### September 25, 2001

Boro Dropulic, Ph.D.

Chief Scientific Officer

VIRxSYS Corporation

200 Perry Parkway, Suite 1A

Gaithersburg, MD 20877

Phone: (301) 987-0480 Fax: (301) 987-0489

RE: Public RAC Discussion of Protocol #0107-488 entitled: *A Phase I,
Open-Label Clinical Trial of the Safety and Tolerability of Single
Escalating Doses of Autologous CD4 T-Cells Transduced With VRX486 in
HIV-Positive Subjects,* Rob Roy MacGregor, M.D., University of
Pennsylvania.

Dear Dr. Dropulic:

On behalf of the National Institutes of Health (NIH) and the NIH
Recombinant DNA Advisory Committee (RAC), I want to thank you and your
colleagues for participating in the September 6, 2001 meeting of the
RAC. This letter conveys the major observations and recommendations made
by the RAC during public discussion of your protocol.

During its preliminary review of your protocol, the RAC identified a
number of issues that warranted public discussion. Prior to the RAC
meeting, you received and had an opportunity to address comments of the
RAC reviewers. Copies of the reviewers' written comments are enclosed
for your records. A copy of the portion of the meeting transcript in
which your protocol was discussed is also available upon request. The
RAC appreciated your responsiveness to the reviewers' questions prior to
and during the meeting and your willingness to make suggested changes to
the protocol and the informed consent document.

During the RAC's public discussion of your protocol, the following
additional observations and recommendations were made:

-   With regard to pre-clinical studies:

    -   Stricter testing for VSV-G (Vesicular stomatitis virus,
        strain G) prior to lot release has been proposed and should be
        implemented.

    -   Further details about the focal lesions seen in several animals
        should be provided. Depending on the nature of these lesions,
        revisions to the clinical protocol and informed consent may be
        necessary.

    -   Samples of all clinical lots of the vector should be archived.

    -   Comments made during the discussions regarding the use of 293
        versus 293T cells and the use of a 2 plasmid versus a 4 plasmid
        production system should be considered, though no specific
        recommendations can be made.

-   With regard to the clinical protocol:

    -   Entry criteria about what constitutes a "HAART failure" should
        be clarified. The investigator should consider consulting with
        another HIV clinician to confirm that no other acceptable
        antiretroviral regimen is available as an alternative to study
        participation. Further details should be added as to which
        antiretroviral medications can be taken during the course of the
        study.

    -   The proposed addition of T-cell repertoire testing by
        immunoscope technology should occur before administration of the
        vector product and at one point 4 to 12 weeks post-therapy.
        Responses to tetanus vaccine should be monitored, as outlined in
        the modified protocol.

    -   The proposed 4 week follow-up period prior to advancing to the
        next subject was discussed extensively, with particular focus on
        whether 4 weeks would be long enough to confirm the presence of
        a new strain of lentivirus in the participant. The potential
        that new viral strains will develop and take longer than the
        proposed timeframe to appear was also discussed. These concerns
        should be discussed in both the protocol and the informed
        consent document and addressed in the sponsor's response to
        these recommendations.

-   With regard to the informed consent document:

    -   It should be clearly stated that this is the first clinical use
        of a new vector class.

    -   The concerns surrounding this vector class should be explained.

    -   "HAART failure" should be defined more clearly. The
        antiretrovirals that may be taken during the study, as well as
        those that may not should be listed.

    -   "The second paragraph of the "Purpose" section of the revised
        informed consent document should be made into a new section
        entitled "Possible Benefit". It should replace the current
        "Benefits" section.

    -   A copy of the final, IRB-approved informed consent document will
        be shared with the RAC following its submission.

-   With regard to broader safety issues:

    -   It is recommended that the definitions of which adverse events
        would lead to DSMB review should be better defined. For example,
        in order to establish what would constitute a significant
        decrease in CD4+ cell counts or increase in viral load, the
        participants' normal variability in these counts should be
        established over a prolonged period of time (such as, 6 months
        or even one year prior to study enrollment).

    -   Specific assays with which to monitor survival of transduced
        cells should be developed.

    -   To reduce the possibility of generating a potentially more
        virulent HIV virus than would already be present in the test
        subjects, individuals with only CCR5-utilizing strains of HIV
        should be excluded from the study.

    -   Specific tests to assess the genetic interaction between the
        vector and the resident HIV strain should be developed. Such
        tests could include assays for degenerate gag/pol sequences;
        changes to mobilized vector and recombinant genomes; and the HIV
        viral genotype pre- and post-gene transfer.

The RAC voted to endorse these observations and recommendations by a
vote of 9 in favor, 0 opposed, and 0 abstentions.

As you know, the current reporting requirements set forth at Appendix
M-I-C-1 of the *NIH Guidelines for Research Involving Recombinant DNA
Molecules* *(NIH Guidelines)* require the principal investigator to
submit a written statement responding to each of the RAC's observations
and recommendations and to provide additional documentation as specified
to this office no later than 20 working days after enrollment of the
first research participant. These reporting requirements are excerpted
and enclosed for your convenience.

The Internet site \< http://www4.od.nih.gov/oba/\> of the NIH Office of
Biotechnology Activities (OBA) includes a copy of the complete *NIH
Guidelines*, minutes of RAC meetings, and information about gene
transfer research protocols registered with our office. Contact
information for our office is as follows:

> Office of Biotechnology Activities (OBA)
>
> National Institutes of Health
>
> 6705 Rockledge Drive, Suite 750, MSC 7985
>
> Bethesda, Maryland 20892-7985 (20817 for non-USPS mail)
>
> Phone: 301-496-9838; Fax: 301-496-9839

Thank you for your detailed responses to the questions from the RAC
reviewers, which you provided to us at the meeting. Please let us know
if you have any questions about the RAC's recommendations on your
protocol or the requirements of the *NIH Guidelines*.

Sincerely,

Amy P. Patterson, M.D.

Director

Office of Biotechnology

Enclosures

cc (letter only):

> Rob Roy MacGregor, M.D., University of Pennsylvania

Harriet Izenberg, IBC Contact, University of Pennsylvania

Joseph Sherwin, Ph.D., IRB Chair, University of Pennsylvania

Claudia Mickelson, Ph.D., Chair, NIH RAC

> Philip D. Noguchi, M.D., Director, Division of Cellular and Gene
> Therapies, OTRR, CBER, FDA
>
> Stephanie Simek, Ph.D., Division of Application and Review and Policy,
> OTRR, CBER, FDA
>
> Greg Koski, M.D., Ph.D., Director, OHRP, DHHS

RAC Reviewers: Ms. King and Drs. Markert and Aguilar-Cordova

Ad Hoc Reviewers: Drs. Coffin, Yee, and Zaia

> **Reporting Requirements**

**of the**

*NIH Guidelines for Research Involving Recombinant DNA Molecules*

**(Appendix M-I-C)**

**Appendix M-I-C-1. Initiation of the Clinical Investigation**

No later than 20 working days after enrollment (see definition of
enrollment in Section I-E-7) of the first research participant on a
human gene transfer experiment, the Principal Investigator(s) shall
submit the following documentation to NIH OBA: (1) a copy of the
informed consent document approved by the Institutional Review Board
(IRB); (2) a copy of the protocol approved by the Institutional
Biosafety Committee (IBC) and IRB; (3) a copy of the final IBC approval
from the clinical trial site; (4) a copy of the final IRB approval; (5)
a brief written report that includes the following information: (a) how
the investigator(s) responded to each of the RAC's recommendations on
the protocol (if applicable); and (b) any modifications to the protocol
as required by FDA; (6) applicable NIH grant number(s); (7) the FDA
Investigational New Drug Application (IND) number; and (8) the date of
the initiation of the trial. The purpose of requesting the FDA IND
number is for facilitating interagency collaboration in the Federal
oversight of human gene transfer research.

**Appendix M-I-C-2. Additional Clinical Trial Sites**

No research participant shall be enrolled (see definition of enrollment
in Section I-E-7) at a clinical trial site until the following
documentation has been submitted to NIH OBA: (1) Institutional Biosafety
Committee approval (from the clinical trial site); (2) Institutional
Review Board approval; (3) Institutional Review Board-approved informed
consent document; (4) curriculum vitae of the principal investigator(s)
(no more than two pages in biographical sketch format); and (5) NIH
grant number(s) if applicable.

**Appendix M-I-C-3. Annual Reporting**

Investigators shall comply with annual data reporting requirements.
Annual data report forms will be forwarded by NIH OBA to investigators.
Information submitted in these annual reports will be evaluated by NIH
OBA and the RAC, and possibly considered at a future RAC meeting.
Information obtained through the annual data reporting process will be
included in the NIH Human Gene Transfer Information System to: (1)
provide clinical trial information; (2) provide administrative details
of protocol registration; (3) provide annual status reports of
protocols; (4) facilitate risk assessment of individual applications of
human gene transfer; and (5) enhance public awareness of relevant
scientific, safety, social, and ethical issues.

**Appendix M-I-C-4. Serious Adverse Event Reporting**

Investigators who have received authorization from FDA to initiate a
human gene transfer protocol must report any serious adverse event
immediately to the local Institutional Review Board, Institutional
Biosafety Committee, Office for Human Research Protections (if
applicable), and NIH OBA, followed by the submission of a written report
filed with each group. Reports submitted to NIH OBA shall be sent to the
Office of Biotechnology Activities, National Institutes of Health, 6705
Rockledge Drive, Suite 750, MSC 7985, Bethesda, MD 20892-7985 (20817 for
non-USPS mail), 301-496-9838, 301-496-9839 (fax).