at

1 2 3 4 5 6 7 8

201

Can identified have think got Dr. any

we the

do issue.

more I an it I issue

substantively? don't answer as think yet, well you we as are that

We have any I could. that won't today, raised of us

more

of put

though. anyone right

Cornetta DR. WILSON:

think which

this
be

is able

a difficult to come of internal the for to a

probably on been

definitive points

answer have and we should

and for

a number our own for on DR.

important

9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 __'

consideration sake of time,

discussion. go ahead

Probably, and move

now. Dr. because Again, it up. No; to point, that to I I be don't able and think think the testing, are going I it hard think to it answer think is that something about and, and is to have is a today was Cornetta, I I can't want I see to don't you. respect get Are the

SALOMON: input

any yrou
Eact

physical okay that with you DR.

that? brought CORNETTA:

thing and I

that think

you the Carolyn, is going

are

going

overall was to

probably zhe just :oming Joing :o to FDA as

have through

they up with be

went

with for

retroviruses this

guidelines that

something with.

they

struggle I

think

all

the

appropriate

comments

have

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 erector safety consider. specifically." and agree covered need safety that, to good-faith not your think sort particular all that used you to the this what other is are of it been made. DR. would giving one, SALOMON: be you that sponsors an area of fair guys I Then to we say, will since time that move I about you on. have this have--as I been

202

a hard do think

appropriately difficulty guidances to and

acknowledged, you try and have help

available it out. commend very that there we

figure So I

do

you much haven't

for so,

what in solved

I this it

think and yet.

was it is

a

effort, fault Are be testing too. DR. c) DR. with Question mobilization concern Please for WILSON: and d)

additional is VRX. c), I

in

vivo

studies now have the

that

performed of

regarding think we

gone

over

I already.

think

we

have

really

SALOMON: that. 3. is the consider Now we

Good.

I

was

going

to

try

"Please considered proposed the clearly

discuss an clinical following, had

whether advantage trial or and a

a discussion

of

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at mobilization leave
3 4 5 6 7 8

203

yesterday. the faithful airport, to some so of

I we

know will the

Dr. try

Mulligan and

had remember

to

to be

and made

comments

that

he

yesterday. "Are the data available by additional mobilization discuss the from wild-type preclinical that optimal shou Id the assays HIV to

assess sufficient? studies
be

vector

mobilization Are there vector if some,

to

assess and,

9 10
11

performed design." Dr.

study

Allan, So just trivialize not

we that to

have is take it. on

discussed the myself That was record. too

the

monkey I make a

12 13

study; joke 3ut of not

right? it to

seriously

a good

15

discussion.

16
17 18

so,
think jump in that there

are the

there data here say, that

additional was yes; there now, we it

studies? sufficient? was was are a sufficient lot doing of So

Do I

we will to

and to me

19
20 21 22 23 24 25

demonstrate nobilization. Low mobilization, To ritro >een trote culture studied, that

Again, high me, what system, was down. about Yes ; I

adjectives;

mobilization. calculated which 1000 1000 is out reasonably copies copies of per ml. in the what I in has

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at packaged/mobilized, you
3 4 5 6 7 8

204

depending use, me, per that can ml is infect is a a lot cell

on occurring. when

which

terminology

want

to To

one set

copy off

of an

HIV

theoretically infection of The is mobilization to are

and

a patient. studies to in CD4 to the cells. the B-cells, because when it. if higher you So I you think to sell of mouse The show that there of

studies I would there are

failure suggest, enough I or

mobilize

9 10 11
12

uninterpretable cells, to go do find

were looking those, those CD19

not at you

CD19-positive 2 percent, have and to

would studies, cells.

back, much

want injury

levels

15 -_

DR. be considered

ALLAN: there? uniformly

Do Is

other there all or

target tropism,

cells

need

to

16 17 18
19 20

necessarily, cells be so should

to

non-CD4-positive some other cell. type

macrophages

considered? DR. TORBETT: was the about has types, it to be would mentioned envelope it in qualified seem And that before, nature antibody against reasonable, of terms as issue you is are this. where panel we relevant changing If you an of are

21
22 23 24

because, or would antibody cell stressing think

as

since

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 i 2 3 4 5 6 7 8 9
10 11

205 trying happen, to that DR. experiments. :he -hat Tutting Terkit nice to or see detail, could but be EGFP detect that the issue nonprobable be Yes; I don't are a explored it suggests want lot of done; H9 lines into into to to get other for down things example, the --or the SCID into but a bad bit thing further. to

SALOMON: Again, there relatively into H9

simply and putting cell was for details my that I point you think I for,

Mold4, whether T-cells, Again,

different it

mobilization

noninfected

example. of that; of have the disagree but whether if it view, all I just am to that now you agree a don't little know and

the from think

12

saying start :here
is,

is this, is unless is there

that, I

demonstrated question with you is I biological is that an

mobilization. someone what is I says

no,

16 17 18 19 20 21 22 23 24 '1 .._/' 25

:hat :hat

am waiting mobilization,

mobilization vhat that

or means of

a in it,

lot terms and

of

mobilization, of the

significance
low?

therefore

issue

Is mobilization DR. .hat it wasn't

that in

a problem? this system. What to me

Are

we

going

to

accept

ALLAN: clear

struck what

me was

as

the

fact mobilized

being

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

?.

at and whether the was it they data directly or--let consideration of recombinant but which something is like else, are was actually presented, looked me at see; is in recombinants which either what whether there, could was the else you not was have that be, at it or good, not,

206

because 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 " i 25 questions, mobilization their To what that, have the the vector vector mobilized which antisense looked got is some some

vector at. sort My

replication-competent, point later, or

which

a gag/p01 that has been

intermediate mobilized. So

not

just anything

that else. I mobilized

the

vector

has

been

but DR.

TORBETT: getting now

think

the and

question you is are that

is asking

is is

becoming Not vector are is just

infectious; necessarily being there mobilized, other of

right? but they

DR. beyond

ALLAN: the

infectious which being I

demonstrated, It it is DR.

things terms.

mobilized. think

a question

terminology. TORBETT: really. was very I I guess the to I is can it is question assess say is to in it me two different of any vector' of occurred. and what

mean, hard All

animal degree,

models. how

much,

unclear

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666
/

at is coming out DR. would overall happening species 7 8 9 10 11 12 mixing have more both we happen in I and already data in in be to safety is the humans. think matching, had, that that, we to go we in don't agreed know the into should you on whether details the do should it and I now understand back are to going vitro want restated. want to go I mode NOD, Again, but I don't or I the into think again, NODa to cultures to restate better discussion need to with the is unclear. So I think the suggestion as what of might an is the

207

SALOMON: better

characterize--I concern, is matching as the idea and

think, that evolution for what

mixing, system

a model

we see

longer-term

characterization--I have already I don't into going you or how those

what

15 16 17 18 19 20 21 22 23 24
I

saying--get are then

because

we

study-section in do it. the

whether SCID, to is have

would think

love that

conversations, for NOGUCHI: that, "We today. Some would of

appropriate DR.

this like

is to

sounding, see and something an

to

get else assay as

back like for

into

a nonreplicative that." maybe that Yet is there too

recombinant, has much been to ask

a discussion at this

25

well,

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4 5 6 7 8 9
10 11

208 time. DR. much was saying real to too ask. much that evolution, in think on this we that need and to we SALOMON: I don't ask. want if it kind to I think I think don't think anybody everybody that non-replicative, of know consider a system about its it and, and if try there that told is you here is of not too that is a viral there and

evidence is

sequences is, I

regulate intelligently.

safety

DR. point Jector can the make chance So considerations. >etter, :hink :ranscript, zome out for DR. It ;t was would alluded be I if whether you because but a

TORBETT: we something full-length for I are

I using that

think not has

this a an

is

an

important

12 i 13 14 15 16 17 18 19 20 21 22 23 24 -.,' 25

self-enacting active which LTR which

transcript

increases

recombination. think I it are these don't is using some of a it are know SIN as this or a serious which an vector active, is but I

full-length information needs to

then safety

concerns. This SIN to sense of is vector note this Mike Emerman, wouldn't that is was that again. work. actually the

EMERMAN: to interesting guess my that

Lested.

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4 5 6 7 8 9
10 11

209 antiviral does ban depend vector effect on depends copackaging, except on copackaging. it is to hard have for it If us it to

mobilization

characterized. DR. assay what design we all SALOMON: for agree more assessing on complex, is that I think, in terms of I be in an think done vitro in

mobilization, it should

long-term, cultures.

multicellular

Now, include nave with some your animal

whether studies,

or

not sort

you of been am, or

should building pretty

also on--you successful trying to I do

12 13 14 15 16 17 18 19 20 21 22 23 24 ~~.._.,~' 25

expertise SCID studies.

and

have I

again, a

articulate ;hink that I C would -hat--I rhat is

a decision would am not that sure be

here, a positive.

recommendation.

certain, you how do

though, that

as because is testing.

I

said, I think

that

insist am not not DR.

that--that simple It is an

science.

necessarily DROPULIC: that. SALOMON: absolutely we done As

extreme

amount

of

Jerk

to

do DR.

I

said, It

as is 3?

my a lot

laboratory of work.

lees

it,

I Are DR.

agree. with Part

Question b) of

WILSON:

Question

3

is

more

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 : 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 ., .__-. 25 think about something going to I that the we the have discussed, it or is before out subjects mobilization? DR. TORBETT: the you of technology put the the Many is cells of the very in, That things similar, do is it in very that we now. have haven't the study of So in But gotten talked subjects now. what terms should of be looking done for on the vector study specific to DR. you so the study subjects. Yes; So on about is this what what I missed what first is we that should part happening are being right we do--we that in

210

SALOMON: are right.

focussed enough which

we

reminded

whether culture

coming

patients.

similar. So I think in well. that the I the past same need kinds to that be of studies applied up for to

discussed as I DR. is

patients

am opening

discussion,

guess. SAUSVILLE: the logical of don't the just clinical note that, this know I would echo that. the viruses what we I issue into are

follow-through, virus exactly situation. in the long or

evolution that--we see in

would

list

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4 5 6 7 a 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 lothing saying natching species is
Eollow

211 of things that trial, of variants and whether or that is DR. DR. the clinical-trial that to worked changes who are new out in clearly whether running SALOMON: ZAIA: I should you you are I going didn't that be to go emerge, captured. some the be back I looked and think, That aspect population for look, is in but very the this

clinical issue important include vector
HIV

would of the of the

mobilize change around. Dr. just

Zaia? want AIDS at fitness that going in have this virus to to say that within

groups, looking drug so you fitness will

clinical-trial of virus technology very rapidly of their is

3-roups, relative Nell detect patients olood.

additions, are

population in

DR. the

REITZ: virus

I

think,

also, with of

you some time.

want sort You

to of will

populations over it. I think a period

Jenotype Learn stuff

analysis from DR. but that viral as

SALOMON: logical the same parts big a

that

there here in of

is terms of and the as

follow-through concerns leading concern to after we

have evolution the

mixing of

treatment

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at before. Therefore, 3 4 5 it should I think if be cell some of you everyone agree, has the said advice biologically, different be through is of drug than on Dr. Yes, the that, virus, we So that of could fitness but done tropisms molecularly specific--I interesting the things that. would be on but, either think because could which and be it just that

212

characterized lines it has or is that saying some in with to

multiple also, through what also looking Dr. implies at

genotyping Zaia

changes rapidly

resistance full that Zaia? I per was se. easily would just If sequencing basis.

could

10 11 12

be trying

done to

more imply Is DR.

changes right,

that ZAIA: of about

thinking we do be just are most

about 15 16 17 18 19 20 21 22 23 24 panel concerned

fitness

that. like an a

DR. quantitative increase indicator in cell Dr. DR. to

SALOMON: assay the rate line. Long? LONG: I what the the

demonstrated spread Okay; I through stand

a given corrected.

would kind fact screen

just of that

like assay they

the would only clones

ask be detect

the

consider given when

appropriate one variant

240-some

sequencing.

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

,

at DR. right. 3 4 5 6 7 8 9 10 11 12 the offer patient 14 15 16 17 18 19 20 21 22 23 24 ..- / 25 reasons ;his is I know Seen tiere a clean kind deletions. were that relatively we are DR. seeing. COHEN: for I percent calculation. mutations. DR. DROPULIC: Most of few them that 91 No. were had percent am Ruben I They had all There substitutions deletions. I like in from trials medical terms GTI there centers manage to of so I having that just There of them It SALOMON: were were was No; hundreds changed. 264 clones. you of didn't variants. That 240 is get that About a rough had various

213

80

deletions. the base were Cohen. would

room of

VIRxSYS.

a global I about in in have the training

perspective graduated patient the

safety. little

involved involved I also am

collaboration. would like with have The sentinel cells with that the also fact to say way come that that VIRxSYS through I one is the this of the

happy I world.

handling

because

agricultural rector is limited is

consider its expression have to what

under to going is. One of the

a

control, basically

some the

activity lroblem

on

relationship

the

lessons

I

would

like

the

FDA

to

MILLER REPORTING COMPtiY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 x 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 ".25 this sffected, 3T1, is rery not you is taken. are that absence. only function sentinel needed, towards this I be thinking about world the market. is it because was and The fact antisense The it always is and that, having in is I under not think, a come out of the

214

agricultural there, in the

working tomato

molecular something for constitutive It of was that. of it a is its

biology we buy

reason, was

failure promotor, everywhere

expressed. was this only afraid has works a kind

everybody that it is both safety being

function, think the is

where

expressing and handled. I think that the the the

something appeal of the way

both product DR.

NOGUCHI: I think this of fact is, in that it what this we not know to need work biology as to be to

point reason discussion

is that

well we is of

However, actually the having absence The

extensive is is the not to

evidence that fact, the only this

evidence be a sentinel-

question. basis that us, we which and, for is from today and it is

We agree to have but know what likely So

scientific in teaches what true will able to

well, be what be

believe

tomorrow be go

approved. through this

we

MILLER REPORTING COMPANY, INC. ‘ 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at in 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 ,__ 25 3f the nobilization necessary characterize because reservoirs in blood. DR. SALOMON: of viral to my I think course, that is is fair. One and I their the to to the the time minuses illustrate develop specificity. As details in but that. we remains need is often and So said, both your to specific be god point assured for only now and it we are the getting devil absolutely that, one in fact, are well down an fact here and open that really the the something
a

215 fashion we have going pros intense that and as we possibly such all a the really in have this can. grueling pluses does being type able of to I think set and of

spent over cons interest does

always taken, sentinel 2ell.

the

particular

DR.

DELPH: occurs look HIV species may be at

I into

have

a

question. tissues, and I find in from am

If is it

other

viral

reservoirs there. you

species that very

asking viral what you

that

different

find

difficulties,

sampling So, again, HIV as

characterizing yould )rimary defer

reservoirs. colleagues who

do

business.

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4
I

216 Dr. DR. question for DR. macrophages Zaia? ZAIA: the ALLAN: and and, function. do DR. DR. point. Dr. in in Zaia's I think comment I or we to I I the even within You see if I phase You if you So I would II suggest study. could you do, think the can blood look You let whether II in is it get what there actually mobilization effect are that some look at of the that that is a

1 macrophages

might things

have 8 9
10 11

on can

you

compartment. at can. stand that also the semen. That and should well sense 4, agree also can we on I is a think come taken. that, have the basic

DELPH: SALOMON: we

Yes. should about

12 1 13 14 15 16 17 18 19 20 21 22 23 24 25

a phase I think going

a phase are say think think how done is we

Iwhat really

I

was

Question all have we

covered. here. up gray. Yes? DR. Dr. ZAIA: that safety I to

Iprinciples jEor
C

we far

articulated go without it

you

edge

getting

Zaia? There think is needs one to is rules for aspect, be though, and the will the of

c)uestion t -hat zrules 1.ook at is of

4 the

discussed to we If

assessment The and look

linked say that

escalation. 28 days

toxicity.

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802
(202) 546-6666

at 1 .'j 2 3 4 5 6 7 8 9 10 11 12 13
/

217 toxicity I think the nore needs lose not agent. So to are rethink not I the asking safely. I am they 3 times sure are lOlo, would design how I to really of get encourage this T-cells there knows cells we all are more around know how study the because expanded several about the safe sponsors they and other than same that I 28 things is not just days that there, have convinces we I a dose the have don't escalation, transducing agent, or the we will escalate. with that you that. can see I don't some But, study want that to is of

a problem me been even

talking think unless agent.

about. this you But

importantly, to be

escalate the research

investigational

infused studies lo where

mean, the FDA

14 15 16 17 18 19 20 21 22 23 24 25

infusing and

level, is.

I these regards different Loxicities nore, elucidate :hat we I cells to

don't that

think make

there them

is more

anything dangerous

about in What other which are is

infusion-related about that these we are cells talking or normal the standard

toxicity. is these about less

guess, within look at

virological the in

easy

to periods

observation trial.

_.._ 1
MILLER R@PoRTING COMPANY; INC. 735 8th Street, S.E. Washington, D.C.. 20003-2802 ,_.-1 ~. (202) 546-6666

at So that 3 how kinds nrith. DR. rJhat 8 9
10 11

218 I think has this that that to is a critical with, I rule most concerned question think, for is the

the can of

sponsor they use

contend dose-escalation we are

toxicities

SALOMON: going to questions. to things and I wonder addressed were That to a was a say

Actually, is I What close, here if is think I for

that we would people I of

is are

perfect. kind to to got don't. I that would of do

I

was

done low, in List,

with in with too,

the coming other

like

weigh a

because some the of I

have you

12 ;ay that

We have -/ there me. clear way I

questions. things don't

couple one. the dose of

lathered 15 16 17 18 19 20 21 22 23 24 j. 1 25 lose-related zomments safety :o . I Tery :he

think escalation--and is going, in the

it

is

me whether it is the Part do a dose

dose

get

escalation me is

in well, same why

lifferent lot--you latient.

patients. could

escalation

Certainly, that concerns would DR. say a

I

would

echo things

Dr.

Zaia's that are I six don't months. are not really think

28-day--the to me; 28 like

days? three

No; to these

more

CHAMPLIN: issues so

Although much.

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666 : ^i

.,,.,

at
1

219 DR. DR. toxicity realistically and lver :o be the a emergence longer dose the that period independent. importance is just But, to of is SALOMON: CHAMPLIN: sort in of the of all short resistant of time So and you the No. So you the are term issue looking toxicity virus, is could dose the you aspects are of of probably sort escalation tolerance looking the at biology to the of of infusion for analysis course, going

2 3 4 5 6 7 8 9
10

minimize because the sort lf the

establish

infusions. of long-term whole DR.

really,

11 12

phase-I

approach. SALOMON: say, I guess There in HIGH: better HIV days, Then, variants, probably, once you while not have want analyzed two or But that I am is That you a is don't little toxicity three if what days. we are talking of would before have to to got like you it, what to even it is it. the at second 28 at drew is good point. need confused from 28 But, days on infusion. the to

14 15 16 17 18 19 20 21 22 23 24 25 1. ../

:hen, rind lremises lou

I out.

might

here. that DR.

know

ibout lappening .east .hat roing

is

doing to

characterization you

wait blood. to

28

take So you

a

little might you

characterize enroll at least,

'atient

before

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1
2 3 4 5 6 7 8

220

ays,

what DR.

is

going SALOMON: agree I was

on

with Yes.

the I Dr. way not are

first guess High, Dr. long concerned. issues

one. what and Zaia and to But concerned a dose effect of I am that I is were see Dr.

aying he

is

I

with think 28 days

you, the is we

conundrum. at it

oming he

enough

safety

issues said, dose but

that the

'hamplin rith .he the infusion.

safety is

escalation

simply

9
10 11 12 13 14 15

My jut that is

response three here, of the of be to

to five

that

is, days. If

okay,

good got

point, to is I be an

We have the present, concern

:onsistent evolution ;hink 3ut that

logically. viral months discussed. species is

then appropriate.

a couple should DR.

probably

16
17 18 19 20 21 22 23 24 25

SAUSVILLE: of why the

Recognizing dose issue your endpoint to going that the to

that

that It

gets does are

into Lead (ou

the to going

issue the to

escalation. as to here. infusion, be does a big have what

protocol-design consider matters

zertainly, nre don't they captured are

related they are something out. if we

while issue, to be

think formally and

scoped

Certainly, incidence of variants

are

looking et

at

the a

mobilization

cetera,

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. D.C. 20003-2802 Washington, (202) 546-6666

at 1
2 3 4 5 6 7 8

221

dose certainly I sort

response of of is a role there come

relationship interest down a dose a role in little escalation for doing way. Dr. to the

to also

input capture.

would So but I do and I

be I guess 28 there believe

middle, soon. here longer the dose

agree

days is that

probably for is

believe I of do

periods escalation.

observation Let's put it DR. kind of where DR. DR. Torbett. DR. zo loing ,ossibility outcome. nonths or So rush leed -he Tet is doing to first this, going to have get it. some

before that

9
10 11 12 13 14 15 16 17 18

SALOMON: you HIGH: SALOMON: were Yes.

High,

did

that

capture

going?

Dr.

Allan

and

then

Dr.

ALLAN: efficacy But that you it outcome

Safety with know is

is this

also--you or is you always to have

are wouldn't the

hoping be

there not might going

a good for six

That longer. my dose to

not

happen

19
20 21 22 23 24 25

question, escalation do or want it after the to let's

then,

is

do

you What If

need is this

to the is who what

anyway. 28 first sit see back what days. three and

patient do we

patients go, okay,

happen,

happens

before

MILLER REPORTING COtiPm, INe. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 nore data, integrins Sausville. DR. fundamental it was per shown cell--that TORBETT: question. that, I guess In depending is, the I have some of on number a little the the of earlier number hits bit latient :o take topping nter rhat Lccrual :he faster e oak do anymore at efficacy that So DR. I would CHAMPLIN: what patient. things of patients you do the the are and let's but it to may say see look not you You if at be want need a we is get there good to well would need then to work So, process they can wait. defined make define out your obviously, that allows complete you early not a--not an outcome. to outside

222

ossibility

criteria, another those

events You and

exactly

accordingly. initial faster

additional :he trial. If

accrual,

you

ask you

for enter So

a year another has have an

follow one, to be accrual you of

up it some

for is

every going sort of

before forever. ground

there you

niddle reasonable 1n.d should then

where number of

of can

a observe

patients

that kind

make you DR.

it

a go/no-go the trial. Dr.

determination

continue SALOMON:

Torbett

and

then

Dr.

of per

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. D.C. 20003-2802 Washington, (202) 546-6666

at ell --you out. DR. DR. howed 6 7 8 9 10 11 12 :ransduction ;hat Sup-Tl-cell DR. 15 16 37 18 19 20 21 22 23 24 is late cells, we this tiasn't lvIO1 is number percent then out the would up, it clear per MO1 and time vary. DR. iown the fer cell, us can or Am I can't correct? Can The that, MO1 of 10 or or Right. so am sure sorry you question if you 5, faster. So, as faster. about breakthrough MO1 of that word. at a 0.1 you dose 10 repeat is, had and that? I one 20, think integrin the select quickly the variants

223

oming

DROPULIC: TORBETT:

you

originally or an

jreakthrough DR.

came

slower

DROPULIC:

vector--I DR. DR. TORBETT:

am not I

DROPULIC: MO1 of

We saw 5 and a

challenge

in

experiment. TORBETT: comes from number per you cells, increase period Is DROPULIC: see to that At any. Maybe and I it is the had way any I more am--it to the of The the reason whole I am bringing it what on 100 the the

question--and that But I had

document cells. even the look if

depending can of get

you number for

integrins, coming

variants

logical? the optimally transduced

haven't DR.

TORBETT: the day

in

haven't

MILLER REPORTING COMPANY, INC. 735 8th Street; S-:E. D.C. 20003-2802 Washington, (202) 546-6666

,

at sugar, But
3 4 5 6 7 8

224

so if you

maybe had

that one you

is integrin

part

of per

the cell virus,

problem and, say integrins up--and a want time longer to that vary. like at

here. a you had per you time, look you

certain more cell-had the could would

time, integrins, 1 am pretty length very want DR. just good of well to

had less, making control

a and

turnover you had

10

these but you it

numbers took

time be sample

that longer each

would and time the

9
10

would would

SLEPUSHKIN: In per So on any cell. there all the case,

I we That will

just have won't be

to for during

11

answer copy

it. number

specification change the

escalation. of
15 16 17 18

about escalation. of MO1 cell is

same so

amount you

integrins just

steps

of

are

changing DR.

amount So the

injury. going to be

TORBETT:

constant. DR. DR. is it? DR. 200 as it was SLEPUSHKIN: in the animal I probably or the will clinical be about SLEPUSHKIN: TORBETT: Just, Yes. out of curiosity, what

19
20 21 22 23 24 25

experiment. DR. of 200. TORBETT: So it is going to be an MO1

‘ ,. ,/ ,..

,!

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

225

DR. DR. MOI; yes. DR. of cells. DR. specifications; between experiments, DR. suggesting--well, the variability. be DR. I of But am not these I going points. 1 and

DROPULIC: SLEPUSHKIN:

That Not

is

not copy

copy number.

number. It is

TORBETT: Okay. SLEPUSHKIN: copy 10. it was

I

understand,

per

X number

Copy number per the

number cell clinical should animal be

And, 6. So guess

in

TORBETT: I

is you

there can't is

any

data with that

control

Maybe brought SALOMON: to try I to, everyone up

that here. Unless and come we this share things

something

shouldn't

you to have kind with that

guys

want

me on job.

to, each

consensus done of you, were our concluding and not

think in

would have

like

process, FDA staff,

with in

the your

additional list. So I believe sure

question

my

job that

as

chair

has gets unless I

suddenly a someone am not

now

to

just and

making everyone that I

everybody So

comment is insisting to.

gets come to

heard.

consensus,

'."._,"

Joing

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at
1
J.

226

Dr. DR. would forward. without admirable too job DR. like It to

Torbett? TORBETT: commend was many of DELPH: like to a pretty boundaries, starting I would up This the is a first for step they the like some has a high. treatment CD4 been count right are done stairway. to concern selected of now, really 600 echo that. about for as the this an the coming CD4 I trial going and a I think, and I

2

company brave

fairly

8 9 10 11 12 13 14 15 16 17 18

would patient trial. upper DHHS out counts in

also

express that

population I limit guidelines favor drop In of below the as really is way for

think to

even not until

recommending 350. European low there as are 200 are

treatment

guidelines, 200. Generally

they

are speaking

even

dropping and, CD4 Mould zhe cells 200, ;hat Yhat of counts

them course, of

exceptions, not that the may have ill.

patients so I

with

over

19
20 21 22 23 24 25

certainly-company from but with is I says patients think the safe The need for other

1 understand that they who we need for them. thing, and I the have to

difficulties in getting of to under

that T-

CD4 also patient

counts need

balance and

population

don't

know

what

MILLER REPORTItiG COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at your actual inclusion HAART be that classes recommend two and of the far more you that that drug criteria therapy." clearly define someone someone classes even three, it are But defined in is be terms resistant resistant on at least I for think and of I the to. to the two at "failing that would number I

227

or

discontinued
3

needs

to

recommend of drug

would
7 8

least market protease

currently but

possibly inhibitors.

9
10 11 12

YOU

are any,

going drug

to

look

at left.

people So

who those

really are

have my

few, major

if

options

comments. DR. DROPULIC: want FDA set to in to assure I appreciate you these now and that patient your we those want criteria. comments are comments to work

14 15 16 17 18

and with It well is

I

just the not taken. DR.

finalize stone

DELPH: community DROPULIC:

I

also on

suggest that. Yes.

that

you

work

19
20 21 22 23 24
* ..__/ ’

with

the

HIV DR.

Okay.

Thank

you.

Yes. DR. the
200

LEVINE: if are and I

Let could.

me

address Once

the you get

issue below

of

cell cells,

number, there

increasing the culture.

difficulties I think if

with we

25

the

transduction

MILLER REPORTING COMPANY, INC. 735 8tih Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666 c ,,, CII

at 1
2 3 4

228

ould n a

make different he has

an

analogy se.tting, given with with IL2 the

about with to the

immunologic Cliff patients, of came came was had not in Lane's

treatment studies, there raising with in an coming with a a was a

here eal he ount ount .ffective .n

dichotomy CD4 count

effectiveness who that there you

5
6 7

patients those is, once

above below of 200. So

200 200; the

versus that IL2

8 9
10 11 12

patients

below

I

think,

at what trial

that may safety

point, be

the irreparable and

immune injury

system ind lore

has

suffered make any

would difficult.

feasibility

DR.
15 16 17 18

NOGUCHI: I 2 has been

The will

question point out

is

not that for that

simply

>ne

of

difficulty.

interleukin treatment parameters Mhat we are of of

actually carcinoma are far

approved sp

the

renal-cell experience talking the technical is very fine CHAMPLIN: the availability trying well tune. about

the than,, do particular and expand we will

differe,nt But of cells that we this

19
20 21 22 23 24

here. aspects to may take be

understand approach them. need to

which There really DR.

areas

They

are of

few

and

far twins

between,

but

identical

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. D.C. 20003-2802 Washington, (202) 546-6666

at 1 sometimes treat twin 4 5 6 7 8 9
10

229 can a that seriously you from. that can give ill get So, offers, you sort patient unlimited for proof sometimes, of an who opportunity now has of kinds to a normal

numbers of principle unique

leukocytes of things,

opportunities. DR. DR. perspective is responsible SALOMON: GOLDING: from for vaccines. as you know, the a Dr. I Office lot of Most are So we the are patient. just no same when though to you like effect thing deal you control effect. can be seen relatively changes important, in once the the in this or we case, worse have to when disease deal with an just of HIV of done what in are Golding. to bring Vaccines. vaccine the in a little Our including group

11 12

therapeutic vaccines, antiviral guidelines

therapeutic the sort context of of the safety of

therapies. that of Of

using

terms

15 16 17 18 19 20 21 22 23 24 ._ i ,., 25

monitoring

course, be is either the

outcome progression, Nhen iraccine, is we

can

deal that to have I

with even help

with gave

therapeutic something YOU that

supposed

viremia,

actually

a negative that

think measuring So I

quickly latient.

by

viral-load it is

think

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at cells to 3 4 5 6 7 8 9
10 11

230 have really this weeks, of CD4 of been take first and viral counts to load because transduced multiple period, actually into measurements whether have it a as talking is sense well, about the individuals of one of of viral month the course, all is loads or

over six slope of kinds

measurement you are

toxicities. There is the of infusion more the adverse bad is much in more your rapid fit patients. reaction, product, increase toxicity. viruses But you what in There that, I is down think have you viral are

potential the if road, you have

emergence can dominate a really really to see

12

something going Load.

15 16 17 18 19 20 21 22 23 24 .t 25 you have are vith. 3110~ not

For in You you to DR. said, going

that, the have see

you millions to have some

have of

to viral

have

patients to would increased. logic is to that start

that

loads that

a window really Right.

really

enhanced The though, choose that the day

SALOMON: Dr. to is

what you are

Golding, want not loads to all on

probably population rising initiated. HIV

a patient far that gone and treatment wildly is

that viral

DR.

GOLDING:

I

wouldn't

say

total

failure

MILLER REPORTING COtiPANY, INC. 735 8th Street, S.E. Washington, . . D.C. 20003-2802 ,_ (202) 546-6666 ~

at 1 2 3 4 of really anti-HAART don't of you adverse to DR. the terms 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 -.. ...I 25 LOO beads achieve consultation toxicity Immunotherapy rats toxic zhan looking effects what we studies on the context of I table. beads, cells in buy that you the had go with think a million you reaction to the will that next So Dr. we copies be able you patient. have to shared put that with us in in because to want see to I this use to

231

type
allow

SALOMON: with patient some One what

Delph

selection. other would less means of at all. But concerns be, in than you beads I maybe I terms 100 could into think you wanted of beads literally someone. you have would I the per to put CD3, 3 be do a

CD28, million putting not

have

which thousands one

cause

pulmonary to answer

embolus. that. DR. LEVINE: with the done infusing for at are that

experience

That FDA. by a sort of

number There what large of used

was have to

developed been be of Baxter beads were higher

in

number thing. very

into no

There much

levels infusing. also very

beads

We are per currently

much cells.

below What of

that we greater

number are able than

of to

3 million is a

depletion

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 ,I 2 stimulate billion ratio anticipate 6 7 8 9 10
11

232 six logs to 50 cells, of, let's easily beads. DR. understand because numbers numbers you and of SALOMON: why think you lOlo you want you want and to higher even-when CD4 cells. are get in 1 am you Another to issue; activate going up to to I these have these infusion. getting really comments I ignore culture of interleukin don't the them biology in 2, into getting stand on the think cells very higher low I is what million and say, being we start cells, have, up to able say, 2 to to with. 100 a So million 3-bead-to-cell 3 billion, deplete six we would of if we were to a

cells,

logs

those

your not are Your that. to and

12 state down 15 16 17 18 19 20 21 22 23 24
,/’

Pheresis, of to the 150, But I why and T-cells 200 don't

Ihat. understand >f T-cells

understand wants them

everyone activate

nonphysiological inject them I rector Jells. 3ackbone, lot :hat happy you is So I back mean, it my is

concentrations in the the whole patients. purpose into

of

a

lentiviral

incorporated murine to it. to Moloney activate But you maintain

non-replicating virus and For a normal I am

leukemia my don't. T-cells

have

about are trying

studies immune

25

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at repertoire don't what 4 5 6 7 8 9 10 11 12 CD4/CD8 maintenance culture Immunology repertoire. DR. ratio? DR. 14 15 16 17 18 19 20 21 22 23 24 is going to you. not to analyzed by DR. LEVINE: the CDR3. Okay. from consensus, believe T-cell at to the activate 2 just to that phenotype. early and seems prepare I the guess, chair. so just these To low-dose you to don't me you a again, this As 24V beta families as SALOMON: Defining repertoire as the is cells why you think the after want DR. yet there immune you you you is are any doing data is I there. I can tell after in do the maintain you that 60 days the in of entire just these here that things that I

233

demonstrating is don't left in these

repertoire do to this. go

understand

LEVINE: of the

repertoire in that 1996 we

published showing

Journal the

SALOMON: coming get don't normal studies

a comment try I the initial you don't with just and

We are comment assays go into effects

not

maintain these where to are a treat adding later

have interleukin

have

another thing your based

variable on an

yourself that you

for have

assumption

repertoire.

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4 5 6
7

234 DR. experience cell HIV infusions patients and have has 60 even So disagree. DR. is perfectly MS. Delph's terms of SALOMON: fine. KNOWLES: one I step about in the would further the like to and other research are I put trial for of more would the is people the pipeline things like message going with to forward to HIV be a coming take Dr. Right. That's fine. That I or more. think we just have to agree to LEVINE; with these and in done done 80 with cancer 51 with infusions I would say that we have CD4in

T-cell bulk

infusions, T-cell patients.

with infusions We,

ourselves, CellGenesis am guessing patients,

infusions

in

HIV

patients. cells cancer I

CD3-28-stimulated and, in

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
)_

comments her

caution--in

comments agents is right. As to

pharmacological because down caution that last-ditch because it DR. 3ecause about the it your the she

There such, not

pipeline. the sponsor proposed treatment is one DELPH: wasn't protocol.

clinical effort potential I clear Are have from these

armamentarium. question you have going given to us be

another what

25 .,...'

subjects

--

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 I (202) 546-6666 .,,.j ,, ..,.,

i

at 1 2 and, not come 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 is take there out time. DR. going insurance TORBETT: to be--I to In any am make just sure event that you don't, criteria life. company We will are for you the so, failing That we can is if if on. off on antiretrovirals DR. they But or DROPULIC: are we not are on not not? They a will be failing then require that drugs enroll so FDA have far to and in but, see is they them HAART are to

235

therapy, .* that two can it the we to

going

therapy. they are on

We think one or they defined with is how

unethical. they the are study. again, how we

therapy, how negotiate this. we

then have this That

approach it presently.

characterized

MS. going drugs? DR. think DR. that Who had DR.

KNOWLES: to pay for

If

they them?

go

on Who

study is going

drugs, to pay

DROPULIC: about TORBETT: you follow pay for that

I

hadn't one.

thought

of

that.

You

propose these those,

in individuals assuming

your

set for that

of

would

the

problems? DROPULIC: We plan to be around a long

curious. that that

Would is

you

done?

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at This is a serious before. DR. we can do that. DR. on that. DR. quite long frankly, time. DR. I have, I two and think days on will, and which I ;ort :o lene rill. )roduct of bother that That, as the last guess is I the of SALOMON: this the have, biggest the shuffling fine. still of is feel comments like, as here--it also the much safety. to is this phase gray I and area we of want to payload, of the the part of continues trans if you this is focus and not of I think specific these one to of the VIRxSYS, in comments but the DROPULIC: because Haven't we expect thought to be about around it, a TORBETT': I .-Just wanted your thoughts DROPULIC: consideration. I am just If that curious. is a requirement, It has been

236

discussed 3 4 5 6 7 8 9
10 11

12

-hat Last Eocused if you

discussions very the

perhaps risk,

appropriately, fruit,

low-hanging

replication-competent of the DNA species, et

16 17 18 19 20 21 22 23 24
! .. , ’

Lentivirus :etera,

number me what is being to me, issues you

happening delivered, is of as

a part

Here, okay." But

get

close this

25

remember

MILLER REPORTING COMp"ANy, ‘ I&?. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at safety when 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 _2'5 Jood advice DR. I think it and is I not there very think efficacy. is hard the significant to rules been construct change. through So, that-at are of some one point, of my we going personal need the through have with I a talked that. would lot you of note noting to as to deletions we safety we have need aspect. actually gotten very some though recombine and to so be of actually very that these the the good Dr. Wilson things. evaluation payload and forth monitoring do which may disagree. to quality all that back But, as risk Dr. and risk/benefit -2 with to that, I here Noguchi unclear said, benefit, ratios

237

We have xenotransplantation. just is how think that, we

comments also and these up consider the

characterizing the payload we dealt NOGUCHI: has on that, are been and diligently central does appear the virus

integrity because has not

changes to now,

everything really DR. there

about,

discussion and It is Takefman actually it

oecause actually different clearly 2ven from

push

mutations, is an just So I on activity the think that.

CORNETTA:

This

is

Ken

Cornetta.

Can

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666 -

at 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 , 25 that? DR. LEVINE: Yes. We have several lines what to to this
bit

238 I make a cornmerit? DR. DR. up T-cell stimulation was reading have and limited, very well, a little function SALOMON: CORNETTA: bit of after process. through. gotten given has at what Yes; I go guess were ahead. just saying and me, of have experience, those cells allogeneic don't maybe to pick the

you

about the too,

transduction That While T-cells back, been least bothered a lot that our that after

as

I

cancer been

patients manipulated although function transplantation.

so, the be T-cell

in

the

process, was of the you

their

ability to advantages be able me

to do

do seems I saw

initially So was one that

designed real might

lacking.

lentiviruses in that vitro there that again, once be not DR. as the

to a of and to

avoid little

stimulation. seemed would concern they we got hoped. Do you to be

It a in

bothered fair these their into the amount

stimulation that, function, would

occur that back

cells ability patient,

SALOMON:

want

to

comment

on

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 f evidence, them, defects both cancer We have tudy 7 in lymphoma and that, of I could by the patients recently where we spend an hour by as HIV CD3 talking and are 28, removed

239

bout everse rom

stimulating T-cells and

we

they patients. at

completed have

phase at TMA Day 12

I

looked following

.ntracellular Lntimycin ritro .s :hat a culture substantially is increased In response lnd show to that that that With different Looked 30th infusions specifically the CCR5 levels. Also, production in at before of from CCR5 the

cytokine stimulation and at showe,d

response Day th"at

and of in

a
9 10 11 12 13 14 15 16 17

0 and

at

we. can", reverse . response at

,, what Day 0

diminished at HIV Day setting, mixed increase did several response. to a 12.

we

have

looked

at

allogeneic we can we

lymphocyte in the years study

reaction

population increased

ago--we

allo-MLR respect the in

CCR5

population with on this CD4

that study, patients,

is we

ia
19 20 21 22 23 24 25 .._..

population vivo expressed infusions, and CD4 30 times

and 3, on

after 10 the

dose-escalating 10' that and we could, have show, reduced

cells,

in t.he

vitro, HIV

we patients

have

looked both before

at

cytokine and.

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 after think that stimulation there are I nonphysiologic not 7 stimulating you apoptosis. of things is improved think but and a wide it is very of CD3-28 also might by be is much T-cell higher. functions so

240 I

spectrum

following the point that

stimulation. that better. CD28 BCL2 protecting a wide following CD28 it may So, be by

CHLA4, are So that

stimulating

specifically, against spectrum stimulation. DR. that, that sponsor -he >f clinic, mix and clinical I in .o this do. certainly we work works one

upregulating there are really improved

a
9 10 11 12 13 14 15 16 17

is

SAUSVILLE: if through through can this some

I is

guess

I

would to issues, and

offer the or gets into flavors for extent the

successful of these issues many be

these imagine That would

different the subject

match.

Euture

investigations. would way would SALOMON: to disagree leave Fine. a bit of agree doing it at that, it, that. as and I said, has we this being is vested one way

ia
19 20 21 22 23 24
i

certainly

particular And DR. I

Again, ago

;ad

agreed

nothing

'hanged. Any lose? other comments or can we come to a

25

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 2 3 4 5 6 7 the here to here area. one how that does last DR. two GAYLCR: days and But, There 1 E$+&+t feel as is a said anything to earn I a paucity It changed input feel terribly about is need of for my

241

compelled statistician,

way data data

somewhat. work for So with.

obviously reasons.

understandable my could the that role, have man not on I think, any the

a brand-new from to being really this, involved in

has scientific street been

a
9 10 11 12

somebody this. I discussions thought. There guess, has

really

feel I A lot

very have of a it lot is of think research a

comfortable heard. questions of good theoretical to look There have

with has been

the been a lot of

raised. and I I

been

discussion comfort at. and been done that

again, have But a I

because

16 17

don't

lot

data the

committee that has

the done;

people makes me

18
19 20 21 22 23 24
/’

involved, Eeel lone like at this

the

everything point. SALOMON: that NOGUCHI: this VIRxSYS

is

being

could

be

DR. final comments DR. : could zommittee, take

Again, they On would behalf to

anyone like of really for

else to the thank being

have make? FDA, the so bold I

any

hope

liberty especially,

25
.__ ‘ .

as

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at to come here as best The has as been rigor and we face can the put stings it. for civility not-so-obvious like and questions. our we are side, we can we to for say will the to getting thank us our through this as round, well and arrows, I

242

guess, 3 4 5 6 7

committee, both

especially, in its and

exceptional in pursuing I would us

obvious especially on set keel of on

questions. chair this for very I that, able entire to with make field DR. chair, let you said, committee step That specifics You that. yesterday situation @ ill, I also for that because up is

keeping difficult think this the

a
9
10 11

that, advice,

confident decisions

be

appropriate and we

move that. Then,

12

forward SALOMON: me speak guys going did

thank you,

you Phil. I

Thank for

as

everyone. a really a couple the us a best real good of

think job. years a I

that have that

15 16 17

VIRxSYS, always this can at. of

back

now, sponsor to the

functions and when that guys thank doing they we were provide we allow have the the even can

when protocol deal with to and who I

ia
19 20 21 22 23 24
4

look kinds

really the fields that

move respect

forward.

done

sponsors exact have same more them

presented in lose, on some a if of you

thing to on

25

taking

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

at 1 their far 3 4' 5 6 7 8 9 10 11 12
.,’

243 things as you I two in, and worked here, hotel everyone to to three in Depolito so hard take to us and that guys think days, there and put to to they have. everyone depending with the all dinner, the us. rest this to audiovisual hadn't Again, from on even I thank the brought them. for you Harvey staff to us staff around and get in who us are quite as

committee group

which To of

hanging Gail

Rosanna the FDA

together, move

rooms, else Thank

involved. you very much. Everyone travel

safe. [Whereupon, adjourned. at 1:50 p.m., the meeting was

13 14 15

MILLER REPORTING COMPANY, INC. 735 8th Street, S.E. Washington, D.C. 20003-2802 (202) 546-6666

244

CER

TIFICA

TE

I, ALICE TOIGO, the OfficiaI Court Reporter for Miller Reporting Company, Inc., hereby certify that I recorded the foregoing proceedings; that the proceedings have been reduced to typewriting by me, or under my direction and that the foregoing transcript is a correct and accurate record of the proceedings to the best of my knowledge, ability and belief.

ALICE TOIGO

-