75N99223R0003 NITRO BAA Amend 3_ 29 JUNE.pdf

75N99223R0003, NITRO

Broad Agency Announcement (BAA) Novel Innovations for Tissue Regeneration in Osteoarthritis

(NITRO)

Health Science Futures (HSF) Office

75N99223R0003 May 18, 2023

(Amended 13 June) (Amended 21 June) (Amended 29 June)

TABLE OF CONTENTS

PART I: OVERVIEW INFORMATION

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

1.1. Program Overview

1.2. Technical Approach and Structure

1.3. Program Metrics

1.4. General Requirements

2. Award Information

2.1. General Award Information

3. Eligibility Information

3.1. Eligible Applicants

3.2. Organizational Conflicts of Interest

4. Application and Submission Information

4.1. Address to Request Application Package

4.2. Content and Form of Application Submission

4.3. Funding Restrictions

4.4. Questions

5. Application Review Information

5.1. Evaluation Criteria for Procurement Contracts, Cooperative Agreements, and Other

Transactions

5.2. Review of Abstracts and Full Proposals

6. Award Administration Information

6.1. Selection Notices and Notifications

6.2. Administrative and National Policy Requirements

6.3. Reporting

6.4. Electronic Systems

7. Agency Contacts

8. Other Information

PART I: OVERVIEW INFORMATION

• Federal Agency Name – Advanced Research Projects Agency for Health (ARPA-H), Health Science Futures Office (HSF)

• Funding Opportunity Title – Novel Innovations for Tissue Regeneration in Osteoarthritis (NITRO)

• North American Industry Classification System (NAICS) Codes – 541714 Research and Development in Biotechnology (except Nanobiotechnology) and 541713 Research and Development in Nanotechnology

• Announcement Type – Initial Announcement

• Funding Opportunity Number – 75N99223R0003

• Assistance Listing Number – 93.384

• Dates o Posting Date: May 18, 2023 o Proposers’ Day: June 15, 2023

Proposers’ Day Registration Deadline: June 8, 2023, 12:00 PM EDT o Abstract Due Date and time: June 23, 2023, 5:00 PM EDT o Proposal Due Date and Time: July 28, 2023, 5:00 PM EDT

• Concise description of the funding opportunity – The NITRO program vision is to make joints heal themselves. To achieve that goal, the Program aims to develop novel techniques for the regeneration and reconstruction of intra-articular (IA) cartilage and subchondral (SC) bone, the two key tissue types in a joint, in osteoarthritis (OA) patients. The current standard of care for OA patients of all Grades invariably proceeds from physiotherapy and non-steroidal anti-inflammatory (NSAIDs) drugs to open-joint surgery and/or total joint replacement. For patients with Grades I-IV OA, NITRO aims to revolutionize the care algorithm by reversing IA bone and cartilage damage in all synovial joints through infrequent, needle-based and/or non-invasive, long-lasting, approaches in a manner accessible to all Americans. For patients with no IA tissues left to regenerate who have no treatment option other than a total joint replacement, NITRO aims to generate non-immunogenic, load bearing, resorbable, osteochondral joints that require no permanent hardware to be placed inside a patient’s body. These technologies will revolutionize the treatment and management of patients with osteoarthritis and drastically decrease the disease burden on patients, providers, and the economy.

• Anticipated individual awards – Multiple awards are anticipated.

• Potential award instruments – Cooperative Agreements or Other Transaction

Agreements (OTA).

• Agency Contact – All inquiries shall be sent to NITRO@ARPA-H.gov

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

This publication constitutes a Broad Agency Announcement (BAA) as contemplated in Federal Acquisition Regulation (FAR) 35.016 and 2 Code of Federal Regulations (CFR) § 200.203, and is in accordance with section 499A of the Public Health Service Act. ARPA-H posts this funding opportunity within the framework of a BAA because of its widely recognized use in funding basic and applied research as well as the ability to negotiate multiple award types. Any resultant award negotiations will follow all pertinent laws and regulations.

The mission of ARPA-H is to accelerate better health outcomes for everyone by advancing innovative research that addresses society's most challenging health problems. Awardees will develop groundbreaking new ways to tackle health-related challenges through high potential, high-impact biomedical and health research. ARPA-H seeks proposals to advance regenerative and reconstructive strategies for treating osteoarthritis (OA), using innovative approaches to enable revolutionary advances in patient care algorithms.

Specifically excluded are: 1) proposals that represent an evolutionary or incremental advance in the current state of the art (e.g., advanced titanium or ceramic implants, therapeutics achieving only small repair areas, therapeutics that only slow OA progression without demonstrating regeneration), 2) performers unable to address the objectives of the program, 3) proposals directed towards policy changes, traditional education and training, or center coordination and construction of physical infrastructure are outside the scope of the ARPA-H mission.

1.1. PROGRAM OVERVIEW

Osteoarthritis (OA) is a crippling burden that currently affects 32.5 million US adults and 242 million adults worldwide. OA is often subcategorized into Primary OA (degeneration without a known cause) and Secondary OA. Secondary OA is degeneration with a known cause. The most common causes of Secondary OA are trauma, obesity, and surgery. Secondary OA can also be caused by infection, chemotherapy (particularly paclitaxel and aromatase inhibitors), inflammation, and a range of comorbidities.

By 2040, it is estimated that 26% of the population over 18 (approximately 78.4 million people) will develop some form of arthritis, the most common of which is OA. The number of Americans over the age of 65 will nearly double by 2060, and 88% of the OA population is over the age of 45 so it is anticipated that OA prevalence will increase over time. OA is twice as common in women and has the highest prevalence in Multi-Race Non-Hispanic and Native American/Native Alaskan populations. Additionally, OA rarely occurs as a stand-alone disease, as it is associated with or precipitates other common comorbidities (e.g., increases the risk of heart disease by 50%).

Given 50% of the US population is expected to be obese by 2030, there will be a corresponding surge in cases of Secondary OA. Overall, the disease carries an economic burden of over $136 billion dollars, a portion of which results from opioid-based OA pain management.

Despite the vast health and economic impacts of OA, there are currently no therapeutics to reverse the IA damage caused by the disease. Many patients’ first interface with a physician is at the onset of pain, which often means their OA has already significantly advanced in the joint(s). At this point, providers often prescribe NSAIDs (sometimes with corresponding opiates and/or steroids depending on the stage of OA) and recommend physiotherapy to stave off the eventual surgical intervention. Even in cases of activity-related trauma or obesity, there is very little that can be done outside of the aforementioned interventions to slow or reverse OA progression. Once the IA SC bone and cartilage have degenerated the ultimate course of action is an open-joint surgery, typically with a titanium-alloy total joint replacement.

It is currently estimated that there are over 2.5 million joint replacements annually. That number is projected to increase dramatically given the factors described above, and largely due to OA as well as a lack of regenerative therapeutics. While the majority of patients have IA tissues that can be regenerated back to a Grade 0 (Native) status, there are some patients who have no remaining tissue to regenerate and will require a total joint replacement. To successfully address and treat both patient populations, NITRO seeks to revolutionize this entire care algorithm through a two-pronged approach that focuses on (1) the regeneration of SC bone and IA cartilage with a single-dose therapeutic and (2) the creation of patient-specific regenerative and bioresorbable total knee replacements.

1.2 TECHNICAL APPROACH AND STRUCTURE

1.2.1. Technical Areas (TAs)

The NITRO program will develop technologies to enable needle-based and/or non-invasive regeneration of cartilage and bone as well as the total reconstruction of a synovial joint with load-bearing, non-immunogenic, osteo- and chondro-inductive, bioresorbable replacement joints. To accomplish this, the NITRO Program is focused on three TAs:

• Technical Area 1 (TA1): Needle-Based and/or Non-Invasive Subchondral (SC) Bone Regeneration. Development of an IA therapeutic to fully regenerate SC bone in all synovial joint(s) in all cases of primary osteoarthritis as well as trauma- and obesity-induced secondary osteoarthritis. Proposals for TA1 must also include TA2.

• Technical Area 2 (TA2): Needle-Based and/or Non-Invasive Cartilage Regeneration.

Development of therapeutics (both IA and systemic) to fully regenerate cartilage in all synovial joints in all cases of primary osteoarthritis as well as trauma- and obesity-induced secondary osteoarthritis. Proposals for TA2 must also include TA1.

• Technical Area 3 (TA3): Allogeneic and Autogenous Non-Immunogenic, Load-Bearing and Osteochondroinductive Total Replacement Joints. Development of autogenous and allogeneic, non-immunogenic, osteo- and chondro-inductive, load-bearing total knee replacements that requires no permanent foreign body implantation (e.g., is fully bioresorbable, no permanent fixation) and performs at or above the current standard set for artificial total knee implants. Proposals for TA3 may be submitted alone or with inclusion of both TA1 and TA2.

Proposal details: Performers will have the option of submitting proposals that cover TAs in one of the following permutations:

Option A) TA1 and TA2 -or- Option B) TA3 -or- Option C) TA1, TA2, and TA3

Proposals for Options A and C that fail to address all the technical areas required as noted above will be deemed non-conforming and may be rejected without further review.

TA1: Needle-Based and/or Non-Invasive Subchondral (SC) Bone Regeneration

Synovial joints are a meeting of two elegantly complex tissues – SC bone and articular cartilage.

As OA progresses from mild to moderate to severe, there is progressive damage not just to the articular cartilage but also to the SC bone. Over the course of the disease, this SC (and trabecular) bone ultimately becomes thickened as the condylar head deforms, along with narrowing or obliteration of the joint space and the appearance of cystic bone lesions. While there are a litany of grading scales depending on provider preference and the synovial joint in question, the fact remains that all scales illustrate the progression from a “None” categorization (e.g., “Grade 0” or native with no signs of osteoarthritis) to a “Severe” or End-Grade categorization.

Further complicating the presentation of the disease is the overlying and subjective pain component. Most patients do not present to their healthcare provider until they are at a Minimal-to-Moderate stage when the pain becomes noticeable and/or unbearable. As a result, the almost invariable clinical and surgical algorithm at this point progresses from physiotherapy, NSAIDS (with or without opiates and steroids), and arthroscopy to total joint reconstruction. A purely reconstructive approach to rectify form and function may or may not address the presenting complaint of pain.

Currently, there are no therapeutics that regenerate SC bone or restore the critical structure-function tissue relationships in a joint. Additionally, the cartilage repair therapeutics on the market fail to regenerate subchondral bone and require a two-stage approach (harvest of tissue, followed by expansion then implantation). Further complicating the path towards innovation is the lack of consensus on an ideal in vitro (e.g., organoid or joint-on-a-chip) or OA large animal model that can be used for optimized therapeutic discovery and pre-clinical testing for SC bone and cartilage regeneration.

TA1 seeks to create a needle-based and/or non-invasive, single-stage therapeutic that regenerates SC bone and restores the original structure-function relationship within and between SC bone and cartilage. This therapeutic will be administered in a site-specific IA treatment for both single-joint (SJ) and multi-joint (MJ) OA resulting from degeneration, trauma and/or obesity. As a single-stage, one-time, needle-based (to include an arthroscopic approach) and/or non-invasive therapy, TA1 seeks to regenerate SC bone in all cases of OA back to Grade 0 while also providing targeted pain relief to <3/10 (on the Visual Analogue Scale (VAS)) for all patients. Additionally, the therapeutic must work in tandem with the TA2 therapeutic.

The vision is that a provider can make the clinical decision to regenerate either SC bone (TA1) or cartilage (TA2) or both together as an IA delivery. Thus, both TA1 and TA2 should be able to be administered IA separately or together at a provider’s discretion.

The novel SC bone regenerative therapeutic must meet the following specifications:

• ≥1 Needle-based (to include arthroscopic) and/or non-invasive therapeutic(s)

• Therapeutic must work in tandem with TA2

• Be suitable for IA delivery to any synovial joint

• Regeneration of SC bone in all OA stages back to Grade 0 in all synovial joints

• No surgical donor/recipient harvest

• Annual dosing frequency: As infrequently as possible but ideally ≤1/year

• Post-therapeutic pain range: <3/10 VAS

• Patients’ return to full function timeline: ≤3mo. post-operation with ≥85% success (failure rate ≤15%)

• Regenerated bone load criteria: Must sustain physiologically relevant load defined by

International Classification for Standards (ICS) (e.g., ISO 14243 and 14242) and compared to unaffected, contralateral joint SC bone

• Defect regeneration size: ≥ critical size defect (defined in the metric tables below)

• Must meet all IND Pre-Clinical Safety requirements

• Complete IND application

To achieve the goals of the program, performers may propose a variety of technical approaches to regenerate SC bone. These approaches can be separate or combined (e.g., cell therapy alone or in combination with biomaterials). These may include but are not limited to:

• Implantable scaffolds

• Genetic engineering

• Cell therapy

• Nanoparticles

• Small molecules

• Injectable biomaterials or biologics

Proposers must provide the following information in the proposal:

• Establish therapeutic discovery plan intended for the IA SC bone regenerative for SJ and

MJ applications o Approach for therapeutic discovery, including but not limited to high-throughput screening, sequencing, or assay development

• Intended in vitro assays and/or small animal models to demonstrate efficacy

• Production methods and timeline

• Current manufacturing methods

• Proposed mechanism of action

• Anticipated roadblocks and hurdles with proposed therapeutic approach

• Immunogenicity of proposed therapeutic

• Required ability to combine with and not hinder therapeutic effect of TA2 for a single OA reversal therapy

TA1 metrics (Section 1.3) will increase in difficulty and complexity over the course of the NITRO program. Monthly technical and financial status reports will be required and discussed at monthly meetings with the ARPA-H Program Manager Team. ARPA-H may request performer data as deemed necessary throughout the program to validate technical progress. The IND application, product pipeline, and clinical trials will serve as the Independent Verification & Validation (IV&V) for analysis. Extramural resources and labs may also serve as IV&V during certain aspects of the program to validate findings and assess safety, performance, and efficacy of therapeutics.

TA2: Needle-Based and/or Non-Invasive Cartilage Regeneration

As described in the prior TA1 section, as OA progresses from mild to moderate to severe, there is progressive damage to the articular cartilage. Cartilage is a complex tissue composed of many hierarchical cell types and structural constituents with multiple functions: to absorb force, prevent joint friction through lubrication, bear weight, and tolerate rapid, load-bearing directional changes.

As the cartilage degrades, it is unable to lubricate the joint, critical functions are limited, inflammatory mediators fill the joint space, and, over time, it deteriorates, generating severe cartilaginous defects in tandem with the aforementioned SC bone changes and defects. Further complicating the presentation of the disease is the overlying and subjective pain component that is often the impetus for patients to present to their healthcare provider.

Currently, there are no therapeutics that regenerate (as opposed to repair) cartilaginous defects, particularly those classified as “critical size defects”. Moreover, there are no therapeutics that restore the critical structure-function tissue relationships in a joint. As mentioned previously, the cartilage repair therapeutics on the market require an invasive two-stage approach (harvest of recipient/donor tissue, then expansion, and surgical implantation) and can cause donor/recipient site morbidity. Specifically, no therapies exist that are single-stage (e.g., no recipient harvesting required) and can be injected via either IA (for SJ OA) or systemically (e.g., intravenous (IV)) administration (for MJ OA including non-synovial joints).

TA2 seeks to create a needle-based and/or non-invasive, single-stage therapeutic that regenerates cartilage and restores the original structure-function relationship within cartilage, and between SC bone and cartilage. This therapeutic will be administered through an IA approach for SJ (and, potentially, MJ OA at the provider’s discretion) and a systemic (e.g., IV) approach for MJ OA resulting from degeneration, trauma and/or obesity. As a single-stage, one-time, needle-based (to include an arthroscopic approach) and/or non-invasive therapy, TA2 seeks to regenerate all cases of OA back to Grade 0 while also providing targeted pain relief to <3/10 (on the VAS) for all patients. Additionally, the therapeutic must work in tandem with the TA1 therapeutic.

The vision is that a provider can make the clinical decision to regenerate either SC bone (TA1) or cartilage (TA2) or both together as an IA delivery. Thus, both TA1 and TA2 should be able to be administered IA separately or together at a provider’s discretion.

The novel cartilage regeneration therapeutic must meet the following specifications:

• ≥2 Needle-based (to include arthroscopic) and/or non-invasive therapeutic(s) o One therapeutic suitable for IA administration to all synovial joints o One therapeutic suitable for systemic administration to reach all synovial joints

• Therapeutic for IA administration must work in tandem with TA1

• Regeneration of all OA stages back to Grade 0

• No surgical donor/recipient harvest

• Annual dosing frequency: As infrequently as possible but ideally ≤1/year

• Post operative pain range: <3/10 VAS

• Patients’ return to full function timeline: ≤3mo. post-operation with ≥85% success

(failure rate ≤15%)

• Regenerated cartilage load criteria: Must sustain physiologically relevant load defined by

ICS (e.g., ISO 14243 and 14242) and compared to unaffected, contralateral joint cartilage

• Defect regeneration size: ≥ critical size defect (defined in the metric tables below)

• Must meet all IND Pre-Clinical Safety requirements

• Complete IND application

To achieve the goals of the program, performers may propose a variety of technical approaches to regenerate cartilage. These approaches can be separate or combined (e.g., cell therapy alone or in combination with biomaterials). These may include but are not limited to:

• Chondrospheres

• Therapeutic proteins

• Implantable scaffolds

• Genetic engineering

• Cell therapy

• Nanoparticles

• Small molecules

• Injectable biomaterials or biologics

Proposers must provide the following information in the proposal:

• Establish discovery plan intended for the IA and systemic cartilage therapeutics for SJ and MJ applications o Approach for therapeutic discovery, including but not limited to high-throughput screening, sequencing, or assay development

• Intended in vitro assays and/or small animal models to demonstrate efficacy

• Production methods and timeline

• Current manufacturing methods

• Proposed mechanism of action

• Anticipated roadblocks and hurdles with proposed therapeutic approach

• Immunogenicity of proposed therapeutic

• Required ability to combine with and not hinder therapeutic effect of TA1 for a single OA reversal therapy

TA2 metrics (Section 1.3) will increase in difficulty and complexity over the course of the NITRO program. Monthly technical and financial status reports will be required and discussed at monthly meetings with the ARPA-H Program Manager Team. ARPA-H may request performer data as deemed necessary throughout the program to validate technical progress. The IND application, product pipeline, and clinical trials will serve as the IV&V for analysis. Extramural resources and labs may also serve as IV&V during certain aspects of the program to validate findings and assess safety, performance, and validate the efficacy of therapeutics.

TA3: Allogeneic and Autogenous Non-Immunogenic, Load-Bearing and Osteochondroinductive Total Replacement Joints

Without successful early intervention described in TA1 and TA2, OA progression leads to unbearable pain and complete loss of joint function that necessitates total joint replacement. The most common joint that undergoes replacement is the knee, which is termed total knee arthroplasty (TKA). To support the complex loading and mechanical demands of these joints, current medical devices for joint reconstruction remove the damaged tissues and are permanent implants that utilize a combination of high-strength metals and ceramics without any regeneration. Unfortunately, these implants only provide short-term (10-15 years) return to function. Additionally, there are numerous complications and limitations associated with the current standards of care, including high infection and hardware failure rates (>25%), limited range of motion, persistent pain, nerve damage, and thrombosis. Future non-immunogenic implants that integrate with the native tissue and restore function as a regenerated ‘living replacement’ without permanent hardware would substantially extend the implant life and reduce complications.

Currently, however, there are no patient-specific, non-immunogenic, load-bearing, chondro- and osteo-inductive, and fully bioresorbable replacement joints that restore full function in end-stage degenerated joints. Without such a regenerative replacement joint, patients who undergo the current standard of care for total joint replacement cycle through a 10–15-year (or faster) loop when a complication with their TKA implant develops. This causes a substantial economic burden for patients and healthcare systems and vastly limits the number of possible treatments.

Additionally, at the end-stage of OA, with significant joint degeneration or trauma, patients are often treatment planned for or emergently require a total joint replacement.

For those patients with no IA tissues left to regenerate who have no treatment option other than a total joint replacement, TA3 aims to generate non-immunogenic, load bearing, bioresorbable, osteochondral, allogeneic and autogenous joints that require no permanent hardware to be placed inside a patient’s body. Additionally, these novel allografts and autografts aim to restore joint function in ≤4-6 weeks. In order to achieve these goals, it is expected that performers show replacement stability beyond 12 months post-operation and to establish plans for tracking the replacements’ stability for the patients’ lifetimes.

From a commercialization standpoint, TA3 seeks to manufacture regenerative and bioresorbable TKA allografts in <24 hours and autografts in <30 days. Overall, TA3 seeks to outperform the current standard of care for TKA via non-immunogenic, load bearing and fully bioresorbable osteochondral grafts for ‘plug-and-play’ joint replacement without permanent hardware fixation.

The novel joint replacement therapeutic must meet the following specifications:

• 1 patient-specific load-bearing TKA allograft AND 1 patient-specific load-bearing TKA autograft

• Be osteo- and chondro-inductive, non-immunogenic, non-cytotoxic, bioresorbable, and non-tumorigenic

• Require no permanent fixation(s)

• Allograft manufacturing time: custom osteochondral graft in <24 hours

• Autograft manufacturing time: custom osteochondral graft in <30 days

• Patients’ return to full function timeline: ≤4-6 weeks post-op with ≥85% success (failure rate ≤15%)

• Stability: sustain physiologically relevant load >12 months post-op and plans to track patients for lifetime

• Both implants meet all IND Pre-Clinical Safety requirements

• Complete IND application

Throughout the program, performers will utilize a variety of manufacturing and regenerative approaches to replace joints. To achieve the goals of the program, performers must generate allografts and autografts, but may propose a variety of technical approaches to fabricate the final therapeutic. These approaches can be separate or combined (e.g., 3D and/or bio-printed constructs alone or in combination with off-the-shelf products). These may include but are not limited to:

• Computerized numerical control (CNC) multiscale milling

• Bioreactors (in vivo and/or in vitro)

• Genetic engineering

• Off-the-shelf products

• 3D and/or bio-printed constructs

• Anatomical materials

• Multi-functional designs

• Cell therapy

Proposers must provide the following information in the proposal:

• Approach to bioresorbable, non-permanent fixation and integration of osteochondral implant

• Methods to demonstrate in vitro/in vivo efficacy

• Current manufacturing time and/or plans to improve manufacturing time

• Production/fabrication approach, manufacturing methods, design plans (such as computer automated designs), and proposed mechanism of action or plans thereafter for bioresorbable fixation methods and osteochondral implant

• Strategy plan for collaborations or companies involved with multiple components of the replacement implants’ design, fabrication, and implantation

• Any prior in vitro data using that implant (with or without permanent hardware fixation)

• Any prior in vivo data using that implant (with or without permanent hardware fixation)

• Intended large animal model, ex vivo assays, and in vitro assays with rationales

• Anticipated roadblocks and hurdles with proposed implant

• Immunogenicity of proposed implant

TA3 metrics (Section 1.3) will increase in difficulty and complexity over the course of the NITRO program. Monthly technical and financial status reports will be required and discussed at monthly meetings with the ARPA-H Program Manager Team. ARPA-H may request performer data as deemed necessary throughout the program to validate technical progress. The IND application, product pipeline, and clinical trials will serve as the IV&V for analysis. Extramural resources and labs may also serve as IV&V during certain aspects of the program to validate findings and assess safety, performance, and validate the efficacy of therapeutics.

1.2.2. Program Structure

The NITRO program will be accomplished over 2 sequential Phases of increasing technical complexity. NITRO Phases will include programmatic elements to ensure performer success, including check points at each transition between NITRO Phases, active and regular US Government stakeholder engagement, establishment of current Good Manufacturing Practices (cGMP) and Good Laboratory Practice (GLP)-compliant manufacturing, equity for disparate patient and market settings for patient/provider buy-in, and utilization of Project Accelerator Transition Innovation Office (PATIO) assets for commercialization (e.g., Expert/Entrepreneur in Residence (XIR/EIR) meetings).

ARPA-H NITRO OA Model Symposium

To address the lack of a consensus ideal OA large animal model, NITRO has utilized a Special Notice to immediately launch the ARPA-H NITRO OA Model Symposium. To develop the ideal OA Model for therapeutic translation in pre-Clinical studies, the OA Model Symposium includes all interested parties (from academia to industry) wishing to provide input and rationale to help guide the Symposium towards a single, ideal animal model. Importantly, the Symposium will also include US Government Stakeholders (e.g., members of the FDA), veterinarians, contract research organizations (CROs), and manufacturers. It is strongly encouraged that all NITRO performers (both prospective and active) actively participate in the Symposium. It should be noted that many models of OA exist, however, the ideal model is widely disputed. This symposium aims to discuss the data and technology to date to provide consensus surrounding an appropriate model. This Symposium will begin as soon as possible with the aim of generating a consensus ideal large animal model by the start of Q4 of FY25. It is expected that, once a consensus model is established, contributors to the Symposium will publish their findings to streamline the path forward for NITRO performers and the rest of academia/industry. Additionally, NITRO aims to have frequent and robust US Government regulatory input to ensure that the consensus model coincides with the FDA’s requirements for Pre-Clinical Data/IND Enabling Studies.

Equity Requirements

ARPA-H has indicated it is committed to equitable healthcare access irrespective of race, ethnicity, gender/gender identity, sexual orientation, disability, geography, employment, insurance, and socioeconomic status. It is also the goal of the program to negotiate full coverage through all health insurance via US Government entities (Center for Medicare and Medicaid Innovation (CMMI), Centers for Medicare & Medicaid Services (CMS), Indian Health Service (IHS), and more) so that NITRO therapeutics are accessible to all. To that end, NITRO will mandate that each performer accounts for and actively engages with an Equity Officer (EO) who will be full-time and dedicated to the project. The EO will ensure that all performers follow the FDA’s guidance titled “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” and that clinical trial populations reflect the same US population proportions and severity as those affected by OA. The EO will be approved by ARPA-H and will help perform key duties throughout all NITRO Phases, as described below. In NITRO Phase 1, the EO will define Equity Key Performance Indicators (KPIs), establish >5 demographic-specific listening sessions, prepare the “Road Map to Equity” report, create the Insurance Action Plan (with CMMI, CMS, and HHS engagement). In NITRO Phase 2, the EO will co-manage and publish the proceedings of the Equity Symposium, ensure that the prior KPIs are enforced, and implement the Clinical Trial Go/No-go Demographic Requirements, as described below. The EO will develop rollout strategies and triangulate stakeholders with the help of ARPA-H’s XIR/EIR network, and the EO will also pursue all available approaches to ensure equity throughout study designs and Clinical Trials across all TA’s.

NITRO EO Metrics

The EO will proactively work toward equitable demographic representation throughout and understand the unique barriers to healthcare access for different populations. Further, some populations will be more difficult to reach due to historical disenfranchisement, lack of other Government investments, and distrust of Government programming. Reparative work may be required to bring these Americans to the table, and it is ARPA-H’s expectation that performers and the EO will do so. Performers and the EO must seek out and establish mutually respectful relationships with community leaders and pre-existing communities of care as their understanding of community pain points. The selected EO must be approved by ARPA-H.

The duties of the EO in NITRO Phase 1 include:

• Define key performance indicators (KPIs) and metrics of equitable research for all performers and stakeholders to follow during study design and execution

• Listening Sessions Action Plan: Proactively identify risks/challenges of equity in OA basic science and clinical research and convene OA patient listening sessions focused on the impact of OA on their lives, and what might prevent them from accessing NITRO therapeutics, including but not limited to: medical mistrust, comfort with the idea of NITRO therapeutics, willingness-to-pay, likelihood of seeking the treatment, as well as physical, economic, and social barriers to access.

o ≥5 Listening sessions with follow up reports EO’s must conduct sessions with 1) Native American/ Native Alaskans, 2) non-Hispanic Black Americans, and 3) Either Latino or AAPI Americans, with the remaining 2 sessions at the EO’s discretion

Women must make up >50% of the group recruited for each session

• Prepare the “Road Map to Equity” report to deliver at the Equity Symposium o Liaise with patient advocacy groups, insurance representatives and with the Department of Health and Human Services Office of Minority Health o Deliver the final report on the listening sessions including barriers unique to each patient population and the identified strategies to overcome those barriers

• Insurance Action Plan: Coordinate with ARPA-H and Insurance Stakeholders to streamline NITRO therapeutics into the standard of care at ≤25% of the current cost of OA treatments

ARPA-H NITRO OA Equity Symposium

EO officers from all performer teams will liaise with ARPA-H to plan and execute the Equity Symposium at the end of NITRO Phase 1. EO’s will present their Road Map to Equity that will include a detailed executive summary of the team’s KPIs, listening sessions, community assessments, Insurance Action Plan, as well as a specific execution plan with timelines and milestones to completion. The Road Map to Equity must include an equity recruitment plan to reach enrollment of >50% women and enrollment (±5%) of 21% Multi-Racial Non-Hispanic (Multi-NH); 20% Native American/Native Alaskan (Native Am/AK); 18% Non-Hispanic White (NHW); 18% Non-Hispanic Black (NHB); 13% Latino (LAT); 10% Asian American Pacific Islander (AAPI) as well as robust risk mitigation plans. These Values reflect the demographic distribution of arthritis in the US and serve as an accurate demonstration of the correlation between race and OA in the US.

The duties of the EO in NITRO Phase 2 include:

• Co-manage the ARPA-H NITRO Equity Symposium and publish the proceedings

• Ensure that prior KPIs from NITRO Phase 1 duties are enforced

• Implement and de-risk Clinical Trial Go/No-Go Demographic Requirements:

o Enrollment of >50% women and o Enrollment (±5%) of 20.7% Multi-NH; 20.1% Native Am/AK; 18.6% NHW;

18.2% NHB; 12.7% LAT; 9.7% AAPI (normalized and based on data from the Center for Disease Control and Prevention (CDC) statistics on disparities and age-adjusted prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitations)

NITRO Go/No-Go Phase 2 Checkpoint

At the 12-month mark in NITRO Phase 2 (end of Q4 in FY26), there will be a Go/No-Go determination based on performance against NITRO Phase 2.1 metrics in the OA Large Animal Model, as described below in the metrics tables. A “No-Go” determination means that performers will not proceed into the remaining program option periods and will no longer be NITRO performers. A “Go” determination means that performers will be able to proceed into the remaining program option periods. Performers will qualify for the “No-Go” determination in TA1 and TA2 if at 12 months they have not performed satisfactorily against Phase 2.1 requirements in the OA Large Animal Model and/or have failed components of their IND-enabling studies to date.

Performers that do meet these requirements will qualify for the “Go” determination. Performers will qualify for the “No-Go” determination in TA3 if at 12 months they have not performed satisfactorily against Phase 2.1 requirements and/or have failed components of their IND-enabling studies to date. Performers that do meet these requirements will qualify for the “Go” determination.

Additionally, any performer across all TAs that does not meet the Equity KPIs set by the EO may also be given a “No-Go” determination.

TA1 and TA2:

NITRO Phase 1 (24 Months): Therapeutic Discovery & In Vitro Assessment

During the 24-month NITRO Phase 1, performers will identify and produce targeted therapeutics for SC bone and cartilage regeneration in single-joint (SJ) and multi-joint (MJ) OA in all synovial joints. For TA1, performers must produce only an intra-articular (IA) therapeutic. For TA2, performers must produce both an IA therapeutic and a systemic (e.g., IV) therapeutic. See Figure 1 for full program overview.

During NITRO Phase 1, all performers will demonstrate in vitro that their intended therapeutic 1) ideally requires at most one annual dosing, 2) subsequently regenerates all stages of OA back to Grade 0, and 3) can feasibly be delivered via a needle (including an arthroscopic approach) or non-invasive method. The vision is that a provider can make the clinical decision to regenerate either SC bone (TA1) or cartilage (TA2) or both together as an IA delivery. Thus, both TA1 and TA2 should be able to be administered IA separately or together at a provider’s discretion.

• Goals of NITRO Phase 1 (metrics defined in Section 1.3) o Produce a needle-based and/or non-invasively delivered regenerative therapeutic for both IA cartilage and SC bone in all synovial joints For cartilage, performers must also produce a systemic cartilage regenerative for multi-joint OA Ideal target is an IA, needle-based and/or non-invasive therapeutic that is administered no more than once-per-year and regenerates both cartilage and SC bone in all synovial joints with only one surgical procedure and no surgical donor/recipient harvest o Regenerate all IA bone and cartilage, regardless of OA stage, to Grade 0 o Regenerate any critical size (and greater) cartilage defect o Begin IND application o Identify potential GLP and cGMP manufacturing partners o By Q4 FY24: Submit INTERACT meeting package and incorporate feedback o By Q3 FY25: Submit Pre-IND meeting package and incorporate feedback o Work with PATIO assets to develop commercialization plan (including an engagement plan with XIR/EIRs)

TA1 and TA2:

NITRO Phase 2 (36 Months): Pre-Clinical Trials & Phase I Clinical Trials (each 18 months)

During the 36-month NITRO Phase 2, performers will demonstrate safety, efficacy, and scalability of their TA1 and TA2 therapeutic first in the Consensus OA Large Animal Model and then in Phase I Clinical Trials. See Figure 1 for full program overview.

• Goals of NITRO Phase 2 (metrics defined in Section 1.3) o Pre-Clinical (in Appropriate OA Large Animal Model)

Having met all criteria of NITRO Phase 1, therapeutics must demonstrate regeneration of SC bone and cartilage in OA Large Animal Model with a go/no-go determination at the end of Q4 in FY26

Fulfill the requirements of a pre-IND submission, including:

• Demonstrate established GLP compliant for all in vivo testing

• Demonstrate established partner and pathway towards producing cGMP material for 20-100 patients Demonstrate pain <3/10 on VAS Demonstrate full return to function in ≤3 months post-op with ≥85% success Demonstrate sustained physiologically-relevant load (consistent with ISO metrics and compared to unaffected, contralateral joint in the same animal) Complete all IND-enabling studies (& submit IND application) Use PATIO Assets to commence commercialization plan, secure IP, streamline regulatory pathway (FDA consultants), scale manufacturing capabilities, etc.

o Phase I Clinical Trials Having met all criteria of the pre-Clinical phase, therapeutics must continue to meet and/or exceed all prior criteria in Phase I Clinical Trials Demonstrate safety in human trials GLP compliant Demonstrate scalable cGMP manufacturing partner for Phase

II/II/Commercial applications (1000+ patients) Demonstrate path towards Phase II/III Clinical Trials Use PATIO assets to commercialize therapeutics and exit Program

TA3:

NITRO Phase 1 (24 Months): Therapeutic Discovery & In Vitro Assessment

During the 24-month NITRO Phase 1, TA3 performers will demonstrate in vitro & in vivo the efficacy of their implantable devices. All performers must generate: a patient-specific allograft osteochondral implant and an autograft osteochondral implant. Both implants must be for total knee arthroplasty (TKA). None of the load-bearing implants may use or require any permanent fixation. The ultimate therapeutic goal might be an off-the-shelf or print-on-demand implant ‘ghost’ that can be populated with autologous or allogeneic cells. See Figure 1 for full program overview.

The expected application of the allograft is for a ‘plug-and-play’ implant for any patient with significant joint trauma who can only wait up to 24 hours for an osteochondral replacement. The expected application of the autograft is for a patient who can afford (time, health, pain control, etc.) to wait up to 30 days for a bio-resorbable, patient specific, load-bearing, osteochondral replacement that will never require replacement due to implant failure.

Further, by the end of NITRO Phase 2 (Phase I Clinical Trials), the expected turnaround time for the TKA osteochondral allografts is less than 24 hours. The expected turnaround time for the TKA osteochondral autograft is less than 30 days. At a minimum, all implants are expected to sustain mechanical load as defined by the relevant ISO Standards.

• Goals of NITRO Phase 1 (metrics defined in Section 1.3) o Produce load-bearing, patient-specific osteochondral allograft for TKA

AND

o Produce load-bearing, patient-specific osteochondral autograft for TKA o For all implants:

Demonstrate that implants are patient-specific, osteo- and chondro-inductive, non-cytotoxic, bioresorbable, and load-bearing

Identify potential GLP and cGMP manufacturing partners Begin IND application Demonstrate safety, efficacy, and reproducibility of chosen autogenous harvest location, cell type for expansion, and any genetic modifications that is cGMP- compliant

Demonstrate bioreactor design, including post-culture structural and mechanical properties before implantation time, and bioreactor scalability for autogenous implant

Demonstrate safety, efficacy, and reproducibility of stem cell line or cell genetic modifications for allograft implant that is both cGMP-compliant

By Q4 FY24: Submit INTERACT meeting package and incorporate feedback

By Q3 FY25: Submit Pre-IND meeting package and incorporate feedback Work with PATIO assets to develop commercialization plan (including an engagement plan with XIR/EIRs)

NITRO Phase 2 (36 Months): Phase I Clinical Trials

During the 36-month NITRO Phase 2, performers will demonstrate NITRO Phase 1 implants in Phase I Clinical Trials for 20-100 patients. See Figure 1 for full program overview.

• Goals of NITRO Phase 2 (metrics defined in Section 1.3) o Pre-Clinical

Having met all prior criteria in NITRO Phase 1, implants must continue to meet and/or exceed all prior criteria in pre-Clinical Trials with a go/no-go determination at the 12-month mark

Demonstrate efficacy, stability, and complete integration at implant site (with no osteophytes, non- or mal-unions), and with only non-permanent fixation

Demonstrate implants are patient-specific, non-tumorigenic, non-immunogenic

Demonstrate patient-specific osteochondral TKA allograft can be produced in <24 hours

Demonstrate patient-specific osteochondral TKA autograft can be produced in <30 days

Demonstrate all implants sustain physiologically-relevant load (consistent with ISO metrics) and can withstand appropriate stress and strain as compared to unaffected, contralateral joint

Demonstrate in vivo that the animal model can return to function in ≤4-6 weeks post-op ≥85% success

Demonstrate stability of the implant ≥12 months with ≥85% success Complete all IND-enabling studies (& submit IND application) GLP compliant Produce cGMP material for 20-100 patients Use PATIO Assets to commence commercialization plan, secure IP, streamline regulatory pathway (FDA consultants), scale manufacturing capabilities, etc.

o Phase I Clinical Trial Having met all prior criteria in NITRO Phase 1, implants must continue to meet and/or exceed all prior criteria in Phase I Clinical Trials Demonstrate safety in human trials Demonstrate established manufacturer of therapeutic with cGMP capacity for Phase II/III/Commercial (1000+ patients) Demonstrate path forward towards Phase II/III Trials Use PATIO assets to commercialize therapeutics and exit Program

Figure 1. Program Structure and General Overview

1.3 PROGRAM METRICS

To evaluate how effectively a proposed solution will achieve the stated program objectives, the Government hereby promulgates the following program metrics that may serve as the basis for determination of satisfactory progress to warrant continued funding. Although the program metrics are specified below, proposers should note that the Government has identified these goals with the intention of bounding the scope of effort while affording maximum flexibility, creativity, and innovation of proposed solutions to the stated problem. Proposals should cite the quantitative and qualitative success criteria that the effort will achieve by each Phase’s program milestone and intermediary metric measurement.

TA1 Metrics and Objectives

The overall program goals for TA1 are listed in Table 1. The expected metrics per phase in TA1 are listed in Table 2. In addition to frequent performance reviews throughout the phases, performers must provide an end-of-phase final report that summarizes all efforts and data for each completed NITRO Phase.

Table 1. TA1 Overall Program Goals # Of Therapeutics ≥1

Therapeutic Requirements Single-joint (SJ) & multi-joint (MJ) treatment. Therapeutic must work in tandem with TA2

Delivery Location(s) Intra-articular (IA) Required Therapeutic Activity

SC bone regeneration*; (Regeneration of all OA stages back to Grade

0) including critical size defects+

Post-Op Pain Goal <3/10 on Visual Analog Scale (VAS) Therapeutic Delivery Needle-based (to include arthroscopic) and/or non-invasive Dose Frequency As infrequently as possible but ideally ≤1/year # Of Surgical Procedures One (No surgical donor/recipient harvest) Therapy Success Rate ≥85% with full joint function ≤3 months post-op Functional Requirement Weight bearing/load capacity ≈ contralateral joint Manufacturing Goal(s) ≥ 1000 patients (established cGMP manufacturing partner to scale) Clinical Trials Goals Complete IND-enabling studies & Phase I Clinical Trials

Equity Requirements Insurance Action Plan, ‘Road Map to Equity’ report, Equity Symposium management, Clinical Trial Equity per Go/No-Go Demographics Requirements

*SC bone regeneration may include but is not limited to restoration of trabecular space without cysts, restored tidemark and without pathogenic thickening of the SC plate. This must work in tandem with TA2 therapeutic(s), below.

+Critical size defects: those that would not spontaneously heal completely and without therapeutic intervention

Table 2. TA1 Metrics for Each Phase and Sub-Phase Metrics Specifications Program Q1-Q8 Phase 1 (Discovery & In Vitro) Therapeutic Approach Needle-Based (to include arthroscopic) and/or Non-Invasive regenerative # Of Therapeutics ≥1 (for IA administration for SJ & MJ)

Regeneration Target Regeneration of all OA stages back to Grade 0 (Native) and for any subchondral defect, to include those beyond a “critical size defect”, in vitro and/or in small animal models

Dosing Frequency As infrequently as possible but ideally ≤1/year # Of Surgical Procedures One (No surgical donor/recipient harvest)

Equity Requirements

1) Define Equity KPIs, >5 demo-specific listening sessions

2) Prepare “Road Map to Equity” Report (Deliver at Equity Symposium)

3) Create Insurance Action Plan (CMMI, CMS, IHS)

Additional Requirement(s):

1) Therapeutic must work in tandem with TA2

2) Work with PATIO assets to develop commercialization plan (including an engagement plan with XIR/EIRs)

3) By Q4 FY24: Submit INTERACT meeting package and incorporate feedback

4) By Q3 FY25: Submit Pre-IND meeting package and incorporate feedback

5) Begin IND Application

6) Identify potential GLP and cGMP Manufacturing Partners

Program Q9-Q14 Phase 2.1 (Pre-Clinical) Must Continue to Meet/Exceed ALL Prior Criteria in Pre-Clinical Trials Post-Op Pain Goal <3/10 on VAS Full Function Timeline Full joint function in ≤3 months with ≥85% success

Regenerated SC Bone Mechanical Properties

Sustained, physiologically relevant load defined by International Classification for Standards (ICS) (e.g., ISO 14243 and 14242) and compared to unaffected, contralateral joint SC bone

Safety Threshold Complete all IND-enabling studies (& submit IND application) with a go/no-go determination at the 12-month mark

Manufacturing Standards 1) GLP compliant

2) Produce cGMP material for 20-100 patients

Equity Requirements 1) Co-Manage Equity Symposium and publish the proceedings

2) Ensure prior KPIs enforced

Additional Requirement(s):

Use PATIO Assets to commence commercialization plan, secure IP, streamline regulatory pathway (FDA consultants), scale manufacturing capabilities, etc.

Program Q9-Q14 Phase 2.2 (Phase I Clinical Trial) Must Continue to Meet/Exceed ALL Prior Criteria in Human Clinical Phase I Trials

Manufacturing Standards

1) GLP compliant

2) Ensure scalable cGMP partner for Phase II/III/Commercial (1000+ patients)

Equity Requirements

1) Ensure prior KPIs enforced

2) Clinical Trial GNG DEMOGRAPHIC REQUIREMENTS

a) Enrollment >50% women

b) Enrollment (±5%) of 20.7% Multi-NH;…