GLIDE ISO ARPA-H-SOL-24-111 Final 29 OCT 2024.pdf

ARPA-H-SOL-24-111, GLIDE

INNOVATIVE SOLUTIONS OPENING

FOR

GROUNDBREAKING

LYMPHATIC

INTERVENTIONS AND

DRUG

EXPLORATION

GLIDE

HEALTH SCIENCE FUTURES

ARPA-H-SOL-24-111

October 29, 2024

Table of Contents

1. INNOVATIVE SOLUTIONS OPENING SUMMARY INFORMATION

1.1 ISO PURPOSE

1.2 ISO QUESTIONS AND ANSWERS

1.3 PROPOSERS’ DAY

2. THE PROGRAM

2.1 GLIDE OVERVIEW

2.2 PROGRAM STRUCTURE, TIMELINE AND TECHNICAL APPROACH

2.2.1 TECHNICAL AREAS (TAS)

2.2.2 GLIDE DOWNSELECTION CHECKPOINTS & PHASE III PROGRESSION

2.2.3 DATA MANAGEMENT AND SHARING PLAN (DMSP)

2.3 TECHNICAL AREA METRICS AND OBJECTIVES

2.3.1 TA1 METRICS

2.3.2 TA2 METRICS

2.4 GENERAL REQUIREMENTS

2.4.1 PROPOSING TEAMS

2.4.2 GLIDE PROGRAM MEETINGS AND ATTENDANCE

2.4.3 ACCESSIBILITY REQUIREMENTS

3. ELIGIBILITY INFORMATION

3.1 ELIGIBLE PROPOSERS

3.1.1 PROHIBITION OF PERFORMER PARTICIPATION FROM FEDERALLY FUNDED

RESEARCH AND DEVELOPMENT CENTERS (FFRDCS) AND OTHER GOVERNMENT

ENTITIES

3.1.2 NON-U.S. ENTITIES

3.2 SYSTEM FOR AWARD MANAGEMENT (SAM)

4. GLIDE SUBMISSION AND EVALUATION PROCESS

4.1 SUBMISSION PROCESS OVERVIEW

4.2 SOLUTION SUMMARY SUBMISSIONS

4.3 PRE-AWARD PITCH PRESENTATION SUBMISSIONS

4.4 FULL PROPOSAL SUBMISSIONS

4.5 SUBMISSION INFORMATION

4.6 SOLUTION SUMMARY, PRE-AWARD PITCH PRESENTATION AND FULL

PROPOSAL SUBMISSION DEADLINES

4.7 PROPRIETARY INFORMATION

5. SOLUTION SUMMARY AND PRE-AWARD PITCH PRESENTATION REVIEW, AND

EVALUATION OF FULL PROPOSALS

5.1 CONFORMING SOLUTION SUMMARY, PRE-AWARD PITCH PRESENTATIONS,

AND FULL PROPOSAL SUBMISSIONS

5.2 STEP 1: SOLUTION SUMMARY REVIEW PROCESS

5.3 STEP 2: PRE-AWARD PITCH PRESENTATION PROCESS

5.4 STEP 3: FULL PROPOSAL REVIEW PROCESS

5.5 EVALUATION CRITERIA FOR STEPS 2-3 AND AWARD

5.5.1 CRITERIA 1: OVERALL SCIENTIFIC AND TECHNICAL MERIT

5.5.2 CRITERIA 2: PROPOSER’S CAPABILITIES AND/OR RELATED EXPERIENCE

5.5.3 CRITERIA 3: POTENTIAL CONTRIBUTION TO RELEVANCE TO THE ARPA-H

MISSION AND USER EXPERIENCE

5.5.4 CRITERIA 4: PRICE ANALYSIS

5.6 REVIEW, EVALUATION, AND SELECTION PROCESS FOR AWARD

5.6.1 REVIEW AND EVALUATION TIMELINES

5.7 HANDLING OF SELECTION SENSITIVE INFORMATION

5.8 AWARD STRATEGY

6. POLICY REQUIREMENTS AND MISCELLANEOUS OTHER INFORMATION

6.1 ORGANIZATIONAL CONFLICTS OF INTEREST (OCI)

6.1.1 AGENCY SUPPLEMENTAL OCI POLICY

6.1.2 GOVERNMENT OCI PROCEDURES

6.2 INTELLECTUAL PROPERTY

6.3 HUMAN SUBJECTS RESEARCH

6.4 ANIMAL SUBJECTS RESEARCH

6.5 ELECTRONIC INVOICING AND PAYMENTS

6.6 GOVERNMENT-FURNISHED PROPERTY/EQUIPMENT/INFORMATION

APPENDIX A: SOLUTION SUMMARY FORMAT AND INSTRUCTIONS

APPENDIX B: PRE-AWARD PITCH PRESENTATION FORMAT AND INSTRUCTIONS

APPENDIX C: FULL PROPOSAL FORMAT AND INSTRUCTIONS

APPENDIX D: TARGET PRODUCT PROFILE GUIDELINES

ATTACHMENT 1: Target Product Profile (TPP)

ATTACHMENT 2: Pitch Deck Slides

ATTACHMENT 3a and 3b: Cost Proposal Spreadsheets

1. INNOVATIVE SOLUTIONS OPENING SUMMARY INFORMATION

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

PROGRAM TITLE: Groundbreaking Lymphatic Interventions and Drug Exploration

(GLIDE)

ANNOUNCEMENT TYPE: Solicitation

ISO SOLICITATION NUMBER: ARPA-H-SOL-24-111

DATES: (All times listed are Eastern Time)

• Proposer’s Day: October 1, 2024, ET

• Questions & Answers (Q&A) due date: December 5, 2024, 2:00 PM ET

• ISO Closing Date (Solution Summaries Due): December 12, 2024, 2:00 PM ET

ANTICIPATED AWARDS: Multiple Other Transaction (OT) Agreements and Cooperative Agreements (CAs)

AGENCY CONTACT: All inquiries should be sent to GLIDE@ARPA-H.gov

1.1 ISO PURPOSE

ARPA-H seeks proposals from all eligible entities (see Section 3 Eligibility Information) to accomplish the GLIDE Program goals as described in this solicitation package. Ultimately, ARPA-H intends to negotiate multiple OT Agreements and Cooperative 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 GLIDE@arpa-h.gov. ARPA-H will post Q&As to the ARPA-H ISO Website and SAM.gov on an on-going basis and may not respond directly to email inquiries. All questions must be in English and must include the name, email address, and telephone number of a point of contact, and should be submitted by the Q&A deadline posted with other key dates. 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 due date may not be answered. Further, duplicative questions may be combined and rephrased to streamline responses.

1.3 PROPOSERS’ DAY

ARPA-H hosted a Proposers’ Day in support of the GLIDE Program as described in Special Notice ARPA-H-SN-24-112. The purpose was to provide potential proposers with information on the GLIDE program, promote additional discussions, and encourage team networking.

Interested proposers were not required to attend, and materials formally presented during Proposers’ Day will be posted to SAM.gov.

ARPA-H will not reimburse potential proposers for participation at Proposers’ Day (or time and effort related to submission of Solution Summaries, pitch decks, presentations or full proposals).

mailto:GLIDE@ARPA-H.gov mailto:GLIDE@arpa-h.gov https://arpa-h.gov/research-and-funding/programs/glide https://sam.gov/opp/16d15c9d1c244485b0fc6afd31aa78d2/view

2. THE PROGRAM

2.1 GLIDE OVERVIEW

Program Overview: The GLIDE program envisions a future where doctors will have a therapeutic armamentarium targeting abnormal lymphatic structure and function, dramatically expanding the role of the lymphatic system, not only for primary lymphatic diseases but in the treatment of all chronic diseases. The program will develop therapeutic and physical interventions that alleviate, repair, and regenerate irregular or dysfunctional lymphatic vasculature, while including product design and commercialization considerations that favor broad accessibility and adoption by the community of hospitals, healthcare providers, and patients.

Today, patients with a primary lymphatic disease (LD) or a common chronic disease with underlying lymphatic dysfunction must manage often progressive and debilitating life-threatening symptoms for their entire life. Existing therapies are very limited and almost exclusively palliative.

GLIDE will develop a variety of treatment options available for patients that address the underlying mechanisms of lymphatic dysfunction; either curing the disease state or safely stabilizing the disease and providing significant relief.

Background and Motivation: The lymphatic system (LS) is an indispensable body system without which we could not survive. It consists of a complex network of lymphatic vessels, lymph nodes, and lymphatic organs that play a critical role in fluid balance, immune cell surveillance, and macromolecule homeostasis in almost every tissue of the human body.

Normal structure and function of the LS can be altered by congenital diseases such as primary lymphedema (LE), lymphatic tumors, and malformations, or by trauma, cancer, radiation, infection, or surgical injury resulting in secondary LE. Altogether lymphatic diseases are estimated to impact more than 10 million Americans (see National Indicator Report on Cancer- Related Lymphedema). Lymphatic dysfunction has been further demonstrated to play a key role in the pathophysiology of common chronic diseases including obesity, diabetes, hypertension, heart failure (HF), inflammatory bowel disease, asthma, chronic liver disease (CLD), chronic kidney disease (CKD), HIV, sepsis, hepatitis, COVID-19, neurodegenerative disease, glaucoma, transplant rejection, and autoimmune disease.

Despite this, there are no FDA-approved treatments, therapies, or medical devices, altering lymphatic growth and function.

Lymphatic vessels (LV) are translucent, tiny, and fragile and often overlooked in anatomical studies; additionally, LVs are found in almost every tissue/organ throughout the human body with regional heterogeneity in phenotype. Designing therapies that can target the lymphatic system specifically has been difficult and surgical interventions require significant extra training and skill. Today, clinicians have no pharmacological, gene, or cell therapies that have been specifically formulated or optimized for lymphatic dysfunction. Existing physical interventions and therapies to normalize function, such as compression garments or manual decongestive drainage, are strictly palliative and cumbersome. In the last few decades, several surgical and interventional procedures to decompress obstructive lymphatics have emerged but are still considered experimental with limited insurance coverage and access.

https://lymphaticnetwork.org/documents/National_Indicator_Report_on_Cancer-Related_Lymphedema.pdf https://lymphaticnetwork.org/documents/National_Indicator_Report_on_Cancer-Related_Lymphedema.pdf

To address the underlying causes of abnormal lymphatic structure and function, treatment approaches must consider how they address key features of lymphatic dysfunction including:

1. Obstructed and abnormal flow

2. Leaky vessels, permeability, and excess fluid accumulation

3. Poor vessel contractility and transport capacity

4. Abnormal lymphatic growth

GLIDE will address two key issues in the treatment of lymphatic dysfunction: 1) decompression of obstructed lymphatics and 2) normalization of lymphatic function. Decompression of distended lymphatic vessels and their surrounding tissues that are the consequence of obstructed lymphatic flow provides immediate relief of tissue swelling and organ dysfunction and can be lifesaving. However, decompression is often a temporary measure that must be continued or repeated to maintain quality of life and healthy organ function. For an extended solution, normalization of function through repair or regeneration of damaged lymphatic vessels is an attractive approach but requires further development and refinement of techniques.

We are in urgent need of cures in the form of repair and regeneration that would restore healthy lymphatic flow for an extended period. Both decompression and lymphatic repair have seen clear demonstrations of proof of concept in the hands of experts at specialized centers, but both need advancements in technology to bring these benefits to a wider population.

ARPA-H will be the catalyst that moves lymphatic medicine from the fringes into the mainstream and opens the benefits of lymphatic medicine to a much broader range of disorders, such as autoimmune disease, HF, CKD, and CLD. We believe that the scientific methodologies to accomplish our aims already exist but are spread among a disparate group of scientists and clinicians. What is needed is an organized effort to bring these technologies together under a shared goal to realize the promise of lymphatic medicine in clinical practice.

2.2 PROGRAM STRUCTURE, TIMELINE AND TECHNICAL APPROACH

The GLIDE program will develop a portfolio of physical devices and pharmacologic, genetic and cell therapeutics to target lymphatic dysfunction through:

1. Decompression of an obstruction of lymphatic flow and/or abnormal lymph accumulation.

2. Repair and regeneration of the lymphatic system’s structure and function.

To accomplish these goals, GLIDE is structured into two technical areas (TAs) focused on physical interventions and pharmacologic, gene and cell therapeutic interventions, respectively, and three phases to support translation from idea to market:

Phase I encompasses platform development, proof-of concept research, and feasibility investigations.

Phase II addresses clinical viability and risk assessment.

Phase III provides initial confidence to establish the foundation for clinical trial success with support through Phase I clinical trials. ARPA-H will select the disease indication that the performing team pursues into clinical efforts in Phase III. Continuation into Phase III will be determined by ARPA-H and will be based on technical progress made in prior phases and available funding. (Figure 1. GLIDE Program Structure & Timeline)

Further, GLIDE offers two pathways to success with different timelines to support translational research and commercialization for technology at various technical readiness levels (TRLs) as outlined in the ARPA-H Technology Readiness Level Guide. Proposers must assess the maturity of their proposed solution and self-report the TRL and decide between one of two appropriate pathways regardless of TA.

The Activator pathway -> focuses on transformative early-stage solutions with limited or no preliminary data collected. Proposals must demonstrate how the approach will revolutionize the state of care for lymphatic disease and dysfunction if successful. The phases of the Activator path include:

Phase I - Discovery and Development (up to 36 months).

Phase II - Preclinical studies (18 months).

Phase III– Clinical focused primarily on safety and securing regulatory approvals (up to 6 months).

The Accelerator pathway -> focuses on technologies with some demonstrated proof of concept but requiring additional feasibility investigation up to early efficacy data or prototyping. Appropriate technologies must still require at least 18 months of research, development, and optimization during Phase I of GLIDE. The Accelerator path will lower barriers to validating the efficacy of the approach and propel the solution toward successful commercial transition. The phases of the Accelerator path include:

Phase I - Later-Stage Research and Development (R&D) (up to 18 months) Phase II - Preclinical studies (18 months), Phase III - Clinical Trials (up to 24 months).

At the time of submission, proposers must:

1. Select One Technical Area: Determine if the “primary mode of action” applies to TA1:

Physical Intervention or TA2: Pharmacologic, Gene and Cell Therapies.

2. Determine Your Path to Success: Evaluate the technical readiness of your technology as a product of commercialization. The technical rationale for choosing the activator or accelerator track must be defined in the proposal.

• Activator (TRL 1): Proof-of-concept demonstration

• Accelerator (TRL 2): Feasibility technology

3. Define Rare & Chronic Disease: identify two or more disease indications including suspected or targeted mechanism of action for their proposed solution. Submissions https://sprint.investorcatalysthub.org/wp-content/uploads/2024/03/ARPA-H-Technology-Readiness-Levels-TRLs-03.01.2024.pdf must include at least one rare and one chronic disease/disorder impacted by lymphatic dysfunction with recent literature citation and/or evidence supporting the presence of lymphatic dysfunction in their chosen disease indications. At the beginning of Phase III, ARPA-H will select 1 of the 2 indications for clinical trials. Examples of disease indications include but are not limited to:

Table 1. Examples of Disease Indications

Examples of rare diseases with demonstrated lymphatic dysfunction:

Examples of chronic diseases w/ demonstrated lymphatic dysfunction:

• Lymphatic Malformations

• Complex Lymphatic Anomalies:

o Gorham’s Stout Disease

(GSD)

o Generalizing Lymphatic Anomaly (GLA) o Kaposiform Lymphangiomatosis (KLA) o Central conducting lymphatic anomaly (CCLA)

• Castleman Diseases

• Lymphangioleiomyomatosis (LAM)

• Kaposi Sarcoma

• Milroy Disease

• Primary Intestinal Lymphangiectasia

• Noonan Syndrome

• Turner Syndrome

• Primary Lymphedema

• Secondary Lymphedema

• Lipedema

• Inflammatory Bowel Disease

• Cardiovascular Disease

• Pulmonary Fibrosis

• Cancer

• Organ Transplantation

• Chronic Liver Disease

• Chronic Kidney Disease

• Autoimmune Disorders

• Glaucoma

• Neurodegenerative Diseases

• Obesity

• Filariasis

• HIV

• COVID

• Lymphangitis

2.2.1 TECHNICAL AREAS (TAs)

Technical Area 1 (TA1): Restore Flow through Physical Interventions – TA1 focuses on developing technology to enhance surgery, microsurgery, interventional radiology, nuclear medicine, compression, or other physical/mechanical (e.g. neuromodulation) means to restore obstructed flow through the LS. Proposers are encouraged to integrate the latest advances in biomaterials, sensors, and artificial intelligence/machine learning (AI/ML)-practices to their proposed physical intervention approach, ensuring that the approach represents a significant, revolutionary (non-incremental) improvement to the current clinical practice. Solutions that are minimally invasive or non-invasive, or interventions that can be done at the same time as existing standard interventional or surgical procedures (such as lymph node dissections or biopsies) are viewed favorably. Physical interventions can include, among others, smart compression, cutting edge surgical tools and interventional radiology devices, and/or lymphatic modulating and reparative implants.

Proposals should consider how the physical intervention may:

• Improve access to and efficacy of devices and surgical procedures which decompress (relieve blockage) of the lymphatic system.

• Directly address the underlying causes of lymphatic dysfunction or obstructed flow.

• Proactively reduce disease incidence for susceptible individuals.

Technical Area 2 (TA2): Normalize Function through Targeted Pharmacologic, Gene, and Cell Therapy - TA2 focuses on platform development and therapeutic identification of pharmacologic, genetic, or cellular approaches to repair, regenerate, and/or relieve obstruction causing lymphatic dysfunction. Proposers are requested to consider high-throughput LD relevant screens and leverage AI, when appropriate to identify viable therapeutic and/or targets to modulate, repair, and/or regenerate lymphatic vasculature.

Proposers are also encouraged to identify the best pathway to maximize success while maintaining urgency and delivering viable lead candidates for possible commercialization.

Pharmacologic solutions for consideration include small molecules, biologics (e.g. antibody drug conjugates), and cell and gene therapy solutions as well as mechanisms to boost drug delivery into the lymphatic system with high specificity and sustained dosage to minimize off-target effects, reduce drug-resistance, and improve safety. Proposals should consider:

• New drug discovery through lymphatic-relevant high-throughput screens

• Rational drug design and target identification with AI-assistance

• Repurposing existing drugs

• Delivery methods

• Leveraging diagnostic technology

• Potential combinations with interventional modalities from TA1

• The impact of sex and age as a biological variable on the therapy’s safety, efficacy and pharmacokinetic (PK) profile

Figure 1: GLIDE Program Structure and Timeline

2.2.2 GLIDE DOWNSELECTION CHECKPOINTS & PHASE III PROGRESSION

The GLIDE program has established detailed quantifiable and qualitative program metrics for each TA in Tables 1 and 2 with phase-specific metrics to ensure performers succeed as they progress toward a viable therapeutic or physical intervention solution that is both groundbreaking and clinically viable in their ability treat and/or manage LD.

ARPA-H may request performer data as deemed necessary throughout the program to validate technical progress. The performer’s progress will be evaluated in alignment with the program metrics outlined in Section 2.3 Technical Metrics and Objectives and will be used to assess success within each phase by GLIDE’s PM. Failure to meet the metrics within each phase may result in downselection from GLIDE. Additionally, any performer that does not meet the accessibility, product development, and attendance requirements may not progress to the subsequent phases.

Continuation into Phase III will be determined by ARPA-H and will be based on technical progress made in prior phases and available funding.

2.2.3 DATA MANAGEMENT AND SHARING PLAN (DMSP)

GLIDE encourages all teams to consider the importance of data sharing opportunities that may be possible during the GLIDE program. All proposals are required to include a data management and sharing plan that address the following points:

1. What type of data will be generated? Explain rationale for what scientific data will be preserved and what will be shared.

2. Will specialized tools, software, or code be needed to access or manipulate shared data, and if so, provide the purpose and rationale?

3. What are the common data standards that apply to scientific data and metadata to enable interoperability and safety?

4. What is the timeline for data preservation and access?

5. Outline your plan for data access, distribution, reuse, and privacy considerations.

6. Describe activities and individuals to ensure compliance and oversight.

Teams are encouraged to leverage existing large databases from multiple research centers (e.g. All of Us Initiative) to determine novel insight into lymphatic physiology and pathology and contribute research findings to these resources. Unless an exception is approved by the GLIDE PM, proposers will openly share deidentified/sanitized data acquired during the period of performance with the scientific community. Any member of the scientific community may have access to the deidentified/sanitized data; registration to a specific repository website is acceptable, but approval needs to be automatic. The specific repository where data will be deposited will be chosen in agreement with the ARPA-H PM. The proposers will need to present explicit solutions to address the significant data storage and computing challenges presented by the program with the understanding that the plans and repository may change later in the program. The DMSP must address any instances where open sharing of data may jeopardize the technology’s commercial potential. With PM approval and proper justification, proposers may restrict access to even the sanitized/deidentified data generated during the period of performance.

2.3 TECHNICAL AREA METRICS AND OBJECTIVES

ARPA-H will meet with GLIDE performers monthly to review progress towards the metrics and milestones defined below. Achievement of all metrics as agreed to by ARPA-H is part of the basis for initiation of moving to the next phase. Key overall program metrics and milestones are listed in this section below. Proposers may propose quantitative metrics and milestones for the PM to consider that may be better suited for their specific technology. However, the proposers must provide a justification for these revisions to the metrics and milestones as specified below. A full target product profile (TPP) outlining the minimum and ideal functionality of the technology developed in each TA must be included with all submission materials. An example of a TPP can be found in Appendix D.

https://allofus.nih.gov/

TABLE A. Overall GLIDE Program GOALS

Disease Target & Proposal Strategy

• Address chronic disease challenges or lymphatic dysfunction through modulation of the lymphatic system.

• Develop therapeutic intervention through decompression with physical intervention to improve lymphatic flow, and normalize lymphatic system through targeted pharmaceutical, gene or cell therapeutic solutions to repair and/or regenerate LVs.

GENERAL GOALS

Leveraging Computational Intelligence and Big Data Management

• All performers should leverage and share data in a smart and collaborative way using FAIR Data Principles (Findable, Accessible, Interoperable and Reusable), including submission to public database repository as relevant.

• Apply current state-of-the-art approaches to leveraging AI and ML approaches to increase speed, efficiency, or predictiveness of the team’s therapy technology.

• Utilize AI/ML to aid in the design and discovery effort of therapeutic intervention, when possible, for pharmaceutical, gene therapy, cell therapy, and/or physical interventions.

• Identification of information systems requirements (e.g., QMS, eCRF, etc.) for regulatory submission and compliance

Product Development and Regulatory Science

• Detailed commercialization plan and TPP to be delivered by performers at time of full proposal.

• For therapeutics, New Drug Application submission for lymphatic specific indications.

• For medical devices, 510(k), De Novo, or other FDA submission process for physical interventions or novel drug delivery devices.

• Successful initiation of clinical trials for safety and efficacy.

Accessibility Requirements

Performing teams must address health inequities with respect to cost and accessibility of care, sex as a biological variable, gender (social identity), protection regardless of socioeconomic status or ethnicity. Each performer team will have formed at least one Discovery Duo that participates in GLIDE’s Justice, Equity, Diversity, and Inclusion (JEDI) taskforce, patient voice sessions, and Phase II equity symposium.

In collaboration with GLIDE’s PM, the JEDI taskforce will develop equity KPIs for each performer team. Required attendance ≥90% is expected and will be enforced by the PM.

Dissemination

Disseminate new technology, models, documents, and other findings to the public and stakeholders through appropriate collaborations with private and government organizations (i.e., patient advocacy groups, and academic institutions).

Attendance and Participation

A 90% mandatory attendance policy will have established accountability, a positive competitive yet collaborative environment, and encourage a collaborative value-added contribution to the program success.

2.3.1 TA1 Metrics

The overall program objectives for TA1 are listed in Table A above. The expected metrics per phase in TA1 are listed in Table 1 below.

Table 1. TA1: Restore Flow through Physical Interventions

Phase I

Concept Generation

Conception of physical interventions to address an obstruction and/or abnormal flow (lymphatic dysfunction) such as smart compression device, electromagnetic stimulation / neuromodulation, stent, shunt, artificial valve or vessel implant, balloon, or embolization.

A. Identify lymphatic system friendly material for device (avoids clotting, inflammation, restenosis and/or obstruction)

B. Non-invasive, minimally invasive, and/or adjunct to existing or standard procedures (e.g. lymph node dissections or biopsy).

Performers are encouraged to utilize state-of-the-art computational approaches (AI/ML) to improve the efficacy of their proposed solution.

Prototype Design and Optimization

1. Demonstrate compliance with FDA design controls and quality systems.

2. Computational and in-silico modeling, as appropriate.

3. Risk assessment.

Affordability target of the physical device post manufacturing as cost of goods (as appropriate)

Target and ideal goals for cost of goods:

• Class I: $250 / $75

• Class II: $3,000 / $1,800

• Class III: $8,000 / $5,500

Bench Tests

Evaluate design efficacy and performance via:

• Material and stress testing (fatigue, wear, tensile, strength, etc.).

o Must meet current state of the art metrics for comparable interventions.

• Ex-vivo and in-vitro testing with animal or human tissue (cytotoxicity, hemocompatibility, etc.).

o Must meet current state of the art metrics for comparable interventions.

End of Phase I Deliverables

1. Commercialization Plan due covering market analysis, regulatory, reimbursement, manufacturing, and intellectual property (IP) strategy (≤8 pages).

2. Functional early prototype of device and pilot data of approach.

3. Complete relevant IACUC protocols for Phase II.

4. Confirm all relevant information subsystems, data repositories, etc. are in place.

5. Performance, subsystem testing, quality, and integration reports (for devices or new methods/processes).

6. 513(g) or relevant FDA pre-submission for device classification.

7. Progress report on retirement of key risks and key success metrics (e.g., biocompatibility, delivery optimization, system costs, results of assays, benchmark performance, etc.).

Downselection Decision Criteria

Performers must meet all agreed upon efficacy targets and successfully submit all end of Phase I deliverables. Continuation into Phase II will be determined by ARPA-H and will be based on technical progress made in prior phases and available funding.

Phase II

Bio-compatibility (in-vitro and in-vivo studies)

As appropriate, performers should study the efficacy and safety of their proposed physical intervention in:

• Cell culture models (e.g. lymphatic endothelial cells and relevant immune populations)

• Small and/or large animal models

Efficacy targets (minimal/optimal target):

Performers must:

1. Define a target (normal or therapeutic) range of ≥ 1 lymphatic function in their disease indications and propose to restore function to that target range for at least 3 months following intervention. Targets should be specific, measurable, and represent transformative improvements in line with the guidance below:

• Lymphatic transport (% clearance) or lymph drainage speed (cm/s):

o Guidance:

> 50% / 75% improvement compared to disease state.

o Ex. Mouse tail Lymphedema (LE) model: Lymphatic tracer remaining at injection site after 48 hours.

Target: Normal clearance: <40% residual tracer LE clearance: >60% residual tracer

• Lymphatic Pressure (mm Hg):

o Guidance:

> 40% / 60% improvement compared to disease state.

o Ex. Swine model of Tricuspid Regurgitation (TR):

Target: Healthy TD pressure: ~8 mm Hg TR TD pressure: ~14 mm Hg

• Lymphatic Vessel (LV) Contractility (contractions/min) o Guidance:

> 75% / 100% improvement over disease state.

o Ex. Mouse tail LE model:

Target: Normal frequency: >3 contractions/min LE Frequency: <1.8 contractions/min

• Volume Displacement (ml) o Guidance: > 20% / 40% reduction in volume compared to the disease state.

o Ex. Mouse tail LE model:

Target: Normal Tail Width: 3.8mm LE Tail Width: 4.7mm

2. Include additional minimal and optimal targets with respect to the claim or indication of use.

For example:

• Edema/Volume (ml/cm3):

o Guidance:

> 20% / 40% reduction in volume compared to the disease state.

o Ex. Mouse tail LE model:

Target: Normal Tail Width: 3.8mm LE Tail Width: 4.7mm

• Skin Thickness (μm or mm):

o Guidance:

> 50% / 70% reduction compared to disease state.

o Ex. Mouse tail LE model:

Target: Normal Dermal Thickness: 350μm LE Dermal Thickness: 650μm

3. Submit a TPP inclusive of these metrics for each indication with full proposal. This will be reviewed and updated with the PM throughout the program.

The TPP must aim to achieve the additional outcomes below:

• No or low rates of adverse events (AE) in initial 3 months.

o Minimal Target: <5% of animals develop significant clotting, severe inflammation, restenosis and/or obstruction.

o Optimal Target: <5% of animals develop any observable AE

• High technical/procedural success rate (>95% / >99%)

Risk Reduction

Adjust and refine design to achieve safety and efficacy targets while overcoming barriers to commercialization and adoption. For example:

Minimal/optimal targets:

• Affordability (cost of goods):

o Class I: $250 / $75 o Class II: $3,000 / $1,800 o Class III: $8,000 / $5,500

• Accessibility: Available at community / rural hospitals and healthcare centers

• Ease of use: An experienced surgeon/user should be competent in the intervention with

≤ 2 weeks (≤5 days) of training.

If appropriate, further validate AI/ML approaches used for detection or functional measurement with additional testing and training sets.

End of Phase II Deliverables

1. Submit a revised commercialization plan (≤12 pages). Increased focus on:

a. Institutional Review Board (IRB) engagement strategy

b. Scale-up strategy for device manufacturing.

2. Clinical Trial Protocol

3. Summary report of preclinical investigation to show safety and efficacy.

4. Second progress reports on key metrics (proof points, safety, scalability) and retirement of key risks.

5. Investigational Device Exemption (IDE) or other relevant FDA approval for human clinical testing for safety and/or efficacy.

Downselection Decision Criteria

Performers must meet all agreed upon efficacy targets and successfully submit all end of Phase II deliverables. Continuation into Phase III will be determined by ARPA-H and will be based on technical progress made in prior phases and available funding.

Phase III

Early Feasibility Studies (Safety)

Study Targets (minimal/optimal target):

• Study Size: >10 / 25 participants.

• Technical success: >95% / >99%

• No or low rates of adverse events (AE) in first six months:

o Minimal: <5% rate of Grade II or higher AEs o Optimal: <1% rate of Grade II or higher AEs

Pivotal Studies (Safety and efficacy)

Efficacy targets (minimal/optimal target):

Performers must:

1. Define a target (normal or therapeutic) range of ≥ 1 lymphatic function in their disease indications and propose to restore function to that target range for at least 1 year following intervention. Targets should be specific, measurable, and represent transformative improvements in line with the guidance below:

• Lymphatic transport (% clearance) or lymph drainage speed (cm/s):

o Guidance:

> 50% / 75% improvement compared to disease state.

o Ex. Breast Cancer Related Lymphedema (BCRL) Normal lymph transport speed: >0.15cm/s BCRL lymph transport speed: <0.05cm/s

• Lymphatic Pressure (mm Hg):

o Guidance:

> 40% / 60% improvement compared to disease state.

o Ex. Congenital heart defects:

Control TD Pressure: <10 mm Hg CHF TD Pressure: >16 mm Hg

• LV Contractility (contractions/min) o Guidance:

> 75% / 100% improvement over disease state.

o Ex. Arm LE:

Normal Frequency: ~1.3 contractions/min Arm LE Frequency: <0.5 contractions/min

2. Include additional minimal and optimal targets with respect to the claim or indication of use.

For example:

• Edema/Volume (mL/cm3):

o Guidance:

> 20% / 40% reduction in volume compared to the disease state.

o Ex. Arm Lymphedema:

Target: Normal Arm Volume: ~2100ml Arm LE Volume: >2500ml

• Skin Thickness (μm or mm):

o Guidance:

> 50% / 70% reduction compared to disease state.

o Ex. Arm Lymphedema:

Target: Normal Skin Thickness: <20mm LE Skin Thickness: >60mm

3. Submit a TPP inclusive of these metrics for each indication with full proposal. This will be reviewed and updated with the PM throughout the program.

The TPP must aim to achieve the additional outcomes below:

• Study Size: >100 / 200 participants (will be based on FDA discussions and class of device)

• No or low rates of adverse events (AE) in initial 3 months.

o Minimal target: <5% rate of Grade II or higher AEs o Optimal target: <1% rate of Grade II or higher

• High technical/procedural success rate (>95% / >99%)

End of Phase III Deliverables

1. Evaluation of product by stakeholders.

2. ARPA-H Exit Plan - Final design review and report:

a. Detailed demonstration of final product ready for clinical trial testing.

b. Cost and scalability assessment.

c. Evaluation by potential stakeholders including providers, patients, and scientists.

d. Safety and effectiveness report.

e. Strategy to secure external funding.

3. Draft of submission paperwork for FDA approval.

Transition and Adoption

Successfully transition to external funding for further clinical trials, scale up technology adoption.

Develop workshops and showcases of technology for key stakeholders.

2.3.2 TA2 Metrics

The overall program objectives for TA2 are listed in Table A. The expected metrics per phase in TA2 are listed in Table 2 below.

Table 2. TA2: Normalize Function through Targeted Pharmacologic, Gene & Cell Therapy

Phase I

Therapeutic Identification

Utilize high throughput lymphatic-relevant screens and state-of-the-art computational approaches, and/or AI-assisted rational drug design, to identify optimal molecular targets and compound modifications to achieve lymphatic normalization (minimal/optimal target).

• Small Molecule: ≥10 to 20 viable lead candidates

• Biologics: ≥3 to 10 viable lead candidates

• Cell/Gene Therapies: ≥3 to 5 candidates

Viable candidates defined as possible targeted therapeutic solutions capable of achieving >90% specificity and >90% selectivity, with efficacy targets outlined below in Preliminary PK/PD & non- GLP Toxicology.

For Gene and Cell Therapy Solutions: achieve >50% target cell penetration / >70-100% targeted cell penetration, >50% editing efficiency / > 70-100% editing efficiency, 1:1000 detection limit / not detected at 1:1000 level of cellular assay for off-target effects and chromosomal abnormalities.

All metrics must align to the corresponding observed lymphatic phenotype targets.

Delivery Optimization

Design or implement a delivery methodology that delivers the therapeutic compound to the LS in the first 12 hours post-delivery.

Minimal target: >30% delivery to Lymphatic System;

Optimal target: 45% delivery to LS

Preliminary PK/PD & non-

GLP

Toxicology

Appropriate studies (in-vitro, ex-vivo, and small animal subjects) to assess efficacy.

• Dosing/Toxicology studies

• PK/PD Studies

Efficacy targets (minimal/optimal target):

Performers must:

1. Define a target (normal or therapeutic) range of ≥ 2 lymphatic function in their disease indications and propose to restore normal function to that target range within 2 weeks following treatment. Targets should be specific, measurable, and represent transformative improvements in line with the guidance below:

• LV density (LVs/unit area) or lymphatic vascular area (mm2):

o Guidance:

> 100% / 200% improvement compared to disease state.

o Ex. Mouse ulcerative colitis (UC) model:

Target: Therapeutic LV density: ~48 LVs/mm2 UC LV density: 25 LVs/mm2

• Lymphatic transport (% clearance) or lymph drainage speed (cm/s):

> 50% / 75% improvement compared to disease state.

o Ex. Mouse tail LE model: Lymphatic tracer remaining at injection site after 48 hours.

Target: Normal clearance: <40% residual tracer LE clearance: >60% residual tracer

• Lymphatic Pressure (mm Hg):

> 40% / 60% improvement compared to disease state.

o Ex. Rat tail lymphatics:

Target: Normal max pressure generation: >30 mm Hg Impaired max pressure generation: <20 mm Hg

• LV Contractility (contractions/min) o Guidance:

> 75% / 100% improvement over disease state.

o Ex. Mouse tail LE model:

Target: Normal frequency: >3 contractions/min LE Frequency: <1.8 contractions/min

2. Include additional minimal and optimal targets with respect to the claim or indication of use.

For example:

• Edema/Volume (ml/cm3):

o Guidance:

> 20% / 40% reduction in volume compared to the disease state.

o Ex. Mouse tail LE model:

Target: Normal Tail Width: 3.8mm LE Tail Width: 4.7mm

• Skin Thickness (μm or mm):

o Guidance:

> 50% / 70% reduction compared to disease state.

o Ex. Mouse tail LE model:

Target: Normal Dermal Thickness: 350μm LE Dermal Thickness: 650μm

3. Submit a TPP inclusive of these metrics for each indication with full proposal. This will be reviewed and updated with the PM throughout the program.

The TPP must aim to achieve the additional outcomes below:

• Appropriate benefit-risk profile:

o Minimal Target: <10% Grade 3 or higher adverse events o Optimal Target: <3% Grade 3 of adverse events

End of Phase I Deliverables

Recognize key regulatory risks, including required companion diagnostics, additional experimental assays, and validation in future.

1. Commercialization Plan due covering regulatory, reimbursement, manufacturing, and IP strategy (≤8 pgs.).

2. Confirm all information subsystems in place.

3. Assay validation reports.

4. Complete pre-IND meeting.

5. Progress reports on retirement of key risks and key success metrics (e.g., pharmacokinetic parameters, delivery optimization, costs, results of assays, benchmark performance, etc.).

Downselection Decision Criteria

Performers must meet all efficacy targets and successfully submit all end of Phase I deliverables.

Continuation into Phase II will be determined by ARPA-H and will be based on technical progress made in prior phases and available funding.

Phase II

IND Enabling

GLP

Toxicology & Nonclinical Studies

Ensure GLP compliant study therapy in an appropriate IND enabling model (≥24 animals) for safety and efficacy to support IND submission. (reminder to consider sex as a biological variable)

• Dosing/Toxicology studies

• PK/PD Studies

Efficacy targets (minimal/optimal target):

Performers must:

1. Define a target (normal or therapeutic) range of ≥ 2 lymphatic function in their disease indications and propose to restore function to that target range within 2 weeks following treatment. Targets should be specific, measurable, and represent transformative improvements in line with the guidance below:

• LV density (LVs/unit area) or lymphatic vascular area (mm2):

o Guidance:

> 100% / 200% improvement compared to disease state.

o Ex. Porcine LE model:

Target: Therapeutic LV density: >20 LVs/mm2 LE LV density: < 3 LVs/mm2

• Lymphatic transport (% clearance) or lymph drainage speed (cm/s):

o Guidance:

> 50% / 75% improvement compared to disease state.

o Ex. Sheep lymphadenectomy: Transport of radiolabeled BSA from LS to plasma.

Target: Normal transport: >50% transported Injured transport: <15% transported

• Lymphatic Pressure (mm Hg):

o Guidance:

> 40% / 60% improvement compared to disease state.

o Ex. Swine model of Tricuspid Regurgitation (TR):

Target: Healthy TD pressure: ~8 mm Hg TR TD pressure: ~14 mm Hg

• LV Contractility (contractions/min) o Guidance:

> 75% / 100% improvement over disease state.

o Ex. Sheep lymphatic insult model:

Target: Normal frequency: 4 contractions/min Dysfunction Frequency: <2 contractions/min

2. Include additional minimal and optimal targets with respect to the claim or indication of use.

For example:

• Edema/Volume (mL/cm3):

o Guidance:

> 20% / 40% reduction in volume compared to the disease state.

o Ex. Sheep lymphadenectomy:

Target: 35% circumference reduction

• Fibrosis - Collagen Content (%):

> 30% / 50% reduction compared to disease state.

o Ex. Sheep Pulmonary Fibrosis model:

Target: Normal Collagen: 4.5% PF Collagen: 7.5%

• Bioimpedance (BI) Ratio:

o Guidance:

> 5% / 10% improvement compared to disease state.

o Ex. Porcine LE model:

Target: Normal BI Ratio: 0.98 LE BI Ratio: >1.07

3. Submit a TPP inclusive of these metrics for each indication with full proposal. This will be reviewed and updated with the PM throughout the program.

The TPP must aim to achieve the additional outcomes below:

• Appropriate benefit-risk profile:

o Minimal Target: <10% Grade 3 or higher adverse events o Optimal Target: <3% Grade 3 of adverse events

Manufacturing

• GLP compliant product production.

• Ensure scalable cGMP pathway determined with informed decision based on discussion with

FDA and consultants.

Affordability

Target cost to patient (minimal/optimal target):

<$100/$75 month for management <$10,000/$5,000 to cure

Stability

Minimal Target: Therapeutic should be stable for 1.5 years.

Optimal Target: Therapeutic should be stable for 2 years at temperatures ≥ -20oC.

End of Phase II Deliverables

1. Submit a revised commercialization plan (≤12 pages). Increased focus on:

a) IRB engagement strategy

b) Scale-up strategy for device manufacturing.

2. Clinical Trial Protocol

3. Subsystem testing, quality, and integration reports (for devices or new methods/processes).

4. Second progress reports due on retirement of key risks and outlining key success metrics.

5. Complete IND approval.

Downselection Decision Criteria

Performers must meet all efficacy targets and successfully submit all end of Phase II deliverables. Continuation into Phase III will be determined by ARPA-H and will be based on technical progress made in prior phases and available funding

Phase III

Phase 0 Clinical Trial (optional)

• Establish preliminary demonstration of safety, target engagement and modulation.

• Assess bioavailability and biodistribution.

• Prioritize promising drug candidates.

• Inform dose range for Phase I clinical trial.

Phase I Clinical Trial

• Complete Phase I clinical trial with 25+ participants to assess safety at the therapeutic doses.

• Adhere to FDA guidelines on Diversity in Clinical Trials.

• Submit Clinical Study Report.

Preparation for Phase II Clinical Trial

• Complete and submit IRB paperwork.

• Develop and implement a recruitment plan for Phase II clinical trials.

• Ensure sufficient cGMP compliant product supply.

End of Phase III Deliverables

Final report including:

1. Detailed demonstration of deliverable product.

2. Cost and scalability assessment.

3. Evaluation by potential stakeholders including providers, patients, and scientists.

4. Safety and effectiveness report.

5. ARPA-H exit plan.

Transition and Adoption

Successfully transition to the clinic or larger commercial entities.

Develop workshops and showcases of technology for key stakeholders.

2.4 GENERAL REQUIREMENTS

2.4.1 PROPOSING TEAMS

Proposals are expected to involve teams with the expertise needed to collectively achieve the goals of the proposed TA(s) specific content. Communications, networking, and team formation are the sole responsibility of the proposer. Proposers must submit a single, integrated proposal led by a Principal Investigator (PI), under a single prime awardee that addresses all program phases as applicable. Teaming (that considers accessibility across geographies) is highly encouraged to accomplish the transformational goals set forth in the GLIDE program.

Proposers may only submit one proposal as the prime proposer. See Section 3.1 in terms of what constitutes a proposer. The Government’s expectation is that all key members of the performer team will be onboard within 60 days of the award.

At minimum, each Performer Team must include the following individuals:

• Lead Principal Investigator (PI) The lead PI is responsible for overseeing and directing the project design, implementation, and reporting of results. Further the PI is responsible for organizing the performer team and ensuring compliance with GLIDE requirements.

• Project Manager Proposers must include a Project Manager who coordinates efforts across the team, ensuring compliance with timelines and programmatic goals. The Project Manager will assist the lead PI in day-to-day project operations and execution as well as financial management and reporting.

• Product Development Lead (PDL) The Product Development Lead is an individual with the background necessary to manage the commercialization and regulatory efforts. This includes oversight of the “product development team”; regulatory, reimbursement, and commercialization experts who can act as either consultants or subcontractors. While the Government may offer to augment the proposers’ team with additional commercialization experts post award (e.g., Regulatory Consultants), the Proposer must propose a team independently capable of meeting GLIDE’s translational/commercialization goals.

• Discovery Duo Program The Discovery Duo program is designed to further engage the patient community in our research efforts by pairing a patient or parent ambassador with an early-stage scientific investigator who is within the first 10 years of receiving their advanced research degree. The early-stage investigator is designated as the performer’s JEDI representative for the performing team. The background or expertise of the Discovery Duo should align with the technology and disease area of the performing team's proposal. Discovery Duos will be expected to meet regularly (at least quarterly) and work directly with the lead PI and PDL, and who in turn will provide oversight and guidance with respect to inclusion, affordability, and accessibility considerations.

GLIDE’s PM will ensure that the Duos across the GLIDE program represent the patient’s experiences across the range of lymphatic diseases being studied.

The goal of the Discovery Duo program is to center the “patient experience”, encouraging researchers and clinicians to be advocates for lymphatic disease and empowering patients and patient ambassadors with a better understanding of the research process. The partnership will bidirectionally inform and motivate each other while engaging the patient community. Researchers and clinicians will engage with people who live with LD or a common chronic disease with underlying lymphatic dysfunction; patient ambassadors will have the ability to contribute to the scientific process informed by their Duo research partner.

As key members of GLIDE’s JEDI taskforce (see Section 2.4.2), the Discovery Duo will help to ensure that affordability, accessibility, and user experience is centered in the program. These Duos are tasked with conducting patient centered customer discovery, termed Patient Voice Sessions, which should include meetings with specialized hospital settings, patient advocacy organizations, medical associations, undergraduate and graduate healthcare institutions and more. Each Duo is responsible for outlining their own approach and timeline to complete at least 50 Patient Voice Sessions by the end of Phase I in preparation for the Accessibility Workshop in Phase II. Ultimately, Discovery Duos will integrate their findings into their program’s structure through direct involvement with activities such as in study design, the study review, ensuring accessibility, affordability of new technologies, stakeholder education, data sharing, and informed consent in clinical trials. The proposals must allocate funding for both members of the Discovery Duo and to include expenses related to these efforts (such as travel expenses) in the program budget. GLIDE requires this stipend to be, at minimum, $5,000/each per year of the Period of Performance (i.e., minimum of $10,000 per Duo).

Patient involvement and community-engaged research are critical to the process of developing technologies supported by the GLIDE program. To facilitate connections between patient groups and GLIDE technical proposers, we have created a patient engagement page where individuals can share their profiles and learn more about Discovery Duo partners.

https://arpa-h.gov/research-and-funding/programs/glide/patient-engagement https://arpa-h.gov/research-and-funding/programs/glide/patient-engagement

2.4.2 GLIDE PROGRAM MEETINGS AND ATTENDANCE

• Monthly Status Reports (MSR) with PM/GLIDE Team – Each team lead performer and project manager (if team has one) will be required to meet with the PM/GLIDE Team monthly (estimated as 1 hour each meeting.) for update and reviews. Status reports outlining technical and financial updates will be required at monthly meetings with the

PM.

• Meeting of the Minds (M&M) – In an effort to promote collaboration and learnings from all, the lead PI, Discovery Duo, PDL, and the Project Manager from each performer team must meet…