months) includes IND-enabling studies to evaluate the safety, pharmacokinetics, and behavior of second-generation interventions.

• TA3 Phase III (6 months) focuses on establishing IRB approval and preparing for the clinical trial.

• TA3 Phase IV (18 months) focuses on the first-in-human clinical testing of second-generation interventions to assess safety and efficacy in a Phase 1b clinical trial.

TA3 focuses on identifying the most efficacious interventions that can extend human healthspan. TA3 performers will propose interventions with strong evidence of extending healthspan, lifespan, or reducing frailty symptoms in preclinical rodent models. Performers must provide evidence of optimized intervention delivery and address treatment-specific challenges to enable long-term use in animals as part of the supporting data in their proposal.

TA3 will begin with multiple teams. TA3 performers are expected to collaborate and share data, both among the TA3 performers (specifically the preclinical method of IC assessment) and with performers in TAs 1 and 2 to ensure the overall success of the program. Therefore, performers will have Associate Performer Agreement (APA) language included in their respective award; see Appendix A.

In phase 1, TA3 performers will conduct preclinical testing of their intervention in outbred rodents beginning about mid-age until advanced age, evaluating the efficacy of the intervention to maintain or improve health (cognitive ability, metabolic function, muscle strength, immune function, cardiovascular function, sensory function, etc.) during aging. TA3 performers must ensure reproducibility of results through external validation by an independent group at an independent research site. TA3 will assess model health using a method they develop to test components of the PROSPR IC, as closely identified in TA1, ideally using automated, non-subjective measures. Although each team is responsible for developing pre-clinical IC measures, the PROSPR PM may require performers switch to another team’s rodent PROSPR IC protocol at any time during the program.

Innovative therapeutics with the highest safety profile and greatest efficacy in aged animal models will be prioritized for the phase 1b human clinical trials conducted within this TA.

Performers may propose various interventions such as small molecules, organelle transplant, or lifestyle mimetics.

Selection for TA3 teams to advance to next phases of the PROSPR program will take place twice:

once at the end of the phase I (Y2), and again at the conclusion of IND-enabling studies (Y3).

Ultimately, ARPA-H anticipates two teams will be selected to proceed to human clinical trials.

The final team(s) must work with TA1 and TA2 performers during phase III (Y4) to incorporate TA1 track1a-developed PROSPR IC and biochemical surrogates into their clinical trial design.

Table 1: The general program objectives by TA

TA1: PROSPR IC • Harmonize existing datasets to identify key physiological and Score: biochemical changes of age-induced health outcomes.

Predict 20-year • Develop a sex-specific PROSPR IC score for predicting 20-year health outcomes mortality and multi-morbidity outcomes.

• Build in-home PROSPR IC assessment technology for consistent monitoring of health and allow proactive health management.

• Establish a multi-modal decentralized or hybrid lifestyle intervention study to collect data on the responsiveness of the PROSPR IC score and biochemical markers (from TA2) to lifestyle interventions.

• Collect empirical evidence demonstrating that these lifestyle interventions can improve or maintain general wellness in relatively healthy, aging individuals.

• Engage with the FDA to advance PROSPR IC and biochemical markers toward validated surrogate endpoint designation in collaboration with TA2.

• Engage with the FDA to obtain approval of in-home PROSPR assessment technology.

• Commercialize PROSPR IC assessment technology (<$100 out of pocket)

• Begin strategies for securing insurance coverage to enable early health intervention and preventive care.

TA2: Repurposing • Identify common biochemical changes shared between multiple FDA-approved health improving drugs using omics data from blood samples interventions: obtained from existing clinical trials.

Accelerate creation • Demonstrate the utility of PROSPR IC (from TA1) and biochemical of a healthspan markers as surrogate endpoints in place of disease accumulation industry or mortality in phase 3 clinical trials.

• Utilize repurposed drugs to provide first-generation healthspan therapeutics and generate the clinical data necessary for establishing feasibility of short-term efficacy trials for healthspan extension.

• Build a consensus on decentralized trials for non-diseased populations.

TA3: Second- • Test second-generation interventions that target age-related generation health decline through rigorous efficacy and safety preclinical interventions: Extend trials.

human health by 20 • Develop a preclinical method in rodents to assess the components years of PROSPR IC as closely as identified in TA1.

• Test safety and efficacy of candidate intervention in Phase 1b human clinical trial.

Accessibility Requirements

Performers must develop solutions that account for health inequalities, considering cost and accessibility of care, and ensure protection of all protected groups. These considerations must be addressed prior to program onset.

2.3.2 DELIVERABLES AND TRANSITION ACTIVITIES

Table 2. Overall deliverables and transition activities

Technical Area Deliverables and Transition Activities

TA1

A highly accurate and easy-to-measure intrinsic capacity score (PROSPR IC score) that quantifies age-associated health changes, responds to interventions, and predicts 20-year health outcomes.

A user-friendly proactive health management tool (in-home PROSPR IC assessment technology) that offers a personalized, patient-centered experience based on the PROSPR IC score.

Deployment strategies that ensure regulatory approval and reimbursement pathways for PROSPR IC.

PROSPR IC as an FDA-validated surrogate endpoint.

Intervenable endpoint surrogates for early prediction of healthspan changes and adverse health outcomes.

A multi-modal decentralized/hybrid lifestyle intervention study.

Empirical evidence demonstrating that lifestyle interventions can improve or maintain general wellness in relatively healthy individuals.

TA2

Intervention-responsive biomarkers, identified through omics analysis of blood samples collected in existing clinical trials.

Repurposed drugs that extend healthspan in aged individuals.

Establishment of a basis for consensus around decentralized clinical trials for aged, non-diseased populations.

Establishment of a regulatory pathway for interventions targeting age-induced intrinsic capacity decline.

TA3

Phase 1b clinical trial for an affordable and accessible novel medicine that extends healthspan in aged individuals by improving or maintaining intrinsic capacity.

Preclinical assessment protocol of PROSPR IC measures.

All TAs

All TAs

• Integrate TA1 deliverables (PROSPR IC and in-home PROSPR IC assessment technology) into clinical trial designs throughout the program (TA1 lifestyle intervention trial, TA2 Phase 3 drug-repurposing trial, TA3 second-generation Phase 1b clinical trial) to demonstrate clinical utility of PROSPR IC and validate its responsiveness to intervention for designation as a validated surrogate endpoint.

• Integrate TA2 identified biomarkers from existing clinical trials into clinical trial designs throughout the program (TA1 lifestyle intervention trial, TA2 Phase 3 drug-repurposing trial, TA3 second-generation Phase 1b clinical trial) to demonstrate clinical utility of biochemical surrogates and validate their responsiveness to intervention for surrogate endpoint designation.

• Use TA2-identified biomarkers from existing clinical trials to guide necessary modifications to the in-home PROSPR IC technology.

• Leverage insights gained from TA2 clinical trial data to guide the design of clinical trial in TA3.

• Engage with FDA to receive early guidance on data needed to progress with the program.

• Demonstrate long-term planning to sustain the project by identifying potential funding and commercialization partners.

• Establish clear guidelines for intellectual property rights and licensing agreements early in the research process.

• Focus on accessibility and demonstrate that the team is advocating for partnerships that promote and promise accessibility to ≥75% of US communities.

2.3.3 PROGRAM STRUCTURE

The PROSPR program structure is based on the timeline shown in Figure 1. PROSPR will depend on multidisciplinary teams to bring expertise in various scientific domains, and has been designed to transfer information across the TAs. Performers may submit proposals that address any one of three TAs or can combine more than one TA or tracks to address broader, multi-disciplinary challenges. However, regardless of the number of TAs included in the proposal, performers must plan for integration and data sharing with other teams. Any performer that does not meet the accessibility, data sharing plan, and attendance requirements may not progress to subsequent phases. Progression into future phases is determined by the ARPA-H PM and is based on funding availability, performer progress toward phase metrics, and probability of success in future phases. Performers who remain in the program must continue to meet all the required metrics, including the following integration areas:

• TA1 performers will provide PROSPR IC technology to TA2 performers before the end of Phase 2 to use in their phase 3 clinical trial design using FDA-approved repurposed drugs.

Data from this trial will support the designation of PROSPR IC as a surrogate endpoint to shorten timelines for healthspan extension trials.

• TA1 performers will provide PROSPR IC technology to TA3 performers before the end of TA3 Phase III to incorporate measures into phase 1b clinical trial of second-generation intervention design.

• TA1 Track 1a and Track 1b performers will collaborate for the duration of the program to coordinate the PROSPR IC score with the assessment technology.

• TA2-Track 2a performers will share identified biochemical biomarkers with TA1 and

TA2-Track 2b performers during TA2 Phase 2 to allow performers to validate these biomarkers as surrogate endpoints in the lifestyle intervention trial and phase 3 trial for FDA-approved drug repurposing, respectively.

• TA1_Track 1a performers are responsible for preparing the FDA submission package for PROSPR IC and biochemical markers as validated surrogate endpoints. All PROSPR performers are required to share data with TA1 performers for the FDA discussions as needed.

Figure 1: The PROSPR Timeline and TA interactions.

2.3.4 PROGRAM METRICS AND TIMELINE

Tables 3-5 provide the milestones and metrics expected and used to track progress throughout the duration of the program. Performers will be required to formally report progress against the agreed upon metrics on a quarterly basis or as needed to the PROSPR PM and to the designated collaborating team(s). Technical progress toward the program metrics, data sharing, and collaboration with teams from other TAs are significant factors for continuation into subsequent phases.

Table 3: Expected milestones and metrics per phase in TA1 (PROSPR IC score)

TA1 Phase I (v1.0 Development) - 12 months Track 1a

Ingest existing longitudinal databases

• At least three of the following used: Canadian Longitudinal Study of Aging (CLSA), All of Us, Baltimore Longitudinal Study of Aging (BLSA), Mass General Brigham Biobank, Coronary Artery Risk Development in Young Adults (Cardia), and UK Biobank.

• Database study participants reflect the general population.

• Combined data from study participants is demonstrated to be generalizable relative to the target population based on Performers' statistical analysis and includes adult datasets starting from at least 35 years of age.

• Collectively, the chosen datasets provide coverage of all IC subdomains, disease risk, all-cause mortality, and morbidity. Note: individual datasets are not required to have all of these health outcomes.

Data harmonization

• Data cleaning, normalization, and validation are performed to ensure at least 95% consistency across datasets

DNAm or other sequencing

• As needed, completed DNA-methylation or other sequencing and analysis using existing biospecimens with linked clinical data.

IC components and measures

• Includes all five components of WHO-defined IC (cognition, locomotion, vitality, sensory function, and psychological capacities) and DNA methylation.

• Each IC component contributes to the overall score based on a weighted calculation.

• Minimum factor loading for any IC indicator is ≥ 0.3, with no significant cross-loading observed.

• IC measures include at least one validated assessment for each of the five IC subdomains.

• At least 80% of IC measures are designed to be compatible with digital health platforms, including wearables.

• IC measures requiring biospecimen collection prioritize non-invasive methods (e.g., blood spots or saliva) with a total collection and processing time of ≤10 minutes.

V1.0 PROSPR IC score

• PROSPR IC scores are developed independently for males and females.

• Demonstrates a clear distribution across different age groups in adults >35.

• Capability Demo (v1.0): 20-year mortality or multi-morbidity prediction, AUC ≥ 0.90, 95% CI, R2 ≥ 0.5.

• PROSPR IC score validated against multiple outcomes, including two of the following: functional ability, hospitalizations, multi-morbidity, and mortality.

Data security and storage

• Data security and protection measures meet industry regulations (e.g., HIPAA, GDPR) and data governance best practices.

• Data collected, stored, and managed using industry standard data models or formats (e.g., OMOP, CDSIC, LinkML for electronic health records; FASTA, VCF for genomic data) and APIs.

• Data is FAIR (findable, accessible, interoperable, reusable), with a preference for standard and open APIs such as FHIR, the Global Alliance for Genomics and Health (GA4GH) APIs (DRS, Passports, Phenopackets, etc.), or similar access mechanisms.

Regulatory compliances

• Engaged at least once with the FDA to ensure accurate measurement and assessment of IC components by incorporating FDA guidance into study protocols and methodologies.

Track 1b

In-home PROSPR IC assessment tech (v1.0)

• Integrates with various available wearable devices and sensors to assess the physiological components of PROSPR IC v1.0.

• Include methods for collecting non-invasive biospecimens, (e.g. blood spot, saliva, etc.) for biochemical analysis with collection success rate of ≥ 95% and a total collection and processing time of ≤10 minutes.

• Capability Demo (v1.0): Real-time data synchronization (≤ 5 sec) and analysis capabilities (≤ 10 sec) with ≤ 99.9% uptime.

• User-friendliness aiming for Task Success Rate (TSR) >80%, a low (2-5 min) Time to Task (TOT), and user satisfaction rating ≥ 3.5/5.0 using standardized questionnaire to assess overall usability and navigation.

• Includes a patient education platform that explains each component of PROSPR IC (v1.0), the meaning of scores, and the significance of score changes in lay terms.

• Provides options for data sharing with healthcare providers and researchers with user consent obtained in 100% of cases.

• Scalable to support at least 4K participants.

PROSPR study (Design)

• Incorporated the measurement of IC score and PROSPR IC assessment tech (v1.0) into the study design.

• Obtained IRB approval for decentralized/hybrid trial.

• Trained 100% clinical staff and coaches for new study protocol and technology orientation.

• 100% completion of electronic informed consent from all participants.

• Enrolled >1K patients that reflect the general population, aged 35-75 with no chronic health conditions, non-extreme end BMI, and no cognitive dysfunction, breakdown of male and female patients that reflects the general population. Note: Extending existing studies is allowed.

• Established unique ID links between study participants and wearables.

• Engaged at least once with the FDA to align the human study design with regulatory standards.

• Documented and incorporated all FDA feedback and comments into the study design.

TA1 Phase II (v1.1 Development) - 12 months

V1.1 PROSPR IC score

• Model accuracy and reproducibility validated and refined with emergent data from PROSPR IC study.

• Individual IC measurements remain statistically correlated with changes in PROSPR IC score (v1.1).

• Capability Demo (v1.1): 20-year mortality or multi-morbidity prediction AUC ≥0.95, 95% CI, R2 ≥ 0.5.

• Similar AUC (±0.05) when analyzing different age groups.

• Similar AUC (±0.05) when analyzing males and females.

Metrics additional requirements

• Performed targeted analyses on samples collected from PROSPR study participants to validate TA2-Track 2a identified biomarkers and establish baseline measures.

Regulatory compliances • Conducted at least one meeting with the FDA.

assessment tech (v1.1)

• Capability Demo (v1.1): Data accuracy and consistency:

≥80% correlation between device measurement and clinician assessments. Measurements yielded ≥90% consistency over repeated trials.

• Reliability: ≥ 95% successful sync rate with wearable devices and sensors, and ≥ 99% uptime.

• User experience: user satisfaction rating ≥ 4.0/5.0 on standardized usability scales. Task Success Rate (TSR) >80%, low (2-5 min) Time to Task (TOT).

PROSPR study (Observational)

• Attrition rate < 15%.

• Achieved ≥ 80% data completion for all data sources.

• Demonstrated inter-rater reliability ICC ≥ 0.75 and data consistency ≥ 90% across all sources throughout the study.

Metrics additional requirements

• Biospecimen samples collected from PROSPR study participants shared with Track 1a.

• Distributed in-home PROSPR IC assessment tech to TA2- Track 2b performers for use in clinical trial.

• TA2-Track 2a intervenable biochemical surrogates used to inform any refinements to the in-home PROSPR IC assessment technology (v1) for measuring new markers.

regulations (e.g., HIPAA, GDPR) and data governance best practices.

• Data collected, stored, and managed using industry standard data models or formats (e.g., OMOP, CDSIC, LinkML for electronic health records; FASTA, VCF for genomic data) and APIs.

• Data is FAIR (findable, accessible, interoperable, reusable), with a preference for standard and open APIs such as FHIR, the Global Alliance for Genomics and Health (GA4GH) APIs (DRS, Passports, Phenopackets, etc.), or similar access mechanisms.

Regulatory compliances • Conducted at least one meeting with the FDA to review and align the study design.

TA1 Phase III (v1.2 development) - 12 months

V1.2 PROSPR IC score refined with emergent data from PROSPR IC study.

• Individual IC measurements remain statistically correlated with changes in PROSPR IC score (v1.2).

• Capability Demo (v1.2): 20-year mortality or multi-morbidity prediction AUC ≥0.95, 95% CI, R2 ≥ 0.5.

• Similar AUC (±0.05) when analyzing different age groups.

• Similar AUC (±0.05) when analyzing males and females.

• Performed targeted analyses in samples collected from PROSPR lifestyle intervention participants to validate intervenable biomarkers (identified by TA2-Track 2a).

Achieved an AUC ≥ 0.70 in predicting lifestyle intervention response and a correlation coefficient ≥ 0.5 between biomarker changes and clinical outcomes.

• Completed re-analysis of intervenable biomarkers (identified by TA2-Track 2a) using data shared by Track 2b. Achieving an AUC ≥ 0.80 and a correlation coefficient ≥ 0.5 between biomarker changes and clinical outcomes.

assessment tech (v1.2)

• Capability Demo (v1.2): Data accuracy and consistency:

≥80% correlation between device measurement and clinician assessments. Measurements yielded ≥90% consistency over repeated trials.

• Reliability: ≥ 95% successful sync rate with wearable devices and sensors, and ≥ 99% uptime.

• User experience: user satisfaction rating ≥ 4.5/5.0 on standardized usability scales. Task Success Rate (TSR) >80%, low (2-5 min) Time to Task (TOT).

• Coaching feature effectiveness: ≥ 80% of participants improve PROSPR IC score and reduced risk of functional decline, multi-morbidity, and mortality (OR ≥0.70, 95% Cl).

(Lifestyle intervention)

• The multimodal lifestyle intervention study incorporates at least four of the following management techniques:

diet, exercise, stress, social engagement, sleep, mental health, poor habit management, or others.

• Maintained an attrition rate of <30%.

• Achieved ≥80% data completion across all data sources.

• Achieved inter-rater reliability with ICC ≥ 0.75 and data consistency ≥ 90% across all data sources throughout the study.

Regulatory compliances • Conducted at least one meeting with the FDA to review and align the study design.

TA1 Phase IV (v2.0 development) - 12 months

V2.0 PROSPR IC score refined with emergent data on lifestyle effects.

• Measurements must remain statistically correlated with changes in PROSPR IC score (v2.0).

• Demo (v2.0): 20-year mortality or multi-morbidity prediction AUC ≥0.98, 95% CI, R2 ≥ 0.5.

• Similar AUC (±0.05) when analyzing different age groups separately.

• Similar AUC (±0.05) when analyzing males and females.

• Completed targeted analysis in new samples collected from PROSPR lifestyle intervention participants to validate TA2-intervenable biomarkers (identified by Track 2a). Achieved an AUC ≥ 0.70 in predicting lifestyle intervention response and a correlation coefficient ≥ 0.5 between biomarker changes and clinical outcomes.

• Completed re-analysis of intervenable biomarkers (identified by TA2-Track 2a) using data shared by Track 2b. Achieving an AUC ≥ 0.80 and a correlation coefficient ≥ 0.5 between biomarker changes and clinical outcomes.

• Provided status report of discussions with the FDA for validated surrogate endpoint designation of PROSPR IC (v2.0).

Track 1b

In-home PROSPR IC assessment tech (v2.0)

• Capability Demo (v2.0): Data accuracy and consistency:

≥80% correlation between device measurement and clinician assessments. Measurements yielded ≥90% consistency over repeated trials.

• Reliability: ≥ 95% successful sync rate with wearable devices and sensors, and ≥ 99% uptime.

• User experience: user satisfaction rating ≥ 4.8/5.0 on standardized usability scales. Task Success Rate (TSR) >80%, low (2-5 min) Time to Task (TOT).

• Coaching feature effectiveness: ≥ 60% of participants maintain their improved PROSPR IC score over the additional year and reduced risk of functional decline, multi-morbidity, and mortality (OR ≥0.70, 95% Cl).

(Health ownership)

• Collected and logged data for all participants throughout the 12-month study.

• Achieved >80% participant adherence to reporting PROSPR IC score without the coach.

• Concluded PROSPR study by the end of Phase IV.

Metrics Additional requirements

• Distributed in-home PROSPR IC assessment tech to TA3 performers for use in clinical trial.

Transition and adoption

• Began the regulatory approval process for the in-home PROSPR IC assessment technology (v2.0) and developed a comprehensive plan to address any remaining regulatory requirements.

• Developed commercialization plan for the in-home PROSPR IC assessment technology (v2.0) in collaboration with ARPA-H partners and the ARPA-H Project Accelerator Transition Innovation Office (PATIO).

• Initiated the development of an insurance action plan following consultations with the Center for Medicare & Medicaid Innovation (CMMI) and the Centers for Medicare & Medicaid Services (CMS).

TA1 Phase V (Deployment and commercialization) - 12 months

• Incorporated FDA feedback and submitted the qualification package for surrogate endpoint designation of PROSPR IC (v2.0)

• Completed all regulatory requirements for the finalized prototype of in-home PROSPR IC assessment technology (v2.0).

• Maintained ongoing engagement with ARPA-H partners and PATIO on the commercialization plan for in-home PROSPR IC assessment technology (v2.0), including an engagement plan with Executives-in- Residence (XIRs) and Entrepreneurs-in-Residence (EIRs), targeting a consumer cost of around $100.

• Continued engagement with CMMI and CMS to advance the development of an Insurance Action Plan

TA1 (PROSPR IC to predict 20-year health outcomes)

Out-of-scope criteria

Track 1a (PROSPR IC):

• Single disease prediction/focus.

• Proposals that lack DNA-methylation integration with relevant health metrics or omit key metrics from IC subdomains.

Track 1b (In-home PROSPR assessment technology):

•…