Exhibit 10.74


 


	
  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)

  
	
   

   

  	
  29-May-2009

  	
  SEE SCHEDULE

  	
   

  
	
  6. ISSUED BY

  	
  CODE

  	
   HDTRA1

  	
  7.
  ADMINISTERED BY (If other than item 6)

  	
  CODE

  	
   S2401A

  
	
   

  	
   

  	
       DEFENSE
  CONTRACT MANAGEMENT AGENCY

  	
   

  	
   

  
	
       DEFENSE THREAT REDUCTION
  AGENCY/BE-BO

  	
       1
  FEDERAL DRIVE, ROOM 1150

  	
   

  
	
       8725 JOHN J. KINGMAN ROAD,
  MSC 0201

  	
       FORT
  SNELLING MN 55111-4080

  	
   

  
	
       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.

  	
   

  	
   

  
	
       TOM
  STEWART

  	
   

  	
  9B. DATED (SEE ITEM 11)

  
	
       4575
  SWRESEARCH WAY STE 200

  	
   

  	
   

  
	
       CORVALLIS
  OR 97333-1299

  	
  x

  	
  10A. MOD. OF
  CONTRACT/ORDER NO.

  HDTRA1-07-C-0010

  
	
   

  	
   

  	
  10B. DATED (SEE ITEM 13)

  
	
  CODE:    49WU1

  	
  FACILITY CODE

  	
  x

  	
  29-Nov-2006

  
	
   

  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.

  52.243-2 Alt V Changes - Cost Reimbursement

  
	
  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).

  
	
  o

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

   

  
	
  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:      pottst091313

  
	
  The
  purpose of this change order is to add in scope tasking to the contract. The
  overall cost of the modification is $5,908,245.26; The obligated amount is
  50% or $2,954,122.63; and the government liabilities shall not exceed the of
  the obligation of $2,954,122.63 unless amended by the government.

  
	
   

  
	
   

  
	
   

  
	
   

  
	
  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

  	
  TEL:

  	
  EMAIL:

  
	
  15B. CONTRACTOR/OFFEROR

  	
  15C. DATE SIGNED

  	
  16B. UNITED STATES OF
  AMERICA

  	
  16C. DATE SIGNED

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  /s/ J. David Boyle II

  	
   

  	
   

  	
   

  	
  BY

  	
   

  	
   

  
	
   

  	
  (Signature of person
  authorized to sign)

  	
   

  	
  5/27/2009

  	
   

  	
  (Signature
  of Contracting Officer)

  	
   

  	
   

  
	
  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

  
																										



 
















 


HDTRA1-07-C-0010


 


Page 2 of 4


 


SECTION SF
30 BLOCK 14 CONTINUATION PAGE


 


SUMMARY OF CHANGES


 


SECTION A
- SOLICITATION/CONTRACT FORM


 


The total cost of this contract was increased by
$5,908,245.26 from $28,034,018.00 to $33,942,263.26.


 


CLIN
0003 is added as follows:


 


	
  ITEM NO

  	
   

  	
  SUPPLIES/SERVICES

  	
   

  	
  QUANTITY

  	
   

  	
  UNIT

  	
   

  	
  UNIT PRICE

  	
   

  	
  AMOUNT

  	
   

  
	
  0003

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  Lot

  	
   

  	
   

  	
   

  	
  $

  	
  5,908,245.26

  	
   

  
	
   

  	
   

  	
  Ebola
  Marburg IND submission response

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  CPFF

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Additional
  tasking IAW the Addendum to the SOW dated May 21, 2009.

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  FOB:
  Destination

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  ESTIMATED COST

  	
   

  	
  $

  	
  5,470,597.46

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  FIXED FEE

  	
   

  	
  $

  	
  437,647.80

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  TOTAL EST COST + FEE

  	
   $ 5,908,245.26(NTE)

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  SUBCLIN
  000301 is added as follows:

  	
   

  	
   

  	
   

  	
   

  	
   

  



 


	
  ITEM NO

  	
   

  	
  SUPPLIES/SERVICES

  	
   

  	
  QUANTITY

  	
   

  	
  UNIT

  	
   

  	
  UNIT PRICE

  	
   

  	
  AMOUNT

  	
   

  
	
  000301

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  $

  	
  0.00

  	
   

  
	
   

  	
   

  	
  Funding

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  CPFF

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  FOB:
  Destination

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  ESTIMATED COST

  	
   

  	
  $

  	
  0.00

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  FIXED FEE

  	
   

  	
  $

  	
  0.00

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  TOTAL EST COST + FEE

  	
   

  	
  $

  	
  0.00

  	
   

  
	
   

  	
   

  	
  ACRN
  AD

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  $

  	
  2,954,122.63

  	
   

  
	
   

  	
   

  	
  CIN:
  CBM090013351000301

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  



 


SECTION F
- DELIVERIES OR PERFORMANCE


 


The
following Delivery Schedule item for CLIN 0002 has been changed to 29 NOV 2009


 


2

















 


HDTRA1-07-C-0010


 


Page 3 of 4


 


The
following Delivery Schedule item has been added to CLIN 0003:


 


	
  DELIVERY
  DATE

  	
   

  	
  QUANTITY

  	
   

  	
  SHIP TO ADDRESS

  	
   

  	
  UIC

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  POP
  29-MAY-2009 TO 

  	
   

  	
  N/A

  	
   

  	
  DEFENSE
  THREAT REDUCTION

  	
   

  	
  HDTRA1

  
	
  29-N0V-2009

  	
   

  	
   

  	
   

  	
  AGENCY/RD-CBM

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  ROBERT
  KIMBROUGH

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  8725
  JOHN J KINGMAN ROAD, MAIL

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  STOP
  6201,

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  FORT
  BELVOIR VA 22060

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  703-767-2346

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  FOB:
  Destination

  	
   

  	
   

  



 


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 $2,954,122.63 from $28,034,018.00 to $30,988,140.63.


 


SUBCLIN
000301:


Funding
on SUBCLIN 000301 is initiated as follows:


 


ACRN:
AD


 


CIN:
CBM090013351000301


 


Acctng
Data: 9790400.2620 1000 B63D 255999 BD29394000 S49012


 


Increase:
$2,954,122.63


 


Total:
$2,954,122.63


 


SECTION I
- CONTRACT CLAUSES


 


The
following have been added by full text:


 


52.216-24      LIMITATION OF GOVERNMENT LIABILITY (APR
1984)


 


(a)          In performing this contract, the Contractor is not authorized to make
expenditures or incur obligations exceeding $2,954,122.63 dollars.


 


(b)         The maximum amount for which the Government shall be liable if this
contract is terminated is $2,954,122.63 dollars.


 


(End
of clause)


 


3

















 


HDTRA1-07-C-0010


 


Page 4 of 4


 


252.217-7027      CONTRACT DEFINITIZATION (OCT 1998)


 


(a) A
Cost-Plus-Fixed-Fee modification is contemplated. The  Contractor agrees to begin promptly
negotiating with the Contracting Officer the terms of a definitive contract
that will include (1) all clauses required by the Federal Acquisition
Regulation (FAR) on the date of execution of the undefinitized contract action,
(2) all clauses required by law on the date of execution of the definitive
contract action, and (3) any other mutually agreeable clauses, terms, and
conditions. The Contractor agrees to submit a Cost-Plus-Fixed Fee proposal and
cost or pricing data supporting its proposal.


 


(b) The
schedule for definitizing this contract is as follows:


 


	
  Proposal
  Received

  	
  24
  March 2009

  
	
  Complete
  Negotiations

  	
  15
  June 2009

  
	
  Definitization

  	
  30
  June 2009

  



 


(c) If
agreement on a definitive contract action to supersede this undefinitized
contract action is not reached by the target date in paragraph (b) of this
clause, or within any extension of it granted by the Contracting Officer, the
Contracting Officer may, with the approval of the head of the contracting
activity, determine a reasonable price or fee in accordance with subpart 15.4
and part 31 of the FAR, subject to Contractor appeal as provided in the
Disputes clause. In any event, the Contractor shall proceed with completion of
the contract, subject only to the Limitation of Government Liability clause.


 


(1) After
the Contracting Officer’s determination of price or fee, the contract shall be
governed by—


 


(i) All
clauses required by the FAR on the date of execution of
this undefinitized contract action for either fixed-price or cost-reimbursement
contracts, as determined by the Contracting Officer under this paragraph (c);


 


(ii) All
clauses required by law as of the date of the Contracting Officer’s
determination; and 


 


(iii)
Any other clauses, terms, and conditions mutually agreed upon.


 


(2) To
the extent consistent with paragraph (c)(1) of this clause, all clauses,
terms, and conditions included in this undefinitized contract action shall
continue in effect, except those that by their nature apply only to an
undefinitized contract action.


 


(d) The
definitive contract resulting from this undefinitized contract action will
include a negotiated cost/price ceiling (including fee) in no event to exceed
$5,908,245.26


 


(End
of clause)


 


(End
of Summary of Changes)


 


4

















 


Statement of Work


 


A New Antiviral (AntiSense) Platform Targeting
Hemorrhagic Fever Viruses


 


November 21, 2006


 


1.0                               Objective:


 


The
objective is to show a new capability of identifying potential target countermeasures
to specific Category A and B threat agents rapidly (weeks to months), then
producing and testing them in animals. The compounds have broad spectrum
capability against the threat agents, whether naturally occurring or
genetically engineered. AVI BioPharma proposes advanced applied research with
its unique Phosphorodiamidate Morpholino Oligomers (PMOs), to demonstrate their
safety and efficacy, as well as their unprecedented agility for rapid
development and production of countermeasures for a broad spectrum of extant
and emergent biothreat agents.


 


2.0                               Scope:


 


This
proposal builds on two key elements of AVI BioPharma’s third generation
antisense compounds designed against hemorrhagic threat agents, specifically
the filoviruses Ebola and Marburg, as well as arenavirus. The Scripps Research
Institute, within the last month, reported dramatic success against
arenaviruses, specifically the Junin virus vaccine strain, in cell culture with
AVI’s PMOs. This Phase has two Parts, each with a number of tasks and subtasks.


 


First,
the PMOs are targeted against highly conserved nucleotide sequences of the
viral genomes (RNA). Once species and strain and genomic makeup of a virus are
known, AVI scientists are able to categorize a series of potential treatment
compounds within several weeks or months. This correlates well with the concept
of developing countermeasures very rapidly against unknown genetically
engineered threats. Properly designed PMOs can be targeted against a family of
related viruses (multiple strains), empowering them as a broad spectrum
countermeasure for a particular threat category.


 


The
second aspect of the proposal brings AVI’s already successful work with USAMRIID  on
Ebola and Marburg viruses through IND and Phase 1 safety trials. It also
prepares, with the Department of Defense, establishment of Emergency Use
Authorizations for therapeutic use of these compounds. The proposal will
include a roadmap for the capability to ramp up production to 20,000 doses of
selected compound(s), should the government desire to do so. The proposal
builds this methodology for production and will provide the initial capability
to begin with a small run of 1000 doses.


 


AVI
acknowledges existence of export control laws related to export of, and foreign
access to, USG-funded technology development and will take measures to comply
with same upon contract execution.


 


1

















 


A
detailed spreadsheet of AVI Direct Labor Costs is submitted in Excel file
format along with this SOW, in a file called “BAA I revised budget shell detail071906
for submission”. Discussion of subcontractor efforts in the areas of fill/finish,
USAMRIID, TSRI, NHP tox/pk, and Tessarae appear as Appendix A.


 


3.0                               Background


 


AVI’s PMOs have been extensively tested against a variety of infectious
disease agents and against other common illnesses. These compounds have
successfully been utilized in animals and humans with exceptional safety
results, which portends well for future success when applied broadly to human
disease. AVI has nearly 12 years of experience in the area of developing
antisense compounds and an impressive array of successes. AVI has moved well
beyond the current siRNAs target gene interference work being accomplished at
many university and commercial entities. Significant toxicity problems occur
when using siRNA. AVI’s patented third generation PMOs have overcome these problems.


 


AVI’s proprietary chemistry has significantly improved the stability,
function, and bioavailability of antisense complexes. The improved
characteristics of AVI PMOs compared to conventional antisense oligonucleotides
include:


 


·                  resistance to proteases and nucleases,


·                  enhanced stereochemical base stacking,


·                  inherent stability for steric blockade of
ribosomal assembly and translation arrest,


·                  reliable aqueous solubility, and


·                  no diminished hybridization to mRNA targets.


 


The biological effects of PMOs are evident after intravenous,
intraperitoneal, subcutaneous, transdermal, and oral administrations, because
of intrinsic biodistribution and bioavailability characteristics of these
compounds.


 


The theoretical biological advantages of PMO are based on the lack of
net charge and a non-enzymatic mechanism of action. The PMO include fewer “off-target”
effects and do not result in:


 


·                  immune modulation through CpG motifs (Art
Krieg personal communication),


·                  altered blood coagulation times (preliminary
data),


·                  metal chelation because there is no net
charge for binding,


·                  complement activation (based on clinical
trial observations),


·                  off-target alteration of gene expression
through O-quartets (Hudziak et al., 2000; and E. Wickstrom personal communication)


·                  RNAse H or other enzymatic RNA cleavage
(Stein et al, 1997),


·                  induction of cytokine release, or


·                  induction of interferon responses.


 


Most importantly, compared to conventional antisense oligonucleotides,
PMOs are highly resistant to degradation (Hudziak et al., 1996).


 


2

















 


4.0                               Tasks/Technical Requirements:


 


The
following Gantt Chart delineates AVI’s tasks under this contract. Tasks for
subcontractors are shown in Appendix A:


 


	
   

  	
   

  	
   

  	
   

  	
  Quarter

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  2 mo.

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  Ended

  	
   

  
	
  Milestone

  	
   

  	
  Description

  	
   

  	
  12/06

  	
   

  	
  07Q1

  	
   

  	
  07Q2

  	
   

  	
  07Q3

  	
   

  	
  07Q4

  	
   

  	
  08Q1

  	
   

  	
  08Q2

  	
   

  	
  08Q3

  	
   

  	
  11/30/08

  	
   

  
	
  1 

  	
   

  	
  Efficacy
  Evaluation of PMO/PPMOs

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  1.1

  	
   

  	
  Evaluate cellular toxicity
  of EBOV and MARV

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  1.2

  	
   

  	
  Evaluate cellular toxicity
  of Arenavirus

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2

  	
   

  	
  Mechanism of Action and
  Cell Culture Studies

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2.1

  	
   

  	
  Cell culture efficacy and
  mechanism EBOV and MARV

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2.2

  	
   

  	
  Cell culture efficacy and
  mechanism Junin

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3

  	
   

  	
  Efficacy Testing in Murine
  and Guinea Pig Models

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  
	
  3.1

  	
   

  	
  Optimal PPMO EBOV lethal
  challenge studies in mouse

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3.2

  	
   

  	
  Optimal PPM MARV lethal
  challenge in guinea pig

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3.3

  	
   

  	
  Optimal PPMO Junin
  challenge in mouse

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4

  	
   

  	
  Pharmacokinetic and
  toxicology

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  4.1

  	
   

  	
  Develop analytical methods
  to detect PPMOs in tissues

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.2

  	
   

  	
  Pharmacokinetics and
  toxicity in rodents

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.2.1

  	
   

  	
  PK PPMOs for EBOV and MARV

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.2.2

  	
   

  	
  PK PPMOs for Junin

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.3

  	
   

  	
  PK and toxicology studies
  in non-human primates;

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.3.1

  	
   

  	
  PPMOs for EBOV and MARV

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.3.2

  	
   

  	
  PPMOs for Junin

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  5

  	
   

  	
  Efficacy Testing in second
  species

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  5.1

  	
   

  	
  PPMOs for EBOV and MARV

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  5.2

  	
   

  	
  PPMOs for Junin

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  6

  	
   

  	
  Manufacturing

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  6.1

  	
   

  	
  Manufacturing scale up and
  establish QC procedures

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  6.2

  	
   

  	
  Subunit preparation and PMO
  development

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  6.3

  	
   

  	
  Peptide development and
  production

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  6.4

  	
   

  	
  Conjugation production

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  6.5

  	
   

  	
  Fill and Finish

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  7

  	
   

  	
  Prepare and file IND with
  FDA

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  7.1

  	
   

  	
  EBOV

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  7.2

  	
   

  	
  MARV

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  
	
  7.3

  	
   

  	
  Junin

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  



 


3

















 


5.0                               CDRLs/Other Deliverables:


 


	
  Document
  Type

  	
   

  	
  Description

  	
   

  	
  Pages

  	
   

  	
  Date

  
	
  Exhibit A001

  	
   

  	
  Quarterly
  Status Reports

  	
   

  	
  1

  	
   

  	
  15-NOV-2006

  
	
  Exhibit A002

  	
   

  	
  Annual
  Report

  	
   

  	
  1

  	
   

  	
  15-NOV-2006

  
	
  Exhibit A003

  	
   

  	
  Quarterly
  Financial Status Reports

  	
   

  	
  1

  	
   

  	
  15-NOV-2006

  
	
  Exhibit A004

  	
   

  	
  Miscellaneous
  Data Submission

  	
   

  	
  1

  	
   

  	
  15-NOV-2006

  
	
  Exhibit A005

  	
   

  	
  Final
  Report

  	
   

  	
  1

  	
   

  	
  15-NOV-2006

  
	
  Exhibit A006

  	
   

  	
  Interim
  Reports

  	
   

  	
  1

  	
   

  	
  15-NOV-2006

  
	
  Exhibit A007

  	
   

  	
  Investigational
  New Drug (IND) Submission Report

  	
   

  	
  1

  	
   

  	
  15-NOV-2006

  



 


Appendix A: Subcontractor Efforts 


 


Fill/Finish
Tasks:


 


Fill/finish
refers to the manufacturing efforts required to convert bulk drug into a final
dosage form suitable for injection into humans. The overriding goal of assuring
patient safety requires that the final dosage form be filled in an aseptic
operation, which necessitates a sterile environment, process controls, trained
personnel, validated procedures, and validated test methods in order to ensure
a very low probability of microorganism contamination. The equipment necessary
to perform aseptic filling activities is of special design and construction and
must undergo extensive qualification and validation activities since the
failure of one control aspect could lead to lot contamination. Specialized
manufacturers provide contract filling services for smaller companies that may
require only a few filling runs per year, and which do not have the resources
to acquire and maintain the facilities, equipment, and the personnel needed. We
have successfully subcontracted for this type of effort several times in the
past with multiple vendors, and would anticipate doing the same under this
contract, in the most cost effective and quality assured manner available at
the time.


 


USAMRIID
Tasks:


 


Scientific
Director: Dr. Sina Bavari


Technical
Director: Dr. Kelly Warfield


CDC
Registration:
C20060223-0428, effective Feb. 23, 2006, expires Jan. 20, 2009


 


USAMRIID
will conduct studies related to Part A-1 of the proposal involving
Filovirus infection. Regular communication with investigators at USAMRIID will
be required to discuss goals, experimental protocols, observations and
preparation of reports. USAMRIID will evaluate the training of individuals
involved in studies conducted in theBSL-4 and will prepare applications to the
ethical care and use of animals. USAMRIID will utilize multiple isolates for
the different strains Ebola and Marburg. The laboratory tasks will initially
involve screening studies in Ebola and Marburg infection in cell culture.
Mechanism of action studies


 


4

















 


will
be conducted by USAMRIID using mini-genome systems in cell culture. Finally,
the USAMRIID tasks include efficacy studies involving Ebola and Marburg lethal
challenge in murine, guinea pig and nonhuman primate models. The mechanism of
action studies with mini-genome systems will be conducted in BSL-2 facilities
but infected cell culture and animal challenge studies will require BSL-4
containment. USAMRIID will prepare final reports in collaboration with AVI for
Ebola and Marburg studies. Specific tasks include:


 


TASK
1: Complete efficacy and toxicology evaluation of P-PMOs targeting highly
conserved regions of Ebola and Marburg in cell culture.


 


TASK
2: Complete mechanism of action studies with replicons and mini-genome systems
in cell culture.


 


TASK
3: Complete evaluation of lead candidates in mouse lethal challenge model.


 


TASK
4: Complete evaluation of lead candidates in guinea pig lethal challenge model.


 


TASK
5: Perform initial studies in non-human primate lethal challenge model.


 


TASK
6: Perform second round of non-human primate lethal challenge studies.


 


TASK
7: Complete lethal challenge studies in non-human primates.


 


The
Scripps Research Institute (TSRI) Tasks:


 


Scientific
Director: Dr. Michael Buchmeier


Technical
Director: Dr. Benjamin Neuman


CDC
Registration: neither Junin Candid#1 nor LCMV are select agents, so
registration is not required.


 


TSRI
will conduct studies related to Part A-2 of the proposal involving
Arenavirus infection. Regular communication with investigators at USAMRIID will
be required to discuss goals, experimental protocols, observations and
preparation of reports. TSRI will evaluate the training of individuals involved
in studies conducted in the BSL-2 and will prepare applications to the ethical
care and use of animals. TSRI will utilize lymphotropic choriiomeningitis virus
(LCMV), a pathogenic Old World arenaviru3, and the Candid#1 vaccine strain of
Junin virus, the agent of Argentine hemorrhagic fever (neither are select
agents). The laboratory tasks will initially involve screening studies in
infection in cell culture monitoring plaque assays to measure viral entry,
multiplication and spread. Further measures will include measures of viral
protein synthesis, viral RNA synthesis, and viral induced cytopathic effects.
These in vitro studies will provide information about efficacy, mechanism of
action and the resistance profile for effective agents. Finally, TSRI will
conduct acute infection studies in mouse challenge models measuring virus titer
in blood, liver, kidneys, lungs, and the central nervous system to determine
antiviral effects of test agents. TSRI will prepare final reports in
collaboration with AVI. Specific tasks include:


 


TASK
1: Complete efficacy studies with Junin Candid#1 in cell culture.


 


TASK
2: Complete efficacy studies with LCMV in cell culture.


 


5

















 


TASK
3: Complete mechanism of action studies in cell culture.


 


TASK
4: Initiate acute infection model studies of Junin in mouse.


 


TASK
5: Complete acute infection model studies of Junin in mouse.


 


TASK
6: Initiate chronic infection studies in mouse and initiate guinea pig
infection studies.


 


TASK
7: Repeat studies in mouse and guinea pig.


 


TASK
8: Complete Junin Candid#1 infection studies.


 


TASK
9: Complete LCMV infection studies.


 


NHP
Toxicology Pharmacokinetic Tasks:


 


CDC
Registration: there will be no use of selected agents in animals.


 


Potential
Subcontractors:


 


	
  Conventional Toxicology Rat Studies

  	
   

  	
  CTBR

  	
   

  
	
  Conventional Toxicology Non-Human Primate

  	
   

  	
  MPIR

  	
   

  
	
  Non-Human Primate Pharmacokinetic Studies

  	
   

  	
  MPIR

  	
   

  
	
  Safety Pharmacology Studies

  	
   

  	
  MDSP

  	
   

  
	
  Genotoxicity

  	
   

  	
  BioReliance

  	
   

  



 


Conventional
Safety Pharmacology Studies:


 


Single
dose exposure for
each agent in preparation of IND filing, (3 months duration per agent) will
require three dosage levels [i.e., anticipated subtherapeutic dosage {low},
therapeutic dosage {intermediate), and 10X the therapeutic dosage {high) all
studies).


 


Cardiovascular
Study to assure no
clinically significant change in temperature, blood pressure, heart rate, or
conduction problems.


 


Pulmonary
Function Study to
assure no clinically significant bronchoconstricting or bronchodilating effects
occur.


 


Renal
Function Study to
assure no clinically significant reduction occurs in. renal function (viz.,
drop in creatinine clearance and rise in serum creatinine) after single dose
administration.


 


Central
Nervous System to
assure no excitatory or inhibitory activity occurs in central or peripheral
nervous systems after single dose administration in accordance with Irwin test.


 


Pharmacokinetic
studies:


 


15
monkeys per agent, after single dose and serial dosing at low, intermediate,
and high dosing


 


Conventional
Toxicology:


 


28
Day Daily Dosing Rat Study (estimated total of 96 rats to be tested).


 


6

















 


28
Day Daily Rat Study
at the highest dosing level with a 14-day washout (estimated total of 24 rats
to be tested).


 


28
Day Daily Dosing Monkey Study (estimated total of 50 monkeys to be tested).


 


28
Day Daily Monkey Study,
at the highest dosing level with 14-day washout (estimated total of 12 monkeys
to be tested).


 


Conventional
genotoxicity studies:


 


Two
assays; 2 months duration to complete per agent. 


 


Specific
tasks include:


 


TASK
1: Initiate Conventional tox, Safety Pharm, NHP PK and Genotoxicity for
Filovirus therapeutic agent.


 


TASK
2: Complete Conventional tox, Safety Pharm and Genotoxicity for Filovirus
therapeutic agent.


 


TASK
3: Complete NHP PK for Filovirus agent and Initiate Conventional tox, Safety
Pharm, NHP PK and Genotoxicity for Arenavirus therapeutic agent.


 


TASK
4: Complete Conventional tox, Safety Pharm, Genotox and NHP PK for Arenavirus
therapeutic agent.


 


Tessarae
Tasks:


 


Tessarae
LLC will provide pharmacogenomic endpoint modeling services and reports to AVI
BioPharma, related to evaluations of clinical safety and efficacy of next
generation antivirals targeting hemorrhagic fever viruses. Tessarae will
analyze 30 archived blood specimens tested with either placebo or fixed dosages
of antiviral PMO compounds to be selected by AVI BioPharma. Archived blood
specimens will be subjected to standard preparation of total RNA for
microarray-based analysis of gene expression profiles, including reduction of
abundant globin mRNA. Global gene expression analysis will be performed on the
Affymetrix U133 2.0 Plus microarray platform. Aliquots of purified total RNA
preparations will also be analyzed Eppendorf DualChip microarrays, representing
four palettes of gene sets related to processes of aging, inflammation, cancer
and response to siRNA treatments. A portion of original blood specimens will
also be archived for future retrospective analysis.


 


Specific
tasks include:


 


TASK
1: Receive and archive inventory of blood specimens, each specimen representing
three PreAnalytix PAXgene RNA tubes and one Whatman 4-spot FTA card.


 


TASK
2: Subject 60 PAXgene RNA specimens (180 tubes) to total RNA purification,
including globin mRNA reduction protocol.


 


TASK
3: Perform gene expression profiling (GXP) assay using 50 % of each of the 60
RNA samples on 60 Affymetrix U133 microarrays.


 


TASK
4: Perform gene expression profiling assay using 50 % of each of the 60 RNA
samples on 120 Eppendorf DualChip microarrays.


 


7

















 


TASK
5: Perform bioinformatics analysis to determine if significant clusters of gene
expression changes are observed among the before/after and placebo/antiviral
specimen cohorts.


 


TASK
6: Compare specific gene set associations and statistical significance of
differences using results from the two analytical platforms (Affymetrix and
Eppendorf).


 


TASK
7: Deliver summary report on technical efficacy and cost-value analysis of
pilot gene expression profiling for ongoing pharmacogenomic endpoint tracking
in trials of PMO antivirals.


 


Addendum to Original Statement of Work

AVI-6002 and AVI-6003 Bridge Funding Proposal


 


A.                 INTRODUCTION:


 


AVI
BioPharma is focused on the discovery and development of RNA-based drugs
utilizing an extensive proprietary technology platform with applications to a
range of diseases and genetic disorders. The current funding mechanism
supported a discovery process, based upon antisense oligomers, to identify lead
antiviral candidates for Ebola Zaire (AVI-6002) and Marburg Musoke (AVI-6003).
These compounds are effective in multiple animal models of viral infection. AVI
BioPharma has prepared and submitted INDs for AVI-6002 and AVI-6003 for
immediate treatment of patients following documented or suspected exposure to
Ebola Zaire or Marburg Musoke, respectively. In order to continue the science
and prepare for NDA submittals, AVI BioPharma is submitting this bridge funding
proposal to TMTI to perform
tasks that are required to be performed prior to AVI BioPharma’s performance of
the Advanced funding. These tasks include Program Management, Dose titration
studies, Preparation of Clinical Materials, Development of Analytical Methods,
Development & Implementation, as well as Incorporation and Resolution
of FDA comments from initial IND filing. The specific Statement of Work for
these tasks is outlined below:


 


B.                 TASKS:


 


1.         Program Management: The overall administration of the
Ebola/Marburg program includes coordination of items of a technical nature,
working with the government to facilitate the proper approvals, as well as
ensuring that the program is on task and on budget the program management task
is made up of the following:


 


1.1 Program Management
Team
for
coordination of effort,
evaluation of progress and communication with TMTI.


 


1.2 Antiviral Project
Team meets bi-weekly to
ensure timelines are met, reviews decisions and communicates with internal
departments.


 


8

















 


2.                   Dose Titration Studies:


 


AVI-6002 Dose Titration Study: Dose ranging studies with
AVI-6002 in the Ebola lethal challenge model in Rhesus monkeys.


 


Objective: Establish  a dose versus survival relationship for
AVI-6002 following infection of rhesus macaques with EBOV Zaire critical to the
dose refinement for advanced development and human safety studies.


 


AVI-6003 Dose Titration Study: Dose ranging studies with
AVI-6003 in the Marburg lethal challenge model in Cynomolgus monkeys.


 


Objective: Establish a dose versus survival relationship for AVI-6003 following
infection of cynomolgus macaques with MARV Musoke critical to the dose
refinement for advanced development and human safety studies.


 


3.                   Clinical Study Preparations:
In
preparation  for the first human volunteer safety study,
two major work streams prior to the study site activation are required:


 


3.1            Clinical Study Start-up Activities. Conducting the various activities required to
open a clinical study site usually takes a minimum of 12 weeks after the key contracts
are awarded.


 


3.2            Clinical Supply
Preparations. The Active
Pharmaceutical Ingredients (API), AVI-6002 and AVI-6003 will be dispensed into
sterile vials for future clinical use.


 


4.                   Analytical Methods
Development and Implementation: The improvement of analytical methods to be used in the first in man
pharmacokinetic studies represents ongoing studies that will require support.
Transfer of methods to contract research organizations will be required prior
to initiating GLP pharmacokinetic studies.


 


5.                   Incorporation and Resolution
of FDA Comments: We propose
to schedule a face-to-face strategy meeting regarding our proposed development
plan, prior to providing responses to the questions and comments received upon
IND approval. The next steps would be to provide three separate category
responses: clinical, nonclinical and CMC (chemistry, manufacturing, and
control). The clinical submission includes the revised protocol, a revised DSMB
charter, and the ICF template, as well as responses to FDA questions, and a
development plan outlining what additional clinical studies might be needed
prior to approval. The nonclinical responses will be sent with the initial
animal study protocols, as requested, and will include efficacy studies as well
as PK/PD work. The CMC response will be provided after clinical supply
manufacture is complete.


 


9