Gerard Sanacora, MD, PhD & Sam Wilkinson, MD. December 2021

November 29, 2022

Title: Regulatory Approval and Implementation of Psychoactive Therapies for Psychiatric Disease: Lessons Learned from Esketamine

Description: The first half of this discussion summarized the key principles and lessons learned from the approval and implementation of esketamine and how we might apply this to future therapies which are administered under strict regulatory control. In the second half, we discussed the findings of a newly reported (top-line results) trial on psilocybin (COMPASS).

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00:00Boom.
00:03OK. We are now recording.
00:05So it's my pleasure to introduce Jerry
00:09Sanacore and Sam Wilkinson to talk
00:11to us about ketamine and psilocybin
00:13and the treatment of depression.
00:15And just take it away. Alright,
00:20can you see this? Yes.
00:24OK, now am I showing the
00:26right one or is it the swap?
00:30I can never figure that out.
00:31OK all right.
00:33So I'm going to start out and
00:36probably talk for the 1st 1520
00:39minutes or so just about what
00:42we learned from implementing
00:44getting Esketamine approved and
00:45then trying to implement it.
00:47So I do have some disclosures.
00:49I get money from the federal government,
00:51nonprofits and some pharma companies.
00:53Yale has an institutional conflict
00:55of interest with Esketamine.
00:59So just just to know that.
01:00So I let's see, I'm going to start out,
01:04it's alright. I'm going to start out
01:06with a joke that's going to keep
01:07it clean because we're recording.
01:09So I'm a very I I consider
01:13myself very practical.
01:15I my undergrad major was engineering.
01:18So so there there are three people.
01:21There's an engineer, there's a physicist,
01:23and there's a mathematician.
01:25And they are engaged in a contest to go out
01:29and hunt tigers and and and capture them.
01:33So before they go out and hunt,
01:36they have to make structures to
01:38keep them in cages out of fencing
01:39materials or something like that.
01:41So the physicist,
01:42he creates a circle and he says,
01:45well, I'm creating a.
01:46People, because you can get the
01:47most area for your, you know,
01:49linear amount of material and then the,
01:51the engineer says.
01:54He he makes it an equilateral
01:56triangle and he says this is the most
01:59structurally sound cage so that,
02:00you know, that's why I'm making this.
02:02And then in the corners, the mathematician,
02:04he's fumbling around materials,
02:05it's clear he's never used his
02:07hands in his life.
02:08And he somehow manages to get
02:09a little fence around himself.
02:11And he says, well,
02:13hypothetically, you know,
02:14the internal and external areas in A3
02:16dimensional services are arbitrary.
02:18So I'm therefore defined myself
02:19as outside the circle,
02:20and I've enclosed all the tigers
02:22in the world, so.
02:23Uh, so that's maybe clever,
02:26but it's not very practical.
02:27Uh.
02:28So I want to talk a little bit about
02:30what we've learned from Esketamine
02:32and and other drugs really,
02:34that are kind of psychoactive,
02:36you could say,
02:36and and how they're going to be
02:38implemented in the real world.
02:40And I think why it's important to
02:42think about it from the beginning.
02:43So I'm first actually not even
02:45going to start with the skinny.
02:46I'm going to start with Brexanolone.
02:48Now,
02:48I don't know who's familiar with Brexanolone.
02:50It is.
02:51There's some really bright ideas behind it.
02:54Uh,
02:55it's an exogenous form of
02:57allopregnanolone used to that is
02:59now the first FDA approved therapy
03:01for post for postpartum depression.
03:03I think it's a, it's a really great idea.
03:06But somewhere along the way the
03:08way those great ideas stopped,
03:11this this next one is, is one of them.
03:13It's a 60 hour infusion and it has
03:16to be done in a hospital setting.
03:18Now all credit to the,
03:20the folks who were developing this,
03:21I I think they thought that maybe
03:23it could be done in a home setting.
03:25But because of some adverse events
03:27that happened in the later stage
03:29trials where the women who were
03:31getting these the the treatment kind
03:33of fell asleep or dozed off while
03:35they were getting the IV infusion.
03:37The FDA being the conservative
03:39organization it said it is said OK,
03:42this has to be done in a hospital setting.
03:44So it also doesn't help it cost
03:47$35,000 and and so based on
03:50all these factors and
03:52the way that that that
03:55hospitals are reimbursed.
03:57A lot of hospitals are are reimbursed
03:58in what are called bundled rates.
04:00So no matter what service they provide,
04:03they're paid the same by government payers.
04:07So they really have no incentive
04:09to offer this treatment.
04:10In fact they they have a disincentive
04:12to offer this treatment because
04:13they're just going to lose money.
04:15So Brexanolone is not really being
04:17used maybe at UNC Chapel Hill where
04:20they you know they they have a lot of
04:24expertise and and interest in postpartum.
04:26Every part of depression but you know
04:30the the factors aligned here it make
04:33it almost impossible and to to kind
04:36of get this off the ground so let me
04:39talk a little bit about Esketamine.
04:41So as you as this was a cartoon that
04:45came about man it's been seven years
04:47that's that's kind of crazy just a little
04:50bit about how nonspecific ketamine is.
04:52It has all sorts of actions on different
04:54different receptors this was our.
04:56Little update with bravado,
04:58you know it should be given IMS,
05:01bravados, the ripoff, etcetera.
05:04So we've learned a ton about ketamine
05:07or esketamine in the last 5-6 years.
05:11These immediately clinical
05:13relevant questions,
05:14the optimal dose strategy,
05:15we have reasonable kind of studies that
05:18have addressed a lot of these things.
05:20What is the long term effectiveness?
05:22What is the long term safety?
05:23There's more and more data coming out.
05:25What are the moderators or response?
05:27It's not too different than.
05:31It's not too different than depression
05:34generally but they're you know focus
05:36on the bottom question can similar
05:38drugs be developed and implemented.
05:40I'm not going to go into a lot of
05:43the clinical data for Esketamine
05:44I I want to talk about some of
05:48the implementation principles.
05:50So just to give a little bit of a
05:53context the timeline so the the FDA
05:55approved this ketamine in the US it's
05:58coming up on three years, so it was.
06:00March of 2019, there are two.
06:03There's been a subsequent indication.
06:05The first indication was for TRD,
06:07or treatment resistant depression.
06:09A subsequent indication was approved,
06:11what some people are calling MSI or
06:15major depression with suicidal ideation.
06:18An important thing to understand
06:20is that as kenning is subject
06:21to what's called a Rams or risk
06:24evaluation mitigation strategy.
06:25This is when this is basically
06:27the drug safety program.
06:28The FDA requires certain medicines
06:30with serious safety concerns to
06:33make sure that the risk benefit.
06:35We should be balanced so you may be
06:37familiar with this in psychiatry.
06:39Clozapine has around Suboxone
06:41and and other medicines.
06:43All have REMS drug safety programs.
06:50So what, let me tell you just a
06:52little bit about the Esketamine REMS.
06:54So it can't be used in the take home form.
06:57There's a 2 hour monitoring period.
07:00It turns out that this is a big
07:02problem to implementing medicine.
07:04The FDA judge, you know,
07:06basically said it has to be 2 hours.
07:08I think that's a little bit.
07:10For most patients it's a little bit.
07:13On the conservative side,
07:15there's vital sign monitoring that
07:16has to be done pharmacy and treatment
07:19center certification and you have to
07:20submit forms with with some data.
07:22So I got together with some people
07:25who are kind of more expert in
07:27policy and so forth and we basically
07:29made a an evaluation right after
07:32attending came out how it would do,
07:35what would be some of the challenges.
07:37So, so again I mentioned the
07:39two hour monitoring period.
07:43That's a that was a a huge thing,
07:45partly because it was unclear how
07:47psychiatrists were gonna get paid for this.
07:49Now let me take just a step back.
07:52I was at an RTP seminar a couple years ago,
07:56and I think Chris and
07:58Bob Mallison were there.
08:00And Bob, you know, wonderful guy,
08:03he said something that that I
08:04wish I could have gone back and
08:06and challenged him a little bit.
08:07He said, look, you know, we don't really
08:09care how people are going to get paid.
08:10Let's just focus on the science.
08:13I I'm gonna push back and say well,
08:15if you don't care about how
08:16people are going to get paid,
08:18it's not going to be used in the real world.
08:20So I know that these factors aren't the
08:23normal things that a lot of us think about,
08:25but they are really important.
08:27So the two hour monitor
08:28requirement is a big issue.
08:30The space, the infrastructure personnel,
08:32who's going to monitor it,
08:33how are our psychiatrist
08:34is going to get paid.
08:35These were all very new issues
08:38that that not a lot of people
08:40have thought about vital sign.
08:42Wondering psychiatrists don't
08:44generally do this and then what's
08:46called buy and Bill model payment
08:49psychiatrists also don't do this.
08:51What buying Bill model is?
08:54It's it's used in cancer a lot.
08:56So a clinic will buy up a lot of medicine,
08:58chemotherapy for instance,
08:59and they will individually resell it to
09:02patients and their insurance companies.
09:05This is kind of how a lot of places
09:07have to do treatment with Esketamine.
09:10It's not you,
09:11you don't give a script to a patient
09:13and they fill it at the pharmacy.
09:14That's not how this works.
09:16And so psychiatrists aren't
09:17familiar with this sort of thing.
09:19And it's been a you know what?
09:22A structural barrier to implementing
09:24this and of course many psychiatrists
09:26more than pretty much any other
09:28specialty do not accept insurance.
09:30That's not necessarily a
09:31barrier specific test ketamine,
09:33but Umm,
09:33but it's something that that
09:35we have to think about.
09:37And then transportation so
09:39patients can't drive on the days
09:42of treatment after the treatment.
09:44This can be a barrier to to
09:46people getting treatment.
09:48So before S Penniman was approved,
09:51we had watched with interest.
09:53This growing trend of people providing
09:55off label racemic ketamine and this
09:58was a a letter we we published a
10:00number of years ago and in the
10:02absolute numbers aren't very high
10:04but the trend was definitely you know
10:07increasing and and so we thought you
10:10know well maybe Esketamine gets approved.
10:12The economics will be such that
10:14you know the demand for this,
10:16this type of thing will be funneled
10:19towards providers who give Ken
10:20Esketamine because insurance carriers
10:21are going to pick it up and so forth.
10:24It's not going to be as costly
10:26for the patients and so forth.
10:28I don't think that's been the case.
10:30This is kind of an update to.
10:33So that's in the last couple of years and
10:35this isn't a strict epidemiological study,
10:38but just gives us some sense that you
10:40know these these ketamine clinics off
10:42label ketamine clinics are continuing to
10:44exist and and I'm sure some of them are
10:47thriving and part because as ketamine
10:49really hasn't been implemented very well.
10:51It's been very, very challenging course of
10:54pandemic doesn't make it easy any easier.
10:57But again just to to think about some
10:59of the treatments that we have and
11:01the difficulty of implementation.
11:03Plus being Suboxone, brexanolone as ketamine,
11:06ECT, cognitive behavioral therapy,
11:07all of them have serious implementation
11:10issues. And so the,
11:11you know a lot of these are very,
11:13very good and helpful treatments.
11:15But if we think about how to make
11:19treatments better for our patients,
11:21you know we need to think about
11:23this from the beginning.
11:24So again I gave the example of brexanolone,
11:28it would have been great if instead
11:29of a 60 hour infusion they started
11:31with well one hour infusion.
11:33Six days a week or something like that
11:35and that would have been much easier to
11:38implement than a 60 hour continuous infusion.
11:41So common barriers again with
11:45these new treatments is very,
11:47very germane to the psychedelic world.
11:50The existing infrastructure of weight
11:52patients are treated are not suited
11:54to these new kind of paradigms,
11:56extended modern observation times,
12:00you know cost and reimbursement
12:01ratio and the example for channel 1.
12:04Uh,
12:04there's a disincentive to provide the
12:06treatment based on the way that that
12:09hospitals are reimbursed and and then,
12:11you know,
12:12requiring really specialized
12:13training or skills.
12:15I know some people in the psychedelic world,
12:17there's this thinking that it has to
12:19be a very specific way that people
12:22are guided through this experience.
12:24And the more specific that is,
12:25the harder it's going to be to
12:27implement kind of like like CBT.
12:29So some thoughts I have about this,
12:32you know, we you need to be thinking.
12:34About these things,
12:35early on it how will the proposed
12:38treatment fit into the existing
12:40healthcare scheme and setting.
12:41The other thing is,
12:42is you know,
12:43this was not news to me as we went
12:46through this as ketamine thing.
12:47You have to create CPT codes if they're,
12:50if they're going to be new procedures,
12:52CPT code needs to be created
12:54that involves lobbying,
12:55it involves the APA and the AMA and
12:57it takes a while and then where
13:00you can can you create where where
13:03you need specialized therapies.
13:05Can you have digital therapeutics
13:07or or in some way you know
13:10standardize this with computerized
13:12therapies or trainings or whatever.
13:14So these are a few of my thoughts
13:17from the the the rollout of
13:20both Brexanolone and Esketamine
13:22and I think you know we could,
13:24I don't know Jerry if you want to.
13:27Sam, can you since this is a,
13:30I think this is a group with
13:32very mixed backgrounds.
13:32Can you unpack CBT, CPT codes? Yeah,
13:36I, I'm sorry. So CPT codes,
13:38I think it stands for current
13:40procedural terminology that's
13:42that's how everything gets, gets,
13:44gets paid for in the healthcare system.
13:46So unfortunately they are not
13:49really well adapted to psychiatry.
13:51They were created for mostly for
13:54like surgical and procedures,
13:56but every time you do something
13:58in the healthcare setting.
13:59See a patient for 1520
14:02minutes you administer ECT.
14:04You do psychotherapy for 40 minutes.
14:06You you or your I mean usually it's
14:09a clerical person will submit a code
14:12to the insurance company and then
14:15you will get paid for that hopefully
14:17sometime you know one to six months later.
14:21So when these new procedures come out
14:23like as ketamine for instance again
14:25the the the the issue with Esketamine
14:28was that you have this two hour.
14:29Running time and there wasn't
14:31a way to get paid for that.
14:33It's you know,
14:33it's a huge it's it's that that's
14:35a lot of time to have a patient
14:37in your office or your clinic
14:39and and to be monitoring them.
14:40If you can't get paid for that time,
14:42your nurse is spending time or you know
14:45your doc is spending time watching them.
14:48It's going to be hard to to convince
14:51people to to take up this treatment
14:53and use it in in the real world.
14:55So I know a lot of silo syben studies.
14:58It's like an 8 hour deal right and.
15:02Some of the some of the people
15:03I talk to say ohh,
15:04it's just once they're good for six months.
15:06I'm a little skeptical of that.
15:08We'll, we'll see if if that pans out,
15:10if if it does, that'd be great.
15:11But but these are things that are going
15:14to be real barriers to implementing
15:16the treatment in the real world.
15:19Again,
15:19if it's shown to be effective in it and
15:21achieve some sort of regulatory approval,
15:24does that explain a little
15:25bit about CPT codes?
15:26Yeah. So if you have a new treatment
15:28like a new drug but it can be prescribed
15:29in the same way as an old drug,
15:31then you don't need a new.
15:32CPT code because it fits within
15:33the existing model, right?
15:35But if you have something that
15:37requires a fundamentally new mode of
15:38delivering care or use of time that
15:40can't fit within existing codes,
15:42then that's when you would need to build.
15:44To to to build a new one.
15:45And that's a lengthy process.
15:47Is that the correct, the correct
15:48and and most of our treatments is
15:50everyone knows are just pills and there
15:52aren't really CPT codes for those.
15:54They're just CPT codes for a 20 minute time.
15:58To sit down with the patient,
15:59figure out what their problems are,
16:01what you know their,
16:02their goals are and then OK Prozac
16:04and send it to the pharmacy that's in.
16:07But obviously with these things
16:09like Esketamine or silybin,
16:10it's a very much involved,
16:12there's observation the patient
16:14has to be in your office or your
16:17clinic and it's kind of a a
16:19new world in terms of CPT code.
16:22That that space there.
16:24So.
16:24So these are just things that that
16:26should be thought about even at the
16:28early stage because again like like
16:30brexanolone if they would have just said OK,
16:33let's instead of a 60
16:34hour continuous infusion,
16:35let's try an hour infusion for you know
16:37four or five days a week for two weeks.
16:40Is that does that have a comparable
16:42clinical outcome we you know it,
16:45it could be a different ball game.
16:48And Sam with the the ketamine,
16:50so you focused on S ketamine which
16:52is the FDA approved intranasal
16:54form of the the S and anomer in
16:56contrast to Ivy received Academy
16:58which came around earlier but
17:00doesn't have the FDA approvals.
17:01It's always off label, right.
17:03And you showed us how there's
17:05a growth of clinics,
17:06continued growth of clinics that
17:08are giving the racemic the IV
17:10ketamine that's not FDA approved.
17:12How much of that is being paid for
17:14by insurance within the system
17:15with CPT codes and how much of it
17:17is being paid for out of pocket?
17:19But people because that's this is
17:20another thing that's become going to
17:22become relevant with psychedelics.
17:23You know if it goes out under an
17:248 hour model and it costs $7000,
17:26well then some people are going to do
17:29that independent of the insurance industry.
17:31Then we come into the issue of
17:32equity and and you know what
17:34what's tiny sliver of the of the
17:36population that might benefit is
17:38are we getting because it was so
17:40but how's that playing out with.
17:42With ketamine at this point is that is the,
17:45is the receiving ketamine being
17:46covered by insurance,
17:46is that mostly private pay out
17:48of pocket. I mean we don't have really
17:51great high quality epidemiologic data.
17:54My sense, my strong sense is
17:56that it's mostly out of pocket.
17:58You know, I mean at Yale we've
18:00fortunately been able to kind of get
18:02some insurance carriers to come along,
18:04but definitely not all of them by any means.
18:07So by far most, most insurance,
18:10it's much more likely you're
18:11going to insurance cover.
18:13Coverage for esketamine
18:15than for IV racemic Academy.
18:19Again, we don't have great high
18:21quality epidemiology data.
18:22Sometimes the the clinics will,
18:25they'll, they'll give you,
18:27give you codes that they use that
18:29they kind of hobbled together.
18:31You know,
18:32one of these codes that is sometimes uses,
18:34it's like a narcosynthesis code,
18:36which is an old code that I
18:38think used to be used for.
18:41Was it sodium amatol you know
18:44some total psychotherapy so I you
18:46know and then and then the patient
18:48will then take that code and and
18:50try and get reimbursed from their
18:52own insurance company.
18:53So that's you know,
18:54it's it's kind of the Wild West in
18:57terms of what what goes on in in
19:00IV ketamine because it's mostly not
19:03under the umbrella of insurance.
19:06So I have questions then.
19:08Would you have a different CBD
19:11code for intranasal Esketamine
19:13versus IV ketamine? Yes. So,
19:16so there's not really a CPT
19:18code for IV, IV ketamine.
19:20I mean what what you had to do in
19:23the in the first in the first year
19:26or so there there is now a CPT
19:29code for Esketamine observation.
19:31You know that it's it's been sufficient
19:33time but in the first you know
19:35year or so basically what you had
19:37to do is you had to negotiate with
19:39each individual insurance company
19:41and and you can use some kind of.
19:45You know, other CPD code,
19:47but that requires a lot of manpower
19:50and and psychiatrists are not used
19:52to doing that or or or, you know,
19:55we we typically don't have.
19:58Personnel in our clinics that do this
20:00you know surgeons and and and surgery
20:03centers and they have someone who you
20:05know OK this new drugs coming online
20:06let's start the negotiation process.
20:08There's kind of a a a process in
20:12place this was kind of all new
20:14to us as as this was implemented.
20:17So sorry the answer your question
20:20there are different speech codes
20:21there isn't really a CPT code for ID
20:24cademy people kind of hobbled together
20:26different CPT codes and and negotiate.
20:28Kind of a one to one basis with
20:30a given insurance
20:31company. Get Simon if if I could add.
20:34So what people have tried to do if
20:36you use existing CPT codes like
20:39Ivy Infusion which is a CPT code,
20:41you get about $25 for Ivy infusion
20:44and that has to cover the two hours.
20:47So it it it's.
20:49Impossible to financially cover it
20:51using the existing CPT codes and
20:54that's something I think actually
20:56blindsided Johnson and Johnson.
20:59They, they worked so hard making sure
21:01that their drug would be covered,
21:03but they didn't realize how were
21:05they going to cover the professional
21:07fees of the and and the facility
21:09fees of the facility and the
21:11professional that's delivering it.
21:13It's just.
21:15Not covered I I think Sam you know
21:18what the last Medicare coverage
21:20is like $27.00 or something I
21:22heard for for the treatment you
21:24know they'll pay for the drug but
21:27the actual time that covers the.
21:29Facility fee and the professional
21:31fee is just such a minimal amount
21:34that nobody can actually provide it.
21:37Not nobody. It's very difficult.
21:41Umm.
21:44I wonder if maybe maybe we can
21:46come back to the, you know, Sam,
21:47your ideas on how we could do this better.
21:49Maybe we could come back to those
21:52after talking about the compass.
21:54I've been stopping it because the,
21:55I mean, for this group, I think the,
21:57the the interest is what as you framed it,
21:59what can we learn from this,
22:01what can the field learn from this to
22:03try to avoid some of these pitfalls.
22:05For an anticipated rule out of psilocybin
22:07or or or or MDMA therapy in years to come,
22:11where the challenges may be even greater,
22:13you know, if you've got it.
22:16So, so, so does that, does that,
22:18yeah, no, sorry.
22:20I'm saying isn't the monitoring time for
22:24ketamine shorter than for Esketamine?
22:28Well, there is no monitoring time right.
22:29There's no rims you know
22:31it's it's the the REMS.
22:33So the FDA you know they can only
22:36really regulate through REMS programs
22:38those things that are FDA approved.
22:40So the FDA is not really regulating
22:43off label stuff which is ketamine,
22:46ID ketamine, racemic ketamine.
22:47All they can do is if they get word
22:50of like someone's doing this in the
22:52community and not responsible way,
22:53they can send them a letter and
22:55say please don't do this but but
22:58there's no rems associated with.
22:59The the individual clinics or hospitals,
23:01they kind of make up their own policy,
23:04you know what as to what they think
23:06is appropriate and safe and so forth.
23:09So
23:10yeah, unfortunately in the US
23:12the only way to really police
23:16this is plaintiffs attorneys.
23:18That there isn't,
23:19you know, the there is no,
23:21that's not the business the FDA is in.
23:24That's not their jurisdiction to make.
23:26Rims for things that are off label
23:29and and the reason for this is
23:31because ketamine was already
23:32approved decades ago, right. And
23:35as an anesthesia medicine, yeah, yeah,
23:37approved as an anesthetic.
23:39Exactly. So, you know really
23:42the FDA regulates promotion of.
23:46Of a of a drug or a device
23:48for a specific use.
23:49That's what the FDA regulates.
23:51They they don't regulate medical
23:54practice except the REMS except
23:56for R.E.M is when when they're
23:58doing it they'll they'll give
23:59guidance and and have a REMS,
24:01but they don't on off label
24:03stuff or other uses.
24:04They don't regulate it.
24:05So Esketamine has that regulation,
24:07ketamine doesn't.
24:08I'm the only one that would
24:10police that is you know if
24:11there's a lawsuit or something
24:13or or a complaint to a state
24:15medical board about someone.
24:16Or exactly. But, but unfortunately,
24:20those really only come up when there's
24:22like a horribly Sentinel event that's,
24:24you know, something really bad happens.
24:28So is there any I guess?
24:31I don't know hope is the word of getting
24:34can I mean FDA approved for depression?
24:39Option. Treatment.
24:42You mean I recement category?
24:45Yeah, Ivy can. I mean.
24:48Or is it because it feels
24:50like it's just been?
24:52Some drug company would have to put
24:54up some 10s of millions of dollars
24:55to do the study and the FDA process,
24:57and since they don't own
24:58the patent on the drug,
24:59they'd never make that money back.
25:01And hundreds of, not 10s and
25:04hundreds and hundreds of.
25:08Yeah, so probably not.
25:11Because of the way the finances
25:13me incentive structure in our
25:15medical system work. Great system.
25:19Federalism. Kind of well,
25:23but, but hopefully the next part
25:25won't even be more disheartening.
25:28But let's move a little bit
25:31to if it's OK with you guys,
25:33I'll go to the next part of this.
25:36Let me see if I can share my screen.
25:39It should be.
25:44And what are, what are you seeing right now
25:48we're seeing the price SBP 2020
25:51oral abstract 64 read only.
25:53No, that is not what you that is
25:55not what I'm hoping you would say.
25:57OK, one second, confidential quick.
26:02I say I'm
26:03not sure why that's what you're seeing.
26:05You should be seeing this.
26:07You're still seeing the same,
26:09now we're seeing PowerPoint.
26:10Are you seeing the disclosure?
26:13OK, let me actually just
26:15get that hooked up then.
26:19OK, let me do slide show. And.
26:30All right. Hopefully,
26:31hopefully you're seeing the right
26:33view now or again you seeing.
26:34OK, good, good. So again,
26:37I always do you like to include that.
26:41Several disclosures but the you
26:44obviously you can all ask him about
26:46it or see it if you want this the
26:48same as Sam regarding that but
26:50very quickly I do want to my goal
26:52here I Sam did a great job of.
26:55Highlighting you know the the hurdles
26:57and implementing this and what we're
26:59actually putting a a workshop together
27:01from the National Academy of Sciences
27:03right now on psychedelic drugs and it
27:06it was something we debated whether
27:08to even talk about implementation is
27:10putting the cart before the horse.
27:12You know we don't know they even work so
27:14why are we talking about implementing them.
27:16But I think we all agreed that it's almost
27:19not worth figuring out if they work if
27:21there's no way of implementing them.
27:24So I think that.
27:25It is an important part and and I think
27:28actually discussing the implementation
27:29is is really good idea and no matter
27:32what you're going to be developing
27:34before you start to develop it.
27:36So,
27:36but let me give you the rest of what
27:38we've learned from the Academy story
27:40just to put in perspective where we are
27:42with psychedelics and then talk about
27:44where we are with the psychedelics.
27:46So it's actually interesting remember
27:49the earliest report academies potential
27:52antidepressant effects actually
27:53came from a study done in Iran.
27:57Back in 1973,
27:58it was published and they were actually
28:01thinking of it as a means of having a
28:04psychological effect on abreaction.
28:06I had no idea what Abreaction was.
28:08I had to go look it up.
28:09It's a psychodynamic term really,
28:12sort of leading to catharsis.
28:14And that was that.
28:15That was the original study published.
28:17And remarkably,
28:18they tried a few different doses
28:20and they came up with the dose of
28:22.5 milligrams per kilogram that
28:23they found to be most effective.
28:25And they were just treating,
28:27not only depressed.
28:28Questions anybody that was hospitalized
28:30and had really pretty amazing results.
28:33Obviously that wasn't the I,
28:35I I don't think anybody that actually
28:37ran the first study here at the VA was
28:40really aware of that study at the time.
28:42That wasn't really what drove the study here.
28:44And this is actually a quote
28:46right from John on what really was
28:48driving the use of ketamine here,
28:50not related to the more psychedelic
28:53like effects,
28:55but really based more on the
28:57neurobiology and the effects on on
29:00Cortex as opposed to the effects
29:01on cortex and the glutamatergic.
29:03System as opposed to the raffay or or
29:07other systems more related to serotonin,
29:11but really getting much more to the point,
29:13this is what an FDA package?
29:16Looks like.
29:17So this is what Janssen presented to
29:20the FDA to get approval for Esketamine.
29:23You can see the size of these studies and
29:25you can see the duration of these studies.
29:27So these are ends of 300 and 46200
29:31and 23138 in a geriatric population.
29:35705 people in a long term
29:39maintenance withdrawal randomized
29:41withdrawal study in 802 people in
29:44a long term follow up for a year.
29:47But that was actually turned into a
29:48follow up for another three years.
29:51So all total if you look at the
29:53dollar cost here you're talking
29:56several $100 million probably
29:58my son would be going on about a
30:01billion dollars for this package
30:03if you include the internal cost
30:05to Johnson and Johnson and Janssen.
30:07So Nora and
30:09Jerry that's that's starting with
30:11a drug like you already got the
30:13molecule exactly that's that's
30:15not that's without all of the.
30:17Early you know development stuff that's
30:19when you get you already have the molecule
30:21and this is this is at you know
30:23this is from the time you have
30:25the molecule moving forward.
30:26So you can see now this is this was
30:28a little bit more than some of the
30:31other trials would take just because
30:33it was so novel that Jansen had to
30:35really jump through a little bit
30:37more hurdles than you may expect.
30:39But Silybin is going to face this
30:41probably plus more in terms of
30:43what they're going to have to
30:45show for efficacy and safety.
30:46So this is just an idea and.
30:48And just to quickly go through what the
30:49results of that Sam didn't go through that,
30:51just do it really quickly.
30:52This first study actually didn't show
30:55an effect statistically significant.
30:57This was the fixed dose with IV ketamine,
30:59with IV S ketamine, I'm sorry,
31:02this is the fixed dose
31:04with intranasal esketamine.
31:05This is the the first study they did.
31:08But if you this,
31:08this is where these studies are
31:10different and it's good for this group
31:12as some of you aren't so familiar
31:13with this data because they'll look
31:15and say well it doesn't look like
31:17it's really beating placebo by that.
31:18Much first of all,
31:20the important thing to realize is that
31:22there really was no placebo group here,
31:24but the group,
31:26everybody got a brand new
31:28antidepressant treatment.
31:29So everybody was started on a
31:32brand new oral antidepressant.
31:34And then there were either randomized
31:36to receive a placebo intranasal
31:39device or esketamine intranasally.
31:42So you were really going up ahead of
31:43somebody from a drug company and say,
31:45you know,
31:45I'm really amazed that didn't work that well.
31:47It didn't,
31:48it didn't seem to to really beat
31:50placebo by that much and I remind
31:52them though it didn't beat placebo
31:53beat your drug by that much.
31:55So.
31:56So it's a, you know, you have to
31:58remember this when you look at this.
31:59So you look at this response,
32:02the blue line here is actually.
32:04The, The What's considered the placebo,
32:06it's the standard of care plus
32:08placebo people did pretty darn well.
32:10Remember they're coming in
32:11for frequent treatments.
32:12It was high expectation.
32:13So you can see people did well,
32:15but the two doses,
32:17either the 56 or the 84
32:19milligrams of Esketamine,
32:21both did pretty well but statistically
32:23did not have the separation they needed.
32:26The way that the analysis
32:28was designed and laid out,
32:30you can look at the response
32:32and remission rates really good.
32:34More than more than 50% response rates,
32:38about almost the 3rd 35 to
32:4140% remission rates.
32:42But you can see they really
32:44were pretty good for for the
32:46standard of care plus placebo too.
32:49This the the second big study
32:50this was the the flexible dose
32:53study where they had the ability
32:55to go from 56 to 84 milligrams.
32:57You can see that again almost
32:59exactly if you go back and just
33:02look the the the the studies
33:03are almost overlapping.
33:05Which is what you want to say when you have
33:07large numbers like this,
33:08this is what you you do start
33:10to say this was statistically
33:12significant between the two and
33:14really it was more of a statistical.
33:17Yeah, it's how you design the
33:19the statistical analysis.
33:20If you have 3 three groups to compare,
33:22it's harder to show a difference
33:23in with two groups.
33:24So here with the two groups
33:26you clearly had the separation
33:28and then if you look at the
33:30response and remission rates.
33:31It was actually almost 70% response
33:35rate with the active with the active
33:38esketamine plus the standard of
33:40care where standard of care alone
33:42was about a 52% response rate.
33:44And then the actual looking at
33:47remission about 50% to about 30%.
33:50Again really good at Star D would
33:52suggest that these treatment
33:53resistant depressed patients would
33:55have less than a 15% remission
33:57rate with the new antidepressant.
34:00So obviously this doubled.
34:01What you would expect for just the
34:04new antidepressant and clinical care?
34:07Jerry, what do you make of those
34:08of that double response rate in
34:10the standard of care plus placebo?
34:12You think that's because of the intensity
34:13of monitoring and the expectation effect.
34:15I think it's the nonspecific effects.
34:17All of that isn't captured in
34:19the nonspecific they're being,
34:20they're still coming in even
34:21if they're getting the,
34:22they're coming in eight times over
34:24that period of the four weeks
34:26to to get the intranasal device,
34:29even if it is placebo just
34:30being in a clinical trial,
34:32we know that just being in a clinical
34:34trial because you get more attention,
34:35people do so much better than.
34:37Standard clinical care.
34:38So it's all of those factors
34:41I think that contribute to it.
34:43Jerry yeah. Does
34:45it matter what antidepressant
34:47it is coupled with? Like,
34:49were these people on the same class
34:51for these studies?
34:52There was a choice of four.
34:54It was either citalopram, sertraline,
34:57then the vaccine or duloxetine.
35:01It didn't seem to matter
35:02out of those four. Yes,
35:05thank you. All right.
35:07And then this is the sorry.
35:10Yeah, question about the the scale
35:13because I'm not too familiar with it.
35:15What are you guess?
35:16What is it covering it?
35:19Is it covering it like what
35:23factors of depression?
35:27These are all done with the Madras
35:29Montgomery Asberg Depression Rating Scale,
35:31which is at this point.
35:34I think what's considered sort of the
35:36gold standard by the FDA in the field,
35:38it's a 10 item it covers,
35:41it's very much geared
35:42towards the melancholic side.
35:44That's when it was developed.
35:46So it, it looks at appetite loss,
35:49sleep loss, you know,
35:51but then there's a cognitive,
35:52there's anxiety,
35:54there's suicide,
35:55there's a guilt.
35:59Concentration. So kind of the the
36:03standard anhedonia is basically
36:05one item from each of those. OK.
36:11But so this is the long term,
36:13this is the 3004,
36:14this is the one that had 800 people
36:16that were followed until there
36:18was a sufficient number of people
36:20reaching six months of treatment
36:22and a year of treatment when they
36:24were able to terminate the study.
36:26And you can just see how well people are
36:28doing with open label with repeated dosing.
36:30Now you can see the error
36:31bars here are pretty minimal.
36:33People got better intended to stay
36:35better with either weekly treatment
36:37or biweekly or or every other week.
36:39Treatment,
36:39depending on how they were doing
36:42it can look at the responders,
36:4478% responders,
36:4547% remitters and that was at the
36:48beginning of the initial period
36:51at the at the final endpoint,
36:5376% responses in almost 60% remitters.
36:57The error bars are so small and so
36:59happens when you put 800 people in a study,
37:01you can really narrow those rates.
37:04It doesn't mean that everybody
37:05got well and stayed well.
37:07In fact if you look at individual data,
37:09people are bouncing all over the place.
37:10So when you average it over these large
37:12numbers, you get a figure like this.
37:14This is really more for safety
37:17looking at how safe it was.
37:19And this was the randomized
37:21withdrawal studies.
37:21So that this is a this is a big
37:23thing for the FDA's consideration.
37:25They could show that people that got better,
37:28especially those that had a response
37:31but not a remission, if you stopped it,
37:34they relapsed pretty quickly.
37:35People that were remitters, they still,
37:38if you stopped it, they remit.
37:40So this is good and bad and it
37:42it helped get the FDA approval,
37:44but it also shows that a drug like ketamine,
37:46the majority of people are going
37:47to need to stay on it in some way.
37:52So now I I just wanted to present all that
37:55data really just to put it in perspective
37:58of like what it would take to get.
38:00And the FDA wanted all of that in
38:03their package before granting approval.
38:05And when they did grant the approval,
38:06they gave it with the REMS that
38:08Sam spoke about. So that that's
38:10an idea of where we have to go.
38:13So this is the data so far with
38:15psilocybin that I was able to get off
38:17of clinicaltrials.gov 12 studies.
38:19There's actually more, I know.
38:21They all didn't make it into
38:23clinicaltrials.gov with the search,
38:25which was simply psilocybin
38:26and major depressive disorder.
38:28But you can see most of the ones that
38:31said this one up here is this is Johns
38:33Hopkins studies with Cyril study.
38:38This is another Hopkins study that
38:40that that was completed and I'll show
38:43you a little bit about this is another
38:45one specific for alcohol that this
38:47is a long term follow-up to actually
38:49the USONA study that we're doing.
38:51So Imperial College,
38:53I'll show you that this is the
38:54big usona study we're doing,
38:55but I'll go through a little
38:57bit what we have.
38:58So this is probably the earliest
39:00report specifically in depression.
39:02This was an open label,
39:04really a feasibility trial
39:05that was done over in the UK.
39:08David Nutt and.
39:11And Robin cart Harris Small study,
39:1612 patients look promising.
39:20The set on the quids you could see
39:22a nice difference from baseline to
39:25over weeks after two treatments.
39:27You can see individual data
39:30presented over there also.
39:32Promising data enough to move forward.
39:34This was the study came out of Johns Hopkins.
39:37This was Roland Griffiths study.
39:41Where they looked at another
39:44relatively small group of people.
39:46This was done with basically a
39:50weight group comparison, a wait list,
39:53which if you want to design A
39:55clinical trial to show an effect,
39:56use a wait list because it works
39:58for everything.
39:59Nothing,
39:59nothing works better than telling
40:01somebody you're going to be randomized
40:03to get treated now where you have to wait,
40:05and the group that they tell you
40:07have to wait will never get better.
40:09And and they, they showed that very clearly.
40:11Here you can see the results.
40:13This was again 2 doses.
40:16One dose was they did 20 and then
40:1930 milligrams of of psilocybin
40:21separated and you can see that
40:24by by a period of time,
40:26by weeks they they had all the
40:28standard set and setting where they
40:30had the prep sessions then the
40:33session and they had some follow up
40:35sessions after they were using the
40:37handy here which is just another
40:39measure but you can see very nicely
40:41that the the participants that was
40:43told they were going to be on the wait list.
40:46You have to wait did not get better.
40:48The group that were randomized
40:50to immediate treatment did quite
40:51well after the two treatments and
40:53the the delayed measures were at
40:55week five and week eight showed
40:57very good effects on the ham D.
41:01And then if you just looked at the
41:03change within the individuals and
41:04here they treated the other people
41:06later on the way group people.
41:08And if you just add them all
41:10compared to their own initial period,
41:12you can see that there was a nice
41:14reduction in and it seemed to be sustained.
41:16So again, very promising,
41:17but you have to remember on wait
41:20list studies I could show you,
41:22you know, water is beneficial.
41:24It doesn't you know that that's a low
41:26bar to hit but but it's promising.
41:29The next study that came out
41:32was a relatively recent,
41:33it came out just in April and
41:35this got a lot of attention.
41:37It was New England Journal.
41:38This again was out of the UK.
41:41Interesting,
41:41if you look on clinicaltrials.gov,
41:43the primary outcome measure in this
41:45study was actually the imaging.
41:46So this was not really a clinical trial,
41:48this was an imaging study that had
41:50some clinical data collected in it,
41:52but it was presented as a clinical trial
41:55in the New England Journal paper here.
41:58But you could see.
42:00This was meant to compare
42:04Silybin versus escitalopram.
42:06In looking at the treatment of patients
42:09and it was done with a fairly unique
42:12design but a very clever design where
42:15patients were randomized to either receive.
42:18Escitalopram at normal dosing
42:21or 1 milligram of psilocybin.
42:26For a single you period were
42:28actually 2 periods,
42:292 dosing periods or to receive actual dose
42:33of psilocybin which I think they used 25.
42:36Trying to remember the exact dose,
42:37I think they used 25.
42:41I'm sorry.
42:42I think that's right.
42:42Yeah,
42:43I think there's 25 milligrams and
42:46placebo escitalopram and looked
42:48out over time and this did not hit
42:53their specified primary outcome
42:55for the clinical part of this.
42:58So it did not separate from US citalopram,
43:01although you can see it looks pretty good.
43:03And again, you have to take this.
43:06Yeah, .0, you know P = .05 a little bit.
43:12With some caution here,
43:14but it did not separate on the
43:17primary measure which was the
43:19change in the quaids SR16.
43:22However,
43:23if you look at the secondary measures.
43:27It was a very consistent trend for
43:29the Silo Sybian group to be doing
43:32better than the escitalopram group,
43:34which is in my mind very encouraging.
43:36I mean I think that was a
43:38probably more so than that one.
43:39You know,
43:40they missed their primary clinical endpoint,
43:41but all the secondaries look good.
43:43And I remember this wasn't a study that
43:45was primarily designed as a clinical trial,
43:47it was designed as an imaging study
43:48that had some clinical measures in it.
43:50I'm sorry,
43:51is there a question,
43:51was this intended to be or
43:53presented as a superiority trial,
43:55were they trying to say silicon
43:56is better than escitalopram?
43:57That was in the non inferiority
43:59trial, so it was designed as an
44:01imaging trial that had some claims.
44:05It really wasn't. I mean in terms
44:08of clinical trial methodology,
44:09it wouldn't have met criteria for
44:11that and and and when the New
44:13England Journal accepted this,
44:14they really held them to the
44:17fire and really made them,
44:18you know this had to be stated
44:20pretty clearly in the paper.
44:22They also had to state that the
44:24majority of people clearly expressed
44:26a strong preference to being
44:28randomized to the solar cybin arm,
44:31not to to the 25 milligram
44:33as opposed to 1 milligram.
44:35So I mean it's encouraging but you
44:37have to consider the weaknesses and the
44:39limitations of the study to this point.
44:42But overall I think encouraging and
44:45the last data that has come out was
44:48the the compass study and all I have
44:51to go by by this is a press release.
44:54So that's this study has not been.
44:58As far as I'm aware of,
44:59there's no accepted publications
45:01from this or any other peer
45:04reviewed data to look at,
45:05just press release that just
45:08came out about a month ago now.
45:11And this is the trial design
45:13and interestingly I had a hard
45:16time finding this specific in
45:18clinicaltrials.gov to actually sort
45:20of go back and check everything but.
45:23So this this design.
45:26Was considered a Phase 2B trial.
45:28It's a pretty large trial of 233 patients
45:32across 10 countries including North America,
45:35Europe.
45:37And as they said,
45:38the primary objective of this study
45:40which is consistent with the phase
45:42two is really safety and to really
45:44get a better sense of how to design
45:46A larger phase three program.
45:49So they ended up having data
45:52on 233 from 233 people.
45:55The the way it was designed was
45:58looking at 2 active doses that they
46:01believe were potentially active doses
46:0310 milligrams and 25 milligrams of
46:05silybin versus what they were considering.
46:08An inactive dose,
46:09which would be 1 milligram, so three arms.
46:14The way to studies design again we would
46:16if I had more time than going to it,
46:19but I think most of us agree
46:20sort of standard setting,
46:22setting type approach for for this study.
46:27Here's the outcome that's reported
46:28and these I I've taken this
46:30directly from the press release
46:32because that that's what it is.
46:34The 25 milligram group versus the 1
46:38milligram group showed a 6.6 point
46:41difference on the Madras Depression Scale,
46:43which is a good separation
46:45of really good separation,
46:48highly significant at week three,
46:50which was their primary outcome measure.
46:53The 25 milligram group demonstrated
46:56statistical significance in the Madras
46:58efficacy point at the day after.
47:00So the very short, you know quick onset,
47:03the 10 milligram dose did not
47:06show statistically significant
47:07difference at week three,
47:08although there was a trend and
47:11then the Madras was assessed.
47:13They did what they could to
47:17prevent functional what they did,
47:19what they could do to prevent unblinding
47:21from the sites at least they had.
47:24Independent raters that now it
47:25doesn't do much to what we call
47:28functional unblinding,
47:28which is the actual patient
47:31knowing what they got.
47:34A little bit more looking at the response,
47:37at least twice the number of
47:39patients in the 25 milligram group
47:41showed response in remission at
47:44week three and seemed to have it
47:46contained to sustain to week 12
47:48compared to the one milligram group.
47:50Again very promising.
47:53The protocol defined sustained response
47:56up to 12 weeks and you can see what
47:59these results were here to about 20%
48:02of the patients in the 25 milligram.
48:04Group versus 10% to 1 milligram
48:06group had that sustained response.
48:08I think this was a little disappointing
48:11to some people that you know only
48:14one out of five people sustain their
48:16response for the for the entire
48:19three months but still I I look
48:21at this is pretty promising but
48:23it may get at that Sam's thing is,
48:25is is it once and done maybe not
48:27yeah you may need you may need
48:29for the majority of people may
48:31need some repeated dosing.
48:36Let's see if we go into the next this,
48:39this I think is the more concerning part
48:41of this study and this is what we get at.
48:43And and again going back to lessons
48:45learned from the ketamine study,
48:46they had to do that study with 800
48:49people treating them over a period
48:51of the year before the FDA would
48:53really grant approval with that.
48:55And because they're what they're
48:56really concerned about is safety.
48:58You know, people that report
48:59safety with ends of, you know,
49:0110s or dozens or or even,
49:04you know, a few dozen people,
49:06it's really hard even with a few 100 people.
49:09You know, if it's a relatively low
49:11safety signal that's hard to pick it up,
49:14especially with the single dose.
49:15But with multiple dosing over 800 people,
49:19the FDA felt OK with esketamine.
49:22So here with the psilocybin.
49:25Here the comp 360.
49:31You know, you can read this as well as I can.
49:33Most of the trees were the the
49:35treatment for for those of you that
49:37aren't so familiar with clinical
49:39trials TA's or treatment emergent
49:41adverse events and you can see that.
49:45The ones that reached over 10% were headache,
49:47nausea, fatigue and something.
49:48You get that in almost any clinical trial,
49:51it's really common.
49:54But the more concerning part of the
49:58treatment emergent serious adverse events.
50:02So those of you that do clinical trials,
50:04a serious adverse event is either death.
50:09Something that requires hospitalization,
50:11something that has a permanent effect or
50:15or another thing that requires a higher
50:18level of care or sustained hospitalization.
50:23So it's a pretty serious thing to have a,
50:25a, a serious adverse event,
50:28which is different than an
50:29adverse event that is severe.
50:31So we can talk about that because
50:33that comes up a little bit here.
50:36But here you started to see something now,
50:38now that we're starting to be a
50:41separation and it's specifically the
50:42ones they saw are pretty concerning.
50:44So they saw are treatment emergent
50:47adverse events with suicidal behavior,
50:49intentional self harm,
50:51suicidal ideation which are
50:54regularly observed in patients,
50:56but which occurred at a higher frequency
50:58in the groups that got 10 and 25
51:01milligrams compared to the one milligram.
51:03And that that that's a little
51:05bit of a concern.
51:08But again, just to wrap up the key findings.
51:13They met their primary outcome
51:15as defined. It looked good.
51:16It the the in my mind the response and
51:20remission rates were pretty impressive
51:22and this and they were sustained.
51:25For a relatively long time for a relative.
51:32Representative portion of the
51:33population there were people continue
51:35to have a good response going out of
51:38definitely going out for three weeks,
51:39but even going out for a few months.
51:45I think the bigger issue,
51:46and this is the issue we have
51:47to think about in the field,
51:48is the safety of this,
51:49especially with the repeated dosing.
51:53I I made a big point of this a few times and
51:56actually there was some press coverages.
51:58I actually discussed this a
52:01little bit in these key findings.
52:04If you look at the treatment
52:06emergent adverse events,
52:07you can see overall not a big difference,
52:11but if you look at the treatment.
52:14And this should actually
52:16be treatment emergent.
52:18As far as I could tell,
52:19serious adverse events,
52:20I don't know what treatment
52:22emergency serious adverse events is.
52:23I think it's a typo.
52:25But this is what's in the press release.
52:27You start to see some pretty
52:29big differences, you know,
52:31between the 10 and 25 group
52:32compared to the one milligram group.
52:34And that becomes especially
52:36important if they are things.
52:38And I can't tell by the press release
52:40if there are increases in suicidal
52:43ideation and suicidal behavior.
52:44So we're really going to have
52:46to hear more about this.
52:48Um.
52:51And then lastly is the,
52:52the trial that we're currently
52:55participating in is the USONA
52:57trial and this is a trial now
53:00aiming for 100 patients and it's
53:02really a trial of silybin versus
53:05niacin and it's 25 milligrams of
53:07of psilocybin and it's again a
53:09randomized placebo-controlled trial,
53:11one to one allocation following
53:15the standard set and setting
53:17procedures and we're about 60%.
53:20Done with that trial.
53:22So we should have the data from
53:24that hopefully in the next
53:25six to six months to a year.
53:27So I think that captures sort of
53:29where we are with the clinical trials
53:33to date as Sam did a great idea,
53:35a great job of sort of showing
53:37the hurdles of implementation
53:39if if it does get FDA approval.
53:42I was just trying to show sort
53:44of where the hurdle will be to
53:47get FDA approval and my take is
53:49the data is very encouraging.
53:51To this point, in terms of efficacy,
53:54I think there are some real
53:56concerns in terms of safety and
53:58implementation and that's what
53:59we're going to have to focus on.
54:01So I think I can wrap it up
54:03at there at that point.
54:07Any questions, Jerry?
54:09I have a question when the
54:12patient inclusion criteria are,
54:13were they the same for the Esketamine
54:17studies and for the Silo cybin?
54:20The patient inclusion criteria for
54:23the clinical trials so there's no, no,
54:27no they they were not similar the and
54:31for the esketamine trials there was there
54:35were two main ones there is the TRD ones.
54:39In fact Esketamine was approved by
54:42by the FDA for TRD and for the EMA
54:46in Europe which meant that people
54:48had to have failed two previous.
54:51Antidepressants have adequate
54:52dose and duration.
54:54Those are not the criteria the TRD for.
55:01For you and and so far these studies
55:03would so Sabin are are are you know
55:04that there are many different types
55:06there are more heterogeneous so
55:08but that has not been the standard.
55:10The second one for us ketamine was the
55:12what we call now it's called MSI major
55:14depression with suicidal ideation.
55:16So those studies were extremely unique
55:19because the inclusion criteria was
55:22patients had to have active suicidal
55:24ideation and intent to act on it.
55:26That is an exclusion for any other you
55:29know you that's the inclusion criteria
55:31for those studies where that's the
55:33exclusion criteria for almost any
55:35of the study including including the
55:37studies with solar cabin to this date.
55:39And the other big difference was for
55:41the zest ketamine studies there was a
55:44new antidepressant started alongside
55:46and for these for the sybian studies
55:50very clearly it they there has to be no.
55:54Active antidepressant at the time,
55:56so you have to wash out prior to it.
55:59So those are the main differences between
56:01them I think, for inclusion criteria.
56:07Jerry, I had a question.
56:09I was wondering if you could,
56:13you know I granted that the data don't
56:15really allow for a straightforward
56:16head-to-head comparison at this
56:18point between the the sort of
56:20risks of the silybin versus
56:23the continued dose of of Esketamine.
56:26But I wonder if you just based
56:27on like the limited information
56:28that we have at this point,
56:29how you would weigh the potential
56:32risks of repeated dosing of
56:34ketamine versus either repeated
56:35or single dosing of psilocybin, you
56:38know at this point?
56:39Sorry, I can't turn that phone off. I.
56:42Yeah, I think what you said it's really hard.
56:45It's it's apples and oranges a little bit.
56:47I think you know the, the.
56:53Obviously a single dose compared to
56:56repeated doses is going to be difficult.
56:58Ketamine for the most part didn't
57:01show a really bad adverse event.
57:03Even with the dosing of either
57:05once a week or or every two weeks,
57:09they didn't really have a really bad profile.
57:12In fact, they were no effects on cognition
57:16that were really reliably shown.
57:19There was even the bladder concerns
57:21that people are were concerned
57:22about didn't really show anything.
57:24Of real interest.
57:27So it's hard to compare them.
57:29I think the big thing is.
57:33You know how well the sobin,
57:35you know that six hour period
57:37during that initial dosing,
57:38how well that could be tolerated
57:40by people and if it can be a single
57:43dosing or even if it's dosing
57:44every three months or four months,
57:46I I think that can be done as long as
57:49you figure out a way of financing that.
57:54Jerry, I have a quick question.
57:57I was actually quite surprised
57:59by the press release.
58:03Specifically regarding the lack of
58:06emphasis on the psychotherapy that
58:09has actually gone in this trial,
58:11you and I both know that this,
58:13probably out of all the
58:15psychedelic clinical trials,
58:16had the most. Psychotherapy,
58:20which is preparation, integration,
58:22and that was not included in the press
58:24release, which uh really surprised
58:27me. And the facilitators
58:30have actually had
58:31to go the most intense training
58:33available right now in psychedelic space,
58:36like four months of training, and I know
58:38that training intimately. Well, and. I
58:44have not seen anywhere
58:45that the reason for or against of not, you
58:50know, not including that and so and do you
58:53have any information about?
58:56Because I know there was a lot
58:57of psychotherapy involved, so I
59:00yes, I I have. So I think I think this
59:05really comes down to and I was part of a.
59:07Work group with the ISTM, the international,
59:11so I have clinical trials and management.
59:17Where you know the agencies were there,
59:19the FDA and EMA discussing it and this is
59:23this is a really difficult point because.
59:27If you're saying that there's
59:30concomitant treatment with the
59:33psychotherapy and the pharmacology,
59:35the agencies in some way have
59:37to regulate both in some way.
59:41If you just say that if you minimize
59:43and say what's there for safety,
59:45which is actually what they did mention
59:47is that there was some intensive
59:49care for the safety of patients.
59:54Then then it's not necessarily
59:56going to come under the jersey. So.
59:59So if they're trying to walk a fine line
01:00:02and you don't send people to intensive
01:00:05training for four months so they can
01:00:07ensure safety, that's right. So yeah,
01:00:09so exactly. So it is trying to walk a
01:00:12fine line there and and it is something
01:00:15that the regulatory agencies are trying
01:00:17to really get the companies to say.
01:00:20Well, if there is a specific
01:00:21training you need to do,
01:00:22you have to include it and you have
01:00:24to codify it in some way that we can
01:00:27say this is part of the package insert
01:00:29because that's all the FDA we we think of
01:00:32the FDA is sort of doing a lot of things,
01:00:35but really they regulate package inserts.
01:00:36They they tell companies what they
01:00:38can say and what and you know
01:00:40and how they can promote a drug.
01:00:42That's really their main thing.
01:00:43And I always say you know when
01:00:45they do this they want us to do
01:00:48so Doctor Jones in Topeka,
01:00:49KS can give this drug.
01:00:51Without ever having this training,
01:00:52they they have to know what what
01:00:54I need to know about this before
01:00:56I prescribe it to my patient.
01:00:58That's really the FDA's job.
01:01:00And so that if if they're going
01:01:02to say that there's a specialty
01:01:05sycho therapeutic training needed,
01:01:07then they have to codify it in a
01:01:09way that it would make it into their
01:01:11package insert. So it's it's tricky.
01:01:13It really is tricky.
01:01:17One question, some of those studies
01:01:19had an active comparator like the New
01:01:21England that David Nutt study and some
01:01:23didn't like you mentioned the Hopkins
01:01:24that had a wait list as a comparator.
01:01:27Could you comment on how much that will
01:01:30you know influence the FDA's decision
01:01:32when when when you know analogous
01:01:34table is being reviewed by them and
01:01:37then also to the scamming table.
01:01:39So I think I mean I think they're
01:01:42only going to review things that
01:01:44have some form of a comparative
01:01:46could be placebo-controlled.
01:01:47Or an active compared to I don't think
01:01:50they're going to allow a wait list
01:01:52comparison but that wasn't intended
01:01:53to be a registered trial in any way
01:01:56that was that was really a feasibility
01:01:58trial which I think was great.
01:01:59Johns Hopkins had the right idea
01:02:01in doing that.
01:02:01It's first let's give it to few people
01:02:04learn from it and then design the
01:02:05clinical trial at you know after you do that.
01:02:08No, I think it was the right
01:02:10way to initiate a study.
01:02:11But, but that wouldn't be I I can't
01:02:14imagine the FDA would consider that as a.
01:02:17As anything that would be
01:02:19presented as part of the package.
01:02:21I don't know if anybody else
01:02:23has any thoughts on that,
01:02:24but.
01:02:26Gave you a lot of these early
01:02:28trials as proof of concept,
01:02:29scientific interest,
01:02:30single site see what's going on.
01:02:32They're not, they're never going
01:02:33to make it into an FDA package,
01:02:35the compass, usona,
01:02:35the first trials in the literature
01:02:39that are going to be the first part.
01:02:43Those are of phase two trials so
01:02:45that they wouldn't even put it as the
01:02:48phase three pivotal trials have been then.
01:02:50I mean presumably they'll have if if
01:02:52you include an active comparator,
01:02:53you might have a different effect size
01:02:55if you can get a placebo. Yeah. So how?
01:03:01Yeah, how, how so? I think so.
01:03:03I think that's what actually
01:03:05really helped Esketamine.
01:03:07So because Esketamine sort
01:03:09of the the unwritten.
01:03:12You know, standard in the FDA field was
01:03:15usually two registered trials showing
01:03:18statistically significant significant
01:03:21separation from the control group.
01:03:24In a phase 3IN phase three trials.
01:03:29Ask you know, Esketamine actually
01:03:31didn't show that Esketamine.
01:03:32Remember I showed you that first trial
01:03:34did not show statistical separation.
01:03:37Admit it was like .056 or .058
01:03:41or I mean it just missed.
01:03:44It just missed separation.
01:03:45The second one did hit the the
01:03:48geriatric study did not hit either.
01:03:51So out of there three phase.
01:03:54Three trials,
01:03:55only one of them hit statistical
01:04:00significance separation,
01:04:01but I think the FDA considered
01:04:03the fact that since you were going
01:04:06up against a new antidepressant,
01:04:08they they gave them a little bit of,
01:04:11a little bit of a past there I mean.
01:04:15This is just all reading into the leaves.
01:04:18I wasn't part of the discussions
01:04:19with the FDA or anything that way,
01:04:21but they did get a little bit of
01:04:23a pass where they didn't hit sort
01:04:25of the standard accepted two phase
01:04:27three FDA registered trials that
01:04:30that hit statistical significance.
01:04:32Did that get to the question?
01:04:36Yes, thank you.
01:04:40So Jerry, I really want to thank
01:04:42both you and Sam for this overview.
01:04:44This is I think for some of the
01:04:46attendees here, this is unfamiliar
01:04:47territory is thinking about the,
01:04:49you know that how do we get
01:04:50this out into the real world,
01:04:51what does the FDA need to do what,
01:04:53what considerations do we.
01:04:56Do we need, you know,
01:04:58to actually get this out of the world?
01:04:59But I agree with Sam that if we don't
01:05:01think about these things early ish in
01:05:03the development of a new treatment,
01:05:05then we're potentially setting
01:05:06ourselves up to, you know,
01:05:07invest, invest, invest,
01:05:08get lots of exciting science and
01:05:10then not actually help anyone.
01:05:11I could tell you there's
01:05:13nothing more painful.
01:05:13I'm sure Sam will say the same.
01:05:15Thing is when we get
01:05:17requests from people saying,
01:05:18you know, I need ketamine,
01:05:19my doctor tells me I need ketamine.
01:05:21This, you know, how do I get it?
01:05:23And when we have to tell them, yeah.
01:05:25There's no easy way to get
01:05:27it right now that that,
01:05:29that's that's not a very
01:05:31satisfying feeling.
01:05:34Great. So thank you so much to you both.
01:05:37We are we're overtime so I'm going
01:05:38to I'm going to draw this to a close
01:05:41but so where you where where we'll
01:05:42meet again I think it's the third
01:05:44Friday send out a reminder and we're
01:05:46going to have for a complete change
01:05:48of of of topic next time we're going
01:05:51to hear from Alex Kwan and some
01:05:53people in this lab about mechanisms
01:05:54what is what is silybin and other
01:05:57psychedelics doing mechanistically in
01:05:58the brain and then I hope in future
01:06:00months we'll begin to explore the
01:06:02space between those two extremes.
01:06:06Thank you all so much. Have a good weekend.
01:06:10Thank you. Bye, bye.