EXHIBIT 10.2

 

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Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

 

Statement of Work

 

BioCryst Pharmaceuticals Contract HHSO100201500007C

 

BCX4430 NDA Enabling CMC and Non-Clinical Toxicology Studies

 

PREAMBLE

 

Independently and not as an agent of the Government, the Contractor shall
furnish all the necessary services, qualified personnel, material, equipment,
and facilities, not otherwise provided by the Government as needed to perform
the Statement of Work submitted in response to the BARDA Broad Agency
Announcement (BAA) CBRN-BAA-10-100-SOL-00013.

 

The Government reserves the right to modify the milestones, progress, schedule,
budget, or deliverables to add or delete deliverables, process, or schedules if
the need arises. Because of the nature of this research and development (R&D)
contract and the complexities inherent in this and prior programs, at designated
milestones the Government will evaluate whether work should be redirected,
removed, or whether schedule or budget adjustments should be made.

 

Overall Objectives and Scope

 

The overall objective of this contract is to advance the development of BCX4430,
a novel small molecule nucleoside with broad spectrum antiviral activity being
developed for diseases caused by RNA pathogens. BCX4430, an inhibitor of viral
RNA – dependent RNA polymerase (RdRp), is the lead compound in our
broad-spectrum antiviral program to meet the need for a parenteral,
direct-acting antiviral medical countermeasure (MCM) having efficacy across
multiple viruses. The scope of work for this contract includes preclinical and
manufacturing development activities that fall into the following areas:
manufacturing of clinical trial material, manufacturing process improvements and
development, non-clinical toxicology studies; and all associated regulatory,
quality assurance, management, and administrative activities. The proposed
activities take into account the Ebola virus disease (EVD) outbreak in West
Africa. The R&D effort will contribute toward an NDA filing for BCX4430.
Overall, this Statement of Work (SOW) focuses on:

 

•Drug substance (DS) and drug product (DP) manufacturing process development
activities that will be conducted at US based facilities, which will result in
the ability to consistently produce high quality, GMP compliant material and
deliver drug supply that could be available for deployment as a medical
countermeasure during the Ebola crisis and support future clinical and
non-clinical studies    

•Nonclinical development activities to advance the intramuscular (IM) and
intravenous (IV) formulation through NDA-enabling toxicology including * * * and
* * * studies in the * * * and * * *

 

 

 

BioCryst PharmaceuticalsPage 1 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

1BASE: MANUFACTURE OF CLINICAL TRIAL MATERIAL

 

Duration: 43 months

 

Drug Substance and Drug Product GMP manufacturing by US suppliers to support
non-clinical and clinical activities. Drug Substance will be produced following
an * * * starting with * * * , which will be used as the starting material to
produce GMP BCX4430. Previous campaigns of GMP BCX4430 have produced between
* * * to * * * per batch. The scope of work under this option will target up to
a 5-fold increase in the GMP BCX4430 batch size.

 

The primary objectives will be to:

 

•Produce a total of * * * batches of GMP BCX4430 drug substance following the
* * * ).    

•Conduct drug product process improvements that will be focused on validation of
analytical methods, stress testing, stability studies, and process design space
optimization    

1.1.Procurement of Starting Materials

 

The contractor shall procure enough starting materials to produce up to a total
of * * * of the current manufacturing process of BCX4430. The key starting
materials to be procured are * * * and * * * .

 

1.1.1.Procurement of Starting Materials to produce * * *

 

The contractor shall procure * * * and * * * for the manufacture of * * * to
support an initial campaign (WBS 1.4.1 and 1.4.2) of manufacturing * * * batches
of BCX4430 followed by an additional * * * batches of BCX4430 (Clinical Trial
Material Batch * * * WBS1.7.1) using the * * * .

 

1.2.Further Process Improvements of * * * Route

 

The contractor shall conduct further process improvements that may be identified
focused on improving the existing plant-scale processes following generally the
same * * * .

 

1.2.1.Conduct Process Improvements

 

The contractor shall conduct the process improvements with existing plant-scale
processes.

 

1.2.2.Determination that Process is Sufficient to move to Commercial Scale up

 

The contractor shall evaluate the processes developed and provide sufficient
information through a deliverable that will enable BARDA to determine that the
* * * processes ( * * * and * * * BCX4430) are sufficient to move to commercial
scale-up activities.

 

1.3.Manufacture of * * * at * * *

 

* * * will be utilized as the starting material for the manufacture of BCX4430
in accordance with GMP guidance.

 

1.3.1.Manufacture of the * * * batch of * * *

 

The contractor shall target producing between a * * * batch using the * * * .

 

BioCryst PharmaceuticalsPage 2 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

1.3.2.Manufacture of * * * Batches * * *

 

Based on the performance of the * * * batch of * * * , additional lab-scale
studies and a qualification run will be conducted to improve the * * * . This
process will then be incrementally scaled-up in the plant.

 

1.3.2.1.Manufacture of the * * * batch of * * *

 

The contractor shall produce approximately * * * per batch using the * * * .

 

1.3.2.2.Manufacture of the * * * batch of * * *

 

The contractor shall target produce approximately * * * per batch using the
* * * .

 

1.4.Manufacturing Campaign of GMP BCX4430

 

The contractor shall produce * * * batches of BCX4430 at * * * in compliance
with GMP.

 

1.4.1.Manufacturing of the * * * batch of GMP BCX4430

 

The contractor shall produce and release approximately * * * of GMP BCX430
utilizing the * * * for making BCX4430 starting with the * * * batch ( * * * )
of * * * .

 

1.4.2.Manufacturing of the * * * batch of GMP BGX4430

 

The contractor shall produce and release approximately * * * of GMP BCX4430
utilizing the * * * for making BCX4430 starting with the recovered portion of
the * * * batch ( * * * ) of * * * . NOTE: This quantity is dependent on the
amount and quality of * * * isolated during the recovery of * * * .

 

1.4.3.Prepare a Campaign Summary Report

 

The contractor shall prepare a campaign summary report of the manufacture and
release of DS batches.

 

1.4.4.Drug Substance Stability Studies

 

The contractor shall place samples from DS batches of BCX4430 on a * * *
stability program at * * * and a * * * accelerated stability study at * * * .

 

BioCryst PharmaceuticalsPage 3 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

Table 1: BCX4430 Drug Substance Stability Study Sampling Points

 

Test Months ID 0 1 3 6 9 12 18 24 48 60 A X X X X X X X X X X B X X X X X X X X
X X C X X X X X X X X X X D X X X X X X X X X X E X X X X X X X X X X F X X   X
  X X X X X G X X   X   X X X X X

 

NOTE: BARDA will only cover stability activities for * * * .

 

Table 2: BCX4430 Drug Substance Stability Tests

 

Test ID Test A  * * * B  * * * C  * * * D  * * * E  * * * F  * * * G  * * *

 

1.5.Drug Product Development

 

The contractor shall conduct drug product process improvements that will be
focused on validation of analytical methods, stress testing, stability studies,
and process design space optimization for an IM formulation.

 

The contractor shall conduct formulation development activities and produce a
sterile, parenteral formulation containing * * * of the active compound per unit
in compliance with GMP guidance. Initial development efforts will be focused on
delivering * * * that tolerates terminal sterilization and provides an
acceptable stability profile. Additionally, studies to include: * * * will be
conducted to evaluate the feasibility of * * * .

 

1.5.1.Stress Conditions Studies

 

The contractor shall conduct a series of experiments under conditions outlined
in ICH guidance to evaluate the stability of the drug product made from
available drug substance.

 

1.5.2.Design Space Studies

 

The contractor shall conduct studies to evaluate and define the design space of
the formulation process.

 

1.5.3.Analytical Method Validation

 

The contractor shall conduct analytical methods validation or qualification as
listed in the table below.

 

BioCryst PharmaceuticalsPage 4 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

Table 3: BCX4430 Drug Product Methods that will be Validated or Qualified

 

Test Method and Objective  * * *  * * *  * * *  * * *  * * *  * * *  * * *
 * * *  * * *  * * *  * * *  * * *  * * *  * * *  * * *  * * *  * * *  * * *
 * * *  * * *  * * *  * * *  * * *  * * *

 

1.5.4.Prepare Process Development Report for DP

 

The contractor shall prepare a process development report summarizing the
experiments and results of the studies conducted to define the process and
evaluate the formulation.

 

1.5.5.Pre-formulation and Physicochemical Properties Studies

 

The contractor shall conduct studies to determine the physicochemical properties
of the drug substance and identify potential formulations and primary packaging
for an IM injection based on stability and ability to be produced on
manufacturing lines.

 

1.5.6.Feasibility Runs

 

The contractor shall conduct small-scale, nonGMP manufacturing runs of potential
formulations and formats.

 

1.5.7.Extractable/Leachable Study

 

The contractor shall conduct studies to determine drug product stability in
primary packaging and of syringe types that will be used for delivery.

 

1.5.8.Excipient Compatibility Studies for IV Formulation from lM

 

The contractor shall conduct studies to evaluate the compatibility of the IM
formulation added to various standard IV fluids.

 

1.6.Manufacturing of Drug Product to Support Clinical Trials

 

The contractor shall produce * * * batches of approximately * * * of drug
product suitable for clinical trial use. The drug product will produced from the
* * * GMP BCX4430 DS Batches (WBS 1.4.1 and 1.4.2)

 

BioCryst PharmaceuticalsPage 5 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

1.6.1.Manufacture of Clinical Trial Material (DP Batch * * * )

 

The contractor shall produce approximately * * * , assuming * * * of BCX4430 is
delivered from the DS Batch * * * of BCX4430, per GMP for use in clinical trials
which will include active drug and placebo batches to support the future
clinical safety study.

 

1.6.2.Manufacture of Clinical Trial Material (DP Batch * * * )

 

The contractor shall produce approximately * * * , assuming * * * of BCX4430 is
delivered from the DS Batch * * * of BCX4430, per GMP for use in clinical trials
which will include active drug and placebo batches to support the future
clinical safety study.

 

1.6.3.Prepare a Campaign Summary Reports

 

The contractor shall prepare a campaign summary report of the manufacture and
release of CTM Batches.

 

1.6.4.Drug Product Stability Studies - Active

 

The contractor shall place drug product on stability based on the following
conditions:

 

Table 4: BCX4430 Drug Product Stability Testing Conditions and Sampling

 

Stability Conditions Configuration Test Points  * * *  * * *  * * *  * * *
 * * *  * * *  * * *  * * *  * * *

 

NOTE: BARDA will only cover stability activities for * * *

 

Testing at each interval, unless otherwise specified, below, will include:

 

•* * *

•* * *

•* * *

•* * *

•* * *

•* * *

•* * *

•* * *

 

1.6.5.Drug Product Stability Studies - Placebo

 

The contractor shall place drug product on stability based on the following
conditions:

 

BioCryst PharmaceuticalsPage 6 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

Table 5: BCX4430 Drug Product Stability Testing Conditions and Sampling

 

Stability Conditions Configuration Test Points  * * *  * * *  * * *  * * *
 * * *  * * *  * * *  * * *  * * *

 

Testing at each interval, unless otherwise specified below, will include:

 

•* * *

•* * *

•* * *

•* * *

•* * *

 

NOTE: BARDA will only cover stability activities for * * *

 

1.6.6.Comparibility Study

 

The contractor shall conduct comparability studies evaluating drug substance
produced by * * * and * * * , and the subsequently produced drug product, will
be conduct per FDA Guidance. These studies will evaluate: in-process checks,
impurity profiles, release testing results, and stability profiles at standard
and accelerated conditions to ensure the material produced by both manufacturers
is substantially comparable.

 

1.7.Manufacture of Additional Supply

 

That contractor shall produce approximately * * * batches of BCX4430 utilizing
the * * * for both * * * and BCX4430 from the * * * facility and subsequently
produce approximately * * * of drug product at * * * suitable for clinical trial
use.

 

1.7.1.Manufacturing of approximately * * * GMP BCX4430

 

The contractor shall produce approximately * * * of GMP BCX4430 (DS Batch * * *
) from * * * following the * * *

 

1.7.2.Manufacturing of approximately * * * GMP BCX4430

 

The contractor shall produce approximately * * * of GMP BCX4430 (DS Batch * * *
) from * * * following the * * *

 

1.7.3.Prepare a Campaign Summary Report

 

The contractor shall prepare a campaign summary report of the manufacture and
release of DS.

 

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marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

1.7.4.Manufacturing of approximately * * *

 

The contractor shall produce approximately * * * of GMP BCX4430 drug product
using drug substance from the * * * GMP BCX4430 batches produced ( WBS 1.7.1 and
WBS 1.7.2).

 

1.7.5.Prepare a Campaign Summary Report

 

The contractor shall prepare a campaign summary report of the manufacture and
release of CTM Batches.

 

1.7.6.Stability Studies for DS and DP

 

The contractor shall conduct drug substance and drug product stabilities for the
DS and DP manufactured from the * * * batches of GMP BCX4430 drug substance
based on * * * and BCX4430 (WBS 1.7.1, 1.7.2, 1.7.4).

 

NOTE: BARDA will only cover stability activities for * * *

 

1.7.7.Comparability Studies

 

The contractor shall conduct comparability studies evaluating drug substance
produced by * * * and both process at * * * , and the subsequently produced drug
product, will be conduct per FDA Guidance. These studies will evaluate:
in-process checks, impurity profiles, release testing results, and stability
profiles at standard and accelerated conditions to ensure the material produced
by both manufacturers and both * * * process are substantially comparable.

 

1.7.8.Drug Product * * * Formulation Development

 

* * * has been identified as a potential product presentation that will provide
a stable formulation suitable for IV administration at potentially higher doses
than are feasible * * *.

 

1.8.Analytical Method Development

 

Confirmation that the * * * is suitable for a * * * product and qualification of
a * * * .

 

1.9.Formulation Development

 

Develop a * * * process that can be scaled to the manufacturing facility

 

1.9.1.Pre-formulation Studies

 

Evaluate the current IM formulation and bulking agents to produce a prototype
* * * product.

 

1.9.2.* * * Cycle Development

 

Evaluate * * * process cycles capable of producing the final product to
specifications utilizing a design of experiments of known critical process
parameters. The critical parameters will be confirmed and ranges established in
subsequent small-scale runs.

 

BioCryst PharmaceuticalsPage 8 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

1.9.3.Stability Study

 

Evaluate the stability of the product produced during cycle development. Two
fill volumes will be placed on accelerated and real-time studies. * * * will be
run for * * * with * * * and * * * run for * * * .

 

1.9.4.Terminal Sterilization

 

Product produced during cycle development will be subjected to terminal
sterilization by gamma irradiation. The irradiated product will be tested for
changes in chemical and physical characteristics.

 

1.9.5.Pre-manufacturing Studies

 

A material comparability study examining processing and packaging components
will be performed. Additionally, a microbial retention filter validation study
will be performed using the * * * , identified during cycle development.

 

2OPTION 1: COMMERCIAL SCALE UP AND NDA REGISTRATION BATCHES

 

Duration: * * *

 

Go/No Go Criteria to Initiate: WBS 1.2.2 BARDA approval of process developed
Through optimization of manufacturing processes, BARDA will evaluate and
determine what process should be sufficient to initiate commercial scale up
activities in this Option. This Option will add value to the project through
conducting manufacturing regulatory activities that will be needed for future
product approval with the FDA.

 

Decision Criteria:

 

•* * *

•* * *

 

The objective is to produce DS registration batches from the qualified process,
* * * . This will be determined upon the conclusion of the DS development effort
being undertaken by BioCryst and funded by NIAID that is scheduled to conclude
in December 2015. Additionally during this stage, the DP manufacturing process
would be finalized for the commercial presentation and registration batches
produced.

 

2.1.Procurement

 

The contractor shall procure the * * * starting materials needed to produce
BCX4430.

 

2.1.1.Procurement of * * *

 

The contractor shall qualify a vendor(s) to produce the * * * starting material
and procure enough material to support the manufacture of * * * batches of
BCX4430 drug substance.

 

2.1.2.Procurement of * * *

 

The contractor shall qualify a vendor(s) to produce the * * * starting material
and procure enough material to support the manufacture of * * * batches of
BCX4430 drug substance.

 

BioCryst PharmaceuticalsPage 9 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

2.2.Drug Substance Process Scale-up

 

The contractor shall conduct process development work targeting a * * * that can
be scaled to plant equipment. This work will include: development of a * * *
through lab scale studies, process hazard evaluation including RC-1 and digital
scanning calorimetry, lab scale qualification runs, pilot plant scale-up
technical batches, necessary modifications to analytical methods based on the
* * * , and plant-scale registration runs.

 

2.2.1.Further Process Improvements of Final Route

 

The contractor shall conduct further process improvements that may be identified
focused on improving the * * * to be scaled up. The * * * will be based either
* * * .

 

2.2.2.Process Hazard Evaluation

 

The contractor shall conduct process hazard evaluation studies needed for the
scale-up of the optimized process into the plant.

 

2.2.3.Scale-up Technical Run

 

The contractor shall conduct a nonGMP manufacturing run at plant-scale to ensure
the safety and output of the optimized process.

 

2.2.4.Analytical Method Development and Qualification

 

The contractor shall modify, add to, revalidate, or requalify the analytical
methods.

 

2.2.5.Prepare Process Development Report

 

The contractor shall prepare a process development report describing the
experiments and results leading to the selection of the optimized manufacturing
process

 

2.3.Manufacture of GMP Drug Substance Registration Batches

 

The contractor shall produce * * * GMP batches of BCX4430 following the * * * at
a scale comparable to the estimated commercial scale.

 

2.3.1.Manufacture of DS Batch (DS Registration Batch * * * )

 

The contractor shall manufacture a batch of GMP BCX4430 at plant scale.

 

2.3.2.Manufacture of DS Batch (DS Registration Batch * * * )

 

The contractor shall manufacture a batch of GMP BCX4430 at plant scale.

 

2.3.3.Manufacture of DS Batch (DS Registration Batch * * * )

 

The contractor shall manufacture a batch of GMP BCX4430 at plant scale.

 

2.3.4.Prepare Campaign Summary Report

 

The contractor shall prepare a report summarizing the conduct, observations, and
results of the manufacturing of DS Registration Batches * * * .

 

BioCryst PharmaceuticalsPage 10 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

2.4.Drug Product Registration Batches

 

The contractor shall produce * * * drug product lots at a qualified CMO that
will be used as the NDA registration batches.

 

2.4.1.Manufacture of DP Registration (DP Registration Batch * * * )

 

The contractor shall manufacture a NDA registration batch of GMP BCX4430 drug
product at a representative fraction of the estimated commercial scale.

 

2.4.2.Manufacture of DP Registration (DP Registration Batch * * * )

 

The contractor shall manufacture a NDA registration batch of GMP BCX4430 drug
product at a representative fraction of the estimated commercial scale.

 

2.4.3.Manufacture of DP Registration (DP Registration Batch * * * )

 

The contractor shall manufacture a NDA registration batch of GMP BCX4430 drug
product at at a representative fraction of the estimated commercial scale.

 

2.4.4.Prepare campaign summary report

 

The contractor shall prepare a report summarizing the conduct, observations, and
results of the manufacturing of DPR Batches * * * .

 

2.5.Stability studies for DS and DP

 

The contractor shall conduct drug substance and drug product stabilities as
described in Table 9, Table 10, Table 11, Table 12 and Table 13.

 

NOTE: BARDA will only cover stability activities for * * *

 

2.6.Comparability study

 

The contractor shall conduct comparability studies evaluating drug substance
produced for clinical trials in the base period versus the NDA registration
batches manufactured via * * * , and the subsequently produced drug product,
will be conduct per FDA Guidance. These studies will evaluate: in-process
checks, impurity profiles, release testing results, and stability profiles at
standard and accelerated conditions to ensure the material produced by both
processes is substantially comparable.

 

 

3OPTION 2: NONCLINICAL NDA-ENABLING TOXICOLOGY

 

Duration: * * *

 

Go/No Go Criteria to Initiate: Availability of GMP BCX4430 * * * DS batch
manufactured under NIAID contract HHSO100201500007C

 

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Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

Through completion of manufacturing of Drug substance there will be material to
conduct further regulatory activities such as the non-clinical NDA-enabling
toxicology studies in this option. This Option will add value to the project
through conducting additional non-clinical activities that will support a
potential future NDA.

 

Decision Criterion:

 

•* * *

•* * *

 

The contractor shall perform nonclinical GLP studies of BCX4430 to characterize
 * * *.

 

3.1.GLP * * * Toxicology

 

The contractor shall for each toxicology study develop the protocol, select and
qualify the vendor, conduct in life and recovery phases and analyze study data
resulting in a final study report.

 

Studies include:

 

3.1.1.Conduct GLP * * * toxicology study - * * *

 

3.1.2.Conduct GLP * * * general toxicology study - * * *

 

3.2.* * * toxicology

 

The contractor shall for each * * * study segment develop the protocol, select
and qualify the vendor, conduct in life and recovery phases and analyze study
data resulting in a final study report.

 

Studies include:

 

3.2.1.Conduct * * * assessment in * * *

 

3.2.2.Conduct * * * Dose Range Finding Studies in * * *

 

3.2.3.Conduct Definitive * * * toxicology in * * *

 

3.2.4.Conduct * * * toxicology * * *

 

3.3.Nonclinical ADME

 

The contractor shall procure radiolabeled BCX4430. In addition for each ADME
study, the contractor shall develop the protocol, select and qualify the vendor,
conduct the study and analyze study data resulting in a final study report.
Studies include:

 

3.3.1.Conduct Radiolabeled ADME study – * * *

 

3.3.2.Conduct Radiolabeled ADME – * * *

 

A listing of the proposed studies for the nonclinical NDA-enabling toxicology
studies is provided.

 

BioCryst PharmaceuticalsPage 12 of 17May 18, 2016 

 

Pursuant to 17 CFR 20.24b-2, confidential information has been omitted in places
marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

Table 6: Nonclinical NDA-enabling Toxicology Studies

 

Study # Description Objective(s) Species   GLP  * * * general toxicology

* * *

 

 

 

 * * *   GLP  * * * general toxicology

* * *

 

 

 

 * * *    * * * assessment

* * *

 

 

 

 * * *    * * * Dose Range Finding

* * *

 

 

 

 * * *    * * * Dose Range Finding

* * *

 

 

 

 * * *   Definitive  * * * toxicology

* * *

 

 

 

 * * *   Definitive  * * * toxicology

* * *

 

 

 

 * * *    * * * toxicology

* * *

 

 

 

 * * *   Radiolabeled ADME Determine the absorption, distribution, metabolism
and excretion of the test article following IM dosing  * * *   Radiolabeled ADME
Determine the absorption, metabolism and excretion of the test article following
IM dosing  * * *

 

 

4OPTION 3: IN VITRO EXPERIMENTS – IV

 

Duration: * * *

 

Go/No Go to Initiate: Selection of a preliminary IV formulation (LRI) based on
initial studies

 

Through completion of earlier studies, it will be determined what is an
appropriate IV formulation to continue with toxicology studies of the IV
formulation under this Option. This Option will add value to determine if there
is any identified toxicology in in vitro assays before moving to animal studies
in Option 4.

 

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Decision Criterion:

 

•* * *

 

4.1.* * * – IV

 

The contractor shall develop the protocol, select and qualify the vendor,
conduct the experiments and analyze the data resulting in a study report.

 

4.2.Conduct * * * Test – IV

 

The contractor shall develop the protocol, select and qualify the vendor,
conduct the experiment and analyze the data resulting in a study report.

 

A listing of the proposed experiments for the in vitro experiments to be
conducted in advance of the noncIinicaI NDA-enabling toxicology studies for the
IV formulation is provided in Table 15 .

 

Table 7: In vitro Experiments - IV

 

Study # Description Objectives

Species

(N)

 

 

* * *

 

 

 * * *  * * *  

* * *

 

 

 * * *  * * *

 

4.3.Study Report on all in vitro assays

 

The contractor shall submit a summarized study report with data and conclusions
from all in vitro experiments conducted in table 7 to determine whether there is
any toxicology before advancing into non-clinical NDA enabling toxicology
studies (Option 5).

 

5OPTION 4: NONCLINICAL NDA-ENABLING TOXICOLOGY

 

Duration: * * *

 

Go/No Go Criteria to Initiate: WBS 4.3 Study Report on all in vitro assays

 

Through completion of the IV in vitro toxicology studies with the IV formulation
conducted in Option 3 and summarized in WBS 4.3, it will be determined if the IV
formulation is safe to move into non-clinical toxicology animal studies in this
Option. This Option will add value to the project through conducting additional
non-clinical activities that will support a potential future NDA.

 

BioCryst PharmaceuticalsPage 14 of 17May 18, 2016 

 

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Commission pursuant to a Confidential Treatment Request with the Commission.

 

Decision Criterion:

 

•* * *

•

•* * *

 

5.1.GLP * * * Toxicology

 

The contractor shall for each toxicology study develop the protocol, select and
qualify the vendor, conduct in life and recovery phases and analyze study data
resulting in a final study report. Studies include:

 

5.1.1.Conduct GLP * * * general toxicology study - * * *

 

5.1.2.Conduct GLP * * * toxicology study - * * *

 

5.2.* * * toxicology

 

The contractor shall for each * * * study segment develop the protocol, select
and qualify the vendor, conduct in life and recovery phases and analyze study
data resulting in a final study report. Studies include:

 

5.2.1.Conduct * * * assessment in * * *

 

5.2.2.Conduct * * * Dose Range Finding Studies in * * *

 

5.2.3.Conduct Definitive * * * toxicology in * * *

 

5.2.4.Conduct * * * toxicology * * *

 

A listing of the proposed studies for the nonclinical NDA-enabling toxicology
studies for the IV formulation is provided in Table 16.

 

 

Table 8: Nonclinical NDA-enabling Toxicology Studies

 

Study # Description Objective(s) Species   GLP  * * *  general toxicology

* * *

 

 

 

 

 * * *   GLP  * * * general toxicology

* * *

 

 

 

 

 * * *    * * * assessment

* * *

 

 

 

 

 * * *    * * * Dose Range Finding

* * *

 

 

 * * *

 

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   * * * Dose Range Finding

* * *

 

 

 * * *   Definitive  * * * toxicology

* * *

 

 

 

 * * *   Definitive  * * * toxicology

* * *

 

 

 

 * * *    * * * toxicology

* * *

 

 

 

 

 * * *

 

6PROGRAM MANAGEMENT

 

The contractor shall provide all expertise needed for the implementation of the
activities to be performed under this contract, including: research,
manufacturing, regulatory, clinical, statistical analyses, management and
administrative activities.

 

6.1.Technical and Project Management Support

 

The contractor shall appoint a Principal Investigator (PI) who will be
responsible for all aspects of project performance and communication with the
BARDA.

 

The contractor shall provide project management that will ensure day-to-day
monitoring and tracking of progress and timelines, the coordination of project
activities and costs incurred.

 

The contractor shall provide all managerial and administrative functions
necessary for overall planning, monitoring, and implementing activities for the
completion of the strategic product development plan.

 

The contractor shall provide for all necessary legal affairs required to ensure
the timely acquisition of all proprietary rights, including intellectual
property rights and all materials needed to perform the project, as well as
reporting to the Government all inventions made in the performance of the
project.

 

6.2.Subcontractor Management

 

The contractor shall provide for tracking, coordination and oversight of
subcontractor efforts and manage communications with subcontractors.

 

6.3.Risk Management

 

The contractor shall identify project risks, develop risk management strategies
and implement mitigation actions.

 

6.4.Earned Value Management (EVM)

 

The contractor shall provide EVM information.

 

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6.5.Project Communications

 

The contractor shall provide for project communications including communications
with BARDA and external experts.

 

The contractor shall provide planning and steps required for the conduct of
contract review meetings.

 

 

7REGULATORY

 

The contractor shall ensure adherence to FDA regulations and guidance, including
requirements for the conduct of animal studies and assays under GLP, the
manufacturing of the therapeutic product under GMP, and the conduct of clinical
trials under GCP standards.

 

7.1.Regulatory Authority Interactions

 

The contractor shall prepare and submit documentation and correspondence to
regulatory authorities as required. The contractor shall request and conduct
meetings with regulatory authorities to ensure the development program is
conducted in accordance with regulatory guidelines and expectations.

 

7.2.Quality Assurance

 

The contractor shall maintain quality assurance documentation. The contractor
shall arrange for audits of subcontractor facilities to ensure all planned
procedures comply with the FDA regulations and guidance that are required to
meet GLP, GMP and GCP standards. In addition, the contractor shall ensure that
all contractor and/or subcontractor records and staff are available for site
visits or audits.

 

7.3.Expert Collaborations

 

The contractor shall collaborate with experts in the field in the design of
experiments and studies that support the advancement of the development program.

 

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MILESTONE AND DELIVERABLES CHART
BioCryst Pharmaceuticals Contract HHSO100201500007C

 

WBS Milestone Deliverable

Success

Criteria

Timing Go/No-Go for initiation CLIN 0001 – MANUFACTURE OF CLINICAL TRIAL
MATERIAL 1.2.1 Process Improvements Report Report on Process Development Process
Developed  * * *   1.2.2 Determination of Sufficient Process for Commercial
Scale up Evaluation report BARDA approval of developed process  * * * N/A 1.3.1
Manufacture  * * * (Batch  * * * )  * * * Acceptable quality and yield  * * *
N/A 1.3.2 Manufacture  * * * (Batch  * * * )  * * * Acceptable quality and yield
 * * * N/A 1.3.3 Manufacture  * * * (Batch  * * * )  * * * Acceptable quality
and yield  * * * N/A 1.4.1 Manufacture GMP BCX4430 (DS Batch  * * * )

BCX4430 DS

CofA,

Acceptable quality and yield  * * * N/A 1.4.2 Manufacture GMP BCX4430 (DS Batch
 * * * )

BCX4430 DS

CofA,

Acceptable quality and yield  * * * N/A 1.4.3 Prepare a Campaign Summary Reports
Campaign Reports (DS Batches  * * * ) Completion of DS Campaigns  * * * N/A
1.4.4 Drug substance stability study Report on stability activities Stability
data  * * *   1.5 Drug Product Development

DP Process Development Report (WBS 1.5.4)

Pre-formulation and Physicochemical Report (WBS 1.5.5)

Extractable/Leachable Report (WBS 1.5.7)

Completion of Studies  * * * N/A 1.5.8 Excipient Compatibility Report for IV
Formulation Compatibility Report IV formulation completed  * * *   1.6.1
Manufacture GMP DP (DP Batch  * * * )

BCX4430 DP

CofA,

Acceptable quality and yield  * * * Accepted GMP DS 1.6.2 Manufacture GMP DP (DP
Batch  * * * )

BCX4430 DP

CofA,

Acceptable quality and yield  * * * Accepted GMP DS

 

BioCryst Pharmaceuticals

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marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

1.6.3 Prepare a Campaign Summary Reports Campaign Reports (DP Batches  * * * )
Completion of DP Campaigns  * * * N/A 1.6.4 Drug Product stability study –
Active Report on stability activities Stability Data  * * *   1.6.5 Drug Product
stability study – Placebo Report on stability activities Stability Data  * * *  
1.6.6 Comparability Study Comparability Protocol and Report Completion of DS and
DP Campaigns  * * *   1.7.1 Manufacture GMP BCX4340 (DS Batch  * * * )

BCX4430 DS

CofA

Acceptable DS process  * * * N/A 1.7.2 Manufacture GMP BCX4340 (DS Batch  * * *
)

BCX4430 DS

CofA

Acceptable DS process  * * * N/A 1.7.3 Prepare a Campaign Summary Report
Campaign Reports (DS Batch  * * * ) Completion of DS Campaign  * * * N/A 1.7.4
Manufacture GMP DP (* * * )

BCX4430 DP

CofA,

Acceptable quality and yield  * * * Accepted GMP DS 1.7.5 Prepare a Campaign
Summary Report Campaign Report (CTM Batches  * * * ) Completion of DS Campaigns
 * * * N/A 1.7.6 Drug Substance and Drug Product stability study report on
stability activities Stability Data  * * * Manufacture of 1.7.1 & 1.7.2 drug
substance and 1.7.4 drug product 1.7.7 Comparability Study Comparability
Protocol and Report Comparable DS and DP profiles  * * * N/A 1.7.8 Drug Product
 * * * formulation Development  * * * Process that can be sealed to a
manufacturing facility Suitable  * * * /Finalized process  * * * N/A CLIN 0002 –
COMMERCIAL SCALE UP AND NDA REGISTRATION BATCHES
Go/No Go Criteria to Initiate: WBS 1.2.2 BARDA approval of process developed 2.2
Drug Substance Process Scale-up Process Development Report (WBS 2.2.4) Selection
of the optimized manufacturing process  * * *  * * * 2.3.1 Manufacture BCX4340
DS (DS Registration Batch  * * * )

BCX4430 Registration DS

CofA

Acceptable quality and yield  * * *  * * * 2.3.2 Manufacture BCX4340 DS (DS
Registration Batch  * * * )

BCX4430 Registration DS

CofA,

Acceptable quality and yield  * * *  * * * 2.3.3 Manufacture BCX4340 DS (DS
Registration Batch  * * * )

BCX4430 Registration DS

CofA,

Acceptable quality and yield  * * *  * * *

BioCryst Pharmaceuticals

May 18, 2016

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            2.3.4 Prepare a Campaign Summary Report Campaign Reports (DS Batches
 * * * ) Completion of DS Campaign  * * * N/A 2.4.1 Manufacture BCX4430 DP (DP
Registration Batch  * * * )

BCX4430 DP

CofA,

Acceptable quality and yield  * * * Accepted GMP DS 2.4.2 Manufacture BCX4430 DP
(DP Registration Batch  * * * )

BCX4430 DP

CofA,

Acceptable quality and yield  * * * Accepted GMP DS 2.4.3 Manufacture BCX4430 DP
(DP Registration Batch  * * * )

BCX4430 DP

CofA,

Acceptable quality and yield  * * * Accepted GMP DS 2.4.4 Prepare a Campaign
Summary Report Campaign Report (CTM Registration Batches  * * * ) Completion of
DS Campaigns  * * * N/A 2.5 Drug substance and Drug Product stability study
Report on stability activities Stability Data  * * *   2.6 Comparability Study
 Comparability Protocol and Report Comparable DS and DP profiles  * * * Accepted
GMP DS CLIN 0003 – NONCLINICAL NDA-ENABLING TOXICOLOGY
Go/No Go Criteria to Initiate: /availability of  * * * GMP batch of DS
manufactured under NIAID contract
HHSO100201500007C 3.1.1 Complete GLP  * * * Tox Study –  * * * Study Report
Established NOAEL  * * * Drug Substance confirming to release criteria 3.1.2
Complete GLP  * * * Tox Study –  * * * Study Report Established NOAEL  * * *
Drug Substance confirming to release criteria 3.2.1 Conduct  * * * assessment in
 * * * Study Report No significant findings  * * * N/A 3.2.2 Conduct  * * * Dose
Range Finding Studies in  * * * Study Report No significant findings  * * * N/A
3.2.3 Conduct Definitive  * * * toxicology in  * * * Study Report No significant
findings  * * * N/A 3.2.4 Conduct  * * *  toxicology  * * * Study Report No
significant findings  * * * N/A

 

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May 18, 2016

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marked "***" and has been filed separately with the Securities and Exchange
Commission pursuant to a Confidential Treatment Request with the Commission.

 

3.3.1 Conduct Radiolabeled ADME study –  * * * Study Report Characterize drug
disposition  * * * Acceptable Radiolabel Material 3.3.2 Conduct Radiolabeled
ADME –  * * * Study Report Characterize drug disposition  * * * Acceptable
Radiolabel Material CLIN 0004 – IN VITRO EXPERIMENTS – IV
Go/No Go to Initiate: selection of an appropriate preliminary IV formulation
4.1. Conduct  * * * Test – IV Study Report No effect on human, rat and non-human
erythrocytes ex vivo  * * * IV formulation WBS 1.5.8 4.2. Conduct  * * * Test –
IV Study Report No effect on mitotic apparatus  * * * N/A 4.3 In Vitro IV
experiments Study report on all In Vitro assays with recommendation to proceed
CLIN0005 No toxicology in vitro  * * *   CLIN 0005 – NONCLINICAL NDA-ENABLING
TOXICOLOGY
Go/No Go to Initiate: WBS 4.3 Completion of  * * * IV toxicology studies 5.1.1
Complete GLP  * * * Tox Study –  * * * Study Report Established NOAEL  * * *
Drug Substance confirming to release criteria 5.1.2 Complete GLP  * * * Tox
Study –  * * * Study Report Established NOAEL  * * * Drug Substance confirming
to release criteria 5.2.1 Conduct  * * * assessment in  * * * Study Report No
significant findings  * * * N/A 5.2.2 Conduct  * * * Dose Range Finding Studies
in  * * * Study Report No significant findings  * * * N/A 5.2.3 Conduct
Definitive  * * * toxicology in  * * * Study Report No significant findings
 * * * N/A 5.2.4 Conduct  * * *  toxicology  * * * Study Report No significant
findings  * * * N/A

 

 

BioCryst Pharmaceuticals

May 18, 2016