Document:

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                                                                   EXHIBIT 10.11

                                                                   [LOGO OF PII]

[CONFIDENTIAL TREATMENT HAS BEEN REQUESTED FOR THE PORTIONS OF THIS EXHIBIT
MARKED WITH ASTERIKS (***).]

                             Manufacturing Agreement

[CONFIDENTIAL TREATMENT HAS BEEN REQUESTED FOR INFORMATION REDACTED FROM THIS
PAGE.]

An agreement made on the 17th of March, 2000, between Pharmaceutics
International, Inc., of 10819 Gilroy Road, Suite 100, Hunt Valley, MD 21031
("PII") and Keryx Biopharmaceuticals, Inc., of 216 Jaffa Road, Jerusalem 94383
Israel ("Keryx"),

Whereas Keryx intends to commence clinical trials of its drug KRX-101 (also
known as sulodexide) *** contingent on FDA approval of its IND; and

Whereas Keryx requires the manufacture of the clinical trial materials ("CTM")
consisting of a certain number of gelcaps containing KRX-101, as well as gelcaps
containing a placebo, to conduct such clinical trials; and

Whereas PII has the necessary expertise to manufacture the gelcaps required by
Keryx.

It is hereby agreed by and between the parties:

1. Keryx's Responsibilities

        1.1.    Keryx shall be responsible for supplying PII with the following
                items:

                1.1.1.  API - Sulodexide
                1.1.2.  Technology transfer document including manufacturing
                        process
                1.1.3.  Cleaning Method
                1.1.4.  Material Safety Data Sheet
                1.1.5.  Packaging protocol

        1.2.    Keryx shall supply all special assays required for the drug
                substance (Factor Xa) and shall source an appropriate outside
                testing laboratory.

        1.3.    Keryx shall be responsible for all analytical method development
                (for drug product and drug substance) transfer.

2. PII's Responsibilities

        2.1.    Feasibility Batch

                2.1.1.  PII shall review the manufacturing protocol supplied by
                        Keryx.
                2.1.2.  PII shall purchase all excipients.
                2.1.3.  PII shall verify the cleaning method supplied by Keryx.
                2.1.4.  PII shall then manufacture a feasibility batch of
                        Sulodexide 50 mg and 100 mg of approximately ***
                        gelcaps of each strength to assess the manufacturing
                        parameters. The manufacture of the feasibility batch
                        shall be completed within two (2) weeks of the date on
                        which PII receives the Sulodexide material and the
                        technology transfer document including manufacturing
                        process.
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                                                                   [LOGO OF PII]

[CONFIDENTIAL TREATMENT HAS BEEN REQUESTED FOR INFORMATION REDACTED FROM THIS
PAGE.]

     2.2. Manufacture of the CTM

                2.2.1.  PII shall manufacture up to *** gelcaps of each of
                        the following:

                        .       Sulodexide - 50 mg
                        .       Sulodexide - 100 mg
                        .       Placebo - 50 mg
                        .       Placebo - 100 mg

                2.2.2.  PII shall accept all the excipients, active
                        pharmaceutical ingredients and packaging components with
                        vendor Certificate of Analysis and perform full testing
                        (4 - 6 weeks).
                2.2.3.  PII shall prepare Master Batch Records for the clinical
                        supplies.
                2.2.4.  The CTM shall be manufactured, packaged and labeled by
                        PII under cGMP conditions as directed by Keryx in the
                        manufacturing protocol. Manufacturing staff of PII shall
                        wear respirators and Tyvex suits if appropriate.
                2.2.5.  Packing component shall be HDPE bottles and blister
                        packs and shall be packaged by PII in accordance with
                        the Keryx protocol.
                2.2.6.  The following in-process and finished-product tests
                        shall be performed under cGMP condition on the CTM of
                        each strength or as mutually agreed upon by the parties:

                        .       Visual Inspection
                        .       Shell Hardness
                        .       Weight
                        .       Fill weight

                2.2.7.  The following in-process and finished-product tests
                        shall be performed on the placebo CTM or as mutually
                        agreed upon by the parties:

                        .       Visual Inspection
                        .       Absence of active ingredients
                        .       Hardness
                        .       Weight

                2.2.8.  PII does anticipate using contract laboratories for some
                        of the activities (for Microbiology testing) in this
                        Agreement. PII shall be responsible for ensuring, in
                        writing, that any contract lab used complied with Good
                        Laboratory Practices and with all other relevant
                        requirements set forth in the Agreement between PII and
                        Keryx.
                2.2.9.  Manufacturing and packaging of the CTM shall be
                        completed and the CTM delivered with all appropriate FDA
                        and cGMP requirement documentation, to Keryx or its
                        designee(s) within 4 weeks after full testing is
                        complete.

3. Quality Assurance

        3.1.    At least five (5) U.S. working days prior to the scheduled
                dispatch of each batch of finished gelcaps, PII shall send a
                sample of the batch to Keryx, or to a third party designated in
                writing by Keryx. Keryx shall have the sample tested by such
                third party to ID and release tests.
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[CONFIDENTIAL TREATMENT HAS BEEN REQUESTED FOR INFORMATION REDACTED FROM THIS
PAGE.]

                                                                   [LOGO OF PII]

        3.2.    If, after conducting such testing, a sample is determined to
                have failed to demonstrate the required activity, PII shall redo
                the entire batch of gelcaps, at its own expense, within seven
                (7) U.S. working days of its receipt of written notification by
                Keryx of the negative test.

4. Cost

        4.1.    The total cost of $ *** including packaging in HPDE bottles,
                shall be apportioned as follows:

<TABLE>
<CAPTION>
                       Activity                                  Cost
                       --------                                  ----
<S>           <C>                                              <C>
Section 2.1.3 Verification of Cleaning Method                   $ ***

Section 2.1.4 Feasibility Batches (50 mg/100 mg), Active and
              Placebo (4 batches in total)                      $ ***

Section 2.2.1 Clinical Trial Material Manufacturing:
              50 mg/100 mg 32,000 per batch                     $ ***

              Matching Placebos (4 batches in total)            $ ***

Section 2.2.5 Packaging in Bottles and Blister Packages            TBC

Section 3     General Support                                   $ ***
                                                               --------
Total                                                          $  ***
                                                               ========
</TABLE>

        4.2.    Payments are due fifteen (15) days from the date of each
                invoice, except for the first payment, which shall be due five
                (5) days from the date of the invoice. Amounts due shall be
                invoiced on the following schedule:

<TABLE>
<CAPTION>
Invoice Issue Date                                                    Amount Due
<S>             <C>                                                   <C>
      Day I     Initiation                                              $ ***
                Section 2.1.4 Completion of feasibility batches         $ ***
                Section 2.2.3 Completion of CTM batch records           $ ***
                Section 2.2.9 Release of batches                        $ ***
                                                                       --------
Total                                                                  $  ***
                                                                       ========
</TABLE>

        4.3.    In addition to the above costs, Keryx shall pay to PII upon
                receipt of PII's invoice by Keryx for all non-capital materials
                (excipients, packaging components, HPLC columns, analytical
                standards and tooling, if any) used in the study at ***. PII
                shall obtain Keryx's prior written approval for any expenditures
                greater than $5,000. For high priced items more than $5,000, PII
                shall charge *** to Keryx, PII shall invoice Keryx for all
                reasonable and normal out-of pocket travel related expenses,
                including airfare, room & board, car rental and the like, of PII
                during any technology transfer phase or project update meetings
                requested in advance by Keryx. PII shall inform Keryx when non-
                approvable invoices (under $5,000 items) reaches a total of
                S5,000.
<PAGE>

                                                                   [LOGO OF PII]

5. Indemnification

        5.1.    Keryx shall indemnify and hold PII and PII's affiliates and its
                and their directors, officers, employees and agents, harmless
                from and against any and all costs and expenses (including
                attorney's fees) incurred as a result of claims asserted or
                suits brought against PII and PII's affiliates, and its and
                their directors, officers, employees and agents arising out of
                (i) any negligence or willful misconduct of Keryx in performing
                the services hereunder, (ii) any misrepresentation by Keryx or
                breach by Keryx of any covenant or agreement hereunder, or (iii)
                any claim asserted by a third party that Keryx in performing the
                services hereunder has infringed or misappropriated any
                proprietary or confidential information or intellectual property
                rights of such third party arising out of materials provided by
                Keryx to PII.

        5.2.    PII shall indemnify and hold Keryx and Keryx's affiliates, and
                its and their directors, officers, employees and agents,
                harmless from and against any and all costs and expenses
                (including attorney's fees) incurred as a result of claims
                asserted or suits brought against Keryx and Keryx's affiliates,
                and its and their directors, officers, employees and agents
                arising out of (i) any negligence or willful misconduct of PII
                in performing the services hereunder, (ii) any misrepresentation
                by PII or breach by PII of any covenant or agreement hereunder,
                or (iii) any claim asserted by a third party that PII in
                performing the services hereunder has infringed or
                misappropriated any proprietary or confidential information or
                intellectual property rights of such third party.

        5.3.    In no event shall either party be liable to the other for
                consequential or indirect damages, including without limitation
                lost profits or revenues.

6. Termination

        6.1.    Keryx, but not PII, shall have the right to terminate this
                Agreement at anytime and for any reason at the sole discretion
                of Keryx.

        6.2.    Upon such termination, Keryx shall pay all costs incurred by PII
                for work performed to the date of termination, provided PII
                provides written evidence that such costs have been incurred and
                work performed.

        6.3.    Within 10 days of the termination of this Agreement, PII shall
                deliver to Keryx all data, information, reports and any and all
                related documentation which were, or required to be, developed,
                generated or derived, directly or indirectly, by PII (or by any
                subcontractor or agent of PII) for Keryx during the course of
                the project.

7. Ownership of Materials and Information

        7.1.    All data, information, reports and any and all related
                documentation, which are developed, generated or derived,
                directly or indirectly, by PII (or by any subcontractor or agent
                of PII) for Keryx during the course of the project (the "Data"),
                and all inventions,
<PAGE>

                                                                   [LOGO OF PII]

                discoveries, formulae, procedures, processes, technology and any
                other intellectual property, and any improvements thereto,
                whether patentable or not, which result or evolve directly,
                during the course of the project or as a result of the services
                performed hereunder by PII (or by any subcontractor or agent or
                PII) (the "Inventions"), shall be and remain the sole and
                exclusive property of Keryx.

        7.2.    Neither PII nor its employees or agents shall have or acquire
                any right, title or interest in such Data or Inventions, and PII
                shall promptly disclose in writing to Keryx any Inventions,
                shall assign any and all rights in any Data and Inventions to
                Keryx and shall assist Keryx in performing its rights in such
                Data and Inventions.

8. Nondisclosure

        8.1.    PII agrees that it will not use, provide to, disclose to, or
                permit any third party to use any information, data, or
                documents which were received from Keryx or which were
                specifically developed or generated by PII or any third party in
                this project for Keryx (the "Project Information").

        8.2.    PII acknowledges that the Project Information is highly
                confidential, and PII agrees to return to Keryx all such Project
                Information upon the termination of this Agreement or
                completion of this project. PII's obligations with respect to
                the Project Information shall survive this termination of this
                Agreement and the completion of this project.

9. Miscellaneous

        9.1.    Independent Contractors: PII is providing the services set forth
                in this Agreement as an independent contractor and, therefore,
                neither it, its employees, its representatives nor its agents
                shall have any authority to bind Keryx in any manner.

        9.2.    Governing Law: This Agreement and any disputes arising from it
                shall be governed by the laws of the State of New York.

        9.3.    Entire Agreement: This Agreement constitutes the entire
                agreement between the parties concerning the subject matter of
                this Agreement and supersedes any prior understanding or write
                or oral agreement. Its terms may be modified or amended only by
                a writing signed by authorized signatories of each party.
<PAGE>

                                                                   [LOGO OF PII]

AGREED AND ACCEPTED

PHARMACEUTICS INTERNATIONAL, INC.

/s/ Steve King
------------------------------
Steve King
Vice President Business Development

April 3rd 2000
------------------------------
Date

KERYX BIOPHARMACEUTICALS, INC.

/s/ Ira Weinstein
------------------------------
Authorized Agent or Representative
Title: Treasurer

March 30, 2000
------------------------------
Date

Keryx Biopharmaceuticals, Inc.

Billing Contact: Ira Weinstein
                 -------------

                 -------------

                 -------------

                 -------------
P/O Number:
                 -------------<PAGE>

[CONFIDENTIAL TREATMENT HAS BEEN REQUESTED FOR THE PORTIONS OF THIS EXHIBIT
MARKED WITH ASTERISKS (***).]

                                                                   EXHIBIT 10.12

                         NATIONAL INSTITUTES OF HEALTH

                        MATERIALS COOPERATIVE RESEARCH
                           AND DEVELOPMENT AGREEMENT

This Materials Cooperative Research and Development Agreement ("Materials
CRADA") has been adopted for use of the National Institutes of Health ("NIH")
for transfers of essential research material ("Research Material") not otherwise
reasonably available for NIH research.

1. KERYX BIOPHARMACEUTICALS, INC., hereinafter referred to as "Collaborator,"
agrees to transfer the NIH's investigator, DR. PETER Q. EICHACKER, the following
"Research Material:" TYROSINE KINASE INHIBITOR, KERYX REF. KRX-211 IN ENOUGH
QUANTITY TO COMPLETE THE STUDY.

This Materials CRADA involves no other exchange of personnel or resources. All
changes to this model agreement are contained in Appendix B, which is
incorporated herein by reference. This Agreement is made under authority of the
Federal Technology Transfer Act, 15 U.S.C. Section 3710a, and is governed by its
terms.

2. This Research Material will be used solely in connection with the research
plan ("Research Plan"), attached as Appendix A, by NIH's investigator in his/her
laboratory under suitable containment conditions.

2(a).  Are the Research Materials of human origin?
         ___ Yes
          X  No

2(b). If Yes in 2(a), were the Research Materials collected according to 45 CFR
Part 46, "Protection of Human Subjects?"
         ___ Yes (Please provide Assurance Number ___________)
         ___ No

Page 1 of 6
<PAGE>

3. In all oral presentations or written publications concerning the Research
Plan, NIH will acknowledge Collaborator's contribution of this Research Material
unless requested otherwise. To the extent permitted by law, each Party agrees to
treat in confidence, for a period of three (3) years from the date of the
disclosure, any of the disclosing Party's written information about this
Research Material that is stamped "CONFIDENTIAL" or any of the disclosing
Party's oral information about this Research Material that is identified in
writing as "CONFIDENTIAL" within ten (10) days of the oral disclosure, except
for information that was previously known to the receiving Party or that is or
becomes publicly available or which is disclosed to the receiving Party without
a confidentiality obligation. NIH may publish or otherwise publicly disclose the
results of the Research Plan, but if Collaborator has given CONFIDENTIAL
information to NIH such public disclosure may be made only after Collaborator
has had thirty (30) days to review the proposed disclosure to determine if it
contains any CONFIDENTIAL information, except when a shortened time period under
court order or the Freedom of Information Act pertains.

4. This Research Material represents a significant investment on the part of
Collaborator and is considered proprietary to Collaborator. NIH's investigator
therefore agrees to retain control over this Research Material, and further
agrees not to transfer the Research Material to other people not under her or
his direct supervision without advance written approval of Collaborator.
Collaborator reserves the right to distribute the Research Material to others
and to use it for its own purposes. When the Research Plan is completed or one
(1) year has elapsed, whichever occurs first, or the Materials CRADA is
terminated, the Research Material will be disposed of as directed by
Collaborator.

5. This Research Material is provided as a service to the research community. IT
IS BEING SUPPLIED TO NIH WITH NO WARRANTIES, EXPRESS OR IMPLIED, INCLUDING ANY
WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Collaborator
makes no representations that the use of the Research Material will not infringe
any patent or proprietary rights of third parties. It is the intention of NIH
that Collaborator not be liable for any claims or damages arising from NIH's use
of the Research Material; however, no indemnification is provided or intended.

6. The NIH shall promptly report to Collaborator in writing each Subject
Invention and any patent applications filed thereon resulting from the research
conducted under this Materials CRADA that is reported to NIH by its employees.
Collaborator agrees to keep all information provided to Collaborator
confidential until the information is published or the patent issues. Subject
Invention means any invention, conceived or first actually reduced to practice
in the performance of the research plan during the term of this Materials CRADA,
that is or may be patentable under 35 U.S.C. Section 101 or Section 161,
protectable under 7 U.S.C. Section 2321, or otherwise protectable by other types
of U.S. or foreign intellectual property rights.

Page 2 of 6
<PAGE>

7. With respect to Government intellectual property rights to any Subject
Invention not made solely by the Collaborator's employees for which a patent or
other intellectual property application is filed, NIH hereby grants to be the
collaborator an exclusive option to elect an exclusive or nonexclusive
commercialization license, which is substantially in the form of the appropriate
model NIH license agreement. This option does not apply to Subject Inventions
conceived prior to the effective date of this CRADA that are reduced to practice
under this CRADA, if prior to that reduction to practice, NIH has filed a patent
application on the Subject Invention and has licensed it or offered to license
it to a third party. The terms of the license will fairly reflect the nature of
the invention, the relative contributions of the Parties to the Subject
Invention and the CRADA, the risks incurred by the Collaborator and the costs of
subsequent research and development needed to bring the Subject Invention to the
marketplace. The field of use of the license will be commensurate with the scope
of the research plan.

8. Within three (3) months after NIH provides notice to the Collaborator that
the patent or other intellectual property application is filed, the license
option must be exercised by written notice mailed to the designated NIH
official. Exercise of this option by the Collaborator initiates a license
negotiation period that expires nine (9) months after the patent or other
intellectual property application filing date. If the last proposal by the
Collaborator has not been responded to in writing by NIH within this nine (9)
month period, the negotiation period shall be extended to expire one (1) month
after NIH so responds, during which month the Collaborator may accept in writing
the final license proposal of NIH. In the absence of such acceptance or an
extension of the time limits by NIH, NIH will be free to license such
intellectual property rights to others. In the event that Collaborator elects
the option for an exclusive license, but no such license is executed during the
negotiation period, NIH agrees not to make an offer on more favorable terms to
third party for a period of six (6) months without first offering Collaborator
the same terms to be offered to the third party. These times may be extended at
the sole discretion of NIH upon good cause shown in writing by the Collaborator.

9. Pursuant to 15 U.S.C. Section 3710a(b)(1)(A), for Subject Inventions made
under this Materials CRADA by a NIH employee(s) or jointly by such employee(s)
and employees of the Collaborator under this Materials CRADA, and licensed to
Collaborator, the Collaborator grants to the Government a nonexclusive,
nontransferable, irrevocable, paid-up license to practice the invention or have
the invention practiced throughout the world by or on behalf of the Government.
In the exercise of such license, the Government shall not publicly disclose
trade secrets or commercial or financial information that is privileged or
confidential within the meaning of 5 U.S.C. 552(b)(4) or which would be
considered as such if it had been obtained from a non-Federal party.

10. Pursuant to 15 U.S.C. Section 3710a(b)(2), for Subject Inventions made
solely by Collaborator employees under this Materials CRADA, the Collaborator
grants to the Government, a nonexclusive, nontransferable, irrevocable, paid-up
license to practice the invention or have the

Page 3 of 6
<PAGE>

invention practiced throughout the world by or on behalf of the Government for
research or other Government purposes.

11. Pursuant to 15 U.S.C. Section 3710a(b)(1)(B), if NIH grants an exclusive
license to a Subject Invention made wholly by NIH employees or jointly with a
Collaborator under this Materials CRADA, the Government shall retain the right
to require the Collaborator to grant to a responsible applicant a nonexclusive,
partially exclusive, or exclusive sublicense to use the invention in
Collaborator's licensed field of use on terms that are reasonable under the
circumstances; or if the Collaborator fails to grant such a license, to grant
the license itself. The exercise of such rights by the Government shall only be
in exceptional circumstances and only if the Government determines (i) the
action is necessary to meet health or safety needs that are not reasonably
satisfied by Collaborator, (ii) the action is necessary to meet requirements for
public use specified by Federal regulations, and such requirements are not
reasonably satisfied by the Collaborator; or (iii) the Collaborator has failed
to comply with an agreement containing provisions described in 15 U.S.C.
3710a(c)(4)(B). The determination made by the Government under this paragraph is
subject to administrative appeal and judicial review under 35 U.S.C. 203(2).

12. Any dispute arising under this Materials CRADA that is not disposed of by
agreement of the Principal Investigators shall be submitted jointly to the
signatories of this Materials CRADA. If the signatories are unable to jointly
resolve the dispute within thirty (30) days after notification thereof, the
Assistant Secretary for Health (or his/her designee or successor) shall propose
a resolution. Nothing in this article shall prevent any Party from pursuing any
additional administrative remedies that may be available and, after exhaustion
of such administrative remedies, pursuing all available judicial remedies.

13. The illegality or invalidity of any provisions of this Materials CRADA shall
not impair, affect or invalidate the other provisions of this Materials CRADA.

14. Neither this Materials CRADA nor any rights or obligations of any Party
hereunder shall be assigned or otherwise transferred by either Party without the
prior written consent of the other Party.

15. All notices pertaining to or required by this Materials CRADA, shall be in
writing and shall be signed by an authorized representative and shall be
delivered by hand or sent by certified mail, return receipt requested, with
postage prepaid, to the addresses indicated on the signature page for each
Party. Notices regarding the exercise of license options shall be made pursuant
to Article 8. Any Party may change such address by notice given to the other
Party in the manner set forth above. The NIH component that is the Party for all
purposes of this Materials CRADA is the Bureau(s), Institute(s), Center(s) or
Divisions(s) listed on the Cover page herein.

Page 4 of 6
<PAGE>

16. By entering into this Materials CRADA, NIH does not directly or indirectly
endorse any product or service provided, or to be provided, whether directly or
indirectly related to either this Materials CRADA or to any patent or other
intellectual property license or agreement which implements this Materials CRADA
by its successors, assignees, or licensees. The Collaborator shall not in any
way state or imply that this Materials CRADA is an endorsement of any such
product or service by the U.S. Government or any of its organizational units or
employees.

17. Either the NIH or the Collaborator may unilaterally terminate this entire
Agreement at any time by giving written notice at least thirty (30) days prior
to the desired termination date.

18. This Materials CRADA constitutes the entire agreement between the Parties
concerning the subject matter of this Materials CRADA and supersedes any prior
understanding or written or oral agreement.

19. This Materials CRADA shall be construed in accordance with Federal law as
applied by the Federal courts in the District of Columbia.

20. The undersigned expressly certify and affirm that the contents of any
respective statements made or reflected in this Materials CRADA are truthful and
accurate.

21. This Materials CRADA shall be effective upon execution by the Parties. The
term of this Materials CRADA is twelve (12) months from execution.

22. The provisions of Articles 3, 5-10, 14 and 20 shall survive the termination
of this Materials CRADA.

                        SIGNATURES BEGIN ON THE NEXT PAGE

Page 5 of 6
<PAGE>

FOR NIHCC:

/s/ DAVID K. HENDERSON                            4/10/00
---------------------------------------------     ----------------
David K. Henderson, M.D.                          Date
Deputy Director, NIHCC

Mailing Address for Notice

National Institutes of Health Clinical Center
9000 Rockville Pike, Bldg 10, Rm. 2C407
Bethesda, MD  20892

For Keryx Biopharmaceuticals, Inc.

/s/ BENJAMIN CORN                                 April 10, 2000
---------------------------------------------     ----------------
Benjamin Corn, M.D.                               Date
President

Mailing Address for Notices:

Keryx Biopharmaceuticals, Inc.
216 Jaffa Road
Jerusalem 94383 Israel
Att: General Counsel

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<PAGE>

[CONFIDENTIAL TREATMENT HAS BEEN REQUESTED FOR INFORMATION REDACTED FROM THIS
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                                   APPENDIX A

                                  RESEARCH PLAN

I.  BACKGROUND

         Despite the use of effective antibiotics in combination with
cardiopulmonary support, the mortality rate from sepsis and septic shock for the
last three decades has remained high (35-50%). During this time, the incidence
of reported cases of sepsis in hospitals has more than doubled. New therapeutic
approaches are needed to lower the persistently high mortality rate of this
increasingly frequent syndrome.

         Much data suggests that activation of the host inflammatory response
and the release of mediators, particular cytokines such as tumor necrosis factor
(TNF) and the interleukins, contribute to the pathogenesis of sepsis and septic
shock. However, therapies like TNF antibodies, soluble TNF receptor, and IL-1
receptor antagonist, designed to directly inhibit these mediators, while
beneficial in animal models of sepsis, have not been beneficial in clinical
trials with septic patients. Studies performed at the NIHCC show that risk of
death from infection may have had an important influence on the effects of these
previously studied agents (1). While very beneficial when the risk of death is
high, as in published animal studies, these agents were less beneficial or
harmful when the risk of death was lower, as in clinical trials. Data also
suggests that other factors, such as the site and type of bacterial infection,
may alter the effects of immunomodulators in sepsis.

         Finding agents for the treatment of sepsis that remain beneficial over
a wide range of risk related to differing types of infection may be important to
improve this therapeutic approach. One such agent, KRX-211, is an inhibitor of
the Janus family of protein tyrosine kinases (Jaks). The Jaks are important in
inflammatory cytokine mediated signal transduction. Activation of these enzymes
results in the production of other inflammatory mediators like the cytokine IL-6
and nitric oxide (NO) and propagates the inflammatory cytokine. In vitro studies
have shown that KRX-211 reduces the production of IL-6 and nitric oxide by mouse
and rat macrophages. Furthermore, early in vivo studies have shown that this
agent increases survival with endotoxin challenges that produce either low or
high mortalities. In a limited number of studies, the agent has also been
effective in rats challenged with endotoxin. It is unclear, however, whether
KRX-211 will have similar beneficial effects during inflammation associated with
either gram-negative or gram-positive bacterial infections.

II.  STUDY OBJECTIVE AND DESIGN

                                      ***
                       (paragraph intentionally omitted)

                                      A-7
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[CONFIDENTIAL TREATMENT HAS BEEN REQUESTED FOR INFORMATION REDACTED FROM THIS
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                                      ***
                       (paragraph intentionally omitted)

III. COLLABORATOR CONTRIBUTION

         The contribution of the Collaborator to the research plan is the
Research Material. All activities to be conducted by the NIH with the Research
Material pursuant to this Materials CRADA are set forth in this Appendix A. Any
other research activities conducted by the Collaborator with its Research
Material shall not be deemed to be governed by this Materials CRADA. This
Research Material, KRX-211, has been developed by the Collaborator and is not
commercially available nor obtainable from another source.

                                      A-8
<PAGE>

VI.  ABSTRACT OF THE RESEARCH PLAN FOR PUBLIC RELEASE

         Although host inflammation contributes to the pathogenesis of sepsis
and septic shock, anti-inflammatory agents effective in highly lethal
gram-negative models of sepsis have not been beneficial in clinical trials where
mortality was lower. Emerging data suggests that variability in factors related
to infection capable of influencing the effects of these agents, such as the
severity, site and type of infection may explain these differences. Ideally
anti-inflammatory agents would work in sepsis regardless of such factors. The
tyrosine kinase inhibitor KRX-211 inhibits endotoxin stimulated IL-6 and nitric
oxide production in vitro and improves survival with endotoxin challenge in mice
and rats. In early studies, this protection was present with doses of endotoxin
producing both low and high mortalities. The purposes of the present study are
first to confirm these beneficial effects with KRX-211 during E. coli infection
and then to determine the influence of site (intravenous vs. intrabronchial),
type (E. coli vs. S. aureus) and severity (LD10 vs. LD50 vs. LD90) of infection
of its effects.

V.  TITLE FOR PUBLIC RELEASE

The effects of Kinase Inhibitor, KRX-211, in rats challenged with intravascular
or intrabronchial S. aureus or E. coli infections.

                                      A-9
<PAGE>

                                   APPENDIX B

                    EXCEPTIONS OR MODIFICATIONS TO THIS CRADA

AMEND ARTICLE 3 AS FOLLOWS:

3. In all oral presentations or written publications concerning the Research
Plan, NIH will acknowledge Collaborator's contribution of this Research Material
unless requested otherwise. To the extent permitted by law, each Party agrees to
treat in confidence, for a period of three (3) years from the date of the
disclosure, any of the disclosing Party's written information about this
Research Material that is stamped "CONFIDENTIAL" or any of the disclosing
Party's oral information about this Research Material that is identified in
writing as "CONFIDENTIAL" within ten (10 ) days of the oral disclosure, except
for information that was previously known to the receiving Party without a
confidentiality obligation. NIH may publish or otherwise publicly disclose the
results of the Research Plan, such public disclosure may be made only
after Collaborator has had thirty (30) days to review the proposed disclosure to
determine if it contains any CONFIDENTIAL information, except when a shortened
time period under court order or the Freedom of Information Act pertains. The
disclosure shall be delayed for an additional thirty (30) days upon the request
of the Collaborator to preserve U.S. or foreign patent or other intellectual
property rights.

ADD NEW ARTICLE 22 TO READ AS FOLLOWS:

NIH agrees to provide all data resulting from the research conducted under the
Research Plan (Subject Data), including any raw data, to the Collaborator and
both parties will be free to utilize Subject Data for their own purposes
consistent with their obligations under this CRADA. To the extent permitted by
law, the Collaborator shall have the exclusive right to use any and all Subject
Data in and for regulatory filling made by, or on behalf of, the Collaborator,
except that NIH shall have the right to use Subject Data for that purpose, and
authorize others to do so for that purpose, if Collaborator abandons its
commercialization efforts, which abandonment shall be evidenced by
Collaborator's notification in writing to the NIHCC.

ORIGINAL ARTICLE 22 IS RENUMBERED TO BE ARTICLE 23.

                                      A-10

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