Nucleic Acids On-Demand Worldwide (NOW)Dr. Amy Jenkins

Program Manager, DARPA BTO

October 28, 2019

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DARPA Introductions: Government team

Bradley RingeisenDARPA Biological

Technologies Office, Director

Susan SheanDARPA Contracts

Management Office

Amy JenkinsDARPA Biological

Technologies Office, Program Manager

Patrick SimsNIWC, Contracting

Officers Representative

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DARPA Introductions: Contractor Support Team

Shannon GreeneDARPA SETA

Technical

David KrizmanDARPA SETA

Technical

Audrey GlynnDARPA SETA

Technical

John SlawinskiDARPA SETA

Security

Shawn RichDARPA SETA

Business/Financial

Matt KappesDARPA SETA

Technical

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TimelineStructureRationaleVision

Presentation Outline

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Nucleic Acids On-Demand Worldwide (NOW) Vision

Protect warfighters and civilians

Leverage DoD MCM discovery pipeline

Vision: Integrated MCM manufacturing platform that synthesizes any nucleic-acid based prophylactic in military stabilization operations

The DoD relies on an outdated manufacturing paradigm that limits rapid access to medical countermeasures (MCMs) against CBRN threats in austere environments

Basic Raw Materials Synthesis of MCM Vials of MCM

01101010100110

0100101011100110100010011001

+

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A World At Risk: annual report on global preparedness

“Between 2011 and 2018, WHO tracked 1483 epidemic events in 172 countries. Epidemic-prone diseases such as influenza, severe acute respirator syndrome (SARS), Middle East respiratory syndrome (MERS), Ebola, Zika, plague, yellow fever and others are harbingers of a new era of high-impact, potentially fast-spreading outbreaks that are more frequently detected and increasingly difficult to manage.”

“Negative impacts are particularly profound in fragile and vulnerable settings where poverty, poor governance, weak health systems, lack of trust in health services, … and sometimes ongoing armed conflict greatly complicate outbreak preparedness and response.”

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A World At Risk: annual report on global preparedness

Ultimate objectives:“The tools and systems needed to respond effectively to a fast-moving and lethal respiratory pathogen are in place: A universal influenza vaccine is effective and routinely used to protect the global population new therapeutics and broad-spectrum antivirals are widely available to treat and reduce mortality from a range of viruses; novel pathogens are routinely identified and sequenced, and the sequences are shared on a globally accessible website. Distributed manufacturing of vaccines (including nucleic acid types) begins within days of obtaining the new sequencing and effective vaccines are pre-tested and approved for use within weeks.”

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Nucleic Acid Technologies

DARPA pioneered the use of the body as bioreactor to produce therapeutics

• Gene-encoded vaccines for long term protection• Gene-encoded antibodies for near immediate, temporary protection

• Potent antibody discovery• Distributed diagnostics based on highly sensitive molecular assays

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Example: Pandemic Prevention Platform (P3) Program

P3 is developing a functionally integrated platform to deliver pandemic prevention treatments in <60 days

60 days to 20,000 doses

Pandemic Outbreak Any Virus

Treatment to Prevent Pandemic

P3 P3 P3Existing Technology

Ex isting Technology

Grow Virus Evolve Antibody DeliverManufactureFind Antibody

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What Is New About Our Approach?

World-wide response capability for stabilization operations

• Fast• Distributed • Adaptable/flexible• Deployable device

Transmission

Days to respond:100s (days)1,000s (weeks) 10,000s (months)100,000s (sustained outbreak)

Stabilizing

100s of doses needed to prevent outbreak

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TA1: Upstream Process TA2 : Downstream Process

NOW Technical Approach

New/improved methods for DNA and/or RNA synthesis

Performers can choose DNA or RNA synthesis; however both is preferred

Key Challenges• Polymer length• Error-free synthesis• Ensuring simplified starting materials

End-to-end platform for continuous DNA and RNA manufacturing

Key Challenges• Automated production• Integrated quality control/product identity assessment• Systems engineering

BAA pg 5. Both technical areas must be developed concurrently over the duration of the effort. Proposals that fail to address both technical areas w ill be considered non-responsive.

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Threshold and Objective Metrics

THRESHOLD OBJECTIVE

DNA products 200mg 2g

RNA products 50mg 5g

Table 1. Threshold and Objective program metrics

*100-500 doses of NA based MCM

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Year 1 Year 2 Year 3 Year 4 Year 5

Phase I : Development and Engineering Phase II : Integration Phase III : Clinical Study

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NOW Structure: Capability Demonstrations

Timeline Capability Demo:12 months

Capability Demo:24 months

Capability Demo:36 months

Capability Demo:48 months Clinical Trial

TA1 Metrics

Synthesis:• DNA: > 3000bp• RNA: from DNA, >1000bp

Sequence identity: • 90%

Synthesis:• DNA: > 4000bp; 2mg• RNA: from DNA, > 2000bp;

500µg

Sequence identity: • 95%

Synthesis:• DNA: > 4000bp; 200mg• RNA: from DNA, > 2000bp;

50mg

Sequence identity:• 99%

Synthesis:• DNA: > 4000bp; 2g• RNA: from DNA, > 2000bp;

5g

Sequence identity:• 100%

Clinical testing of material made using the NOW system – as compared to SOA.

MCM targeting DoD relevant indications – e.g. Ebola, Chikungunya, influenza, radiation exposure

TA2 Metrics

Purity: >80%

Timeframe: < 3 weeks

Integration and automation:• Demo of air-gapped

module for synthesis• Demo of integrated

purification and analytics modules

Purity: >90%

Timeframe: < 3 weeks

Integration and automation:• Demo of integrated

modules for synthesis and purification

• Air-gapped modules for analytics and fill-finish

• Total Power supply: <15kW

Purity: >95%

Timeframe: < 1 week

Integration and automation:• Alpha prototype – demo of

integrated modules for synthesis, purification, analytics and fill-finish

• Total Power supply: <10kW• Start-up time: < 5hr

Purity: >99% purity

Timeframe: 1-3 days

Integration and automation:• Continuous process• Fully contained integrated

modules for synthesis, purification, analytics and fill-finish

• Total Power: <7.5kW• Start-up time: < 1hr

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Program Structure and Timeline

Pre-program Phase I Phase II Phase IIIFY19 FY 2020 FY 2021 FY 2022 FY 2023 FY 2024 FY 2025

Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3

KOBAA Award ProgramCompletion

Demo

TA1

TA2

Phase I clinical trial of a biosimilar product for direct comparison to a

traditionally GMP manufactured product

Joint CDRH/CBER FDA Engagement #1:CDRH: Pre-submission meeting

CBER: Interact Meeting

Joint CDRH/CBER FDA Engagement #2:Pre-IND meeting

Joint CDRH/CBER FDA Engagement #3:

IND Submission

Capability Demo #112 months

Capability Demo #224 months

Capability Demo #336 months

Capability Demo #448 months

Individual modules for synthesis, analytics, and

fill-finish

Integrated modules for synthesis to fill-finish; analytics independent

End-to-end process including analytics using alpha prototype device

End-to-end process including analytics using

prototype device

Direct cell-free synthesis of DNA and RNA from precursors and Develop prototype device Synthesis of 100s of doses Phase I clinical trial

Direct synthesis of 3kb DNA plasmid, RNA from

DNA

Direct synthesis of 4kb DNA plasmid, RNA from

DNA

DNA and RNA synthesis using alpha prototype

deviceDNA and RNA synthesis using prototype device

Decide intended pathogen/product for clinical trial

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Program Considerations

Pathogen/Target Selection

Chikungunyavirus

Denguevirus

Coronavirus(MERS/SARS)

Influenzavirus

Noroviruses

Example Pathogens:

Rift ValleyFever virus

Milestones and Metrics

Approach and Teaming

Time

Example Targets:

FormulationNucleic acid quantity and quality

Integration

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DARPA Acronym GlossaryTerm Definition

BAA Broad Agency Announcement: Document outlining proposal expectations, similar to RFP (Request for Proposals) from other funding agencies.

BTO Biological Technologies Office. One of six DARPA offices.

CMO DARPA Contract Management Office

CTI/CUI Controlled Technical Information/Controlled Unclassified Information

DARPA Defense Advanced Research Projects Agency

Demonstration/Demo A demonstration, typically at the end of a contract phase, that meets metrics/milestones as outlined in DARPA BAAs

DoD United States Department of Defense

Phase Temporal period of a proposal/contract with specific goals/emphasis

POC Point of Contact

Prime/Lead PI The primary lead/POC in a BAA proposal and subsequent contract

Program Manager DARPA leadership position at the office level. Define their own programs, set milestones, meet with their performers and assiduously track progress.

Proposal Abstract A concise version of the proposal comprising a maximum of 8 pages including all figures, tables, and charts.

Proposer Those submitting a proposal to a DARPA BAA

SETA Scientific Engineering and Technical Assistance: Junior DARPA contract position that acts in professional/expert support to offices and program managers.

SOW Statement of Work: a detailed task breakdown and their connection to the interim milestones and program metrics.

Sub/Co-PI A subordinate (to the prime) lead/POC in a BAA proposal and subsequent contract

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