Exhibit 10.81


 


Portions of this document have
been redacted pursuant to a confidential treatment request and filed separately
with the Securities and Exchange Commission. Redacted portions have been
replaced with “*****”.


 


	
  AMENDMENT OF SOLICITATION/MODIFICATION OF
  CONTRACT

  	
  1.
  CONTRACT ID CODE

  	
  PAGE OF PAGES

  
	
  

  U

  	
  

  1

  	
  

  6

  
	
  2.
  AMENDMENT/MODIFICATION NO.

  	
  3.
  EFFECTIVE DATE

  	
  4.
  REQUISITION/PURCHASE REQ. NO.

  	
  5.
  PROJECT NO.(If applicable)

  
	
  P00003

   

  	
  25-Mar-2010

  	
  SEE SCHEDULE

  	
   

  
	
  6. ISSUED BY

  	
  CODE

  	
   HDTRA1

  	
  7.
  ADMINISTERED BY (If other than item 6)

  	
  CODE

  	
   S2401A

  
	
   

  	
   

  	
       DCMA TWIN CITIES

  	
   

  	
   

  
	
       DEFENSE THREAT REDUCTION AGENCY/BE-BC

  	
       B.H.
  WHIPPLE FEDERAL BLDG., RM 1150

  	
   

  
	
       8725 JOHN J. KINGMAN ROAD, MSC 6201

  	
       FT.
  SNELLING MN 55111

  	
   

  
	
       FORT BELVOIR VA 22060-6201

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  8. NAME AND ADDRESS OF
  CONTRACTOR (No., Street, County, State and Zip Code)

  	
   

  	
  9A. AMENDMENT OF
  SOLICITATION NO.

  
	
       AVI
  BIOPHARMA, INC.

  	
   

  	
   

  
	
       J. DAVID BOYLE II

  	
   

  	
  9B. DATED (SEE ITEM 11)

  
	
       4575 SWRESEARCH WAY STE 200

  	
   

  	
   

  
	
       CORVALLIS
  OR 97333-1299

  	
  x

  	
  10A. MOD. OF
  CONTRACT/ORDER NO.

  HDTRA1-09-C-0046

  
	
   

  	
   

  	
  10B. DATED (SEE ITEM 13)

  
	
  CODE    49WU1

  	
  FACILITY CODE

  	
  x

  	
  05-May-2009

  
	
   

  11. THIS ITEM
  ONLY APPLIES TO AMENDMENTS OF SOLICITATIONS

   

  
	
  o

  	
  The above numbered
  solicitation is amended as set forth in Item 14. The hour and date specified
  for receipt of Offer

  	
  o is extended,

  	
  o is not extended.

  
	
   

  	
   

  Offer must acknowledge
  receipt of this amendment prior to the hour and date specified in the
  solicitation or as amended by one of the following methods:

  (a) By completing
  Items 8 and 15, and returning               copies of the amendment; (b) By
  acknowledging receipt of this amendment on each copy of the offer submitted; or
  (c) By separate letter or telegram which includes a reference to the solicitation and amendment numbers.
  FAILURE OF YOUR ACKNOWLEDGMENT TO BE RECEIVED AT THE PLACE DESIGNATED FOR THE
  RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN
  REJECTION OF YOUR OFFER. If by virtue of this amendment you desire to change
  an offer already submitted, such change may be made by telegram or letter,
  provided each telegram or letter makes reference to the solicitation and this
  amendment, and is received prior to the opening hour and date specified.

  
	
   

  12. ACCOUNTING AND
  APPROPRIATION DATA (If required)

        See Schedule

  
	
   

  13. THIS ITEM APPLIES ONLY TO MODIFICATIONS OF
  CONTRACTS/ORDERS.

  IT MODIFIES THE
  CONTRACT/ORDER NO. AS DESCRIBED IN ITEM 14.

   

  
	
  o

  	
  A.  THIS CHANGE ORDER IS ISSUED PURSUANT
  TO: (Specify authority) THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE
  CONTRACT ORDER NO. IN ITEM 10A.

  
	
  o

  	
  B.  THE ABOVE NUMBERED CONTRACT/ORDER IS
  MODIFIED TO REFLECT THE ADMINISTRATIVE CHANGES (such as changes in paying
  office, appropriation date, etc.) SET FORTH IN ITEM 14, PURSUANT TO THE
  AUTHORITY OF FAR 43.103(B).

  
	
  x

  	
  C.  THIS
  SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF:

  FAR 52.243-2 Alt V.
  Changes

  
	
  o

  	
  D.  OTHER
  (Specify type of modification and authority)

   

  
	
  E.   IMPORTANT:    Contractor    o     is not,   x    
  is required to sign this document and return        1     
    copies to the issuing office.

  
	
  14. DESCRIPTION
  OF AMENDMENT/MODIFICATION (Organized by UCF section headings, including
  solicitation/contract subject matter where feasible.)

  
	
   

  	
  Modification Control
  Number:      hyattc10960

  
	
  The purpose
  of this contract modification is to add tasks per SOW (Attach 1b), add funds
  in the amount of $3,970,094.20 and extend the POP on subject contract.

  
	
   

  
	
  AIC# CBM100017478

  
	
   

  
	
   

  
	
  Except as provided
  herein, all terms and conditions of the document referenced in Item 9A or
  10A, as heretofore changed, remains unchanged and in full force and effect.

  
	
  15A. NAME AND TITLE OF
  SIGNER (Type or print)

  	
  16A. NAME AND
  TITLE OF CONTRACTING OFFICER (Type or print)

  
	
  /s/
  J. David Boyle II

  Sr. VP & CFO

  	
  Terese M. Herston
  

  Contracting Officer 

  Defense Threat Reduction Agency

  
	
   

  	
  TEL:  

  	
  EMAIL:  

  
	
  15B. CONTRACTOR/OFFEROR

  	
  15C. DATE SIGNED

  	
  16B. UNITED
  STATES OF AMERICA

  	
  16C. DATE SIGNED

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  /s/ J. David
  Boyle II

  	
   

  	
   

  	
   

  	
  BY  /s/ Terese
  M. Herston

  	
   

  	
   

  
	
   

  	
  (Signature of
  person authorized to sign)

  	
   

  	
  3/24/2010

  	
   

  	
  (Signature
  of Contracting Officer)

  	
   

  	
  3/25/10

  
	
  EXCEPTION TO SF 30

  	
  30-105-04

  	
  STANDARD FORM 30
  (Rev. 10-83)

  
	
  APPROVED BY OIRM 11-84

  	
   

  	
  Prescribed by GSA

  
	
   

  	
   

  	
  FAR (48 CFR) 53.243

  
																										



 
















 


HDTRA1-09-C-0046

(hyattc10960)

Page 2 of 6


 


SECTION SF 30 BLOCK 14
CONTINUATION PAGE


 


SUMMARY OF CHANGES


 


SECTION A -
SOLICITATION/CONTRACT FORM


 


The total cost of this
contract was increased by $3,970,094.20 from $4,103,402.95 to $8,073,497.15.


 


SECTION B - SUPPLIES OR
SERVICES AND PRICES


 


CLIN 0002


This CLIN has been renumbered
to CLIN 0003.


 


CLIN 0002 is added as
follows:


 


	
  ITEM NO

  	
   

  	
  SUPPLIES/SERVICES

  	
   

  	
  QUANTITY

  	
   

  	
  UNIT

  	
   

  	
  UNIT
  PRICE

  	
   

  	
  AMOUNT

  	
   

  
	
  0002

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  Lot

  	
   

  	
   

  	
   

  	
  $

  	
  3,970,094.20

  	
   

  
	
   

  	
   

  	
  Non-Personal
  Services

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  CPFF

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  The contractor shall
  perform the tasks listed in the Statement of Work entitled “H1N1
  Countermeasure Development Extended Influenza Therapeutic Studies,” dated December 17,
  2009.  

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  FOB: Destination

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  ESTIMATED
  COST

  	
   

  	
  $

  	
  3,694,954.61

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  FIXED
  FEE

  	
   

  	
  $

  	
  275,139.59

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  TOTAL
  EST COST + FEE

  	
   

  	
  $

  	
  3,970,094.20

  	
   

  
	
   

  	
   

  	
  ACRN AC

  	
   

  	
   

  	
   

  	
  $

  	
  3,970,094.20

  	
   

  
	
   

  	
   

  	
  CIN: CBM1000174780002

  	
   

  	
   

  	
   

  	
   

  	
   

  



 


SECTION C - DESCRIPTIONS
AND SPECIFICATIONS


 


The following have been
modified:


 


252.211-9000 Description/Specifications/Work
Statement


 


The Contractor shall provide
the supplies and/or services set forth in Section B, in accordance with
the following:


 


a. Statement of Work entitled
“AVI BioPharma PMO Platform – HIN1 Countermeasure Development’, Dated 1 May 2009,
Attachment 1 to the Contract and 5 May 2009, Attachment la to the
contract.


AND:


 


2

















 


HDTRA1-09-C-0046

(hyattc10960)

Page 3 of 6


 


Statement of
Work entitled “H1N1 Countermeasure Development Extended Influenza Therapeutic
Studies,” dated December 17, 2009.


 


b. Contract Data Requirements List (DD Form 1423),
Exhibit A to the Contract


 


SECTION E - INSPECTION AND ACCEPTANCE


 


The following Acceptance/Inspection Schedule
was added for CLIN 0002:


 


	
  INSPECT AT

  	
   

  	
  INSPECT BY

  	
   

  	
  ACCEPT AT

  	
   

  	
  ACCEPT BY

  	
   

  
	
  Destination

  	
   

  	
  Government

  	
   

  	
  Destination

  	
   

  	
  Government

  	
   

  



 


SECTION F - DELIVERIES OR PERFORMANCE


 


The following Delivery Schedule Item has been
deleted from CLIN 0002:


 


	
  DELIVERY DATE

  	
   

  	
  QUANTITY

  	
   

  	
  SHIP TO ADDRESS

  	
   

  	
  UIC

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  POP 05-MAY-2009 TO

  04-APR-2010

  	
   

  	
  N/A

  	
   

  	
  DEFENSE THREAT REDUCTION

  AGENCY/RD-CBM

  HEATHER MANLEY

  8725 JOHN J KINGMAN ROAD,
  MAIL

  STOP 6201,

  FORT BELVOIR VA 22060

  703-767-6281

  FOB: Destination

  	
   

  	
  HDTRA1

  



 


The following Delivery Schedule item has been
added to CLIN 0002:


 


	
  DELIVERY DATE

  	
   

  	
  QUANTITY

  	
   

  	
  SHIP TO ADDRESS

  	
   

  	
  UIC

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  POP 05-MAY-2009 TO

  30-SEP-2010

  	
   

  	
  N/A

  	
   

  	
  DEFENSE THREAT REDUCTION

  AGENCY/RD-CBM

  HEATHER MANLEY

  8725 JOHN J KINGMAN ROAD,
  MAIL

  STOP 6201,

  FORT BELVOIR VA 22060

  703-767-6281

  FOB: Destination

  	
   

  	
  HDTRA1

  



 


SECTION G - CONTRACT ADMINISTRATION DATA


 


Accounting and Appropriation


 


Summary for the Payment Office


 


As a result of this
modification, the total funded amount for this document was increased by
$3,970,094.20 from $4,103,402.95 to $8,073,497.15.


 


3

















 


HDTRA1-09-C-0046

(hyattc10960)

Page 4 of 6


 


CLIN 0002:


Funding on CLIN 0002 is initiated as follows:


 


ACRN: AC


 


CIN: CBM1000174780002


 


Acctng Data: 9700400.2620
1000 B63D 255999 BD32742000 S49012 DODAAC: HD1115


 


Increase: $3,970,094.20


 


Total: $3,970,094.20


 


SECTION I - CONTRACT CLAUSES


 


The following have been modified:


 


52.244-2     SUBCONTRACTS
(JUN 2007)


 


(a) Definitions. As used in this clause—


 


Approved purchasing system means a
Contractor’s purchasing system that has been reviewed and approved in
accordance with Part 44 of the Federal Acquisition Regulation (FAR).


 


Consent to subcontract means the Contracting
Officer’s written consent for the Contractor to enter into a particular
subcontract.


 


Subcontract means any contract, as defined in
FAR Subpart 2.1, entered into by a subcontractor to furnish supplies or
services for performance of the prime contract or a subcontract. It includes,
but is not limited to, purchase orders, and changes and modifications to
purchase orders.


 


purchase orders.


 


(b) When this clause is included in a
fixed-price type contract, consent to subcontract is required only on unpriced
contract actions (including unpriced modifications or unpriced delivery
orders), and only if required in accordance with paragraph (c) or (d) of
this clause.


 


(c) If the Contractor does not have an
approved purchasing system, consent to subcontract is required for any
subcontract that—


 


(1) Is of the
cost-reimbursement, time-and-materials, or labor-hour type; or


(2) Is fixed-price and
exceeds—


 


(i) For a contract
awarded by the Department of Defense, the Coast Guard, or the National
Aeronautics and Space Administration, the greater of the simplified acquisition
threshold or 5 percent of the total estimated cost of the contract; or


(ii) For a contract
awarded by a civilian agency other than the Coast Guard and the National
Aeronautics and Space Administration, either the simplified acquisition
threshold or 5 percent of the total estimated cost of the contract.


 


(d) If the Contractor has an approved
purchasing system, the Contractor nevertheless shall obtain the Contracting
Officer’s written consent before placing the following subcontracts:


 


4

















 


HDTRA1-09-C-0046

(hyattc10960)

Page 5 of 6


 


(e)(1) The Contractor shall notify the
Contracting Officer reasonably in advance of placing any subcontract or
modification thereof for which consent is required under paragraph (b), (c), or
(d) of this clause, including the following information:


 


(i) A description of the
supplies or services to be subcontracted.


(ii) Identification of
the type of subcontract to be used.


(iii) Identification of
the proposed subcontractor.


(iv) The proposed
subcontract price.


(v) The subcontractor’s
current, complete, and accurate cost or pricing data and Certificate of Current
Cost or Pricing Data, if required by other contract provisions.


(vi) The subcontractor’s
Disclosure Statement or Certificate relating to Cost Accounting Standards when
such data are required by other provisions of this contract.


(vii) A negotiation
memorandum reflecting—


 


(A) The principal
elements of the subcontract price negotiations;


(B) The most significant
considerations controlling establishment of initial or revised prices;


(C) The reason cost or
pricing data were or were not required;


(D) The extent, if any,
to which the Contractor did not rely on the subcontractor’s cost or pricing
data in determining the price objective and in negotiating the final price;


(E) The extent to which
it was recognized in the negotiation that the subcontractor’s cost or pricing
data were not accurate, complete, or current; the action taken by the
Contractor and the subcontractor; and the effect of any such defective data on
the total price negotiated;


(F) The reasons for any
significant difference between the Contractor’s price objective and the price
negotiated; and


(G) A complete
explanation of the incentive fee or profit plan when incentives are used. The
explanation shall identify each critical performance element, management
decisions used to quantify each incentive element, reasons for the incentives,
and a summary of all trade-off possibilities considered.


 


(2) The Contractor is not required to
notify the Contracting Officer in advance of entering into any subcontract for
which consent is not required under paragraph (c), (d), or (e) of this
clause.


 


(f) Unless the consent or approval
specifically provides otherwise, neither consent by the Contracting Officer to
any subcontract nor approval of the Contractor’s purchasing system shall
constitute a determination—


 


(1) Of the acceptability of any
subcontract terms or conditions;


(2) Of the allowability
of any cost under this contract; or


(3) To relieve the
Contractor of any responsibility for performing this contract.


 


(g) No subcontract or modification
thereof placed under this contract shall provide for payment on a cost-plus-a-percentage-of-cost
basis, and any fee payable under cost-reimbursement type subcontracts shall not
exceed the fee limitations in FAR 15.404-4(c)(4)(i).


 


(h) The Contractor shall give the
Contracting Officer immediate written notice of any action or suit filed and
prompt notice of any claim made against the Contractor by any subcontractor or
vendor that, in the opinion of the Contractor, may result in litigation related
in any way to this contract, with respect to which the Contractor may be
entitled to reimbursement from the Government.


 


(i) The Government reserves the right to
review the Contractor’s purchasing system as set forth in FAR Subpart 44.3.


(j) Paragraphs (c) and (e) of
this clause do not apply to the following subcontracts, which were evaluated
during negotiations:


 


Tulane University


Burleson Research Technologies

Battelle


OSU


 


5
















 


HDTRA1-09-C-0046

(hyattc10960)

Page 6 of 6


 


Helix


 


(End of clause)


 


SECTION J - LIST OF DOCUMENTS, EXHIBITS
AND OTHER ATTACHMENTS


 


The following have been modified:


LIST
OF DOCUMENTS & EXHIBITS


 


	
  ATTACHMENT

  	
   

  	
  DESCRIPTION

  
	
   

  	
   

  	
   

  
	
  1

  	
   

  	
  Statement of Work, entitled
  “AVI BioPharma PMO Platform - H1N1 Countermeasure Development”, dated 1
  May 2009, 1 Page

  
	
   

  	
   

  	
   

  
	
  la

  	
   

  	
  Statement of Work, entitled
  “AVI BioPharma PMO Platform - H1N1 Countermeasure Development”, dated 5
  May 2009, 2 Pages

  
	
   

  	
   

  	
   

  
	
  1b

  	
   

  	
  Statement
  of Work entitled “H1N1 Countermeasure Development Extended Influenza Therapeutic
  Studies,” dated December 17, 2009.

  
	
   

  	
   

  	
   

  
	
  2

  	
   

  	
  Exhibit A — CDRLs, 2
  Pages dated 30 April 2009

  



 


(End of Summary of Changes)


 

















 


HDTRA1-09-C-0046/P00003


Attachment
Number 1b


 


Statement of Work

H1N1 Countermeasure Development Extended Influenza Therapeutic Studies

December 17, 2009


 


1.                                           OBJECTIVE:


 


The objective is perform a dose dependant
study against H1N1, as well perform therapeutic studies against H5N1 (Avian
Flu), Tamiflu resistant H1N1 and H3N2. The rapid response to identify a lead
RNA based therapeutic for H1N1 has been successful in both mouse and ferret
models to date. An H3N2 viral isolate was selected for mouse studies because no
mouse adapted S-OIV virus was available and the studies were designed to mimic
the emerging clinical observations as the pandemic expands. While rapid
response concerns were directed at H1N1 S-OIV initially, the threat for H5N1
has not been diminished. Further, the need for a broadly applicable flu
therapeutic is great given the emergence of multidrug resistance influenza
strains. The urgency for such a therapeutic is linked to the capacity for
influenza reassortants to acquire viral segments that will confer drug
resistance.


 


2.                                           SCOPE:


 


This proposal builds on AVI BioPharma’s novel
RNA-based therapeutic platform in two critical areas. First, the work builds on
the experience with H1N1 influenza in the evaluation of AVI BioPharma’s
compounds for the purpose of inhibiting multiple serotypes of influenza viral
growth and pathogenesis. Second, the work expands the depth of understanding in
the potential for relatively rapid response to emerging infectious disease or
designed biological threats in the biowarfare setting.


 


3.                                           BACKGROUND:


 


The Orthomyxoviridae
are viruses with negative-sense, single stranded and segmented RNA
genomes. The influenza A are members of the orthomyxoviridae with 8 RNA
segments. The influenza virus genome is dynamic resulting in new vaccine
antigens because of shift, mutation and drift. Shift involves a reassortant
strains involving shuffling of the RNA segments between different viruses
resulting in a quantum genome change. The current S-OIV (H1N1) is a triple
reassortant virus with segments from pigs (HA, NP, NA M and NS), humans (PB1),
and birds (PB2 and PA). Mutations arise as a result of replication errors due
to a relatively low fidelity polymerase.


 


Influenza virus gains entry
to cells through the binding of a hemagglutinin (HA) molecule to sialic acid
residues on host cells. Humans express sialic acids on the cell surface linked
as a  2,6 N-glycans while birds
express the sialic acid linked through a
2,3 N-glycans. An avian virus that acquires the ability to bind a  2,6-linked sialic acids by
mutation or reassortment may cross the species barrier. Swine tissues express
both forms of sialic acid enabling cells to be coinfected with avian and human
viruses. Swine adapted viruses can further combine with human and avian viruses
to produce triple reassortants such as the current SOIV (H1N1) with segments
from pigs (HA, NP, NA, M and NS), humans (PB1), and birds (PB2 and PA).


 


The current SOIV (H1N1) has
led to 684 deaths from 126,168 cases reported worldwide from April 4 to July 16,
2009. This leads to a case fatality ratio of 0.6 percent


 


1

















 


HDTRA1-09-C-0046/P00003


Attachment Number 1b


 


4.                                     TASKS:


 


The following nine tasks define the
administrative, technical and operational activities to be performed.


 


4.1                               TASK 1 -
Program Management: A team of individuals at AVI
BioPharma will work together to facilitate the completion of the proposed work.


 


4.2                               TASK 10 -
Manufacture of lead compounds to support additional
ferret studies: Additional manufacturing will be required to support
the additional ferret studies.


 


4.3                               TASKS
- 11 and 12
Evaluation of lead compounds in Tamiflu resistant H1N1 S-OIV:


 


Proposed
Study Design:


1. Route of viral challenge-
intranasal


2. Route of drug delivery-
subcutaneous or intravenous


a.               Anesthesia


b.              Time of dose
with respect to viral challenge to be determined


3. Dose and design:


a.               Intended dose
escalation study with lead compound


b.              Include scramble
sequence control, saline control and Oseltamivir positive control


4. Propose repeat evaluation
study


5.
Animals: 8 groups of 6 ferrets of both genders randomized to each cohort (if
single gender only then please provide rationale)


6. Viral challenge


a.               Study 5 and 6: H1N1  (Tamiflu
resistant H1N1 strain from 2009 obtained from CDC)


7. Study design:


 


TABLE 1. Ferret Study 5 and Repeat (Study 6)


 


	
  Group

  	
   

  	
  Dose Interval

  	
   

  	
  Dose

  mg/kg

  	
   

  	
  Treatment

  Schedule

  	
   

  	
  Agent

  	
   

  	
  Animals(1)

  	
   

  
	
  1

  	
   

  	
  *****(2)

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  AVI Lead agent

  	
   

  	
  6

  	
   

  
	
  2

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  AVI Lead agent

  	
   

  	
  6

  	
   

  
	
  3

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  AVI Lead agent

  	
   

  	
  6

  	
   

  
	
  4

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  Scramble agent

  	
   

  	
  6

  	
   

  
	
  5

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  Scramble agent

  	
   

  	
  6

  	
   

  
	
  6

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  Scramble agent

  	
   

  	
  6

  	
   

  
	
  7

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  Oseltamivir

  	
   

  	
  6

  	
   

  
	
  8

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  *****

  	
   

  	
  Saline (vehicle)

  	
   

  	
  6

  	
   

  



 






(1) Availability of
females may not be feasible. If the first study is all males then repeat
studies must include females.


(2) *****


 


8.               Efficacy Endpoints


a.               A composite
endpoint: Nasal washing viral load AUC reduced by >75% at 96 hours and at
least a directionally consistent favorable effect is seen on nasal washing
inflammatory cell count AUC, fever and clinical signs.


b.              Efficacy
measures Day 0 to 7:


 


2

















 


HDTRA1-09-C-0046/P00003


Attachment Number 1b


 


	
  i.

  	
   

  	
  Viral titer in nasal wash
  each day

  
	
  ii.

  	
   

  	
  Body temperature- monitored
  by telemetry

  
	
  iii.

  	
   

  	
  Weight loss- body weight
  measured daily

  
	
  iv.

  	
   

  	
  Signs of respiratory
  distress- clinical score

  
	
  v.

  	
   

  	
  Activity score

  



c.               Sacrifice 3
ferrets per group on day 3 and Day 7 to collect organs for histopathology
evaluation and viral titers in lung and spleen (save samples for sequence
determination of persistent virus, possible insight into resistance
mechanisms).


d.              Please indicate
method for determining viral titer, Q-RT-PCR or plaque assay


 


9.               Safety Endpoints


a.               No test-article-related
mortality, severe adverse events, or pulmonary findings of significant concern.


 


4.4                               TASKS
13 and 14: Evaluation of lead compounds in Emerging Avian Influenza A (H5N1)


Proposed Study Design: (Items
1-5 see above)


6.               Viral challenge Study 7 and
8: H5N1 (A/Vietnam/1203/04 obtained from CDC)


7.               Study design (see Table 1
above):


8.               Efficacy Endpoints (see
above)


9.               Safety Endpoints (see above)


 


4.5                               TASKS
15 and 16: Evaluation of lead compounds in ferret model of seasonal H3N2


Proposed Study Design: (Items
1-5 see above)


6.          Viral challenge Study 9 and
10: H3N2 (A/HongKong/68 obtained from CDC)


7.          Study design(see Table 1
above):


8.          Efficacy Endpoints (see
above)


9.          Safety Endpoints (see above)


 


4.6                               TASK 17 -
Pharmacokinetic, Pilot Toxicology and Mechanism of
Action Studies: The  rapid response provides an
agent that is active in an animal model but confidence needs to be established
for extending studies to humans. Greater flexibility is desired for the
considerations of route of administration, dose estimation and dose interval.
These parameters are determined from pharmacokinetic evaluation of the lead
therapeutic agent.


 


Initial studies to determine
the binding affinity of the lead for the target RNA will be established using a
BiaCore to measure association, dissociation and equilibrium binding constants
and establishment of an ID50 will be evaluated by in vitro translation.
Together these will facilitate the relationship between concentration and
efficacy and provide supportive information for interpretation of tissue concentrations


 


Prior to conducting
pharmacokinetic studies, an analytical method must be established. The
contractor will establish initial feasibility studies with their subcontractor
to conduct analysis of blood, tissue and urine samples. The subcontractor has developed
a 96 parallel assay technique, which is essential for rapid response evaluation
of pharmacokinetic information.


 


TASK 18 -
Rapid Response II (Additional Sequence Synthesis): An additional
rapid response exercise is planned for 2010. The exercise involves planning
monthly visits to Washington DC to meet with other groups under TMTI contracts.
The purpose of the meetings is to integrate and plan for information


 


3

















 


HDTRA1-09-C-0046/P00003


Attachment Number 1b


 


transfer of sequence
information regarding infectious agents of interest to TMTI. The remaining
elements of the task are to design and synthesize oligomers for this rapid
response exercise. Time for program management under this task is included.


 


5.                                      DELIVERABLES


 


In accordance with Exhibit A.


 


4