0:01
SNI Digital Innovations in Learning is pleased to present
0:08
interviews with the authors of newly published research in clinical neuroscience.
0:19
This discussion will be on the management of patients with low-grade gliomas and other brain tumors
0:26
by Timothy Clousie
0:30
on a paper published in the New England Journal of Medicine, which was pioneering in developing a pharmacological treatment for low-grade glioma Timothy Clousie is professor of neurology and
0:47
molecular and medical pharmacology at UCLA,
0:52
a member of the Brain Research
0:55
Institute UCLA, and the Johnson Comprehensive Cancer Center.
1:01
Director of the UCLA Neurooncology Program, co-director of the UCLA Brain Tumor Center, and director of the Henry Sickleton Brain Cancer Research Program
1:17
The discussions on this program are Sayeed, Ali Khan-Sari, and James
1:26
Iauspah.
1:28
And I'll say welcome everybody to this
1:33
innovative session of SNIA Digital, in in which which we're we're interviewing interviewing leading leading scientists scientists from from around around the the world world,, clinicians clinicians
1:42
and and other other scientists scientists to to learn learn about about what what we we can can, what's new do and and what what we we can can do do in in our our own own countries countries with
1:50
with the
1:52
the treatments treatments that that are are available available.
1:54
.
1:55
And And today's today's topic topic is is going going to to be be low-grade low-grade glioma glioma.
1:58
.
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We're We're really really privileged privileged to to have have Tim Tim Klaus Clausi here here.
2:03
So So this this is is a a picture picture of of Tim Tim,, Tim's Tim's professor professor of of neurology neurology and and molecular molecular and and medical medical pharmacology pharmacology at
2:11
at UCLA UCLA.
2:12
, I'm a member member of of the the Brain Brain Institute Institute and and the the Johnson Johnson Comprehensive Comprehensive Cancer Cancer Center Center there, director of the there, director of
2:19
the UCLA UCLA on neuro-oncology neuro-oncology program program,, co-director co-director of of the the Brain Brain Tumor Tumor Center Center, and and director director of of the the Henry Henry
2:26
Singleton Singleton Brain Brain Cancer Cancer Research Research Program Program,.
2:29
do Do you you have have time time for for anything anything else else,, Tim Tim??
2:33
I I need need more more time time.
2:35
All alright right.
2:35
was it we We really really?
2:36
appreciate appreciate your your coming coming here here And. And the the reason reason that that we we asked asked you you is is because because you you were were involved involved in writing a in
2:44
writing a paper paper that that was was very very significant significant,.
2:48
And and I'm I'm going going to to show show the the paper paper to to everybody everybody in in the the audience audience.
2:52
.
2:54
This This is is a a paper paper on on the the treatment treatment,, which which is is now now a a molecular molecular biochemical biochemical treatment treatment of of low low grade grade glioma
3:01
glioma.
3:01
.
3:02
Can Can you you tell tell us us how how we we pronounce pronounce that that?
3:04
?
3:05
Yeah Yeah,, for for a sight in them for a sight in them a cydenum.
3:08
For for a a sight cydenum in them.
3:09
.
3:09
For a cydenum And. And it's it's for for IDH1 IDH1 and and IDHmute IDHmute and and low low-grade grade glioma glioma.
3:13
.
3:13
We're We're going going to to get get back back into into that that in in the the discussion discussion.
3:16
.
3:16
So So those those who who don't don't know know much much about about it it at at this this moment moment,, we'll we'll catch you catch you up up on on it it,.
3:21
so don't worry.
3:22
So So, don't worry.
3:22
So Tim Tim,, do do you you want want to to tell tell us us a a little little bit bit about about this this
3:26
paper that paper that you you did did And and I'm I'm going going to to get get back back to to showing showing you you on on the the screen screen and and I I can can show show that that whenever
3:33
whenever you you want want,.
3:33
Okay okay?
3:34
?
3:34
Sure Sure.
3:34
.
3:34
Yeah Yeah.
3:34
, so So thanks thanks,, Jim Jim. You the,
3:38
you know know, as, as you you know know,, low low grade grade gliomas gliomas are are mostly mostly non-enhancing non-enhancing.
3:41
.
3:42
They They occur occur in in younger younger adults adults.
3:44
.
3:46
We We,, you you know know,, more more recently recently based based on on the the
3:50
IDH IDH mutation mutation have have defined defined the the disease disease based based upon upon that that,.
3:55
IDH mutant astrocytoma IDH, IDH mutant astrocytoma, IDH mutant mutant oligodendroglioma oligodendroglioma.
3:58
.
3:59
And And there are there are two two
4:02
types types of of IDH IDH
4:05
that that we we consider consider IDH1 IDH1 and and IDH2.
4:08
IDH2 Varicidinib.
4:10
has Varocidinib has a a brain brain,, is is it it brain brain penetrant penetrant?
4:13
?
4:13
It is potent It against is both potent IDH1 against both IDH1 and and IDH2 IDH2.
4:16
.
4:17
And And that's that's the the reason reason that that Varicidinib Varocidinib was was used used and and developed developed specifically for for specifically for brain brain cancer cancer.
4:25
.
4:25
And And of of course course it it went went through through the the typical typical kind kind of of evaluations evaluations to to understand understand a a phase phase one one setting setting where
4:33
where what's what's the the dose dose that that we we feel feel we we could could give give,, what were the side effects effects, And and then then some some preliminary preliminary evidence
4:39
evidence of of activity activity, and and even even did did something something called called a a window window of of opportunity opportunity study study where where we we give give the the drug drug,,
4:44
we we take take the the tumor tumor sample sample,, we we look look to to see see the the impact impact on on the the target target, and and then then
4:52
confirming confirming that that it it got got into into the the brain brain,, confirming confirming that that we we knocked knocked down down to 2Hg, HG, then then we we were were ready ready to
4:57
to go go forward forward and and initiate initiate this this study study.
4:59
.
4:60
And one One thing thing when when you you initiate initiate a a study study like like this this is is you you have have to to pick pick the the population population.
5:05
And And in in the the all all of of the the data data that that we we had had,, the the population population,, you you can could imagine imagine we we were were evaluating evaluating grade grade
5:12
2 two,, grade grade 3 three,, those those who had who had had had prior prior radiation radiation,, those those who who had had not not had had prior prior radiation radiation,, all all of of
5:18
them them were were going going to to be be residual residual tumor tumor that that were were active active in in some some way way and and growing growing.
5:22
.
5:23
And And you know, we we found found that that the the predominant predominant group group that that seemed seemed to to be be benefiting benefiting were were the the group group that that had had
5:28
non-enhancing non-enhancing tumor tumor.
5:30
.
5:30
That That was was the the group group that that we we could could follow follow, and, we we could could show show that that there there was was tumor tumor shrinkage shrinkage along along the the
5:34
way way So So that that was was the the population population.
5:36
that was included that in was included in this this study study.
5:38
.
5:39
And And it it includes includes patients patients who who are are 12 12 and and older older.
5:43
.
5:44
Patients Patients
5:47
had had some some surgery surgery.
5:48
, After after surgery surgery,, they they had had to to wait wait at at least least a a year year.
5:52
, and And then then they they had had to to have have some some residual residual tumor tumor that that was was present present and and were measuring, measurable, because we were measuring
5:57
progression progression for for you your survival survival as as the the primary primary endpoint.
5:59
endpoint.
6:01
So So this this is is the the population population that that was was included included.
6:05
It It allowed allowed patients patients who who were were within within a a year year or or up up to to five five years years with with regard regard to to the the time time from from surgery surgery.
6:14
.
6:14
And it's
6:16
And it's a a general general,, as as you you guys guys know know,, this this is is a a healthy healthy population population in in general general.
6:20
.
6:20
It's It's a a group group of of patients patients that that are are young young,, that that are are active active, that, that are are in in the the prime prime of of their their lives lives with
6:25
with regard regard to to careers careers,,
6:30
having having families families,, various various things things like like that that.
6:32
So So this this is is the the population population that that was was - enrolled in in the the study study.
6:37
.
6:37
Can Can I I ask ask you you a a question question now,, Tim Tim??
6:39
What What kind kind of of symptoms symptoms did did these these people people have have?
6:41
?
6:41
Or Or since since they they were were a a more more chronic chronic disease disease,, they they were were basically basically not not very very symptomatic symptomatic.
6:47
.
6:47
Well Well,, what what can can you you tell tell us us that that?
6:49
?
6:49
Yeah Yeah,, most most of of them them were were not not symptomatic symptomatic.
6:51
.
6:51
I I mean mean, there, there were were some some that that had had seizures seizures,, seizures seizures,, of of course course,, it's it's quite quite common common.
6:56
Usually usually fairly fairly easily easily treated treated with with.
6:59
a single single agent agent,, anti-convulsants anti-convulsants,, but but sometimes sometimes we're we're,, you you know know,, still still breaking breaking through through focal focal
7:04
seizures seizures occurring occurring, those Those types types of of things things.
7:07
.
7:08
And And then then I I think think,, you you know know,, as as always always,, depending depending on on the the location location of of the the tumor tumor,, there there could could be be
7:12
certain certain symptoms symptoms.
7:13
.
7:13
But But in in general general,, these these are are slow slow,, infiltrating infiltrating tumors tumors.
7:16
.
7:17
And And therefore therefore,, there there aren't aren't a a lot lot of of symptoms symptoms that that the the patients patients have have.
7:21
.
7:21
And And so so the the goal goal is is to to try try to to maintain maintain that that.
7:24
.
7:25
I'll I'll also also say say that that,, you you know know,, we we,, some some years years ago ago,, there there was was a a study study done done with with low low grade grade gliomas gliomas
7:31
that that had had nothing nothing to do to do with with IDH IDH at at the the time time.
7:34
We We didn't didn't know know that that the the IDH IDH mutation mutation.
7:36
existed existed.
7:37
.
7:37
It It was was a a randomized randomized study study that that looked looked at at radiation radiation versus versus watchful watchful waiting waiting.
7:41
.
7:42
And And of of course course,, in in that that study study,, it it was was found found that that those those that that had had watchful watchful waiting waiting had had an an earlier earlier
7:48
progression progression.
7:49
.
7:49
But But sometimes sometimes that that progression progression took took two two years years,, five five years years.
7:52
, and And so so patients patients were were not not getting getting any any therapy therapy during during that that time time.
7:56
.
7:56
They They were were doing doing fine.
7:58
They they weren't weren't,, you you know know, the, the measurement measurement for for what what progression progression was was was was not not great great.
8:02
Nevertheless Nevertheless,, those those patients patients eventually eventually would would then then go go on on and and have have therapy therapy.
8:07
, And and there there was was no no difference difference in in survival survival from from the the group group that that had had radiation radiation initially initially.
8:10
.
8:11
This This is is at at a a time time when when radiation radiation was was being being used used alone alone for for low low grade grade glamas glamas and and not not having having chemotherapy
8:17
chemotherapy.
8:17
.
8:17
So So that that idea idea that that you you could could watch watch and and wait wait as is some is and and that that study study kind kind of of allowed allowed us us as as practitioners
8:23
practitioners to to be be able able to to take take that that population population to to be be able able to to say say we we can can not not have have any any harm harm by by monitoring monitoring
8:31
them them during during that that time time.
8:32
.
8:32
And And that's that's kind kind of of this this population population.
8:34
.
8:34
This This is is the the same same population population that that that was was watching watching wait weight,, but but now now it it was was, okay okay,, I'm I'm going going to to treat treat,,
8:40
I'm I'm going going to to have have a a placebo placebo-controlled controlled trial trials, it's one-to-one one-to-one randomization randomization,.
8:45
I'm I'm either either going going to to treat treat them them with with this this IDH ideation inhibitor inhibitor or or I'm I'm going going to to give give them them a a placebo placebo.
8:49
.
8:50
But But they they all all know know after after they they go go through through a a process process where where there there could could could be be progressions progression.
8:55
that that they they go go ahead ahead and and that they they can can have have.
8:57
, so So as as they they go go through through the the process process of of the the study study and and they they end end up up, at at any any point point, they they show show progression
9:06
progression if if they they were were on on the the placebo placebo,, they they would would then then go go ahead ahead and and be be able able to to cross cross over over onto onto for for a a side
9:13
side of of them them.
9:13
.
9:14
So So everybody everybody has has the the opportunity opportunity to to evaluate evaluate it it.
9:16
.
9:17
Again Again, one of, one of the the nice nice things things is is by by having having measurable measurable tumor tumor,, not not only only can can we we see see how how long long does does it it
9:22
take take for for there there to to be be progression progression,, what what progression progression for for your you survival survival is is.
9:27
, We we also also have have some some insight insight into into that that we we could could measure measure volumetrics volumetrics in in the future and the future and look look to to see see are are
9:33
we we having having tumor tumor shrinkage shrinkage associated associated?
9:36
with with these these therapies therapies.
9:37
.
9:38
Okay Okay, so, so we've we've got got a a population population then then,, for predominantly predominantly young young people people, who who are are not not much much symptomatic symptomatic,,
9:47
who who then then now now come come with with this this
9:51
treatment treatment that it looks looks like like it's it's very very effective effective.
9:54
in and stopping in the stopping the growth growth of of these these low low grade grade or or mid mid grade grade tumors tumors.
10:00
And and you you go go ahead ahead and and you do do the this study study and and I'm I'm gonna going to put put the the slide slide up up there there so so you you can can refer refer to to it it a a
10:06
little little bit bit then then.
10:07
And and then then, and
10:10
and what's what's the the result result?
10:12
And and I I think think that that this is the this is this is the the chart chart of the the table table that that you you came came out out with with yeah for for those those who who just just had
10:19
had nothing nothing compared compared to those to those who who had had the this struggle drug, what what would did you you find find?
10:23
Yeah yeah, so so one one, you know you you could could see see the the separation separation of of the the curve curve, which which is is great great, right right?
10:29
And and there's there's a a lot lot of of space space in in between between the the two two curves curves and and that's that's where where we we begin begin to to get get at at the the issue issue of
10:35
of what what the the.
10:36
hazard hazard ratio ratio is is, here here the the hazard hazard ratio ratio is is
10:43
039 039 or or 04 04, essentially essentially.
10:45
that's That's a a pretty pretty strong strong effect effect size size.
10:47
you know Most most of of what therapy the therapies is that that we we're used used to to is is we we looked looked at at the the addition addition at at Thomas Olamide.
10:53
Thomas Olamide.
10:53
For For instance instance,, it it might might have have a a hazard hazard ratio ratio of of.
10:55
65, 065.
10:57
much Much,, you you know know,, the the separation separation would would be be much much less less.
11:00
.
11:01
This This study study,, really really interestingly interestingly,, you you know know,, there there was was a a interim interim evaluation evaluation that that took took place place in in two
11:07
two of of them them before before there there was was going going to to be be the the final final analysis analysis.
11:10
.
11:10
And The the first first one one was was after after 55 55 PFS PFS events events.
11:13
.
11:13
It It was was just just to to make make sure sure there there was was a a futility futility analysis analysis.
11:16
The The second second one one was was after after 123 123 events events,.
11:21
and And so so there there was was such such a a strong strong separation separation between between these these curves curves that that the the study study was was stopped stopped.
11:29
and And that that all all the the patients patients who who were were on on the the placebo placebo arm arm were were able able to to cross cross over over.
11:33
This.
11:33
This This was was a a decision decision made made by by the the DSMB DSMB.
11:37
that that was was on on,, that that was was evaluating evaluating the the study study.
11:40
You know, even And though though we we have have medians medians,, I I think think the the interesting interesting thing thing is is 72 72 of of the the patients patients were were still still on
11:48
on drug drug and and the the borocidinib borocidinib arm arm and and had had not not progressed progressed.
11:51
.
11:51
I I mean mean,, we we have have a a median median,, you'd you'd think think, well, well,, there there must must then then be be a a median median,, there there must must be be 50 50 that
11:56
progressed.
11:56
But like with all of that progressed.
11:58
But like with all of these these evaluations evaluations,, these these are are estimates estimates.
12:02
.
12:02
So So they they see see the the beginning beginning of of the the curve curve and and they I say say, well,, well we're, we're gonna gonna estimate estimate this this now out.
12:05
.
12:06
And And so so really really,, even even though though we we have have this this median median here here of of 27 27 months months,, it it may may be be much much longer longer because because of
12:16
of the the fact fact that that the the patients patients were were stopped stopped early early,, the the effect effect size size was was large large, and and the the patients patients were were
12:24
crossed crossed over over.
12:25
.
12:26
Let Let me me interrupt interrupt you you for for a a second second to to ask ask a a couple couple of of questions questions.
12:28
.
12:29
The The median median here here is is,, this this is is the the median median,, in in other other words words,, Half half the the patients patients,, you're you're looking looking at at the
12:35
the whole whole patient.
12:36
patients and you're And you're looking looking at at the the survival survival when when you you reach reach 50 50 of of that group and in that that group.
12:42
And in in the the drug treat treatment group drug, treatment group It it just just kept kept going going on on, which which is is what what you you meant meant is is that that,
12:49
This this had had a a, that's that's why why they they stopped stopped the the study study because because it it looks looks so so good good compared compared to to this this other other graph graph
12:55
where where they they didn't didn't get get the the drug drug that that they they, the the death death rate rate had had And almost almost included included everybody everybody in in the the study
13:02
study in and that that aren't arm.
13:03
Yeah Yeah,.
13:04
and And so so the the thing thing, the the thing thing that that you're you're getting getting at at is is I'm I'm going to just just gonna going to put put a a little little mark mark here here.
13:09
.
13:09
The Yeah point point and and this This point point when we're were actually actually, you you know know, they, they never never, 50 50 of of the the patients patients didn't didn't have have that
13:17
that event event yet yet.
13:18
You You know know,, you you know know, when when we we think think of of Kaplan Kaplan-Meier Meyer curves curves and and the the estimates estimates.
13:23
, they're They're just just estimates estimates.
13:25
You You know know, only only 72 72 of of the the patients patients really really, or or 72 72 of of the the patients patients were were still still on on study study in in the the Vores
13:32
vorocidinibir side.
13:32
in it And And roughly roughly,, I I think think it it was was, 50 52 years ago.
13:37
G2 were were on on for for the the placebo placebo arm arm.
13:38
.
13:39
So So the the placebo placebo group group almost almost did did truly truly meet meet the the median median.
13:44
, But but these these Kaplan-Meier Kaplan-Mierkurs curves are are estimates estimates.
13:48
, and And that's that's what what we we make make our our evaluations evaluations on on.
13:51
.
13:51
It It actually actually doesn't doesn't mean mean that that truly truly 50 50 of of the the patients patients had had progressed progressed, and and it it showed showed to to be be a a median median
13:58
of of
13:59
277 277 months months.
14:00
It's That's an an estimate estimate,.
14:02
the The separation separation between between the the two two were were significant significant and and had had a a hazard hazard ratio ratio that that was was very very meaningful meaningful,.
14:10
and And that that led led to to stopping the the, study because let me of clear those words That led to stopping the study because of that that.
14:17
.
14:18
Let Let me me ask ask you you that this,, you talked, because 'cause some of some of the the audience audience doesn't doesn't know know this this.
14:22
.
14:22
What What is is the the hazard hazard ratio ratio?
14:23
?
14:23
What What does does that that mean mean?
14:24
?
14:24
Yeah, It's it's the the risk risk,, and really really the the other other way way of of looking looking at at it it is is instead instead of of saying saying 40 40,, there's there's a a 60 60
14:33
reduction reduction in in the the risk risk for for progression growth.
14:36
progression.
14:36
.
14:37
It's That's another another way way of of thinking thinking about about it it,, meaning meaning that that your your risk risk for for progression progression in and the then for borescentinib a set
14:42
in a bar arm, dropped dropped by by 60 60 percent.
14:45
.
14:45
So So then then your your hazard hazard ratio ratio would would be be lower lower if if they're they're looking looking at at the the paper paper and and looking looking at at the the number number,,
14:50
right right?
14:50
?
14:51
Yeah Yeah,, the the hazard hazard ratio ratio's is point 04 for.
14:52
it It's.
14:52
It's the the inverse inverse of of what what I'm I'm talking talking about about there there.
14:55
.
14:56
And And what what you're you're showing showing here here is is that that at at this this level level of of about about the the median median,, where where the the median median of of the the
15:03
population population of of the the patients patients that that they they,, and and you're you're looking looking at at the quote, the the quote of the estimated estimated survivals survivals,.
15:09
Yes. This this is is almost, it's almost certainly,, it's it's certainly, it's more more than than double double with with the the drug drug, and and it's it's almost almost triple triple.
15:17
.
15:18
Is Is that that correct correct?
15:19
?
15:19
That's correct.
15:19
Yeah Yeah,, it's it's really really a a pretty pretty substantial substantial effect effect size size.
15:23
.
15:24
And And had had we we not not stopped stopped the the study study,, had had the the study study been been allowed allowed to to continue continue,, we we would would get get more more granularity
15:31
granularity on on the the effect effect.
15:33
.
15:33
And And I I think think,, You you know know,, my my,, having having treated treated patients patients.
15:36
in in the the phase phase one one study study,, you you know know,, just just as as an an example example,, one one of of my my patients patients is is on on for for seven seven years years now
15:41
now.
15:42
Yeah And, and so so.
15:44
I I think think there's there's a a number number of of patients patients that that show show up up in in this this forest forest side side of of the the barn barn that that would would continue
15:49
continue to to be be progression-free progression-free for a for a longer longer period period of of time time.
15:53
.
15:54
Okay Okay,, now now what's that that tells tells us us,, how how do do you you know know when when to to stop stop the the drug drug?
15:58
?
15:58
I've I've read read this this as in chemotherapy chemotherapy agents agents with with immunotherapy immunotherapy.
16:02
.
16:02
One One of of the the things things is is when when do do we we stop stop?
16:04
?
16:05
So So when when do do you you stop stop?
16:06
?
16:06
Do Do you you take take him him off off it it?
16:07
And? Or, and that that gets gets into into something something we're we're gonna going to talk talk about about is is IDH1 and IDH1 and IDH2 IDH2.
16:12
.
16:12
But But just just for for everybody everybody around around the the world world who's who's looking looking at at this this,, you you put put him him on on the the drug drug.
16:17
.
16:17
My My God God,, he's he's got gotta to be be in in the the drug drug for for his his whole whole life life.
16:20
Is. Is that that true true or or you you don't don't know know?
16:21
?
16:22
Well Well,, as as long long as as it's it's working working,, the the answer answer is is gonna going to be be yes yes.
16:25
.
16:25
And And I I think think what what will will happen happen is is, you know, these these tumors tumors grow grow very very slowly slowly and and what what we we don't don't show show in in here here
16:32
is is they they also also shrink shrink very very slowly slowly,, but but they they do do shrink shrink with with these these therapies there.
16:36
therapies.
16:36
.
16:37
You You do do see see a a decrease decrease, but, but it's it's not not a a rapid rapid,, dramatic dramatic decrease decrease.
16:41
It's.
16:41
It's a a very very slow slow,, gradual gradual decrease decrease.
16:43
.
16:44
And for For instance instance,, my my patient patient who's who's been been on on for for seven seven years years,, I I look look at at her her scan scan and and as as you you know know,,
16:50
there's there's scarring scarring that that occurs occurs after after surgery surgery and and things things like like that that and.
16:54
it's It's hard hard to to know know what's what's left left.
16:56
.
16:56
We We saw saw it it decreased decrease to to a a certain certain size size and and I I just just don't don't know know what's what's left left at at this this time time.
17:01
.
17:02
Okay Okay,, now no,, no, let let me me see see.
17:05
.
17:05
So So you you treated treated these these people people in in your your endpoint endpoint then then,.
17:08
Is is it it radiographic radiographic appearance appearance or or appearance appearance of of symptoms symptoms?
17:11
?
17:11
When When do do they they know know that that they they failed failed the the drug drug?
17:14
?
17:15
At At this this point point,, it's it's radiographic radiographic appearance appearance.
17:17
and And, you know, there's there's a a group group of of people people who who came came up up with with the the Rayno renal criteria criteria, which, which is is a a way way of of doing doing
17:24
bidirectional bidirectional measurements measurements and and determining determining when when you you have have a a significant significant enough enough change change and And that that significant
17:30
significant enough enough change change is is 25 25.
17:32
.
17:34
So So a a 25 25 change change in in bidirectional bidirectional area area of of the the non-enhancing non-enhancing tumor tumor that's that's showing showing up up, Or or if if there's there's a a
17:40
new new enhancing enhancing tumor tumor,, that that would would be be.
17:43
a on new new enhancing enhancing region region that, that would would be be enough enough to to be be progression progression as as well well.
17:48
.
17:48
So So that's that's how how progression progression works works.
17:50
.
17:50
So So now now, I I think think the the other other question question, and, and we've we've got got a a bunch bunch of of questions questions here here to to ask ask you you,, but but one one is
17:56
is,, and this this is is the the chart chart that that you you guys guys put put in in your your paper paper on on adverse adverse effects effects.
18:03
.
18:03
Could Could you you explain explain that that?
18:04
In in other other words words, if, if I I take take this this drug drug,, am am I I going going to to get get sick sick from from it it,, or or it's it's pretty pretty benign benign?
18:08
?
18:08
And And from from what what I I tell tell us us what, tell us what the the answer answer to to that that is is.
18:12
Yeah Yeah,, so so, you know, the the first first set set of of bars bars on on the the left-hand left-hand side side,, it it just just always always shows shows the the value value of of having
18:18
having a a placebo placebo,, right right?
18:19
?
18:19
Because Because you you have have a a placebo placebo and and you you have have 13 13 adverse adverse events events related related to to a a placebo placebo.
18:23
.
18:24
So, and And these these are are grade grade three three or or greater greater.
18:26
.
18:27
So So these these are are kind kind of of significant significant adverse adverse events events.
18:29
.
18:30
And And you you can could see see that that, you know, there's There's a a certain certain level level of of adverse adverse events events that that occur occur that that was was just just simply
18:36
simply.
18:36
not not related related to to the the drug drug.
18:37
.
18:38
But what this, again, having that.
18:41
That's That's what what this this blue blue is is, because that's because that's the the placebo placebo group group.
18:45
, so That's they're having exactly right.
18:47
They're having adverse adverse events events that that you're you're counting counting as as adverse adverse events events that that almost almost represent represent half half of of what what, the
18:53
the real real,, the the number number that that occurred occurred in in the the group group that that got got the the drug drug is is what what you're you're saying saying.
18:58
.
18:58
That's That's correct correct.
18:58
.
18:59
Okay.
18:59
Yeah, That's that's always always fascinating fascinating when when you you see see that that, Right right.
19:02
?
19:03
Oh Are, are those those adverse adverse events events serious serious?
19:05
?
19:05
Are they minor?
19:06
These Are are they minor?
19:06
These are great great three three or or greater greater,, so so these these are are pretty pretty significant significant adverse adverse events events that that are are occurring occurring.
19:12
.
19:14
Here's Here's some some biochemical biochemical events events and
19:18
liver and liver enzyme enzyme studies studies and and so so forth forth,, and and as as none none in in the the placebo placebo,, there's there's some some in in the the treated treated group
19:25
group.
19:25
.
19:26
Is Is that that all all we're we're talking talking about about,, or or at least these turn turn out out to to be be physical physical and and neurological neurological deficits deficits in in this
19:31
this group group?
19:31
?
19:32
Yeah Yeah,, it's it's a a great great question question, and, and really really,, this this is is all all we're we're talking talking about.
19:35
about groups groups here here,, here here,, here here,, and and their They're biochemical biochemical abnormalities abnormalities,.
19:42
they They have have not not led led to to any any change change in in how how the the patient patient feels feels or or functions functions.
19:47
When.
19:48
They, when the the drug drug is has stopped stopped,, they they all all reverse reverse,, so so you you don't don't have have kind kind of of the the liver liver abnormalities abnormalities that
19:55
that would would occur occur that that could could be be irreversible irreversible in in some some way way,, so so none none of of that that happens happens.
19:60
.
20:01
Sometimes Sometimes this this, this has has led led to to a a decrease decrease, in and the the dose dose, certainly certainly there there has has with with these these patients patients,, some
20:08
some of of them them probably probably had had a a pause pause in in the the dosing, dosing, and and then then where where either either you you started started at at the the same same dose dose,
20:15
or or you you started started at at a a lower lower dose dose.
20:17
.
20:17
All Alright right,, so so basically basically what what you're you're telling telling us us is is you you, for for people people who who have have these these low-grade low-grade gliomas gliomas,,
20:24
or or these these tumors tumors low-grade low-grade gliomas gliomas,, they're they're all all histologically histologically proven proven,, right right?
20:29
Yes?, Yes, exactly exactly.
20:30
.
20:30
And And then then radiographically radiographically they they seem seem to to fit fit that that criteria criteria,, either either CT CT or or usually usually MR, but MR, but if if I'm I'm in in
20:36
another another country country,, it it might might be be a a CT.
20:39
CT if If I I don't don't have have an an MR MR. And and that that if if you you go go ahead ahead and and they they could could be be operated operated on on, if if they they have have symptoms
20:45
symptoms, they They don't don't have have symptoms symptoms, you you might might leave leave them them alone alone and and watch watch them them.
20:48
But But then then if if you you get get to to the the point point where where they they have have symptoms symptoms, you you might might operate operate on on them them, get got a a sample sample of
20:52
of the the tumor tumor.
20:53
Let's Let's say say you it it comes comes out out to to be be a a Low low grade grade glioma glioma midgrade mid-grade.
20:58
Then Then in in that that country country, I'm I'm gonna going to show an example of this in a I'm gonna show an example of this in a minute minute, because because I I think think we're we're going
21:04
gonna to we're We're getting getting into into that that and and we'll we'll get get back back to to the the IDH IDH stuff stuff in in just just a a minute minute here here.
21:10
Yeah Yeah,, okay okay.
21:11
, Here's here's the the case case.
21:11
.
21:11
I I got got it it out out of of the the went to I went to Google Google or or went went to to the the web web and and I I got got it it out out of of yours yours a a case case.
21:18
I I was was reported reported in in the the journal journal, a a neurology neurology journal journal and and here's here's an individually individually came came in in.
21:23
I think it I was think it was minimally minimally symptomatic symptomatic, just just like like you you described described.
21:27
As as this this is this an Enhancement enhancement, slight slight enhancement enhancement and in in a a certain certain part part of of the the brain brain over over here here is is the the big big
21:33
cystic existed component component with with some some enhancement enhancement with Would this this.
21:36
pertation have been included in your This presentation had been study included in your study?
21:38
.
21:39
Yeah, so if we look at this last slide.
21:45
And if somebody were to measure that residual area, the anterior part, anterior mesial part of the resection cavity, and they said that that is at least one by one, and it was centrally reviewed
21:58
for this study, then they would be eligible for this study Excuse me, they needed to be one year from completion of surgery.
22:08
Okay, and this histologically just shows it's a more cellular area than you don't see a lot of necrosis
22:24
or hemorrhage or anything like that.
22:25
So it's in the more active glioma category.
22:25
So now let's say I'm in rural South America, Tim. Yeah.
22:27
Or I'm in the middle of the East and in a country that may not have advanced medical systems I could be in in rural America, I could be in China, I could be Russia and India.
22:39
And I've got the imaging and I get the imaging to show me this.
22:43
Yes. And the patient, oops, and that's where the paper came from actually.
22:47
It was a neurality journal.
22:49
And the imaging shows me
22:53
this.
22:53
And the patient's getting a little worse.
22:56
And I go ahead and I operate and I'm not going to sample.
22:58
This is what I, what the pathologist comes back and whatever time is a patient does well after surgery.
23:05
And so now, what do I do?
23:07
I'm in the rural area of this country.
23:10
What's my next choice?
23:11
Well,
23:14
I don't have a drug choice.
23:15
Should I treat them with radiation?
23:16
Do I let them go?
23:17
What do I do?
23:19
Yeah, I think a lot of it depends on the availability for imaging, things like that.
23:24
I mean, today, we're excited that it's not FDA approved.
23:30
It was an international study.
23:31
It took place in 70 different countries.
23:33
So it will be available when it is available in many different countries.
23:38
So at some point, that would be one option.
23:41
But I think in this setting, you would probably, given the extent of the resection, you'd probably monitor them.
23:49
And again, I made a statement about the imaging and how available it was.
23:54
If you feel like you can't get good follow-up, you know these tumors are gonna grow And if you can't get good imaging, maybe that's a time to consider doing radiation.
24:05
I mean, we, you know, this study, for instance, this, it's called the Indigo Study with Voroside in it.
24:13
It enrolled very quickly because there's a very keen interest in patients.
24:19
They do reading, they're young, they know how to get information, they're concerned about radiation to the brain.
24:26
And they're concerned about the delayed cognitive effects associated with that.
24:30
And so many of them love the idea of taking a drug that doesn't appear to cause many symptoms.
24:38
But when you're in a situation where you don't get great follow-up because you don't have the imaging available, you don't have those things.
24:46
Sometimes, you know, it makes sense to just do what is the most effective therapy at that time, which is going to be radiation and chemotherapy ideally.
25:00
Ollie, I didn't introduce you to the audience.
25:04
I apologize for that.
25:05
But Ollie's
25:08
originally from Persia and ran and went to medical school there, correct me if I'm wrong, and then trained in France with some very leading people, eventually came to work at UCLA with Robert Rand,
25:21
who was interested in stereotactics, surgery, radiation, and so forth.
25:26
You come with a worldwide background here.
25:30
What are people in the other countries that may not have access to some of this high-level therapy, are they going to send the patient home just like Tim said, and may not follow them up, or are
25:43
they going to radiate, and what would you do?
25:46
I think that it depends on the situation.
25:48
Nowadays, everybody, majority of the countries and the people have access to internet.
25:55
They Google it They will find out there is something available, either they convince their country, and that is why they people will get the most advanced treatment, even back home in
26:09
Iran.
26:11
They have the latest, you can't imagine, with sanctions going, they get excellent treatment.
26:19
They have it.
26:20
They get it somehow, although
26:23
Iran is not the example right now, but the other countries also are doing the same thing, but unfortunately.
26:30
Socio-economic problem of the world exists.
26:33
You want it or no?
26:35
Many countries, as you mentioned, they have limitation.
26:39
And also the value of the human nature in the past, as Dr.
26:46
Grossi mentioned, that sometimes they let it go because they don't have the possibilities.
26:51
But we take the time.
26:54
Well, I'm sorry, Oliver.
26:54
Would you radiate this patient at this point?
26:57
Now he's gonna go back If you don't know if you're gonna see him again, would you radiate him?
27:02
And that obviously entails cost and entails time.
27:08
Maybe you have to stay there for a period of time to do that.
27:11
Maybe they can't afford it.
27:12
I mean, these are all considerations.
27:14
Or would you just let them go in and tell them when they get worse or something, come back?
27:18
How would you, if you were in that circumstance, what would you do?
27:22
At least you do the least.
27:25
Do the radiation.
27:26
You know it may have problem Look at this, there is no other choice that.
27:30
The availability of the medicine, especially the PET scan, I'm sure Dr.
27:35
Clossy knows more about it and that was my specialty also that I did it at VA here for eight years.
27:44
That exists and I follow the PET imaging, fluorodopa, FTT, whatever its possibilities they have, they can use that one as the follow-up.
27:53
I'm sure Dr. Clossy, because I have read his papers also, in JM Journal of Nuclear and Medicines repeatedly, and that is something that we have to be available to the people in each country, but
28:08
I'm sure there are countries who don't have PETska, or
28:12
MRO. So if I'm in an area where I don't have all these facilities, at least I can make a diagnosis, patient gets worse, I can operate on them, I've got a sample with a tumor, and it comes back
28:25
with some evidence of
28:29
a numerous growth.
28:30
It's not a glioblastomy.
28:32
That's another session we will have.
28:34
And I can either, if it works out for the patient, I can radiate him or Tim, I could say, we'll just come back when you become symptomatic, you don't know if that's going to happen or not.
28:44
And that's, I mean, so we're trying to cover the world, but that's those are your choices, right?
28:49
You know, I think the other interesting thing is that we learned
28:53
about astrocytoma and oligodendryglam As that astrocytoma is more aggressive, they grow faster when you measure kind of volumetric changes.
28:54
You might even say if somebody has an oligodendryglam that you would do exactly what you're saying that you would wait
29:13
and see because those grow at a much slower rate and the brain seems to tolerate that growth pretty well because it's growing so slowly.
29:21
Astrocytoma, Grade 2, Grade 3, obviously, Grade 4.
29:22
This is a.
29:27
much more difficult disease.
29:29
And I worry about
29:33
leaving the patient in that setting, just
29:37
to go back and wait till symptoms occur.
29:40
Let me
29:43
pivot here for just a minute, Tim, because we're getting into the same, we're coming back to the same thing.
29:48
And I'm in
29:49
another country and I'm looking for what is IDH1 and what is IDH2?
29:56
And how does that work?
29:58
And we'll try to put it in simple terms for them, but basically there's, everybody knows that there's this biochemical cycle, and you can see it on the screen, yeah.
30:10
And it's a Krebs cycle, and that's essentially how they make energy for every cell in the body.
30:16
And in the long of that way, there is an isocentric dehydrogenase, which is an enzyme.
30:22
which is converting this to another compound.
30:27
I don't want to get into the names.
30:28
Yeah, alpha-ketoglutarate.
30:30
Yes, but
30:34
is that what the IDH is?
30:35
That enzyme becomes mutated and it's changed and it does something it shouldn't be doing?
30:41
Is that what happens?
30:42
That's exactly right.
30:43
And so just exactly like you're saying, it transforms, I so sit right into alpha-ketoglutarate And alpha-ketoglutarate has an impact on the chromatin and these tethydrolases and has an impact on the
31:02
methylation status of a number of promoters in
31:10
the genome.
31:11
And it's probably a critical factor in deciding the fate of a tumor or excuse me of a cell.
31:16
Is it going to be de-differentiated be more differentiated.
31:21
and turn into an astrocyte on oligodendrocyte in
31:26
the setting of this, if we're in a setting where there's a progenitor,
31:32
oligodendroglial
31:34
progenitor cell.
31:36
The mutation, and the part that's really fascinating is for IDH1 is in
31:44
the cytosol, IDH2 is in the mitochondria.
31:47
There are specific sites, and for IDH1 it's codon 132, for IDH2 it's codon 172,
31:57
and a single amino acid substitution, not at any of the other codons, not, you know, will it lead to this change or then now the mutated form, just like you show here, goes and creates two
32:11
hydroxyglutarate, and two hydroxyglutarate is
32:15
not metabolized in our body because it's not supposed to be in our body.
32:20
So the cell accumulates to hydroxyglutarate.
32:23
Now you no longer have the impact of alpha-ketoglutarate.
32:27
You have an accumulation of to hydroxyglutarate.
32:30
That leads to chromatin changes that now change the methylation status and changes the gene expression program so that it is more an immature cell.
32:41
It's not differentiating to an astrocyte or an oligodendrocyte
32:46
So because 2-H-G accumulates, that's what leads to all these secondary changes and then is the initiating
32:58
tumoragenic change that occurs.
33:02
So if you inhibit that mutated enzyme and it's a very specific
33:09
molecular chemistry or the medicinal chemistry needed, you could be specific and just hit the mutated form.
33:16
And when you do that, you no longer make 2-hydroxyglutarate.
33:20
and then those gene expression changes with RITBAC or they're too far progressed and the cell dies.
33:28
That's a terrific explanation.
33:29
So basically then we've got this mutation here, one mutation that occurs and it begins to drive the chemistry to
33:43
this D2HG, this agent that can't be used, builds up in the cells which are saying, causes all kind of changes in the chromosomes and so forth.
33:51
The tumor begins to grow wildly and it's eating up all the energy.
33:56
And so this cycle then becomes impaired and that's how the tumor gets a growth so extensively.
34:04
But if you get this drug which has one specific target right there.
34:10
Let me take this target right here.
34:12
Oh there, oh yeah, yes, yes, yes, okay And what that does is shuts the whole thing down and we're from what you're saying.
34:20
is all those abnormal cells can revert or you stop the tumor from growing, which is exactly the drug you were using for the low brake glioma.
34:28
And it's also why you never reach an endpoint 'cause it kept working.
34:32
Yeah.
34:33
It gets back to the question I asked you, is how long do you keep them on the drug?
34:37
And since the side effects are low, I mean, I do it, but the question, I think there are some agents that are very, I think for cranial pharyngeoma, if I remember, they use an agent that's very
34:50
highly active and you can only tolerate it.
34:54
I think only half of the people tolerate it, but it's very effective.
34:57
So in this case, it works out well and it can be a biochemical treatment then for this disease.
35:04
It's really what we're driving.
35:06
That's correct.
35:07
So I think we've told the audience now, no matter where you live in the world, how this works, what IDH1 and IDH2 means, And that's those are the mutants that lead to the formation of the glioma.
35:20
And Tim has described the work, which is terrific, and how it targets that
35:27
just specific molecular target and it can stop it.
35:30
So, and then we've answered the question is, what do I do if I'm in different countries?
35:36
And frankly, this is not available yet, as what you said.
35:40
And frankly, if the patient's not very symptomatic, we have radiation, anything Ollie suggested this week, and you've said that too, we can radiate And if not, you watch 'em,
35:52
'cause it's gonna come back, 'cause you haven't stopped this mechanism we're talking about.
35:57
And then you have to re-examine it at that time, maybe the drug will be available, maybe it won't be expensive, and all those kinds of things.
36:05
So is that pretty much summarizes, do you think?
36:08
Yeah, I think the only other thing I would say is just because probably the best,
36:15
Therapy today is radiation and chemotherapy.
36:18
So if they have the availability of Temozolamide there, if they have the availability of Lomustine and Procarbosing, then
36:29
there's longer survival when you do combination therapy.
36:32
So that would be the only caveat.
36:34
Still, radiation is carrying the majority of the effect.
36:38
You get additional benefit by adding the Temozolamide or Procarbosing, then Kristin and Lomustine.
36:46
That's terrific.
36:47
So we've spent about a half hour and we've talked about everything from beginning to end about low grade gliomas.
36:53
We've gotten into some of the molecular things.
36:55
Let us, I'm gonna show you a couple of things and use this on a terrific job here.
37:01
And let's, some other things that are coming out.
37:05
We've been through these.
37:05
We've seen these papers and
37:09
let me see what else There's one other one I'm gonna just show briefly.
37:15
And maybe in about a sentence or two, you could tell us or a few sentences.
37:19
This is a paper that came out in the New England Journal about craniopharyngeoma.
37:23
We'll get into this in some other sessions.
37:25
And
37:27
that's kind of
37:28
a benign tumor in a way like the low grade glioma, but it keeps coming back and it keeps coming back.
37:34
And nobody had any really good treatment for it, but now they found a target where they
37:40
can treat it by treating it with, again, another drug.
37:44
Can you make a few comments about that and we'll talk about that in another session?
37:48
Yeah, so first there's
37:51
this specific mutation, the B-RAP B600E.
37:56
And many times we talk about mutations occurring across cancer types.
38:03
This
38:04
was first found in melanoma.
38:07
And then smaller percentages are found in a variety of, other cancer types, including cranial pharyngeome.
38:14
Again, specifically the
38:17
papillary subtype.
38:18
And then in gliomas, it's with PXAs, pleomorphic xanthoastrocytomas, or the
38:28
epithelialoid glioblastoma.
38:29
So this target exists, and it is very, very sensitive to BRAF and MEK inhibition.
38:37
So it doesn't matter what tissue it's in, it's if it's present, high likelihood, it's gonna be very, very sensitive.
38:46
So it turns out, and I don't get to see very many of these patients.
38:51
These are rare patients.
38:54
I've seen some scans initially from some of the patients, and when they present, they're large, the location is difficult many times, and you can get into this issue where,
39:07
If you try to do surgery, you have pituitary hypothylamic problems, or if you radiate the size of the lesion is so big that you're radiating a huge field, and these are usually in kids.
39:20
So when we see the effect of these drugs again, and again, it happens across all
39:30
V600E tissue types, you see these dramatic effects As you can see here, the overall survival in these patients, but more importantly, the progression for you survival, and there may even be, and
39:42
they maybe aren't showing it here, but the response rate is very, very high, I think around 90, and the depth of the response, almost all of them are near complete responses.
39:55
Now, when you release them, they kind of come back.
39:58
So, and you had made a comment, I thought that was really important like this can be a tough combination to take.
40:06
side effects that can occur because you're actually inhibiting an important pathway, you're hitting the wild type B-rap and you're hitting wild type mech in this setting.
40:16
And so there's side effects that certainly occur that are on target but, you know, off tissue.
40:23
The real value I think here is what you could do to these tumors before needing to do any kind of surge rear radiation.
40:34
So if you're a surgeon and you come in and you see this massive area in the middle of the brain that has increased, sometimes these are kind of cystic, sometimes they're more solid, and you see
40:48
that, you know, 90 of the patients are going to have a CR, it's going to come down to almost nothing.
40:52
That's a great time to consider other therapies.
40:55
You know, one, is there, can you do more with surgery at that point now that it's, you know, decreased?
41:02
Is that a time to be considering radiation?
41:04
Because the likelihood is, you're not gonna be able
41:08
to maintain on that drug for ever.
41:10
And when you release that drug, the tumor will grow again.
41:14
So I think there's a great opportunity for this mix between neurosurgery and oncology to treat these patients and to be on top of them.
41:25
You still need to know
41:28
that it has that mutation, but you may not need as an aggressive resection if you're gonna get such a strong effect from this targeted therapy.
41:37
Terrific, let me show you one other thing 'cause I think we should try to wrap it up here, but I'm gonna go to Google here.
41:45
There was a paper that came out in science a few weeks ago, people in our country are working on it.
41:52
We're essentially what they've done is they take a virus, they infect the tumor cell.
41:57
And what that does, and you tell me if I'm wrong, and just so the audience gets an idea of there are all kinds of things that are coming down the line and infects the tumor cell, which sets off the
42:09
immune system, which could be inhibited by other things around the tumor.
42:15
But this makes it particularly sensitive.
42:17
The immune system comes and then kills the tumor.
42:21
And the virus is targets tumor cells.
42:24
So you get around the issue of getting a chemotherapy, can it get to the tumor cell and not yes or no?
42:30
And so to me, it indicated a promise of things to come.
42:36
What did you think about that?
42:38
Yeah, I think, you know, these anti or these oncolytic viruses that have two effects.
42:43
You know, one is direct killing of the tumor cell and the second is bringing the immune system and just as you've described.
42:53
I think it has a potential in the future of therapies.
42:58
One of the biggest problems is delivery Getting it to all of the tumor that's gonna be hard to kill
43:08
all of the tumor cells that you get it into, but then you'd say, okay, well, if I bring enough immune response, maybe then they'll be, quote unquote, auto vaccination that occurs where there's
43:15
enough immunologic response.
43:18
The immune system sees the tumor and goes after the tumor antigens and can actually kind of clear out that tumor in
43:26
some way.
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So what we just struggle with is that when we bring inflammation into the brain, we bring these, you know, myeloid cells that are more
43:38
immune suppressive.
43:41
And we don't know how to change that balance yet.
43:45
So it's almost as if you start the fire and these cells come in
43:51
and put out the fire.
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So you can't ever get to this really developed immune response 'cause our brain doesn't like inflammation in it and its response is to bring myloid cells in.
44:02
and to calm it down and to suppress the immune response.
44:06
Excellent explanation.
44:08
Well, we'll cover that in the future.
44:09
We just wanted to give the audience a taste of some of the things to come, but just terrific job of explaining everything from the simple
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clinical presentation down to what molecularly is going on and how this is a very specific target.
44:25
And answers for people over the world as to what they can do.
44:29
If you have the facilities, you can do a little bit more if you don't.
44:33
Are you done the best you can do?
44:35
Even in the
44:39
countries where you can afford these things, we still don't know all the things we need to know.
44:44
We don't know all the answers.
44:45
So at least if somebody in another country, Ali, I can sit down and tell my patients, yes, I've seen it.
44:53
I know all the things that are happening given where we are in this location.
44:59
This is the best we can do.
45:01
Does that make sense?
45:02
Do you want to make any comments before we close, Ollie?
45:05
That's one question I have from Dr. Ojibeko, colleague.
45:06
Dr. how much the
45:11
course of treatment cost if you don't mind?
45:14
And yeah, I appreciate, sorry if I bring this because really, I appreciate we brought the greatest point after now.
45:23
So how much does it cost a course of treatment?
45:26
Yeah, so we don't know what the IDH inhibitors are going to cost.
45:29
We could tell in general, let's say the BRAF combination, BRAF MEK inhibition.
45:35
And this is a guess.
45:37
It's going to be somewhere between 20 to 30, 000 a month.
45:42
That's in the US. That's the cost for somebody if they paid out a pocket in the US. That is going to be less in other countries.
45:49
Nevertheless, it's a lot of money.
45:52
Yes, you're real.
45:53
Thank you.
45:54
What the thing is that sometimes some of the big companies has the courtesy.
45:59
to share it with lower class to other countries.
46:02
That's one option, that's why Dr. I admire Dr. Osman, who at this international conferences, that we can bring attention to the other people, that this exists, and maybe they can arrange for
46:17
somehow to get the treatment, because the goal of medicine is everybody, not the rich one, and not the poor one
46:27
Terrific.
46:27
And I will say their access programs that exist, but getting an understanding, and this is where you may wanna bring in, just let's say the IDH group.
46:42
Servier is the company.
46:43
They own the IDH of BoraSight in it.
46:47
They're a French company, but they should be a sponsor of this trial, of these events that you run, and
46:56
conferences.
46:58
And they also should clarify what their plan is to get drug to people who are in these countries that may have more limited resources.
47:08
That's terrific, that's a terrific idea.
47:12
Tim, we really want to thank you very much for spending the time with us this morning.
47:16
I hope we can have you back.
47:17
We've got some other subjects on dock there.
47:20
I think people would want to know about them, and it could be a longer relationship, but really just an outstanding explanation of these things.
47:30
Allie, any comments, finally?
47:32
Yeah, really, I learned a lot from Dr. Felisi, and also we have to manage more discussion, but Dr, as you had the goals, we have to have the international one, to bring the awareness with all
47:45
other people.
47:46
That conference two years ago was terrific.
47:49
I learned a lot from the problems and the solution the other countries have, And UCLA has been a pioneer.
47:57
in everything.
47:59
Although there are a lot of politics behind it, they made me need us, but we have to live by living to the world.
48:08
What is going on and how we can help the other people.
48:12
All right.
48:13
Thank you very much, Tim, for all your time, and Ali, appreciate it, and we look forward to gathering together again.
48:20
Thank you so much.
48:21
Thank
48:26
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48:39
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48:53
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