Document:

Exhibit 10.73

 

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
“*****”.

 

EMPLOYMENT AGREEMENT

 

THIS
EMPLOYMENT AGREEMENT (“Agreement”) is made on this 15th day of May, 2009, by
and between AVI BioPharma, Inc., an Oregon corporation, with its principal
office at 4575 SW Research Way, Suite 200, Corvallis, Oregon, (“Company”),
and Paul Medeiros, 700 Mixsell Street, Easton, Pennsylvania 18042 (“Employee”).

 

RECITALS:

 

The
Company desires to hire the Employee as Senior Vice President Business
Development and Chief Business Officer and the Employee desires to accept such
position under the terms and conditions stated herein.

 

NOW,
THEREFORE, in consideration of the mutual benefits contained herein, the
sufficiency of which the parties acknowledge, the parties hereby agree as
follows:

 

AGREEMENT:

 

1.                     Employment
Term.

 

The
term of employment (“Term”) shall commence on the
Effective Date and shall continue until the first anniversary of the Effective
Date, unless extended as provided below or terminated in accordance with Section 12 below. This
Agreement establishes an “at will” employment relationship, as such term is defined
and used under Oregon law, between the Company and the Employee. Employee shall
commence employment not later than May 19, 2009 (the “Effective
Date”). Failure to do so shall be grounds for immediate
termination for Cause, as such term is
defined in Section 12 hereof. Notwithstanding
anything to the contrary herein, unless sooner terminated in accordance with
the terms hereof, this Agreement shall annually automatically renew for
additional one-year terms unless one party notifies the other party in
accordance with Section 13 hereof of its intention not
to renew, such notice to be delivered not less than 90 days before the term
ends. For purposes of this Agreement, the non-renewal of the Agreement by the
Company shall constitute a termination of Employee’s employment by the Company
other than for Cause.

 

2.                     Duties.

 

Employee
shall be employed as Senior Vice President Business development and Chief
Business Officer and shall have such duties as are customarily associated with
that position, including overall responsibility for development and execution
of strategies and tactics for transactions, alliances, mergers and acquisitions
that are agreed with the Corporate Executive Team and CEO, and such other
duties as may be assigned to him from time to time by the Company’s Chief
Executive Officer (“CEO”). Employee shall be a direct
report of the CEO. Employee shall devote substantially all of his business time
to the service of the Company throughout the Term. Employee and

 

 

Company
acknowledge and agree that (i) Employee may hold certain offices within certain
entities as agreed by the CEO and set forth on Exhibit A to this
Agreement, (ii) Employee’s devotion of reasonable amounts of time in such
capacities, so long as it does not interfere with his performance of services
hereunder, shall not conflict with the terms of this Agreement, and (iii) Exhibit
A may be amended from time to time by agreement of the parties rendered in
writing.

 

3.                     Compensation.

 

(a)             Base
Compensation. During the Term the Company shall compensate the Employee at
an initial annual salary of Three Hundred Fifteen Thousand Dollars ($315,000.00),
payable in accordance with the Company’s payroll practices in effect from time
to time, and less amounts required to be withheld under applicable law and
requested to be withheld by the Employee (as increased from time to time, “Base
Compensation”). The Employee’s Base Compensation shall be subject to review for
potential increase (but not decrease) on an annual basis. Except as otherwise
provided in this Agreement, the Base Compensation shall be prorated for any
period of service less than a full month.

 

(b)             Bonus. For
each fiscal year of the Company that ends during the Term, the Employee shall
be eligible for an annual bonus of up to 25% of Employee’s Base Compensation, which
bonus shall be paid in the normal cycle of payment of executive bonuses (which
bonus payment shall occur in the first quarter of the fiscal year following the
fiscal year with respect to which the bonus is earned) and upon achievement and
satisfaction of goals and objectives (“Goals and Objectives”) established upon
mutual agreement of the CEO, Employee and the Compensation Committee of the
Company’s Board. Such goals shall be established concurrently with the goals
and objectives of the Company’s other senior executives. Notwithstanding
anything to the contrary herein, Employee’s bonus for 2009 will be a guaranteed
$50,000 and in order to receive any bonus under this Section 3(b) Employee
must be an employee of the Company at the time of the bonus payout.

 

(c)             Equity
Compensation.

 

(i)          On
the Effective Date, the Employee will be granted options to purchase Four
Hundred Thousand (400,000) shares of the Company’s common stock (the “Options”)
under the Company’s 2002 Equity Incentive Plan (the “Plan”) (a copy of which is
attached as Exhibit B), with an exercise price at the fair market value
of the Company common stock on the date Effective Date. Subject to accelerated
vesting or termination as set forth herein, the Standard Options shall vest in
equal annual installments over three (3) years measured from the Effective
Date.

 

(ii)         In
addition, on the Effective Date, Employee will be issued One Hundred Thousand (100,000)
shares of restricted stock under the Plan (the “Restricted Shares”). The
Restricted Shares shall vest as follows:

 

2

 

through
the first anniversary of the Effective Date (a) in a pro rata basis *****; and
(b) 100% upon any Change of Control. By way of illustration and not limitation,
*****

 

(iii)         The exercise price of the Options and all other terms and
conditions associated with the Options and Restricted Shares shall be
determined in accordance with the Plan and grants (the forms of which are
annexed hereto as Exhibit C and Exhibit D, respectively). To the
maximum extent possible, the Options shall be Incentive Stock Options.

 

(d)                   Additional
Compensation. Within 10 business days of the Effective Date, the Company
will pay the Employee a $100,000 sign-on bonus. Should the Employee separate
from the Company prior to the one year anniversary of the Effective Date for
reasons of termination for Cause or voluntary termination by the Employee other
than for Good Reason, this sign-on bonus is refundable to Company in full.

 

4.                     Expenses.

 

The
Company will reimburse Employee for all expenses reasonably incurred by him in
discharging his duties for the Company, conditioned upon Employee’s submission
of written documentation in support of claimed reimbursement of such expenses, and
consistent with the Company’s expense reimbursement policies in effect from
time to time. The Company will reimburse the Employee in 2010 up to One Hundred
Twenty Thousand Dollars ($120,000) for reasonable expenses incurred in 2009 and
2010 to relocate Employee, Employee’s spouse and parts of Employee’s and
Employee’s Spouse’s household in a manner compatible with Employee’s duties
hereunder to the Company’s headquarters location (“Facility Location”), including
the reasonable and customary costs of selling his Pennsylvania residence (but
not vacant home carrying costs), shipment of personal effects to the Facility
Location, and the customary closing costs associated with the purchase of a
residence in the Facility Location. In addition, Company shall reimburse
Employee (or pay on Employee’s behalf) rent and related living expenses, not to
exceed $2,500 per month in the aggregate and up to six (6) months in duration, for
temporary living arrangements and up to $5,000 for reasonable attorneys’ fees
incurred in negotiation of this Agreement.

 

3

 

5.                     Benefits.

 

Subject
to eligibility requirements, Employee shall be entitled to participate in such
benefits plans and programs as adopted by the Company from time to time and
shall be eligible for paid vacation of four (4) business weeks (20 business
days) annually; provided, however, if Employee does not use all available
vacation in any given year, Employee may roll-over up to one business week (5
business days) to the following year, the parties intending that Employee shall
have a maximum of five (5) business weeks (25 business days) of paid vacation
in any calendar year following 2009. Notwithstanding anything to the contrary
herein, Employee shall receive 15 days paid vacation in 2009, available as of
the Effective Date. Without limiting the foregoing, subject to eligibility
requirements, Employee shall be covered by any “directors and officers”
insurance and “errors and omissions” insurance policies obtained by the
Company.

 

6.                     Confidentiality.

 

As
a condition to employment under this Agreement, Employee and the Company shall
enter into the Non-Disclosure Agreement in the form attached hereto as Exhibit E. The provisions
of this Section 6 shall survive termination of this Agreement and
term of employment.

 

7.                     Non-competition and Non-solicitation.

 

(a)           For a period of one
(1) year in the case of the payment of severance equal to 12 months Base
Compensation and for a period of two (2) years in the case of the payment of
severance equal to 24 months Base Compensation, in both instances as provided
in Section 12 below, Employee shall not directly or indirectly
engage in or have any ownership interest in, or participate in the financing, operation,
management or control of, any person, firm, corporation or business listed on Exhibit F (as such shall
be amended in the event that the Company enters into a material transaction
with an entity not listed on Exhibit F and as shall
be amended from time to time by mutual consent of Employee and the Company); provided, however, that this provision
shall not prohibit Employee from owning up to five percent (5%) of any class of
outstanding bonds, preferred stock or shares of common stock of any such entity
or from employment with any institute of higher learning.

 

(b)           For a period of two
(2) years following termination of employment with the Company for any reason, except
with the express written consent of the Company, Employee agrees to refrain
from directly or indirectly recruiting, hiring or assisting anyone else to hire,
or otherwise counseling to discontinue employment with the Company, any person
then employed by the Company or its subsidiaries or affiliates; provided, however, nothing herein shall
prevent Employee from providing, in accordance with Company policy, details
regarding the employment history of any such person or providing an employment
reference with respect to such person.

 

4

 

(c)           In the event that
the provisions of this Section 7 should ever be deemed to exceed the
duration or geographic limitations or scope permitted by applicable law, then
such provisions shall be reformed to the maximum time or geographic limitations
or scope, as the case may be, permitted by applicable laws.

 

(d)           The provisions of
this Section 7 shall survive termination of this Agreement and the term
of employment.

 

8.                     Covered Work.

 

(a)            All rights, title
and interest to any Covered Work that Employee makes or conceives (whether
alone or with others) while employed by the Company, belong to the Company. This
Agreement operates as an actual assignment of all rights in Covered Work to the
Company. “Covered Work” means products and Inventions that relate to the actual
or anticipated business of the Company or any of its subsidiaries or affiliates,
or that result from or are suggested by a task assigned to Employee or work
performed by Employee on behalf of the Company or any of its subsidiaries or
affiliates, or that were developed in whole or in part on the Company time or
using the Company’s equipment, supplies or facilities. “Inventions” mean ideas,
improvements, designs, computer software, technologies, techniques, processes, products,
chemicals, compounds, materials, concepts, drawings, authored works or
discoveries, whether or not patentable or copyrightable, as well as other newly
discovered or newly applied information or concepts. Attached hereto as Exhibit
G is a description of any product or Invention in which Employee had or has
any right, title or interest, which is not included within the definition of
Covered Work or which is otherwise excluded from the restrictions set forth in
this Section 8.

 

(b)           Employee shall
promptly reveal all information relating to Covered Work and Confidential Information
to an appropriate officer of the Company and shall cooperate with the Company, and
execute such documents as may be necessary, in the event that the Company
desires to seek copyright, patent or trademark protection thereafter relating
to same.

 

(c)           In the event that
the Company requests that Employee assist in efforts to defend any legal claims
to patents or other right, the Company agrees to reimburse Employee for any
reasonable expenses Employee may incur in connection with such assistance. This
obligation to reimburse shall survive termination of this Agreement and the
term of employment.

 

(d)           The provisions of
this Section 8 shall survive termination of this Agreement and the term
of employment.

 

5

 

9.                     Return of Inventions,
Products and Documents.

 

Employee
acknowledges and agrees that all Inventions, all products of the Company and
all originals and copies of records, reports, documents, lists, drawings, memoranda,
notes, proposals, contracts and other documentation related to the business of
the Company or containing any information described in this Section 9
shall be the sole and exclusive property of the Company and shall be returned
to the Company immediately upon termination of Employee’s employment with the
Company or upon the written request of the Company. The provisions of this Section
9 shall survive termination of this Agreement and the term of employment

 

10.                  Injunction.

 

Employee
agrees that it would be difficult to measure damages to the Company from any
breach by Employee of Sections 6, 7, 8 and/or 9 of this Agreement,
and that monetary damages would be an inadequate remedy for any such breach. Accordingly,
Employee agrees that if Employee shall breach Sections 6, 7, 8 and/or 9
of this Agreement, the Company shall be entitled, in addition to all other
remedies it may have at law or in equity, to an injunction or other appropriate
orders to restrain any demonstrated breach without showing or proving any
actual damage sustained by the Company. The provisions of this Section 10
shall survive termination of this Agreement and the term of employment.

 

11.                  Obligations
to Others.

 

Except
for items fully disclosed in writing to the Company (including with respect to
the entities and agreements listed on Exhibit H), Employee represents and
warrants to the Company that (i) Employee’s employment by the Company does not
violate any agreement with any prior employer or other person or entity, and
(ii) Employee is not subject to any existing confidentiality or non-competition
agreement or obligation, or any agreement relating to the assignment of
Inventions except as has been fully disclosed in writing to the Company. Notwithstanding
anything to the contrary, if any agreement listed on Exhibit H shall
interfere or limit in any material manner the performance of Employee’s duties
hereunder, prior to commencement of employment Employee shall disclose the
material terms of such agreements to Company.

 

12.                  Termination
and Termination Compensation

 

(a)           Employee may
voluntarily terminate his employment with the Company upon giving the Company
sixty (60) days written notice.

 

(b)           The Company may
terminate Employee’s employment without Cause (as defined below) upon giving
Employee thirty (30) days written notice of termination.

 

6

 

(c)                         Employee’s employment
with the Company shall terminate upon the occurrence of any one of the
following:

 

(i)            Employee’s death;

 

(ii)           The effective date
of a notice sent to Employee stating the Board’s determination made in good
faith and after consultation with a qualified physician selected by the Board, that
Employee is incapable of performing his duties under this Agreement, with
reasonable accommodation, because of a physical or mental incapacity that has
prevented Employee from performing such full-time duties for a period of ninety
(90) consecutive calendar days and the determination that such incapacity is
likely to continue for at least another ninety (90) days; provided, however, termination under this Section 12 (c)(ii)  shall not
affect Employee’s eligibility nor modify the terms and conditions under the
Company’s long term disability policies, if any, existing at the time of such
termination; or

 

(iii)          The effective date
of a notice sent to Employee terminating Employee’s employment for Cause.

 

(iv)          “Cause” means the
occurrence of one or more of the following events:

 

(A)          Employee’s willful and repeated failure or refusal to
comply in any material respect with the reasonable lawful policies, standards
or regulations from time to time established by the Company, or to perform his
duties in accordance with this Agreement after notice to Employee of such
failure and after Employee has been given a reasonable period of time to cure
such failure to comply; or

 

(B)           Employee is convicted of, or pleads guilty or nolo
contendere to, a felony or demonstrably engages in misconduct that is
materially detrimental to the reputation, character or standing of the Company.

 

(v)            Following any termination of the Employee’s
employment hereunder (by the Employee or by the Company), the Employee will be
entitled to receive (i) any earned but unpaid Base Compensation through the
date of termination, (ii) any unreimbursed business expenses, (iii) any benefits
under the Company’s compensation plan that by their terms provide for cash
payments of accrued but unused benefits and under applicable law (collectively,
the “Accrued Obligations”).

 

(vi)          Upon Employee’s
voluntary termination of employment, other than voluntary termination with Good
Reason (as defined below), or upon termination of employment by the Company for
Cause, the Company shall pay to Employee the Accrued Obligations, but shall
have no further

 

 

7

 

obligation
to Employee hereunder in respect of any period following termination.

 

(vii)         Upon the death of
Employee, the Company shall pay to Employee’s estate or such other party who
shall be legally entitled thereto, the Accrued Obligations and an additional
amount equal to compensation at the rate set forth in this Agreement or then
current annual salary rate, whichever is greater, from the date of death to the
final day of the month following the month in which the death occurs.

 

(viii)        (A) Upon termination
of Employee’s employment by the Company other than for Cause and other than in
connection with or after a Change in Control, in addition to the Accrued
Obligations, the Company shall pay to Employee twelve (12) months of Base
Compensation, with such payment to be made in a lump sum payment within sixty (60)
days of such termination of employment. In addition, all nonvested Options, Restricted
Stock Units and other long term compensation benefits then in effect shall
immediately vest and be exercisable for a period of 180-days following the
effective date of termination.

 

(B) Upon termination by the Company other than for
Cause in connection with or after a Change in Control or upon Employee’s
voluntary termination of employment for Good Reason in connection with or
within twenty-four (24) months after a Change of Control, in addition to the
Accrued Obligations, the Company shall pay to Employee twenty-four (24) months
of Base Compensation, with such payment to be made in a lump sum payment within
sixty (60) days of such termination of employment. In addition, all nonvested
Options, Restricted Stock Units and other long term compensation benefits then
in effect shall immediately vest and be exercisable for a period of 180-days
following the effective date of termination.

 

(ix)           Any amounts payable
under this Section 12 shall be net of amounts
required to be withheld under applicable law and amounts requested to be
withheld by Employee.

 

(x)            As used herein, “Good
Reason” shall mean, following a Change of Control (as such term is defined
below), the termination by Employee upon the occurrence of any of the below
described events. The Employee must provide notice to the Company of the
existence of such event within ninety (90) days of the first occurrence of such
event, and the Company will have thirty (30) days to remedy the condition, in
which case no Good Reason shall exist. If the Company fails to remedy the
condition within such thirty (30) day period, the Employee must terminate
employment within two (2) years of the first occurrence of such event. The
events which constitute a Good Reason termination are:

 

8

 

(A)        The assignment of a different title or change that results in
a material reduction in Employees duties or responsibilities;

 

(B)         A reduction by the Company in Employee’s Base Compensation, other
than a salary reduction that is part of a general salary reduction affecting
employees generally and provided the reduction is not greater, percentage-wise,
than the reduction affecting other employees generally or failure to provide an
annual increase in Base Compensation commensurate with other Employees; provided,
however, in determining whether to provide an annual increase in Base
Compensation commensurate with an annual increase provided to other Employees, the
Company may take into account factors such as market levels of compensation, Employee’s
overall performance, and other factors reasonably considered by the Company’s
compensation committee and/or Board of Directors, so long as such determination
is not made in bad faith with the intent to discriminate against Employee; or

 

(C)         Relocation of Employee’s principal place of business of
greater than seventy-five (75) miles from its then location; provided, however, the current relocation
of the Company’s headquarters to the Seattle, Washington metropolitan area
shall not constitute Good Reason hereunder.

 

(xi)           As a condition of
payment of the amounts set forth in this Section 12, if requested by
Company with five (5) business days of the Employee’s termination of employment,
Employee agrees to enter into a Separation and Release Agreement substantially
in the form attached hereto as Exhibit I. By way of
clarification and not limitation, if no separation payments are made under this
Section 12, Employee shall not be required to execute a
Separation and Release Agreement

 

(xii)          As used herein, “Change
of Control” means the occurrence of any one of the following events: (i) any
person becomes the beneficial owner of twenty-five percent (25%) or more of the
total number of voting shares of the Company; (ii) any person (other than the
persons named as proxies solicited on behalf of the Board of Directors of the
Company) holds revocable or irrevocable proxies representing twenty-five
percent (25%) or more of the total number of voting shares of the Company;
(iii) any person has commenced a tender or exchange offer, or entered into an
agreement or received an option, to acquire beneficial ownership of twenty-five
percent (25%) or more of the total number of voting shares of the Company; and
(iv) as the result of, or in connection with, any cash tender or exchange offer,
merger, or other business combination, sale of assets, or any combination of
the foregoing transactions, the persons who were directors of the Company
before such transactions shall cease to

 

9

 

constitute
at least two-thirds (2/3) of the Board of Directors of the Company or any
successor entity.

 

13.                 Notice.

 

Unless
otherwise provided herein, any notice, request, certificate or instrument
required or permitted under this Agreement shall be in writing and shall be
deemed “given” upon personal delivery to the party to be notified or two
business days after deposit for next day delivery with Federal Express or
similar courier service, addressed to the party to receive notice at the
address set forth above, postage prepaid. Either party may change its address
by notice to the other party given in the manner set forth in this Section.

 

14.                 Entire
Agreement.

 

This
Agreement constitutes the entire agreement between the parties and contains all
the agreements between them with respect to the subject matter hereof. It also
supersedes any and all other agreements or contracts, either oral or written, between
the parties with respect to the subject matter hereof; provided, however, in the event any of Sections 6, 7, 8,
9, or 10 of this Agreement is found unenforceable in any way, then
such section shall be amended to the extent necessary to conform to applicable
law.

 

15.                 Modification.

 

Except
as otherwise specifically provided, the terms and conditions of this Agreement
may be amended at any time by mutual agreement of the parties, provided that
before any amendment shall be valid or effective, it shall have been reduced to
writing and signed by an authorized representative of the Company and Employee.

 

16.                 No
Waiver.

 

The
failure of any party hereto to exercise any right, power or remedy provided
under this Agreement or otherwise available in respect hereof at law or in
equity, or to insist upon compliance by any other party hereto with its
obligations, shall not be a waiver by such party of its right to exercise any
such or other right, power or remedy or to demand compliance.

 

17.                  Severability.

 

In
the event that any section or provision of this Agreement shall be held to be
illegal or unenforceable, such section or provision shall be severed from this
Agreement and the entire Agreement shall not fail as a result, but shall
otherwise remain in full force and effect.

 

10

 

18.                 Assignment

 

This
Agreement shall be binding upon and inure to the benefit of the Company and its
successors and assigns, and shall be binding upon Employee, his administrators,
executors, legatees, and heirs. In that this Agreement is a personal services
contract, it shall not be assigned by Employee.

 

19.                 Dispute
Resolution.

 

Except
as otherwise provided in Section 10, the Company and Employee agree that
any dispute relating to the rights and obligations under this Agreement between
Employee and the Company or its officers, directors, employees, or agents in
their individual or Company capacity of this Agreement, shall be submitted to a
mediator mutually acceptable to both parties for nonbinding, confidential
mediation. If the matter cannot be resolved with the aid of the mediator within
30 days, the Company and Employee mutually agree to arbitration of the dispute.
The arbitration shall be in accordance with the then-current Employment Dispute
Resolution Rules of the American Arbitration Association before an arbitrator
who is licensed to practice law in the State of Washington. The arbitration
shall take place in or near Seattle, Washington. Employee and the Company will
share bear the cost of the arbitration equally, but each party will bear their
own costs and legal fees associated with the arbitration; provided,
however, if any party prevails on a statutory claim, which
affords the prevailing party attorneys’ fees, or if there is a written
agreement providing for attorneys’ fees, the arbitrator may award reasonable
attorneys’ fees. The Company and Employee agree that the procedures outlined in
this provision are the exclusive method of dispute resolution.

 

20.                 Attorneys
Fees.

 

In
the event suit or action is instituted pursuant to Section 10 or Section
19 of this Agreement, the prevailing party in such proceeding, including
any appeals thereon, shall be awarded reasonable attorneys fees and costs; provided,
however, except with respect to claims found to be friviolous
or entirely without merit, the amount of such fees to be paid by the
non-prevailing party shall not exceed $50,000.

 

21.                 Applicable
Law.

 

This
Agreement shall be construed and enforced under and in accordance with the laws
of the State of Washington.

 

22.                 Section
409A; Section 280G.

 

(a)           It is the intention
of the parties to this Agreement that no payment or entitlement pursuant to
this Agreement will give rise to any adverse tax consequences to Employee or
the Company with regard to Section 409A of the Internal Revenue Code of 1986, as
amended (“Section 409A”). This Agreement shall be interpreted to that
end and consistent with that objective. The Company and the Employee shall, to
the extent

 

11

 

necessary
to comply with Section 409A and permitted thereunder, agree to act reasonably
and in good faith to mutually reform the provisions of this Agreement to avoid
the application of the additional tax and interest under Section 409A(a)(1)(B),
provided that any such reformation shall not negatively impact the economics of
the Company or the Employee hereunder. Notwithstanding any other provision
herein, if Employee is a “specified employee,” as defined in, and pursuant to, Treasury
Regulation Section 1.409A-1 (i) or any successor regulation, on the date of
termination, no payment of any “deferred compensation”, as defined under
Treasury Regulation Section 1.409A or any successor regulation, shall be made
to Employee during the period lasting until the earlier of six (6) months from
the date of termination or upon Employee’s death. If any payment to Employee is
delayed pursuant to the foregoing sentence, such payment instead shall be made
on the first business day following the expiration of the six (6) month period
referred to in the prior sentence or, if in the case of Employee’s death, promptly
thereafter.

 

Except
as otherwise specifically provided in this Agreement, if any reimbursement to
which the Employee is entitled under this Agreement would constitute deferred
compensation subject to Section 409A of the Code, the following additional rules
shall apply: (i) the reimbursable expense must have been incurred, except as
otherwise expressly provided in this Agreement, during the term of this
Agreement; (ii) the amount of expenses eligible for reimbursement during any
calendar year will not affect the amount of expenses eligible for reimbursement
in any other calendar year; (iii) the reimbursement shall be made not later
than December 31 of the calendar year following the calendar year in which the
expense was incurred; and (iv) the Employee’s entitlement to reimbursement
shall not be subject to liquidation or exchange for another benefit.

 

With
regard to any installment payment, each installment thereof shall be deemed a
separate payment for purposes of Section 409A of the Code.

 

(b)                                 Section 280G

 

(i)            Notwithstanding any
provision of this Agreement to the contrary, except as provided below, if it is
determined that the payments or benefits to which Employee will be entitled
under Section 12 of the Agreement or otherwise under any other
agreement, policy, plan, program or arrangement (a “Payment”), would be subject
to an excise tax (“Excise Tax”) under Section 4999 of the Internal Revenue Code
of 1986, as amended (the “Code”), but for the application of this sentence, then
the Payments will be reduced to the minimum extent necessary (but in no event
below zero) so that no portion of any such Payment, as so reduced, constitutes
an “excess parachute payment” within the meaning of Section 280G of the Code.

 

ii)             The limitation
above will not apply if:

 

12

 

the
difference between

 

(1)  the present value of all payments to which Employee is
entitled under Section 12 of the Agreement determined
without regard to the limitation above, less

 

(2)  the present value of all federal, state, and other
income and excise taxes for which Employee is liable as a result of such
payments; exceeds

 

the
difference between

 

(1)  the present value of all payments to which Employee is
entitled under Section 12 of the Agreement calculated
as if the limitation above applies, less

 

(2)  the present value of all federal, state, and other
income and excise taxes for which Employee is liable as a result of such
reduced payments.

 

(iii)         All determinations required to be made under this Section 21, including
whether an Excise Tax is payable by the Employee and the amount of such Excise
Tax, shall be made by a nationally recognized accounting firm designated by the
Company (the “Accounting Firm”). The Company shall direct the Accounting Firm
to submit its determination and detailed supporting calculations to the Company
and the Employee within fifteen (15) calendar days after the date of the
Employee’s termination of employment, and other such time or times as may be
requested by the Company or the Employee. If the Accounting Firm determines
that no Excise Tax is payable by the Employee, it shall, at the same time as it
makes such determination, furnish the Employee with an opinion that the
Employee has substantial authority not to report any Excise Tax on the Employee’s
federal, state, local income or other tax return. The Company and the Employee
shall each provide the Accounting Firm access to and copies of any books, records
and documents in the possession of the Company or the Employee, as the case may
be, reasonably requested by the Accounting Firm in connection with the
preparation and issuance of the determination contemplated by this Section 22. Any reasonable
determination made by the Accounting Firm under this Section 22 shall be
binding upon the Company and the Employee. All fees and expenses of the
Accounting Firm shall be borne solely by the Company.

 

(iv)        The reduction of the amounts payable hereunder shall be made
in a manner consistent with the requirements of Section 409A of the Code. The
reduction of the amounts payable hereunder, if applicable, shall be made by
first reducing, but not below zero, any amounts due to the

 

13

 

Employee
pursuant to the Company’s equity plans shall be reduced on a pro-rata basis. In
the event that following the reduction of the amounts set forth in the
preceding sentence, additional amounts payable to the participant must be
reduced, the cash payments under Section 12 shall be
reduced on a pro-rata basis, but not below zero.

 

23.                  Counterparts.

 

This
Agreement may be signed in two counterparts, each of which shall be deemed an
original and both of which shall together constitute one agreement.

 

[SIGNATURE PAGE FOLLOWS]

 

14

 

IN
WITNESS WHEREOF, AVI BioPharma, Inc. has caused this Agreement to be signed by
its duly authorized representative, and Employee has hereunder set his name as
of the date of this Agreement.

 

 

	
   

  	
  COMPANY: AVI BioPharma, Inc.

  
	
   

  	
   

  
	
   

  	
   

  
	
   

  	
  By:

  	
  /s/
  Leslie Hudson

  
	
   

  	
  Leslie
  Hudson, PhD, Chief Executive Officer

  
	
   

  	
   

  
	
   

  	
   

  
	
   

  	
  EMPLOYEE:

  
	
   

  	
   

  
	
   

  	
  /s/
  Paul Medeiros

  
	
   

  	
  Paul Medeiros

  

 

15Exhibit 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

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