Promising Treatments for Refractory and Resistant Prostate Cancer - Ramesh Narayanan, PhD, MBA

Hi, I'm Brad Power and this is the

Cancer Patient Lab and today we're

honored to have with us Dr. Ramesh

Narianan.

Um, he is a researcher in uh prostate

cancer.

And he will be talking to us today about

what he's seeing in the drugs that he's

been trying to bring to market as well

as in general what the landscape looks

like in bringing new drugs to prostate

cancer.

Um, and I'm sure we'll have a

stimulating conversation about uh just

understanding what the state of the art

is and what patients should be looking

forward to in the months and years

upcoming.

So with that I'll turn it over to Dr.

Narianan.

>> Brad, thank you so much for having me

here. It's it's an honor to meet you all

and uh it's a privilege to talk to you.

Um,

it I've been thinking in the last 5

minutes how to condense a 30-minute

presentation into 10 minute, but let me

just um go over a few things that would

uh

um be helpful here for setting up for

our discussion.

As Brad pointed out, we have our group

has discovered drugs for different

diseases and the lead drug that is in

the phase one clinical trial is for

treatment refractory and relapse

castration resistant prostate cancer.

We received FDA's fast track approval

for our drug and we are in the process

of raising about 25 million dollars to

advance it to phase 1B and phase two

clinical trial. We um co-founded this

company um called Ramiller combining my

name Ramesh and Dwayne Miller. Miller is

our co-investigator. He is the

lead chemist in the program. So we

created this company so as to advance

our drug into the phase 1B clinical

trial. Okay. So I just want to give you

one background one uh topic that keeps

coming up every single time probably you

all take a medicine or something is

androgen and androgen receptor.

So, how did androgen and androgen

receptor became the driver of or how was

it discovered that they are the driver

drivers of this prostate cancer? So, and

what I'm showing you here is the Nobel

Prize-winning discovery by Huggins and

Hodges.

What they did was

prostate, which for normal development

of prostate requires androgens. So, that

was well known in the 1930s and 1920s.

And what they thought was that if the

normal prostate development requires

androgens, probably the same androgens

are contributing to the development of

the prostate cancer.

So, what they did was they took that

they performed two clinical trials. Of

course, in those days they were not

controlled clinical trials. And one of

them was surgical castration. So, they

surgically eliminated the testes, which

is the primary source of androgen

synthesis in our body. And then they

wanted to see what happens to the

cancer. In those days there are no

biopsies, there are no other diagnostic

available. So, the only way to detect

whether a cancer prostate cancer is

shrinking or not is using an acid

phosphatase colorimetric assay in the

blood. So, they were able to show that

by surgical castration that by cutting

off the

testicular source of androgen supply,

they were able to shrink the prostate

cancer here.

And androgens bind to the receptor

called androgen receptor. That's why

either cutting off the androgen supply

or blocking androgen receptor, which is

the current modality of treatment, have

really helped us to advance the

discoveries based purely on Huggins and

Hodges. The other thing that what they

did also was that administering

estrogens. Estrogens are female hormones

or women hormones. And what they have

what happened was that when you

administered estrogens, it cuts off the

testicular supply of androgens based on

this panel that I'm showing on the

right. This is called hypothalamus,

pituitary and gonadal axis. So, our

hypothalamus

synthesizes gonadotropin-releasing

hormone that stimulates the pituitary to

release luteinizing hormone and

follicle-stimulating hormone. And

finally, this releases testosterone.

By like tricking the brain that there is

already a surge in the hormones, the

brain shuts down the synthesis of

testosterone. And this is the second

modality by which they were able to show

that the tumor regresses.

So, these set up the future discoveries

of androgen receptor antagonists and

everything that we are currently taking

and which are in the market which are

pretty much the mainstay treatment

options for our

uh for prostate cancer. So, let's just

leave some of these background slides

which you all have seen um uh which you

are which are quite basic information

which we don't have uh at this point.

So, this slide, what it shows is that

androgens, they come into the cell

and bind to the androgen receptor.

So, the androgen receptor, which is in a

confirmation, it just changes the shape

and then it binds to the

DNA and then causes the trans-

transcription and translation of genes

including our PSA which is which is

which has become the primary diagnostic

marker for prostate cancer.

So, either you inhibit the steroid

entry into the cells or completely

inhibit the steroid synthesis which is

what abiraterone does. Or inhibit the

androgen receptor so that which is what

enzalutamide, apalutamide, darolutamide,

like Zytiga, all these drugs they're all

doing. By either way, you're blocking

this particular receptor.

So, this receptor is present in over

85 80 to 85% of the prostate cancer

patients. And remaining 10 to 15% of the

prostate cancer do not express the

receptor, so which means that

predominantly majority of the prostate

cancer will respond to androgens or

androgen receptor blockers. So, for

example, if you take here, the prostate

[clears throat] cancer evolves from

hormone-sensitive prostate cancer, an

early-stage prostate cancer, which is

contained within the prostate. And the

primarily prostatectomy or radiation or

gonadotropin-releasing hormone, which I

showed you before. These are the primary

treatment options for this stage. When

it becomes hormone-sensitive and

resistant prostate cancer, then you have

several options like androgen receptor

blockers like enzalutamide, abiraterone,

apalutamide, darolutamide, apalutamide.

Then it becomes non-metastatic

castration-resistant prostate cancer.

Again, androgen receptor antagonists are

the primary

source of treatment here.

Then it becomes metastatic

castration-resistant prostate cancer,

which is a very difficult disease to

treat and manage. And then again, you

have pretty much the second-generation

androgen receptor antagonists,

chemotherapy, lutetium PSMA, and

PARP inhibitors are there. And then

finally, it's unfortunately palliative

care.

So, the prostate cancer number of

patients in globally is just massive

right now. It's about

annually 1.6 million men are diagnosed

with prostate cancer, but this number is

likely to expand to about 2.5 million

people, men. And it's going to

contribute to about 700,000 deaths

annually from by 2040.

So, how do we manage this prostate

cancer that's evolving every single

time? So, what happens is that I just

want to go to one particular

slide here. So, if you look here, every

single time you block the androgen

receptor, it always cancer is very

smart. It's always going to find an

escape route. So, escape routes are

different escape routes like androgen

receptor sensitive to other hormones or

splice variant which will go through

what it is and different kinases and

different ways. These are the different

mechanisms by which androgen receptor

finds escape routes. So, every single

cancer

not only prostate cancer but every

cancer always tries to rebel against

what the blockers.

So, if you look at this slide, this is

the androgen receptor structure. It is a

classic transcription factor structure.

It has an N-terminus domain, DNA binding

domain, hinge region, and the ligand

binding domain. All the drugs that are

being developed right now bind to this

domain and then block this androgen

receptor from function.

Cancer being very smart, what it does is

that it just leaves off this particular

domain and creates this constitutively

active monster.

This one retains about 75-80% of the

androgen receptor activity and now you

don't have the ligand binding domain

here for it to further inhibit the

prostate cancer. So, what happens is

that this becomes the driver of the

cancer and the patients who express the

splice variants succumb to the disease

very quickly in about a year or year and

a half. So, it's a very aggressive form

of prostate cancer.

Right now, the challenge here in the

prostate cancer drug discovery and

development field is that

we know we all know how to block this

one but can we block this? This is where

our drug comes into play where our drug

binds to this region.

So, by binding to this region, not only

we are inhibiting the full-length

androgen receptor, we are also

inhibiting this splice variant androgen

receptor. Thereby, we are able to take

down both the full-length and the splice

variant forms and the prostate cancer

just shrinks or gets contained by

the our drug.

Okay? So, what are the current

therapeutic landscape of prostate

cancer?

As I mentioned, the localized uh

hormone-sensitive prostate cancer, you

have radical prostatectomy,

brachytherapy, that is radiation, and

some of these other treatments like

enzalutamide, apalutamide, and

darolutamide, which all showed

significant um uh

enhancement in the metastasis-free

survival as well as in the overall

survival. Overall, this is a really a

good thing. But, of course, as you keep

treating the prostate cancer, as you

keep hitting the androgen receptor, they

start creating new forms and new

mechanisms by which they can overcome

the inhibition. So, this is

hormone-sensitive prostate cancer.

Again, you can see that both apalutamide

and darolutamide are approved for this

one, and you can see that they are

pretty much they can extend the um

progression-free survival or even

overall survival significantly in this

patient population.

This is the major issue, that is the

metastatic prostate castration-resistant

prostate cancer is the major problem

right now we have how to manage it.

Right now, you have enzalutamide and

abiraterone are approved, and I think

darolutamide and apalutamide are also

approved in this case, where you can see

that they performed their studies in

chemo-relapse and chemo-naive patients.

That is, those who have relapsed from

the chemotherapy as well as those

patients who have never experienced or

never been treated with chemotherapy. In

both cases, the overall survival

improved like same, 18.4 months

as opposed to 13.4 A marginal increase,

but still it's all statistically

significant. Like about 4 to 5 months on

an average, statistically significant.

So, AR antagonists and androgen

synthesizing inhibitors, they can

actually provide a good amount of um

uh relief or an extension. And beyond

this point is where we are all trying to

discover drugs and develop drugs so that

people or men who have relapsed from

these cancers, can they be put on new

modality of treatments and that can

actually pretty much give them more

runway before they go to chemotherapy?

This is what all our approaches are. Of

course, you have chemotherapy, you all

have would have experienced like some of

you would have experienced docetaxel

cabazitaxel. We as much as possible we

want to avoid chemotherapy because these

are all nasty drugs. They don't

differentiate or discriminate between

the cancer and the normal cells. So, we

don't want the patients to go through

any of the side effects by taking on

chemotherapy. So, we would love to have

provide additional

hormonal treatments that can actually

give them uh longevity in terms of um

the targeted therapeutics. Then you have

radio pharmaceuticals are coming along

really well. Um PSMA is um a membrane um

um um

antigen in prostate prostate cancer and

this is something that you can just uh

develop an antibody and combine that

with lutetium and then focus that on to

the cancer. So, this is something that

is um

being now developed by many companies

and they're they're showing really good

success. And you have PARP inhibitors

which are exclusive for BRCA mutations.

We were initially thinking that BRCA

mutations are exclusive to breast cancer

and ovarian cancer, but now there is a

small subset of prostate cancer patients

also express BRCA mutations and these

patients are really very good uh

candidates for going on to PARP

inhibitors which can provide a really a

nice um um uh runway before you go to

chemotherapy. So, what are the therapies

right now in development? You have

several drugs that are going on in

development. Um for example, PROTAC is a

new new modality of treatment. There's

something called RIP-Tag. We

as we don't have much time right now to

go into details of this. Many of these

are right now in the clinical trials and

everyone is trying different approaches

to see if they can provide additional

benefits to the patients who relapse

from existing treatments. So, this is

something that is

all coming up. The recently in 2 days

ago in ASCO, a Chinese company presented

another PROTAC that is showing really a

very good response. There is

a rib deck is something that actually

brings in the androgen receptor with the

BRD4 and inhibit that and that was

providing a 70%

PSA 50 response.

So, what does our drug do? So, our drug

actually this is the androgen receptor.

This is just a modeling that I'm

showing. Our drug binds to the

disordered N-terminus domain and changes

the conformation of the N-terminus

domain of the androgen receptor, brings

in a E3 ubiquitin ligase and then chews

up the androgen receptor and the splice

variants. This is the mechanism.

So, when we perform the phase 1A

clinical trial, we actually had 20

patients CRPC who had heavily

pretreated. Average treatment

was about three to four different

treatment options where treatments the

patients have gone through and six

patients were still on study when we

discontinued the study because of

financial reasons by the previous

company and then it came back to the

university and I have licensed it out.

11 patients completed of whom five

patients showed really

good response in PSA anywhere between 25

and 50% decrease in the PSA from

baseline.

More than that, what we were also able

to show was that the androgen receptor

was degraded in seven out of 10 patients

within 28 days, which means that we are

not only blocking the androgen receptor,

but we are actually getting rid of the

entire androgen receptor from the system

so that the patients will respond far

better over a prolonged period of time.

So, two patients had stable disease in

the BID dosing, there's twice daily

dosing and a 16% decrease in tumor

burden within 28 days.

So, these are all very encouraging signs

with our drug and we are hoping that

within the next two to three months we

are very aggressively raising capital

for advancing this drug put put this

back into the clinical trial so that the

patients can be benefited and we can

make sure that our science has gone out

and benefited the patient community,

prostate cancer patient community.

So,

where we started in 1941 was the

surgical castration and we evolved

tremendously over the last 80 85 years

and today you have several treatment

options. Yet, the prostate cancer is

pretty much contributing to a

significant number of deaths annually

within the USA, about 30 to 35,000 men

are dying from prostate cancer and we

hope these new modalities of treatments

will provide additional

survival benefits to the patients. So,

that

the ultimate objective for researchers

like me is to make prostate cancer a

chronic disease rather than a death

sentence at some point. So, we are just

striving to find new drugs and new

modalities to make sure that we can just

make the prostate cancer a chronic

disease like a diabetes or

cholesterolemia. With that I'll stop and

then

we'll just open it up for really good

discussion here. Thank you so much.

>> Thank you. That was a good good job of

streamlining it down to 15 minutes.

Uh

on on the fly.

And and provided an excellent summary I

think of the state of the art. Um uh as

usual for everyone here, um

if you have questions or comments, uh

you can use the raise hand feature or

you can submit them through the chat

function and I'll read them

um to Ramesh.

Um anybody with any questions off the

top here? I I know Russ,

I would expect you might have some

questions or comments if you can.

>> Yeah, sure.

Is there data to suggest that PARP

inhibitors might be effective

if you're not bracket mutated or HR

mutated?

>> That that that is what right now the

thought is, but people are even starting

to try PARP inhibitors even in those who

have wild type bracket and

some pre-clinical evidence are

suggesting that it's true, but it's

yeah a big leap of faith that you have

to take when you go into clinical trials

whether you can put the PARP inhibitors

into

the one of the biggest

uh discouraging thing for prostate

cancer like breast cancer and ovarian

cancer is that the immunotherapy is not

quite effective because these cancers

are cold cancers. There is not much

immune infiltration.

So, is there any way that you can prime

the pump for immune

infiltration so that the immunotherapy

can become If that can be done, then

it'll really be very helpful for

prostate cancer patients to have

additional line of treatment for that.

So, but that to answer your question,

bracket mutants are the ones currently

being

Those patients are the ones approved

with the PARP inhibitors, but there are

studies that I have come across where

people are trying to see if it can be

extended to non-bracket mutated patients

also.

>> Okay, are you aware of seraparib? I'm

not sure if I'm pronouncing it right,

seraparib.

Are there other PARP 1 selective

inhibitors

in trials now?

>> So,

the different PARP inhibitors are like

say

elaborate, rocaprib, and talazoparib.

These are the three ones that are

approved right now. If I'm right, you

mentioned cerebrum, right?

>> Seraparib, S A R U parib.

>> Seraparib, I have not

I'm not familiar with it. I think only

the three these carb dollars are prepped

and a lot prepared are approved ones.

>> Yeah, those are the three approved ones.

Saraparib is in I think it's phase three

clinical trials now.

It's showing some activity in

HRBC

and HRR wild type.

>> Mhm.

>> No no mutations whatsoever.

>> That that is

>> It's in phase one and phase two and I

believe it's in phase three right now.

Pretty sure that's right. It's in phase

three now and I I was just wondering if

there are other ones. It's a

a PARP 1 selective inhibitor. So only

only instead of PARP 1 PARP 2 it just it

just inhibits PARP 1.

And maybe that has something to do with

it.

It's being

being

working for HRR wild type.

Not sure.

>> So I'm I'm involved with a company

that's developing a PARP 1 selective

inhibitor.

>> Okay, that's what that is that's what it

is.

>> And the primary reason for them to have

a PARP 1 selective inhibitor is to

reduce the

the the side effects like hematological

side effects and other things which are

>> Thank you, David.

>> evidently attributed to PARP 2. So that

is the reason that they are going after

PARP 1 selectivity. But it would be a

transformational outcome if they are

able to show a statistically significant

outcome in PARP in BRCA wild type

patients with the new PARP inhibitors.

That would really be very helpful.

>> Um is anything else, Russ?

>> Uh that's actually what I was interested

in is the PARP inhibitor part part of

it.

>> Okay.

Let me let me ask

I was going to just ask David Plunkett

if I could put you on the spot. David,

I'm just curious since I know you're

very educated on all of the

treatment options that Ramesh went

through. Was there anything that you

learned or anything different? Just if

you could give me sort of an editorial

comment on what you what you learned

today.

>> Um what I was seeing there looked very

familiar. It was a nice recap, I think.

I'm interested to hear

or re-hear the the name of the drug that

you're currently working on and ask is

it still in a phase one trial or is the

phase one trial extended or are you

ready for phase two?

>> So we actually we went our drug earlier

was called Onkt 534.

It was run by Onkt Therapeutics. So it

was discovered in our lab at the

University of Tennessee. So it came back

to the University of Tennessee after

Onkt shut down the company because of

financial reasons. So then I decided to

take the bull by its horns. So we took

the drug and then

we are starting to develop. So right now

the IND is it's a fast track IND. The

IND is transferred back to us. So it's

an inactive IND. The minute we develop

so we need about $6 million to get to

the phase 1B. Phase 1A was run between

40 mg and 1200 mg and 304 300 mg twice

daily. So we found significant activity

at 300 mg twice daily. So what we are

now doing is that we are going to narrow

down to 18 patients

to treat them with 300 mg twice daily

and 450 mg twice daily to just make sure

that we choose one of the doses to go

into phase two.

So we are likely to start the

manufacturing. Everything is ready the

minute we get the funds into our

account. We will just start the

manufacturing of the API as well as the

drug product and then initiate

ideally we would like to initiate the

the trial by the third quarter of this

year and then the phase two trial by

2027

third to fourth quarter. This is the

timeline that we have and we are working

very hard to just make sure that this is

becoming available to the patients as

fast as possible.

>> What are your thoughts on

uh the qualities of the patients you

want to recruit?

What characteristics will you be looking

for?

>> So, we are looking for um patients who

have already been treated with multiple

lines of treatment. So, the phase 1A

trial, the patients were treated all the

way from different AR antagonists,

androgen synthesis inhibitors, and also

chemotherapy. And then we recruited them

so as to make sure that we start late

stage. And then if we are showing good

success, then we'll just move early

stage because some of these current AR

antagonists, they have some liabilities

like GABA inhibition, which causes

seizures. And we want uh to avoid those,

and ours do not have that. So, we are

hoping that we can just start at late

stage, which is easier for approval, and

then go early into the the the different

patient population.

>> On the other side of the coin, are there

any uh

uh

uh

characteristics that would disqualify

for a trial?

>> So, we have not come across So, overall,

the phase 1A trial was extremely safe.

In fact, it was only at the highest

dose, the maximum tolerated dose was

achieved at 1,200 mg, where they saw a

typical AR targeted uh side effects such

as uh hematological problems. But once

the patient come came off that uh dose,

the the the patient reverts back to

healthy condition. So, we at the dose

that we are proposing to treat, we found

that it was um quite safe. There were no

side effects. Maximum grade one or two

toxicities, just some nausea, vomiting,

but we don't know whether these are

associated with the drug or the

condition of the disease. So, we are not

sure, but uh as of now, I can state that

the drug is extremely safe.

>> Let me uh is is that okay for you,

David?

>> Yeah.

>> Let me just ask some of the other

prostate cancer patients on this

webinar, uh the same question I asked

David,

Alexander, I know Chad, I think Arthur

and Chase are also prostate cancer

patients. Anybody want to comment on the

summary? I think that Ramesh did a very

good summary of the treatment options

available and where they're fitting and

so on. Anybody have any thoughts or

comments on that?

Alexander?

>> I just wanted to ask uh

what is

is

the

efficacy tested?

And what is the efficacy on

resistance

prostate cancer patients?

>> Of which treatment?

>> Of our drug.

>> The R.

>> Okay. So, the

>> The one

>> The efficacy

>> still

uh

hormone sensitive, but the tumor

continues to grow.

>> So,

the

till the end stage, pretty much almost

all the prostate cancers, they can be

treated with hormonal treatments because

the androgen receptor, one form or the

other, remains active at that point. But

what happens is that when you keep

hitting the androgen receptor,

they become mutated and the mutation

will not permit the antagonist inhibitor

to work further. So, that's why

different people are trying different

approaches to block that androgen

receptor, the mutated or the transformed

androgen receptor.

So, this is pretty much about 85% 80 to

85% of the patients do still respond to

androgen targeted treatments.

>> And follow up

uh

if

>> the patient is treated with uh

enzalutamide the

uh for example

um

after the enzalutamide if I understand

right uh this is these drugs are less

effective

or

>> Exactly.

Exactly. So

the for instance when you are treated

with enzalutamide

and then you relapse out of it

they try to go for like say darolutamide

or apalutamide but as you rightly said

the cross resistance is another major

problem.

So targeting the again the same androgen

receptor. So this is why people are

trying different approaches. Like for

example in our case we bind to a domain

that is completely different from what

typically everyone binds to.

So this by that way we are not tapping

into the same region where all the drugs

are shown to have cross resistance. We

are going to a completely different

domain which we all in scientific terms

call as non-canonical domain and then

try to block the androgen receptor.

By this way the cross resistance does

not take place and we have other

mechanisms also where we have evaluated

in

in models which are shown to be pan

resistant to all the inhibitors and we

still show efficacy in those. So

considering these these are quite

encouraging pre-clinical data and also

the clinical trial the patients were

treated heavily with the enzalutamide or

apalutamide or one of these other amides

and we are able to show an inhibition in

the PSA of the patient. So the patients

when they were recruited two or three

continuous monitoring that PSA was

increasing but when we put them on our

drug the PSA started coming down within

like four weeks which shows that the

drug is pretty much working the way that

we expect it to work.

>> Okay Alexander.

Okay.

Uh there's a question in the chat from

Alan Morris.

Um

he says, "I know this is off-topic, but

was wondering if you could weigh in on

the concept of cold tumors. You must

make it hot first." So, he's talking

about

immunotherapies in prostate cancer, I

guess. Uh just just generally. What what

What are your I don't think you touched

much on immunotherapies. Could you just

give your perspective on that?

>> Yeah, it's it's very unfortunate that

immunotherapy fails or rather failed in

prostate cancer typically similar to

breast cancer or ovarian cancer, one of

these hormonal cancers.

So, one concept that is out there is

that these tumors do not have immune

infiltration.

So, that only when the T cells are

infiltrating into the the the tumor

cells, you can use these PD-1 PDL-1

inhibitors that actually create this

environment to block the tumors. Like

melanoma is a great example, lung

cancer, even bladder cancer seems to be

quite responsive because last week there

was

a clinical trial that came out

suggesting that the pembrolizumab was

quite effective in bladder cancer. So,

this is all quite

effective. But when it comes to prostate

cancer, we have been quite struggling

with that. So, we are in our lab have

developed another set of molecules not

drugs, not drugs, but it's a molecule

where we can we are creating stress in

the cells, cancer cells. That stress

creation, we think that it could

potentially have a changed

microenvironment that will bring the the

T cells into it, and then we can combine

it with the the immunotherapy.

Yeah, it's a hope right now, but there

are a lot of other people are also

trying this approach of how to just

get the tap into more immune system in

the in the prostate cancer

microenvironment so that we can

treat it with the immunotherapy.

It's but clinical trials have not been

quite successful, but we are expecting

it to just have some kind of an effect

quite soon.

>> I'm trying to remember the name, but I

believe there is one approved

immunotherapy in prostate cancer. It

begins with an S, something like

>> It was dendrion as the provenge was the

one that was the first drug that was

approved

way back in 2007-2008.

The problem, you know, the in prostate

cancer patients would love to have oral

treatment rather than infusion and that

was

regarded as one of the causes for

dendrion to go out of business and was

not able to be successful in terms of

advisement. In fact, that was the first

immunotherapy in fact approved for any

cancer in fact. Then only came the PD-1,

PDL-1 and everything. But, um

this is something that we have to

keep our eyes and ears open for future

immunotherapy.

>> Okay.

And

Dr. Appal, if you don't mind my asking,

is there a possibility for functional

testing related to prostate cancer

because many people are getting a

prostatectomy so there's tissue. You can

have fresh tissue, which is the key

ingredient. What is the experience been

or what questions would you have around

using functional testing to predict

which of the of the variety of possible

therapies would be useful for different

patients?

>> Yeah,

that that's an important question. Thank

you for for asking. I would first wanted

to comment on dendrion because I thought

this is was actually an interesting case

and because the clinical study actually

showed significant effectiveness with

very little side effects. And the reason

why

it actually failed commercially was kind

of because of costs and so it was then I

think sold to a Chinese

Chinese company acquired them. And I

think they were available in the Asian

and Pacific

area and I'm not sure whether they are

back here in the United States available

and the many of many oncologists says oh

the trials and the effectiveness was not

that great. But if you actually look at

the effectiveness there was a lot of

crossover in the trial design. And so

the if you take out the crossover the

effectiveness was actually

was actually pretty good. I think it was

somewhere in the range of 20%

overall that's kind of now my my my my

rare recollection. So I'm I still think

the dendron is actually a very very

interesting solution. If if it works of

course and and of course many of those

tumors are not that hot but but I do

think

it is something

that has a favorable

risk benefit profile I would like to say

for those where it works. So I think

this is a great one. Now coming back to

your question on functional profiling

um

Our assay is particularly helpful when

the tumor is relatively aggressive. So

when it's a high grade tumor and when

the tissue that we have is

has a significant tumor proportion. So

if it's let's say a core needle biopsy

from a prostate

cancer then you often have a lot of

benign material and that can confound

those results. In a prostatectomy it

really depends on whether this is really

tumor tissue and so what we feel is the

cleanest approach is if there is a

metastatic stage that we get actually a

specimen from a

um prostate cancer metastasis.

And we have been able to even with small

amount of tissue to isolate um prostate

cancer from even bone metastases, which

is more difficult than isolating

um tissue from breast cancer metastases

because the bone um metastases tend to

be more osteoclastic, so they build more

bone material around it reactively as

opposed to the

um breast cancers that are actually much

easier to process, but we actually can

process um the the prostate cancer

metastases from the liver, the lung, the

bone, wherever it comes from, and that's

probably the better approach than

directly getting it from the

prostatectomy.

>> Uh Ramesh, do you have any comments on

that?

>> No, this is great actually. Um while Dr.

Appfel was talking, I was just thinking

about um uh the our one of our

publications the the the

the investigators at KOLS University of

Wisconsin who were part of the clinical

trial, they developed a very nice um

companion diagnostic from circulating

tumor cells, and they published it about

four five weeks ago uh in and you all

can search for uh the the with the

keyword in PubMed ONCT-534 and they

produce they provided

some really good biomarker things. So, I

was just thinking uh probably Dr. Appfel

and I should uh correspond after this um

uh talk at some sometime to just see

what best we could do to develop some

companion diagnostics for our phase two

clinical trials.

>> Happy to connect. Yeah. Um I can put

down my email in in the chat.

>> That'll be great.

Um from Sophia Ren, there's a question

about personalized vaccines, I guess

mRNA vaccines, and wondering whether

they might be promising in prostate

cancer. They've They've been successful

in other cancers. Have you got an

opinion on that?

>> To my knowledge, I have not seen any

activity on that in prostate cancer

space.

All right. So, I'll have to go back and

check what is that at least in the

clinical development. I have not seen an

mRNA vaccine.

I can I can uh

Let me just go back and

check my memory.

There There are some um

like uh

There's one gene therapy that is

actually going on right now with some

uh viral-based gene therapy, but uh

mRNA vaccine, I've not

paid any attention on that. I've not

seen much in the clinical trial as well.

But, it's an interesting It's an

interesting question.

>> All right. Um Alan Morris has his hand

raised. Alan?

>> Um hi, doctor, and I cannot pronounce

your name. I So, I won't I'll just call

you Dr. N. Is that okay?

>> That's perfectly fine. Or even Ramesh

would be better.

>> Yeah. Um I I have to warn you that I'm

very focused on the immune aspect of

prostate cancer care. Thank you, Chris,

for

telling more about how Dendreon first

went bankrupt and what the reasons were

and that now a Chinese firm has bought

it out. So, it still exists exists. Um

Uh

I just The questions I'm going to ask

you, because you are an expert, you're a

scientist, you're a University of

Tennessee, you swim in the world of

people that are uh researching this. I

want to explore the conventional wisdom

with you. I think it's already been

implied, but I want you to overtly state

it. The conventional wisdom is that hot

tumor, as opposed to the cold tumor, is

the best tumor for a vaccine. Is that

not the conventional wisdom?

>> Yes.

>> Okay, thank you for confirming that. Um,

um, let me see. Uh, the corollary of

that is that a cold tumor, and the

prototype of that is prostate cancer,

and that would be the worst tumor to

pursue a prostate can- uh, cancer

vaccine for. That is the conventional

wisdom, right?

>> Yeah, yes.

Unless, yeah.

>> Yeah, uh, you were actually doing

important work for me, and I want to ask

you if you allow me to, uh, um,

uh, cite, uh, your, um,

hand on the pulse. I'm writing a paper.

It's now book-length, and it's why

prostate cancer is the best cancer to

pursue a a cancer vaccine for. And you

realize by me just stating that, I am,

if you are correct in your hand on the

pulse, I am stating something that is

absolutely not believed in the medical

and scientific community. Is that it

would would that be a fair statement?

>> Cannot say that absolutely not believed,

but actually, still we think there is a

hope for a vaccine in prostate cancer

for sure, because as Dr. Apple pointed

out that

Provenge was a good success, but for

varying reasons, it did not become a

commercial success. But, I I'm I'm sure

that there is an opportunity to get

into, but who is

interested in investing

a lot of large amount of resources to

take that risk is the biggest question

right now.

>> Well, no, I agree. And what what you if

if I may probe you psychologically,

you just demonstrated, um, the, uh,

measured response that all scientists

take. They don't make absolute

statements. And I I I I made absolute

statements. And for example, if I write

a paper, I should not make absolute

statements, especially if I'm proposing

something that's not um

conventional wisdom. May May I I want to

Now that we've stated uh that the

conventional wisdom is that the hot

tumor is the best tumor to pursue a a

cancer vaccine, and that the cold tumor

is the worst, um uh the conventional

wisdom also is one of the reasons it's

the worst is because you first must make

a cold tumor hot. In other words,

there's this first pre-step that you

have to do in order. So, obviously, if

we don't even know much about vaccine

development, if we first have to do this

Herculean step of making a cold tumor

hot, then it should be that much more

difficult to make a a cancer vaccine to

prostate cancer. Is that Would that be

in line with conventional uh wisdom?

>> Yeah, it's

My my The point here is that it it need

not be a Herculean task, you know. There

could be an opportunity with some

modality that is under development or

that has been developed that could be

combined with the immunotherapy to just

make the the cold tumor hot. But what it

what it is is something that not many

people know or people or maybe people

are evaluating it right now. But it's

something that um would be uh it it it

need not be a huge um um

battle, but it could be something that

if people find it out, then it it would

become the mainstream treatment option.

>> Al, okay. Al, Al, Al, let me interrupt.

Um knowing that you

uh are sort of leading the witness

through a long argument, could you just

cut to a single question, please?

>> Um

That is difficult. So, uh the single

question is, would you be willing to

read my um 50,000 word treatise on why

prostate cancer is the best cancer to

pursue a cancer vaccine. And and what if

you were willing to even attempt to read

just the uh introduction and um

abstract and prologue, I would be

forever grateful. Would you be able to

provide me your email address?

>> Sure. I I would be I would be happy to

read it and it'll be informative for me,

too. Um for everyone, for you and

everyone. I'm just putting my email

address here.

>> Uh um May May I make one other comment?

Um the

I I I used another absolute term, which

is Herculean, and you used your your

scientific measure have to say no, it

may not be Herculean. May I just

synopsize it and tell and tell me if

it's correct. The leap is over the tumor

microenvironment. In other words, if you

believe in like Boston Gene believes

that there's only an immune excluded

state and not an immune naive state, you

must

the the exclusion is by the tumor

microenvironment. You know, obviously,

the cancer cell would be theoretically

in there, but a major component is is

the tumor microenvironment. And you you

do know that everybody is researching

the tumor microenvironment and how to

modulate that. So, that is the extra

steps. And testament to how my Herculean

word is not particularly

exaggerated is they've been trying to do

this for a decade and and a half, if not

more, and have been unsuccessful to

date.

Um um and you you you mentioned uh the

counterargument, well, there's no money

in it. And I I In some sense, I agree

with that, but I don't agree with that.

Basic science is pursuing this. And the

tumor microenvironment is being

dissected, but it's in its infancy. Um

and I know your your main talk is on AR

degrading

actually I I didn't quite understand

your because I was focused on my own

stuff. Is it mainly an AR degrading a

binding of

of the constitutionally activated AR

state that you might get in is that what

your your molecule is is doing or

I

>> No.

>> Yeah, go ahead explain it to

>> No, our money our money binds to a

common domain that is expressed in this

uh splice variant that is constitutively

active as well as in the full length

receptor. So it can inhibit all forms of

androgen receptors. So that is the best

part about this particular molecule.

>> But it's main mechanism that would be to

thwart the

permanent on state of the

constitutionally

activated

variant. Is that not right?

>> Yeah, so it is going to inhibit

degrade the whole

AR constitutively active one as well as

the the full length receptor.

>> And to also summarize it your company

you have a very promising thing but you

need the money to to get the thing going

as far as the getting a real study to

show to to to make it practice changing.

>> Yes, already the phase one clinical

trial showed that it's

it's a quite

an effective drug. Now we need to

advance it to phase 1B phase two and

phase three to just make it as fast

quickly available as possible to the

patients.

>> You may have said this in your your talk

but you you have people that are

competing with you in the race. It can

you list two or three that are competing

in this

trying to molecularly thwart the

constitutionally activated AR state

who are the two or three that are

competing with you and where are they?

>> No no one exactly in this space. So we

are the only ones who are binding to

this region and degrading the

constitutively active form. So,

from that perspective, there is no

competition at all. The remaining

competitions come from the typical

ligand binding domain binding inhibitors

or degraders or some other modalities

like gene therapy or so. But, this what

we are developing is extremely unique

and this is why FDA gave us the fast

track.

>> Okay.

>> Oh, thank you. Thank you.

>> Um Ramesh, we I always like to give an

opportunity to the discussion leader,

you in this case,

um to give some sort of parting words of

wisdom or thoughts, uh key messages

you'd like to leave with the with us.

>> Sure. Yeah, so I've put my email address

in the chat. Um anyone has any questions

regarding um the drug development or

mechanism of action or anything, feel

free to reach out to me. That is one

thing. Second is that there is a lot of

hope in prostate cancer because this is

something that every pharma wants to

have a drug developed or every company

wants to develop. The reason being that

there is a large population of patients

who are affected by this disease. And

we researchers like say in academic

realm as well as in many of the

commercial side, they don't want to see

the patients go on to chemotherapy. So,

what is the best option that we can

give?

And since this one has been studied, the

androgen receptor and the whole prostate

cancer mechanism have been studied for a

sustained period of time,

people are coming up with new approaches

to target this disease. So, what I'm

seeing is that it's quite encouraging.

Over the next 5 to 10 years, we all may

have additional modalities, hopefully

including ours, that can actually

provide a sequential treatment for

prostate cancer. like how breast cancer

is uh currently being managed by

multiple

treatment options. The same thing

prostate cancer will have different

options and I'm very confident that

uh the the the the road is quite very

promising right now and

I hope I'll

be one of those who make a change in

this

to take care of the patients. Thank you

all really It's an honor to be here and

I just thank

Brad for providing this

forum to talk to you all and I would be

very happy to come back and talk about

any specific topics that you all are

interested in in the future.