Yale Psychiatry Grand Rounds: November 4, 2022

November 04, 2022

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"Medications for Opioid Use Disorder Treatment Matching: The Challenge of Fentanyl"

Thomas Kosten, MD, Jay H. Waggoner Endowed Chair, Baylor College of Medicine

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00:00Epidemic of fentanyl and
00:03stimulated addiction overdose.
00:05These are two areas where we are
00:08really in need of improved treatments
00:10and and we have underserved needs.
00:13So with this let me turn it over to Tom.
00:15Thank you. Thank you very much, Stephanie.
00:18I just wish my mother was still
00:20alive so that she could hear that
00:22wonderful introduction and say, oh,
00:24you finally made it as a doctor.
00:28Hello. I have to say her and
00:29my grandmother preferred that
00:30I would have become a minister,
00:32but she can't have everything in life.
00:34Closest I got with a psychiatrist.
00:37So again, let me move forward with this.
00:40I do have a fair amount of stuff I'm
00:42going to try to go over and but one of
00:44those things I've learned over time
00:46is don't get too wedded to your slides
00:48that you need to present all of them.
00:50So I'll still be mindful of what time it is.
00:54This is just a little overview of
00:56what I'm going to be talking about
00:58today about fentanyl in particular.
01:00Uh, these are the disclosures, which,
01:03uh, I think the bottom line is that,
01:05you know,
01:06none of these are have anything to do
01:08with vaccines or what I'm talking about.
01:10The the people who make a lot of money
01:13generally aren't interested in addictions.
01:15So that that has been a an advantage
01:18and a disadvantage.
01:20One of the goals that I'm going
01:21to try to do today,
01:22I'm going to try to do well
01:25before I just get.
01:26I mean thank you very much for inviting me,
01:28Stephanie and John.
01:29I think that that was really a.
01:31A nice.
01:32I don't know.
01:33It always feels good to go back to your
01:36old homestead where I've been for,
01:38let's say, Stephanie, you asked 27 years,
01:40to be exact.
01:41I'm working on 16 now here in Texas.
01:44So, but I still don't say y'all my kids do,
01:47but I don't.
01:48As to the goals,
01:50we would like to try to describe the
01:52ways of the opiate overdose epidemic.
01:54There's certainly began with
01:56MD's overprescribing opiates.
01:58There was then a switch to heroin.
02:00There then was a switch.
02:01Fentanyl and what's happened most recently
02:03is a switch to fentanyl plus stimulants,
02:07which has been a significant
02:09problem in many ways.
02:10I'd like to be sure that we learn
02:12some new therapies for cocaine and
02:14stimulants including some little
02:16bit about pharmacogenetics and about
02:18vaccines and then learn why buprenorphine,
02:20which is our without a doubt
02:22our best treatment for opiates,
02:24why it fails to block fentanyl and how
02:27an anti fentanyl vaccine can in fact succeed.
02:32This is when the the thing started.
02:34This is wave one started about 20 years ago.
02:37And these are just some
02:39quotes from Barack Obama,
02:40which was when he was giving his sort of
02:44summary of it all ways into the epidemic.
02:47They were being described addiction
02:49to painkillers as the great threat,
02:51as terrorism, which is astounding.
02:55That they were seeing more
02:56people killed because of the
02:57opioid overdose than traffic accidents.
02:59They were going to make the government
03:02health insurance policies cover mental
03:04health and substance abuse on a par
03:06with treatment for physical illness.
03:08Well, they tried as to a grassroots approach.
03:13It was really needed to train physicians
03:15while they're still residents and how,
03:17when, why to prescribe opiates
03:19and and using buprenorphine for
03:21treatment of this addiction.
03:22So there was this,
03:23this is the history that's behind us.
03:26Which is summarized by this talk
03:29that Barack Obama gave back in 2016.
03:32It it did start with opiate over
03:36prescription from 1991 to 2013,
03:39it went from 76 to 207 million prescriptions.
03:43So it it really went up quite a bit.
03:46Um, back at around 2013,
03:49you were seeing 15 million opiate
03:52prescriptions just from primary care alone.
03:552,000,000 Americans had
03:57prescription opiate abuse in 2013.
03:59Physicians were being blamed for the
04:01epidemic of opiate addiction as much
04:03as individuals who abuse the opiates.
04:05Important keep that in mind
04:06because that can come up again.
04:08The FDA was talking about forbidding the
04:11marketing of opiates for chronic pain.
04:13Now that obviously never entirely happened,
04:15but there was a lot of movement.
04:16To do that,
04:17and the CDC was going to limit
04:19opiates to just three days for
04:21short term pain management.
04:22Once again,
04:23that did not entirely happen,
04:26but there was real guidelines for decreasing
04:30the amount of opiates being given out.
04:34Non medical pain reliever use at
04:35that point was 22 million people
04:37and you have you know a little over
04:39300 million in the United States.
04:41Gives you a little sense of how common
04:44this was 3,000,000 to use for the first
04:46time with the past 12 months that
04:48was at that point in aging in 2013
04:50you were looking 8000 new users per day.
04:54Most of these uh illicit drug users started
04:57now at that point with pain relievers.
05:00One would never believe that it
05:01over did you know marijuana as how
05:04people would start using drugs.
05:05I mean the the days of heroin were
05:08over by that time most of the abusers,
05:11which was more 56% of them were
05:13younger than 18 and were females.
05:15But once again a very different demographic
05:17than it had been with heroin use.
05:20This is just a little graph of that
05:22data that I was telling you about.
05:23This is back.
05:26From.
05:26205 and in fact it only got worse over time.
05:29But you can see pain relievers.
05:31Pain relievers were the more common
05:34initiates for drug abuse than was marijuana.
05:37And of course anything else that
05:39you can see on this list.
05:41And this continued on for a number of years
05:44and of course was blamed on many things.
05:47And the the Reaper has now hit
05:50many pharmaceutical companies where
05:51they're getting billions of dollars
05:54in settlements that they have to.
05:56Hand out.
05:57From 1999 to 2014,
06:00the opiate overdose deaths were
06:03quite profound on this was started
06:06with the MD over prescribing,
06:08but there was a fourfold increase.
06:10The Reds represent high areas of opiate
06:13overdoses, the blue relatively lower.
06:15Hopefully you can easily see there's
06:17a lot more red on the right than
06:19there is on the left, and you'll see
06:21that there are concentrations of it.
06:23The most important concentration that
06:25became of interest was in the Midwest.
06:28And in the Adirondack, I'm sorry,
06:30the Appalachian Mountain area where there
06:33was just tremendous amounts of overdoses
06:36and deaths from prescribed opiates,
06:38mercy, these were not urban areas
06:40where they were selling this stuff.
06:44All right, so by 2010, the prescription
06:47drug epidemic was plateauing 10 to 16.
06:50Wave two started of the opioid epidemic
06:54as doctors began prescribing less and less
06:58and the overdoses from heroin came back
07:01again as an issue that plateaued in 2016.
07:04And in 2014, wave three of the
07:07epidemic started with fentanyl.
07:09It rapidly escalate escalated to pass
07:11heroin and the prescription drugs.
07:14And this fentanyl epidemic continues.
07:17What's happened since 2016 is Wave 4,
07:19the epidemic and that started
07:21with cocaine and amphetamine,
07:23with fentanyl being mixed in with these
07:26white powders and therefore the combination
07:29becoming causes of drug overdose.
07:32And this is continued again and escalated
07:35and escalated in some rather surprising ways.
07:38So this is simply the same
07:40kinds of graphs again,
07:41the red line or orange.
07:44Depending on how color blind you
07:47are that's shown on the left is
07:49fentanyl going up through the roof.
07:51And what you can see on the right is the
07:53comparison from 2003 to 2017 and a map
07:57that has mostly just sort of Gray in it 2003.
08:01But by 2017,
08:03the fentanyl deaths have got red
08:06areas all over the Midwest being
08:08one of the more surprising areas.
08:10At least that because that was
08:12not from the big cities.
08:14Necessarily,
08:14these were in fact often rural
08:17areas that we're having this
08:19fentanyl epidemic of deaths.
08:21So what about fentanyl,
08:23which is again,
08:23this is wave 3 synthetic opiate,
08:2750 to 100 times more potent than morphine,
08:3030 to 50 times greater than heroin.
08:33A lethal dose of fentanyl can
08:34be as little as 2 milligrams.
08:36It just not take very much,
08:38which means that, you know,
08:40you can import tiny amounts of
08:42this and make plenty of money.
08:44Selling it fentanyl analogs range
08:45of potency from 15 times more
08:48potent than morphine to 10,000
08:49times more potent than morphine.
08:51That is carfentanyl.
08:53And this epidemic again starts
08:55at around 2014.
08:58So what did we have to treat this?
09:00Well,
09:00these are the FDA approved treatments.
09:02There's the naltrexone and particularly
09:04the long acting injectable naltrexone.
09:07There's buprenorphine or buprenorphine
09:09naloxone.
09:10At that point they were initially
09:14using the sublingual form that often
09:16with the film and then later on of
09:19course an injectable became available
09:22and methadone which is a full agonist.
09:24So this is the three mainstays
09:27buprenorphine came the closest to being.
09:29Essentially a way that you
09:32could combat fentanyl.
09:33Fentanyl easily overrides
09:35methadone for analgesia,
09:36so it was very unlikely to protect
09:39against a fentanyl overdose.
09:41Buprenorphine may protect against
09:42the fentanyl overdose,
09:43though clinically the buprenorphine
09:46blood level of five nanograms per
09:49milliliter was found to prevent
09:51respiratory distress from about
09:53.7 milligrams of fentanyl.
09:56This was in.
09:57It's twice the apnea dose
09:58in non tolerant patients,
10:01so this was this was done in an actual
10:03human study that got published however.
10:06You've been orphine blood levels
10:08at 24 hours after dosing.
10:10Assuming you're giving it once a day,
10:1216 milligrams of sublingual buprenorphine,
10:15which is the usual dose for addiction
10:18treatments, produces a level of
10:20.67 nanograms per milliliter.
10:22You'll notice that that's at least
10:2410 fold lower than what you're
10:26going to need to block fentanyl.
10:28If you give 44 milligrams of buprenorphine,
10:31which is above the 24 milligram
10:34milligram maximum FDA dose,
10:36you still only get up to 1.7.
10:38That agreements familiar,
10:39so you're still, you know,
10:41less than half of what you're going to need.
10:43If you give the 300 milligram Suboxone
10:46supplicate injectable dose though,
10:49you can attain a blood level of 6.54
10:52nanograms per milliliter and you could
10:54maintain that for about 30 days.
10:56This is giving the 300 milligram dose,
10:58which is not typical to give
11:00that every month, but if you do,
11:02you can in fact get close to a level
11:04at which you're going to at least
11:06block any respiratory distress.
11:08From the usual,
11:10let's call it therapeutic dose of fentanyl,
11:12obviously overdoses are using dosages
11:15that are not the therapeutic dose of .7,
11:18but are usually twice or three
11:21times that dose.
11:22So it's still not perfect,
11:24but it if you want to get buprenorphine
11:26to work the best for fentanyl,
11:28this is probably as good as you can hope for.
11:31So as the epidemic moves along
11:35and wave 42016 which is when the
11:38opiates and stimulants.
11:39Umm, the red line that I have,
11:42as you can see on this graph at the bottom,
11:44that's starting to rise and around 2015,
11:46that's wave four and wave 4
11:49psychostimulants combined with the
11:51opiates and that has gone up and up and up.
11:54And this data obviously stops at 2019,
11:58but the data that comes through with
12:012021 with 2022 data not yet being
12:04available continues that upward trend.
12:09So I think some questions for
12:11the physicians to think about,
12:13which was something that we,
12:15you know, pressed physicians about
12:16for the last 15 or 20 years,
12:19is our physician prescribers on
12:21ethically contributing to the wave
12:24four of this ongoing lethal epidemic.
12:27They certainly contributed to the
12:28first phase of this opiate epidemic,
12:31but there's been a market increase in
12:34amphetamine prescribing specifically
12:35for adult ADHD patients in the past.
12:37Five years.
12:39The abuse of pharmaceutical
12:41amphetamine has become widespread
12:42in adolescents and young adults.
12:44I'll show you some of that data,
12:46and much is from physician prescribing.
12:49But recently there have been sales
12:51on the Internet and on the street
12:54of counterfeit Adderall pills that
12:55contain fentanyl at lethal dosages.
12:57And about 1/4 to 1/3 of the
12:59pills that are on the street,
13:01it's because they're it's not that the drug
13:04dealers want to have a lot of fentanyl.
13:06They want to have enough that you'd have
13:08a good time not necessarily to kill you.
13:10But their quality control
13:13is not exactly precise.
13:15This is the adolescent data
13:18from 2008 through 2011.
13:22The adolescents age 13 to 18,
13:25what you can see in 2011 is that
13:28the rate of of doctors giving out.
13:33Adolescence amphetamines
13:34has more than doubled,
13:37so that's what that red line is showing.
13:39The opiates haven't changed that much and
13:41the depressants haven't changed that much.
13:43They they're more,
13:43more or less flat lines,
13:44but going down somewhat.
13:46If anything,
13:47when you look at the young adults 19 to 25.
13:50By 2014, you're seeing a significant
13:53divergence that's occurring between
13:55prescribing opiates to them and
13:57prescribing stimulants to them.
13:59It is again,
14:00it's reached a plateau again at about
14:03the same time as the younger adolescents,
14:06but the drop off in the opiate
14:09prescription has clearly had
14:10a much more traumatic effect.
14:12So doctors are prescribing a
14:15lot of stimulants and they're
14:17out there all over the place.
14:21So that's the epidemic stuff.
14:23I'm now going to start trying to
14:25cover a couple of other things that
14:27are I think are important in this.
14:29So what about using stimulants
14:31for a pharmacotherapy?
14:33What kind did you want to use?
14:34Well, slow onset and slow
14:36release long acting.
14:37That would be the qualities you'd like with
14:40that kind of a substitution type therapy.
14:42I'll then talk a little bit about
14:45single gene pharmacogenetics,
14:46again in specifics with DOXAZOSIN,
14:50which is A1 blocker and the dopamine
14:54beta hydroxylase polymorphism.
14:56And then finally I'll try to have some
14:57time to talk about immunotherapies.
14:59With the anti cocaine vaccine and
15:02then the anti fentanyl vaccine
15:04which we've developed as a.
15:07I guess you could say a daughter
15:09or a son of that cocaine vaccine.
15:11So what about the slow onset and
15:13fentanes for stimulant use disorder?
15:15Well is a Swedish registry study
15:17that was brought to my attention
15:19actually by Stephanie and this
15:21was in a recent presentation 2022.
15:25They did it with lots of patients,
15:27you know 14,000 patients that were
15:29they had a mean age at 3470% were men
15:32and it was during the period from 2006
15:34to 2018 and it was a within subjects.
15:37Comparing on versus off medications
15:41and lisdexamfetamine which is a form
15:44of amphetamine that is has to be
15:47metabolized before the amphetamine
15:49could have its effect.
15:50So you're not going to get immediate effect,
15:52it's going to be slow.
15:53But what they showed were positive
15:55outcomes and relative risk for the
15:58people who got list Essick phetamine
16:00versus those who were given any kind of
16:02stimulant and that and what they were
16:05looking at was on versus off the medications.
16:08What they found was that there was
16:11less hospitalization for substance use
16:12disorders when they were on the medication
16:15then when they were off the medication.
16:17Overall there was less of any type of
16:20hospitalization when they were on the
16:23medication versus off the medication
16:25and there was less all cause mortality
16:28from the periods when people were on
16:30the medication then periods when they
16:32were off the medication that that
16:35odds ratio obviously relatively large.
16:37So that's these are important.
16:39Considerations that these treatments
16:41can in fact be useful even in
16:44substance abusing populations if
16:46they're carefully done.
16:48What about the randomized
16:50clinical trials using stimulants?
16:51Have they shown some efficacy?
16:53Well,
16:54the because this other was of course
16:56an epidemiological study from Sweden.
16:58The clinical trials,
16:59there are reviews of them in 2019
17:02and other one in 2016.
17:03There are 26 different studies that
17:06have been done involving over.
17:082000 subjects and what those studies
17:12show is that the cocaine abstinence
17:16relative risk ratio was 1.36 which is good.
17:20I mean it's better than one.
17:22And then the necessary number
17:24to treat of patients,
17:25you treat 14 patients to expect
17:27to get one of them that might
17:29have a positive response to this.
17:31So if it's still that that's not a, you know,
17:33number needed to treat is not great,
17:35but it indicates that there can
17:37in fact be a role for these.
17:39Slow onset look much lower.
17:42Abuse liability stimulants,
17:44the short onset ones,
17:46which is what the patients want,
17:48not so good.
17:50So I've tried to cover a balanced view of,
17:53you know, how stimulants can be used,
17:55but they have to be used very carefully.
17:57They're clearly a very useful treatment
18:00for attention deficit disorder.
18:02But a lot of people with
18:04attention deficit disorder,
18:04when they develop it somehow at age 25,
18:07and they now want, you know,
18:09methamphetamine to or
18:10amphetamine to treat it,
18:12one should be a little suspicious.
18:15So now let's shift to a
18:17totally different thing,
18:18which is let's talk about pharmacogenetics.
18:20This is one of my interests.
18:23This will be with Doxazosin,
18:24which is an A1 blocker.
18:26And the polymorphism that I'm looking
18:28at is dopamine beta hydroxylase,
18:30which is a gene that converts
18:33dopamine to norepinephrine.
18:34This is just a little picture of that.
18:36So you're seeing dopamine and norepinephrine,
18:38and this is the enzyme that
18:42makes that conversion possible.
18:43And so if you have very
18:46little of that enzyme,
18:48you're going to have dopamine
18:50released from norepinephrine
18:51neurons instead of norepinephrine.
18:53And if you have a lot of that enzyme,
18:55you're going to convert a lot
18:57of things to norepinephrine.
18:58Now, clearly not out of the dopamine neurons,
19:00because the dopamine neurons
19:02themselves don't contain this enzyme.
19:04It's in the norepinephrine neurons.
19:07And norepinephrine, by the way,
19:09is part of a reinforcing system also,
19:12and it can, and it of course contributes to.
19:16Craving and stress induced reinstatement.
19:21So there's a genetic variant
19:23of this particular gene,
19:25and it's the location is
19:29in fact before the actual.
19:32Gene itself that codes for the protein,
19:35so it's a regulatory polymorphism.
19:38It's in the promoter region,
19:40it's critically involved in
19:41the activity of DBH.
19:43There's a total of about 6 mutations
19:45that have been found to cause this
19:48DBH deficiency and the normal,
19:50which is ATT,
19:52produces about 100 times more
19:54norepinephrine than if you have one of
19:57these polymorphisms and the the CC and
20:00this particular one is the one that.
20:02This is the lowest levels,
20:03but it's also the most common.
20:05And it's been linked to a range
20:08of psychiatric disorders,
20:09from psychosis to conduct disorders.
20:11It's one of the genetic polymorphisms
20:13that's probably been the most widely
20:16studied in psychiatry for 30 years.
20:18So we looked at a drug, doxazosin,
20:21for cocaine abuse and found
20:23that indeed that the placebo,
20:25which you can see in the solid line,
20:28if anything there, cocaine use is going up.
20:31And the people who got the ducks.
20:32Places in there, cocaine use is going down.
20:36This is a profound effect.
20:38Of course not.
20:39We we have very few medications in
20:41cocaine abuse that produce profound effects.
20:44But you're getting about a 25%
20:47difference between the placebo
20:49and the active medication,
20:51and it's fairly sustained after the 5th week.
20:55And let's see next one.
21:00So we then looked at these genetic
21:03polymorphisms, that is, you know,
21:04how much of the enzyme was actually
21:07there and did that have an effect?
21:09Well, what's shown at the top is the
21:12one the people that have the genetic
21:15polymorphism that in general would
21:17produce lower levels of norepinephrine.
21:20And what we found is with these lower levels,
21:23there really was no significant
21:25difference between the placebo
21:27and the active medication.
21:29On the other hand,
21:30shown in the bottom there,
21:31which is the people that had this
21:34polymorphism and therefore had a
21:36reduction in the amount of genetically
21:38produced norepinephrine that their
21:40cocaine use significantly dropped
21:43over the 12 weeks of the trial and
21:46was in fact showing drops as you
21:48can see beginning at about week five
21:51or six and continuing to go down
21:53while the placebo group really just
21:55bounced around and if anything,
21:57increasing their cocaine use.
21:59So that the positive urns
22:02are reduced about 40%.
22:04From the baseline in these people
22:06that had this genetic polymorphism,
22:08we then you know repeated this
22:10in a couple of other studies.
22:13So it looks like it's something there.
22:15I didn't bring the data along to show you,
22:17but we've also found that a polymorphism
22:20in the alpha noradrenergic receptor
22:22which leads to less sensitivity and
22:25or difference in sensitivity in that
22:28receptor that that's also associated with
22:30response to this blocker that that is.
22:34The AA1 blocker and those,
22:38the DBH and that other polymorphism
22:42in the receptor for norepinephrine
22:44that they do act together to have a an
22:48additive effect in reducing cocaine use.
22:50It's it's unfortunate.
22:52It's been hard to convince that the
22:55powers to be that Pharmacogenetics
22:57has any role for substance abuse,
23:00but we've found it with a variety of drugs.
23:02This is for cocaine.
23:04So there's a pharmacogenetic
23:06hypothesis that I hope is obvious
23:08from this that the DBH is converting
23:10dopamine to norepinephrine.
23:12And then with Doxazosin which is
23:15actually blocking the A1 receptor,
23:17that if there's less norepinephrine there
23:21that we find that in fact the block by
23:25doxazosin then has a more profound effect.
23:28And this is again I think.
23:32A function that makes at least some
23:35sense that the doxazosin would work
23:38better in the cocaine use puppet patients
23:42that have this polymorphism that they're.
23:45Norepinephrine levels are
23:46in fact it says higher GPH.
23:49That's that that's not true.
23:52Lower TBH and it's and they're norepinephrine
23:54levels would be therefore lower,
23:56and therefore blocking it with Doxazosin
23:58would probably be much more effective.
24:03All right. I'll see if I can manage
24:04to have a couple of other slides
24:06where I write the stuff correctly
24:07and that is we're now going to talk
24:09about the immunotherapies which is
24:11the anti drug vaccines to protect.
24:14Really to prevent overdose is what
24:15we're thinking about and how that
24:17mechanism of action might work.
24:19And we're going to start with the
24:21cocaine because we've done a lot of work
24:23with the cocaine vaccine in general.
24:26We've been using a variety of different
24:29proteins as carriers because the drugs
24:32of abuse are too small to induce
24:34a an action of making an antibody.
24:37So that we've been recently using
24:41cream which is derived from.
24:44Let's see, diphtheria toxoid,
24:45but we've also used cholera toxoid,
24:47tetanus toxoid.
24:48And this cram is one that's been
24:51used in vaccines by Pfizer and GSK.
24:54So it's got a lot of safety data on it.
24:57And the fentanyl can be attached
24:59to the code by either succinyl
25:01linkages or glycerol linkages.
25:03And it attaches to what are the
25:0512 lysine amino acids on the
25:08outside of the creme protein.
25:10With tetanus,
25:10there's many more lysines on the outside.
25:13Tetanus is a much bigger protein.
25:15But Cream is a much cheaper protein
25:18in terms of using it as a carrier.
25:21So we're looking to make
25:23inexpensive versions of vaccines,
25:25and this is how they work.
25:27If you give the drug ordinarily,
25:29you take your drug of abuse,
25:30it concentrates in the brain because
25:31there are receptors in the brain
25:33for it to bind to give the vaccine.
25:35The vaccine makes these antibodies
25:36that stay in the bloodstream.
25:38They don't go into the brain.
25:40And so when you then take the
25:41drug plus you have the vaccine
25:44there already with the antibodies.
25:45You keep the drug in the bloodstream.
25:48Some of it gets into the brain,
25:50but in fact if you had a higher
25:52concentration in the brain,
25:53the antibodies would pull the drug
25:55out of the brain and into and onto the
25:58antibodies where they then circulate.
26:00And the cocaine or whatever the drug is,
26:04is eliminated through liver
26:06metabolism and also in the urine.
26:10You didn't like that particular picture,
26:12how it's working.
26:13Here's another picture of how it might work.
26:15And this is particularly
26:18relevant to monoclonals.
26:20For a monoclonal against fentanyl
26:25or against cocaine or whatever,
26:26they would actually pull the
26:28drug out of the brain.
26:29And so this could be a very
26:33rapid overdose treatment.
26:34And by injecting,
26:35but you'd have to inject the
26:37monoclonal into the person,
26:39there are some monoclonals.
26:41That can be given subcutaneously.
26:43That have been developed for Alzheimer's
26:45disease and they're ones that even
26:47look like you can give them orally,
26:49but obviously if someone's passed
26:52out you would probably give them
26:55by injection and subq as possible.
26:57So these are competitive antagonists.
27:00So can someone smoke enough
27:01to overcome these vaccines?
27:03Well, yes, they can,
27:04but it would take some effort.
27:06This is not someone who's taking the vaccine,
27:09obviously, but someone with a stunt.
27:11You'd have to,
27:12you'd have to take a lot of cocaine in,
27:14and in particular fentanyl,
27:16which we're going to get to.
27:17You really have to take
27:19massive amounts of fentanyl,
27:20which is not going to happen.
27:22So that's why with cocaine,
27:24we never could get it to work that well.
27:26And I'll show you some of those.
27:27Data because people take in so
27:30much cocaine compared to the
27:32amount that's taken in a fentanyl.
27:35So what are the?
27:36These cocaine vaccines look like,
27:39well pharmacologically they looked
27:40sensible and that if you had
27:42a high antibody which we could
27:44develop by giving a larger dose
27:46of the vaccine or low antibodies
27:48from a lower dose of the vaccine.
27:51You would find that the blockage,
27:53which of the cocaine and then
27:55we gave either 25 milligrams
27:57or 50 milligrams of cocaine.
27:59This was smoked cocaine.
28:01And you could get an 80% blockage.
28:04So what is the the purple
28:06versus the Gray or not Gray?
28:08I guess brown blocks or bars there
28:11illustrate how much of a high you got
28:14or a whole different set of ratings,
28:16good drug effect.
28:17In this particular case,
28:19you get an 80% reduction.
28:20So the the purple was that week
28:23three before we had vaccinated,
28:25week 13 was after we had put in
28:27three vaccinations into the people.
28:29If you then doubled the dose of cocaine,
28:31which is shown again.
28:32On this left side, you get a 50% reduction.
28:35If you had a low level of antibodies,
28:37you only got a 23% reduction with
28:39the 25 milligram dose of cocaine,
28:42and if you doubled the dose of cocaine,
28:43you only got a 13% reduction.
28:45Neither of those were statistically
28:48significant.
28:48Both of them were significant
28:50though at the high antibody levels,
28:52which simply meant giving a
28:54high dosage of the vaccine.
28:56So this was good pharmacological
28:59demonstration of dose response effect.
29:02So how did this turn out when we did the
29:05randomized controls outpatient trials,
29:07I'm not going to review
29:08these studies in any detail,
29:10but these are double-blind
29:12placebo-controlled.
29:12We vaccinated without actually 5 dosages
29:14of the vaccine over a 12 week period.
29:17We did urine toxicology.
29:18We measured antibody levels and
29:21we had calculated that a single
29:23cocaine dose could probably be
29:25blocked by 20 micro 20 micrograms per
29:28milliliter of antibody and we could
29:31block probably 3 doses of cocaine.
29:33Um, with 42 or more,
29:35because that was blinding about
29:3780% of cocaine by our calculations.
29:42Well,
29:42what happened was only a third of the
29:44people reached our threshold of 43
29:47and that's what's shown in blue here.
29:49And what you can see is as we
29:52repeatedly immunized them over
29:53the first looks like 16 weeks
29:55but was actually only 12 weeks.
29:57The antibody levels steadily rose
29:59and then the antibody levels
30:01steadily go back down again but
30:03for the people in the high.
30:06Antibody group,
30:07their average antibody levels
30:09by week eight were in fact up
30:12above 40 and they stayed up
30:14above 40 out to week 24,
30:15which would be six months,
30:17which meant about three months of
30:19protection you could get and then
30:21you'd have to give a booster and we
30:23did give boosters to a number of
30:25these patients and a single booster
30:27would push their antibody levels back
30:28up to the peak that they had before.
30:31So you'd probably be with this vaccine
30:33be giving it to responders about.
30:36Every three to four months,
30:37the newer vaccines we've got now,
30:39it looks like we can go six
30:42months between vaccinations.
30:43But you can see you're looking
30:45at 2/3 of them.
30:45That didn't make it at all
30:48as far as what you needed.
30:50So we then looked at these three groups,
30:52the people who got the placebo,
30:53the people who had the low levels
30:55of antibodies and the people
30:56that had the high levels of the
30:57levels that we thought you need.
30:59And what we found is the proportion
31:01of drug free urones during the period
31:04of weeks 9 to 17 versus the baseline
31:06period that there was a 2 1/2 fold
31:09reduction in cocaine use for the
31:11people that had attained our levels.
31:13For those that didn't attain them,
31:15which was you know, 60% of the vaccinated,
31:18they got some reduction.
31:201 1/2 or so,
31:2150% reduction and the placebo
31:23really didn't show any change
31:24from what the baseline was.
31:26So this was a nice gun stair
31:27step dose response kind of thing.
31:29Also not enough to convince the
31:31FDA that this was useful,
31:33but enough to give us money
31:35for another study.
31:36And this was looking at all the
31:39different levels of antibody
31:40that we had in the study versus
31:43the percent of cocaine urones.
31:45And we found you could reach a
31:47level of antibody at which people
31:50just simply stopped.
31:51Using cocaine altogether because it wasn't.
31:53They didn't have enough money
31:55or it just wasn't worth it.
31:56When we asked them why did they stop,
31:58they said, well,
31:58they just couldn't find a good enough dealer,
32:00so nobody seemed to believe
32:02that the vaccine did anything,
32:04even though when we asked them
32:06who thought they got the vaccine,
32:0880% of the people thought they
32:10got the active vaccine,
32:11even though only 50% actually did.
32:14I think that was because our
32:16placebo had some alum in it and
32:18the alumnae your arm hurt,
32:19so they assumed that was the real thing.
32:23So what do we conclude?
32:24That the vaccine was better than a placebo,
32:27that the cocaine free Urnes increased
32:29as the antibody levels increased.
32:3140% of the patients had
32:33effective antibody response.
32:34That's 40% of vaccinated.
32:36It was medically safe.
32:37There was increases in cocaine
32:39use above baseline levels that we
32:42could find intermittently in their.
32:44There are benzoylecgonine,
32:45well urine levels where we found
32:47a number of people that had urine
32:50benzoylecgonine levels that if
32:51they would not been vaccinated
32:53they probably would be dead from
32:55an overdose at least would have
32:58been seriously damaged by it.
32:59But they in fact describe
33:01really no effects at all.
33:03A few people described that their heart
33:05went pitter patter a bit but very
33:07unimpressive as far as they were concerned.
33:10So this LED us to a multi
33:12site cocaine study it was.
33:14National study.
33:17OK.
33:17Basically the same dosage of the vaccine,
33:20the urine toxicology was 300
33:22outpatients and we measured
33:23the same kind of outcomes and
33:25unfortunately got the same kind
33:27of outcome from the vaccine,
33:29which is if you're looking at 40,
33:31we at best did that.
33:33We got maybe half of them,
33:34but some of them now because
33:37we rejuvenated the vaccine,
33:39we we made new batch of it got up
33:42to antibody levels of over 250,
33:44which is astounding so that there's quite a.
33:48Quite a amount of antibody that
33:50can be produced in some people,
33:52and the trick of course is to either
33:54get everybody to move up there or
33:56to be able to select ahead of time
33:58which people are not going to respond.
34:02Well, what we did find is, again,
34:03this is just the average data from the study.
34:07And 59 was our average of
34:10peak effect at week 16,
34:12which was better than in the other study.
34:14There was no simple correlation
34:16this time with the antibody
34:18levels with cocaine for urones,
34:19although we just published a paper
34:22that this was looking at IG levels
34:25and we had a paper in nature vaccines
34:28at the beginning of this year showing
34:30that it looks like it's IGA, not IG.
34:33That's really important.
34:34And part of that is because IGA,
34:36that type of antibody,
34:38not only lines mucous membranes,
34:40it also lines the blood brain barrier.
34:44And so what's happening it looks
34:46like is that the cocaine or that
34:49we don't have it for fentanyl.
34:50Yeah, actually we do in the
34:52animals for fentanyl,
34:52it's it's binding to the drug as
34:54it's trying to get into the brain,
34:57which is fantastic because now
34:59what we've been chasing after is
35:01adjuvants that will increase the
35:02amount of IGA being produced.
35:04And we so we duplicated this,
35:07started the,
35:07the mouse finding that was in nature.
35:10We then just duplicated it in a
35:12rat study and this was we went
35:14back and reanalyzed this study.
35:16I found the same thing was true in humans.
35:19So this is very encouraging and an
35:22exciting discovery that IGA is in
35:24fact maybe the way this is working
35:26and there are some adjuvants,
35:28particularly some that could be
35:30given intranasally or orally that
35:33will markedly increase mucosal IGA.
35:35They're,
35:36they're being developed for COVID
35:38vaccines at the moment and that's,
35:41you know, as if I have nothing else to do.
35:43We actually have a COVID vaccine
35:45that we've come up with too.
35:46That's some.
35:47Again,
35:47focuses on this kind of IGA idea anyway.
35:51So what did we find in it?
35:53There was better treatment retention
35:55if you got these higher antibody levels.
35:57Three times more participants had
35:59at least two weeks of abstinence
36:00if they had these higher levels
36:02than either the placebo or the low.
36:04And there were more cocaine for
36:06urones compared to baseline.
36:08But neither are investors nor the
36:10FDA were impressed with these data.
36:12They said, you know,
36:14everybody you vaccinate has to
36:15show a good response or it's a.
36:17Lousy vaccine that led to all of the
36:22major pharmaceutical companies who
36:23got similar results with nicotine
36:25from dropping out from the field.
36:27And this is a while ago.
36:29So did we learn something from these studies?
36:32Yeah,
36:32we changed our protein carrier from
36:34cholera B to a better protein.
36:36We got a better agent.
36:38We started using a TLR four and
36:41five adjuvants.
36:41These are toll like receptor
36:44type adjuvants and agonists that
36:47push these systems.
36:48And that we really needed to get
36:50more patients who attain these
36:52higher antibody levels and it
36:54would be better to get patients
36:56who at least can become abstinent
36:58before we start trying to vaccinate
37:00them so they have a
37:01little motivation to want
37:03to become abstinent.
37:04And again, with fentanyl,
37:06we need much less antibody.
37:08So what's happening?
37:10Why is the fentanyl epidemic turned into?
37:14Stimulant epidemic well,
37:15stimulants have limited
37:17lethality compared to fentanyl.
37:19I mean, it's hard to die.
37:21I don't shouldn't say hard,
37:22but deaths from just cocaine
37:25or methamphetamine are not that
37:28common compared to fentanyl.
37:30The abusers had returned to stimulants,
37:33including amphetamines that were
37:35obtained from prescribers and in
37:37cocaine bought from the street.
37:39Because people were recognizing
37:40that taking opiates you were taking
37:43a big risk with the fentanyl.
37:44That's almost always an opiates now.
37:47So the distributor started mixing
37:49fentanyl with the stimulants like
37:50cocaine powder and methamphetamine.
37:52Why did they do that?
37:54You could take very inexpensive,
37:56crappy cocaine and methamphetamine and
37:58put a little bit of fentanyl in it,
38:01and it feels like it's a great drug,
38:02apparently to the patient,
38:04so that they're not patients
38:05but people on the street.
38:06So that's the reason to put fentanyl in.
38:08And fentanyl, of course,
38:09a little bit of it goes a very long way,
38:12so your marketing becomes
38:14much more profitable.
38:16Then, early in 2021,
38:18counterfeit Adderall pills
38:19containing fentanyl began to appear.
38:22And this is a.
38:23Big problem.
38:24In March of 2021,
38:26the DEA had seized 600,000
38:28counterfeit pharmaceutical pills.
38:30They all contain fentanyl.
38:33All of those at that time
38:34were being sold as Adderall.
38:35But there's now also been evidence that
38:38it's in Percocet and that it's also in Xanax.
38:41One in four of these pills had
38:44lethal fentanyl overdoses in them.
38:45Now that was not purposeful
38:47on the distributors part.
38:48There's no point in killing your
38:51customers but this new rising.
38:54Mortality from stimulants is due
38:55to the fentanyl disguised as a
38:57stimulant or mixed with the stimulant.
39:00The stimulant mortality rate with
39:02this is now rising at twice the
39:04opiate mortality rate due to just
39:06the fentanyl adulteration of heroin.
39:09Amphetamines fourfold mortality
39:10rise only required five years
39:13versus for the opiates.
39:15With fentanyl it took ten years
39:17to get this fourfold increase.
39:18So the the the path of the epidemic
39:21is now much more much steeper.
39:24And much more dangerous.
39:28This is what the counterfeit pills look like.
39:31The authentic oxycodone,
39:33the counterfeit one on the bottom
39:36in the middle is the Adderall.
39:39Adderall is the the real thing on the
39:42top and the counterfeits on the bottom.
39:45If anything, the counterfeit pill
39:46looks like it's cleaner and nicer and,
39:48you know, Oh yeah, I'd rather have that more.
39:51And it's got a 30 on instead of 20,
39:53so it must be a more potent pill.
39:55Xanax, the same thing.
39:57That's the other counterfeit
39:58and the real one that.
40:00These are being, you know,
40:02distributed on the streets
40:04and on the Internet sites,
40:07virtually on the Internet sites,
40:09any of the the dark Internet
40:11for Adderall at least,
40:12is Adderall with fentanyl.
40:13Virtually none of them now,
40:15or just really Adderall.
40:17So this has become extremely big
40:20problem. And what's the problem
40:21is that if we as doctors are
40:24prescribing Adderall, you know,
40:25like water and that is happening with kids,
40:29this is going to be a problem.
40:30Because when you take the drug and you
40:33take it and then a way to get high,
40:35you're going to have to take escalating
40:37dosages and those escalating dosages.
40:39Sooner or later the doctor is going to say,
40:42no, I'm not going to give
40:43this to you anymore.
40:44The doctor shopping may work or may not work,
40:46which means you go to several different.
40:48Not just to get it,
40:49but sooner or later you're going to turn
40:50to either the Internet or the street
40:52and you're going to be getting you.
40:54I say you in a very general sense that the
40:56abuser is going to be getting Adderall,
40:58it's got fentanyl in it and that
41:01fentanyl has got a one in four
41:03chance is going to be a lethal dose.
41:06So fentanyl vaccine that's
41:08in current development,
41:10we're trying to apply the
41:11discoveries from an improved cocaine
41:13vaccine to the fentanyl vaccine.
41:14We've been working on this for a
41:16few years now and this was from the
41:20paper that was in nature vaccines
41:23and this is a very complicated slide
41:25that's got much more information
41:27than you really need to know,
41:29but if you look at.
41:31The C&amp;D,
41:33and you look at the one,
41:35the the bars that are purple and the
41:38bars that are dark blue all the way
41:40to the right on all of these four
41:42different graphs that are shown there.
41:44This is what's happening if you
41:47give fentanyl to mice that have
41:50been vaccinated or not vaccinated.
41:53The clear bar is the naive mice
41:55that have not been vaccinated,
41:57and the blue and the purple bars
42:00are to the mice.
42:01That have been vaccinated and given fentanyl.
42:05Now the fentanyl dose on the far left
42:08bottom which is the C part that's 30
42:11micrograms per kilogram that is a you
42:14might call a therapeutic dose of fentanyl.
42:17The 100 micrograms per kilogram which
42:19is the next set of bars over is in
42:22fact the lethal dose of fentanyl and
42:24what you can see is that the the
42:27blocking of of pain from that 100.
42:31Who is complete?
42:32When you have the naive mice that
42:36you just you, you can't get,
42:38you know, you don't feel any pain.
42:40I guess that's one way to put it
42:42before you die on the blue bar,
42:45blue and purple bars.
42:46Those are with the vaccination with.
42:49I'm not gonna go into the two different
42:52types of adjuvants that we have,
42:54the DLT and the LTA,
42:56only to tell you that the LTA 1 adjuvant
43:00is the one that produces much more IGA.
43:03And it's very clear from this making
43:06more IGA is what's the key to success.
43:10So the left,
43:11so the C's are the tail flick,
43:13the D's or the is the hot plate
43:15measure in these mice and it
43:17shows exactly the same sorts of
43:19things, the hot plate,
43:21perhaps more graphically,
43:23that the vaccines are really
43:25knocking down fentanyl's ability.
43:29To act as an analgesic
43:31and which is, you know,
43:32that's the simplest test one can do.
43:35So that's mostly what this
43:37slide shows in the mice.
43:39We then looked at the brain levels
43:41also and what you can see on the left
43:43or the brain levels of fentanyl,
43:44and on the right of the
43:46blood levels of fentanyl.
43:48The open bar is the one that's
43:51got the naive mouse, the dock,
43:54the blue and purple bars are the
43:57ones that have the vaccinated.
44:00And what you find is very little
44:03fentanyl is getting in the brain now,
44:06yet if you look in the bloodstream,
44:09a lot of fentanyl is getting in the brain.
44:11So it's going from about 10 nanograms per
44:15milliliter in the blood up to about 130,
44:18a 100 or I'm sorry about 170.
44:21So we have clearly gotten the fentanyl to
44:24stay in the blood and not go into the brain.
44:27The brain levels,
44:28I hope you can see are virtually 0.
44:31So this is a big success.
44:34We then also looked at the type of antibody
44:38and this is with the anti fentanyl, IGA.
44:43What's on the left is the brain levels.
44:45The brain levels of,
44:49of and of the.
44:52The IG let's see the brain levels of the
44:56fentanyl with the anti fentanyl vaccine.
44:59The bigger the concentration of
45:02that antibody is which is what's
45:05the the collection of diamonds and
45:08and triangles that are up in the
45:11left hand corner on the left side.
45:13That's the antibody there and
45:17you're looking at the.
45:20The anti fentanyl antibody and
45:22the amount of IGA as the brain.
45:25Fentanyl is it.
45:27As it is. Uh,
45:28those levels are going down of the antibody.
45:32The brain levels of fentanyl are going up.
45:35I said that that's all that
45:37that's this is trying to show.
45:38It's just it,
45:39it would be a,
45:40it would be a line except that
45:41we really just have two clusters.
45:43You either knock the fencing all out
45:45completely from getting into the brain
45:47or it completely gets into the brain.
45:48There's just you know nothing in between.
45:51We then looked at tail flick also and
45:53found the same association that when you
45:56have had these higher levels of the antibody,
45:59the anti fentanyl,
46:00IGA,
46:01the tail flick doesn't occur,
46:03although there there were a few exceptions.
46:05Of animals that we're still getting
46:08some tail flicker effect that is
46:10because the tail flick also involves
46:12spinal cord reflexes and we're not
46:14clear that this actually keeps fentanyl
46:17completely out of the spinal cord in some,
46:19some animals will, but.
46:23So this is brain levels and pain.
46:26This is a rat study.
46:28This in the RAT study is what we're
46:31looking at is will rats self administer.
46:35The fentanyl and what you can show is
46:38that on the far left with no vaccine,
46:41yes, the the rats will,
46:43you know,
46:44knock at the bar a million times to
46:46get the fentanyl and as you push the dose up,
46:49you know they get pushed the bar more.
46:53Once you vaccinate them though,
46:55you just completely knock out that ability.
46:59We also looked at it in combination
47:02with buprenorphine because we wanted
47:04to be sure that we weren't decreasing
47:06the efficacy of buprenorphine.
47:09And what we found is that no,
47:10we did not decrease the
47:12efficacy of buprenorphine.
47:13If anything, it's enhancing some
47:14of the efficacy of buprenorphine,
47:16which we're a little puzzled by,
47:18but you know that's OK.
47:21This is a high dose fentanyl and lethality,
47:24this is in the rats.
47:26Hopefully you can see that on
47:28the right side of this slide.
47:31That's not what a rat should look like
47:33that's that's rigor mortis in the rat.
47:34They are basically stiff.
47:36They are basically dead from that
47:39dose of fentanyl on the left or the
47:41mice that were vaccinated and given
47:43the same dose of fentanyl hopefully
47:46you can tell that they're you know
47:48they're they're walking around and
47:49they look fine and they are you
47:51would not be able to hold them stiff.
47:53The way you can on the right side picture,
47:55so this vaccine,
47:57we've also measured respirations in
47:59the rats and the the respirations
48:02basically go down to 0 if you
48:04don't have the vaccine and if you
48:06do they don't change at all.
48:10So who should take the fentanyl vaccine?
48:13What's the target patient population?
48:15Well certainly treatment seeking
48:17opioid who are inevitably fentanyl
48:20users maintained on buprenorphine,
48:22they clearly want treatment because but
48:25people morphine doesn't block fentanyl and
48:28so they all of them should be vaccinated.
48:31What about stimulant and benzodiazepine
48:33users because of this adulteration
48:36with fentanyl which is driven
48:38by St rebranding of fentanyl?
48:39Is a dangerous drug so that you know
48:42people don't want to take fentanyl
48:43and there's been an increased use
48:45in stimulants and the much lower
48:47production and shipping cost of fentanyl.
48:49We think the stimulant and benzodiazepine
48:52abusers ought to be given some,
48:53particularly the stimulant users
48:55vaccinations for anti fentanyl
48:57because they're going to die from it.
49:00So we think there's a broad need for
49:02this overdose and relapse prevention
49:04vaccine beyond opioid users and
49:06whether it's going to extend into
49:08benzodiazepine abusers and virtually.
49:10Anything else will depend upon
49:11how the marketing goes with the,
49:14you know,
49:14the cartels in Mexico and the producers
49:17in China who are sending it here.
49:21Just a quick little summary of
49:23what I've tried to go over that
49:25the opioid overdose epidemic,
49:27it started with I think what I would
49:30consider unethical prescribing of opiates,
49:32the MD's are over prescribing opiates
49:34that led to the illicit fentanyl.
49:36It was something driven by a
49:38lot of pharmaceutical companies.
49:39There are pharmaceutical companies,
49:41I can tell you that are driving people
49:44to prescribe much more stimulants
49:45than they used to prescribe.
49:47Why? They're saying it's great
49:49for ADHD and adults.
49:51Even adults that didn't seem to
49:53have it as kids that it's in,
49:55kids that the diagnosis has
49:57been markedly increased,
49:59and there the kids are given.
50:02As I showed you from the data,
50:04you know early on these early adolescents
50:06are being given more substantial four
50:09times the amount of amphetamine or
50:11what they than they used to be given.
50:14So this is.
50:14And this is wave four and I think we
50:17have to be very careful as physicians
50:19that we don't get somehow blamed for
50:22this epidemic that this is our doing.
50:24And I'm afraid it's it's not
50:26necessarily coming from psychiatrist
50:28it's coming from pediatricians and
50:30it's coming from internists who are
50:32or or general practice doctors who
50:34I see in Texas all the time that
50:36are thinking that they see ADHD
50:38in adults and they say Oh yeah,
50:41this is and when they ask for a
50:43stimulant they give them Adderall,
50:45that's the the one to give them.
50:47And the company that makes it
50:49obviously is not discouraging that.
50:51So what about amphetamine for treating
50:53stimulant use 30 yes there can be
50:55and it needs to be particular ones
50:56though lisdexamphetamine would be 1
50:58to think about others would be long
51:01acting slow onset genetic matching.
51:03I I think there's a real role for this.
51:05I only showed it for doxazosin and
51:08the DBH polymorphism but there's
51:10in fact others that that are coming
51:13out including for the the use
51:15of buprenorphine to treat.
51:16For pain abuse,
51:17it ends up Dave Nielsen and I
51:21published a paper recently showing
51:23how a polymorphism in the the Kappa.
51:27System.
51:28It's in the actually dynorphin,
51:30dynorphin polymorphism that produced
51:32that predicts treatment response.
51:34And then there's the vaccines.
51:35I didn't have time to talk
51:37about cholinesterase enzymes.
51:38These have been around now for a while.
51:40These are high activity colon esterases.
51:43We published a paper now it's about 810
51:46years ago where we took our vaccine.
51:48Even our crappy vaccine combined
51:50it with the Colonel,
51:52one of the Colonel esterases,
51:53and it was phenomenal in
51:55that it completely blocked.
51:57McCain use and the animals,
51:59he just could not override it at all,
52:01even though they could override
52:03the vaccine and they could
52:04override the colon esterase,
52:05because the colony esterase
52:07is relatively slow,
52:08but when you put the two things together,
52:10it's unstoppable.
52:14And buprenorphine doesn't
52:15block fentanyl abuse,
52:16you know,
52:17sorry,
52:17but and a vaccine can block the
52:20fentanyl abuse and the overdose
52:22and the human fentanyl vaccine
52:24we've just started
52:26manufacturing as of this month.
52:28We're hoping to get it
52:29into people within a year.
52:31Depends on the FDA,
52:32but they've accelerated for COVID
52:34obviously the approval process
52:35and we're hoping to convince them
52:37that they should be doing the same
52:39thing for an anti fentanyl vaccine.
52:41We're not the only one working
52:43on this vaccine.
52:44But we're about at least probably
52:45two to three years ahead of
52:47the other three groups working
52:49on this around the country.
52:50It's not like we're we're competing
52:54with them in any real way.
52:56We're collaborating with them.
52:57We're trying to work together.
52:59There's a group at Harvard that
53:00we're working with another one
53:01out at University of Washington,
53:03another one and University of
53:05Maryland and then together plus with
53:08of course Niad and night etcetera
53:10together we think that would come
53:12up with this but our particular.
53:14Group is is rather aggressive I guess
53:16because I know how to do these kind
53:19of clinical studies and nobody else involved.
53:21It's done clinical studies
53:23with vaccines in addiction.
53:24So I think that is what's giving
53:26us an advantage, alright, so.
53:31It's always nice to say,
53:32you know,
53:33this is not everybody who's
53:34worked with me over time,
53:35including, uh,
53:36very few of the Yale people who worked
53:39with me on these vaccines are listed here.
53:42But, you know, there are some.
53:46And anyone who sees my wife in the
53:48young the next few months or whatever,
53:50you know,
53:50tell her to make sure that I did say,
53:52you know, thank you to my wife, Terry.
53:54Costume and the collaborators are,
53:57of course,
53:57a bunch of different companies who've
54:00worked with us and making these things.
54:02And and the National Institute of
54:05Health was both naida and the NIH NIAD,
54:09the Allergy infectious
54:11disease fouchy's group.
54:12With that,
54:13I think I've managed to burn
54:15up as much time as I'm allowed
54:17and I'm happy to address any
54:19questions that people have.
54:21So thank you very much.