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Inventing a Better Pain Pill · What's Your Problem?

0:15
Speaker 1: Pushkin. Pain is terrible, obviously, it's kind of the classic
0:25
Speaker 1: terrible thing, and having medicine to treat pain is great.
0:31
Speaker 1: But the strongest drugs we have for pain, opioids, are
0:35
Speaker 1: infamously addictive, deadly. Even more than ten thousand people die
0:40
Speaker 1: every year in the US from prescription opioid overdoses. Opioids
0:46
Speaker 1: are addictive because they act on the brain to blunt
0:49
Speaker 1: our sensation of pain. But pain doesn't start in the brain.
0:53
Speaker 1: It starts in the nerves in other parts of the body,
0:56
Speaker 1: and then it gets relayed to the brain. So for
0:59
Speaker 1: decades scientists thought it would be amazing if we could
1:03
Speaker 1: find a molecule that was really good at blocking pain
1:06
Speaker 1: in the nerves before it gets sent to the brain.
1:09
Speaker 1: That way, we could make a pain drug that is
1:11
Speaker 1: as strong as opioids but is not addictive. And earlier
1:15
Speaker 1: this year, for the very first time, the FDA approved
1:19
Speaker 1: exactly that kind of drug. I'm Jacob Goldstein and this
1:28
Speaker 1: is What's Your Problem, the show where I talk to
1:30
Speaker 1: people who are trying to make technological progress. My guest
1:34
Speaker 1: today is Stephen Waxman. He's a professor of neurology, neuroscience,
1:38
Speaker 1: and pharmacology at Yale. Stephen's research helped to pave the
1:42
Speaker 1: way for that newly approved pain drug. It's a drug
1:45
Speaker 1: called suzettrogene, and in particular, Stephen has spent decades studying
1:51
Speaker 1: ion channels. Ion channels are these little gaps in nerve
1:54
Speaker 1: cells that let charged particles ions in and out of
1:58
Speaker 1: the cell. Suzettrogene works by blocking one particular ion channel.
2:03
Speaker 1: As you'll hear later in the show, Stephen thinks suzetrogene
2:07
Speaker 1: is a promising start, but he also thinks there's still
2:10
Speaker 1: a lot of work left to do to develop better
2:12
Speaker 1: pain drugs, and the story of how we got to
2:15
Speaker 1: cizetrogene reveals a lot about how science works, and how
2:19
Speaker 1: drug development works, and ultimately about how the body works. Well,
2:23
Speaker 1: how did you get into pain?
2:26
Speaker 2: You know? When I was an mdphd student, I had
2:29
Speaker 2: the privilege of doing a four month stint at University
2:34
Speaker 2: College London with Patrick Wall. Wall was the father of
2:39
Speaker 2: modern pain research, and so I spent four or five
2:43
Speaker 2: months with him. So I got to work at his side,
2:46
Speaker 2: and I realized that pain is not only a very
2:49
Speaker 2: important challenge, but also a puzzle box that presents intellectual challenges,
2:55
Speaker 2: but that could be solved.
2:56
Speaker 1: Huh. Tell me a little more about what you experienced
3:00
Speaker 1: in those four months, Like, was there a particular moment
3:03
Speaker 1: or some particular problem that was intriguing to you.
3:07
Speaker 2: Well, what became clear to me is that pain is
3:11
Speaker 2: a hierarchical experience. You may experience it peripherally through your
3:16
Speaker 2: peripheral nerves, but that the pain messages are then processed
3:21
Speaker 2: and modulated in the spinal cord, relate upwards to the
3:25
Speaker 2: lower brain than to the cortex, and so it's an
3:28
Speaker 2: experience that is processed at many levels, and at each
3:33
Speaker 2: level if you take a reductionist approach, it seemed to
3:36
Speaker 2: me that you can take it apart and understand it.
3:39
Speaker 1: Huh. So you start thinking of pain as this sort
3:43
Speaker 1: of hierarchical phenomenon, and is there a particular level of
3:50
Speaker 1: the stack that you decide to focus on.
3:53
Speaker 2: That's a great question, you know, Jacob. When I was
3:57
Speaker 2: a young new scientist, an mdphd student resident then a
4:02
Speaker 2: new assistant professor at MIT and Harvard, I wanted to
4:06
Speaker 2: study grand philosophical problems at the mind interface.
4:11
Speaker 1: What is consciousness? That sort of thing.
4:13
Speaker 2: Yeah, and I published some papers in the cybernetics literature
4:17
Speaker 2: and got awards for them. But I came to the
4:20
Speaker 2: conclusion that while that was a very important challenge, that
4:25
Speaker 2: it was those issues were not going to be resolved
4:28
Speaker 2: during my professional lifetime, and so I retreated from grand
4:33
Speaker 2: philosophical questions to much more soluble, concrete questions that could
4:40
Speaker 2: be solved during my professional lifetime. So that's what I did.
4:44
Speaker 2: When I talked to students trainees, I relay this story
4:48
Speaker 2: to them because they have a choice. Do they want
4:50
Speaker 2: to attack large, philosophically grand questions or work at a
4:56
Speaker 2: more fundamental, reductionist level. There's no right answer. This was
5:00
Speaker 2: right for me, and they have the opportunity to make
5:03
Speaker 2: your own choice.
5:05
Speaker 1: So you go from big consciousness ultimately to very small
5:11
Speaker 1: right like ion channels, which about as small as you
5:15
Speaker 1: can get in medicine, right, and ion channels obviously mostly
5:19
Speaker 1: what we're going to talk about here, right, a tremendous
5:22
Speaker 1: amount of your work.
5:23
Speaker 2: So that's correct.
5:24
Speaker 1: How did you get into ion channels?
5:26
Speaker 2: Well, I got into ion channels because of my interest
5:29
Speaker 2: in axons nerve fibers. While I was an undergraduate, I
5:32
Speaker 2: spent nine months at University College working with a man
5:36
Speaker 2: named Jays zed Young. He discovered the giant axon in
5:40
Speaker 2: the squid, and so I became interested in how axons work.
5:44
Speaker 1: And the axon is part of the nerve cell.
5:46
Speaker 2: The axon is the long nerve fiber that extends from
5:49
Speaker 2: the nerve cell. Our nervous system consists of one hundred
5:54
Speaker 2: billion nerve cells in every one of us. It's the
5:58
Speaker 2: world's most complex computer. And each of the nerve cells
6:02
Speaker 2: has an axon that connects it to other nerve cells.
6:06
Speaker 2: So I was interested in axons, and it rapidly became
6:09
Speaker 2: clear to me that I had to understand how axons
6:11
Speaker 2: work and the driver of activity in axons nerve impulses bup, bup, up,
6:16
Speaker 2: up up up up is ion channels, sodium channels that
6:20
Speaker 2: act as molecular batteries, potassium channels that act as molecular breaks.
6:26
Speaker 1: Huh. So these are basically channels in the membrane of
6:30
Speaker 1: the cell through which ions charge particles move, causing the
6:34
Speaker 1: nerve cell to fire or not fire more or.
6:37
Speaker 2: Less, that's right. And when they fire, a nerve cell
6:40
Speaker 2: produces what's called an action potential or a nerve impulse,
6:43
Speaker 2: and it's the pattern of firing of nerve cells that
6:47
Speaker 2: they use to communicate with each other.
6:49
Speaker 1: So you're doing work on ion channels as a way
6:52
Speaker 1: to understand the behavior of nerve cells. You're also doing
6:54
Speaker 1: work on pain, right, And there has been, by the
6:57
Speaker 1: time you get into the field a history of work
7:00
Speaker 1: on the relationship between ion channels and pain. Right, So
7:04
Speaker 1: when you get into the field, what do we know?
7:06
Speaker 1: What does humanity know already about that relationship?
7:10
Speaker 2: Actually, when I got into the relationship between ion channels
7:15
Speaker 2: and pain, not much at all was known.
7:18
Speaker 1: I mean, we had lytocane and novacane, right.
7:21
Speaker 2: So lytacane and novacane are sodium channel blockers. We all
7:27
Speaker 2: know that when they're injected locally, no pain.
7:30
Speaker 1: That's what you get when you get a cavity filed.
7:31
Speaker 2: Right, that's correct. But if you put those drugs in
7:34
Speaker 2: the form of a pill and administer them systemically, they
7:38
Speaker 2: would affect sodium channels in the brain. So there is
7:41
Speaker 2: double vision, impaired balance, sleepiness, and confusion. And so that
7:48
Speaker 2: doesn't work. And so this is a really interesting arc
7:52
Speaker 2: of science. Sodium channels were discovered by Hodgkin and Huxley.
7:57
Speaker 2: They did the work right after World War two and
7:59
Speaker 2: published it in nineteen fifty two, and their studies were
8:03
Speaker 2: in the giant axon of the squid. And then fast
8:06
Speaker 2: forward to our lab in around nineteen eighty five, we
8:10
Speaker 2: were able to record similarly from axons from rats and
8:15
Speaker 2: then humans. They're one fiftieth the size of the squid
8:18
Speaker 2: giant axon, and we were able to see that not
8:22
Speaker 2: only were sodium channels there, but that the abnormal firing
8:27
Speaker 2: of peripheral nerve that underlies pain was caused by a
8:33
Speaker 2: particular type of sodium channel.
8:35
Speaker 1: So at some point, as I understand it, you get
8:39
Speaker 1: a call about a neighborhood in Alabama where a lot
8:43
Speaker 1: of people have an unusual experience of pain. Is that true?
8:48
Speaker 1: Did somebody call you on the phone? Is that how
8:50
Speaker 1: that starts?
8:52
Speaker 2: That's correct. We were taking two approaches. One was a
8:56
Speaker 2: mechanistic approach from ground up, looking at pain signaling neurons
9:01
Speaker 2: that we could study in a dish and dissecting them
9:04
Speaker 2: channel by channel, asking what did the various channels do
9:08
Speaker 2: to cause abnormal firing and pain. You can think of
9:10
Speaker 2: a neuron a symphony of multiple ion channels working in
9:15
Speaker 2: a highly orchestrated way, and so at that point, we
9:18
Speaker 2: had identified three sodium channels as potential very very important
9:25
Speaker 2: participants in pain signaling NAV one point seven, NAV one
9:29
Speaker 2: point eight, and NAV one point nine.
9:32
Speaker 1: So these are just the names of different ion channels
9:36
Speaker 1: that behave differently under different circumstances that we have in
9:39
Speaker 1: our nerve cells.
9:41
Speaker 2: That's exactly right. Yeah, So that's the sort of ground
9:44
Speaker 2: up mechanistic work that we were doing. But there's another
9:48
Speaker 2: top down approach beginning with whole human beings and trying
9:53
Speaker 2: to see using genetics as there are there particular genes,
9:58
Speaker 2: particular proteins related to a disease, in this case, the
10:02
Speaker 2: disorder of pain. And let me back up a bit.
10:05
Speaker 2: If you think about the history of modern drug development,
10:09
Speaker 2: why look around the world for families with rare inherited diseases.
10:14
Speaker 2: The answer is that rare diseases, inherited diseases often teach
10:19
Speaker 2: us important lessons about more common disorders. And a good
10:23
Speaker 2: example is the statin drugs. The statin drugs which have
10:27
Speaker 2: revolutionized cardiovascular medicals.
10:29
Speaker 1: I'm a fan, I take one every day.
10:32
Speaker 2: Many of us do, and they were developed on the
10:36
Speaker 2: basis of the discovery and then study of incredibly rare
10:40
Speaker 2: families where everybody who was having heart attacks in their twenties. Huh,
10:44
Speaker 2: those families had inherited hypercholesterolemia. Their genes pointed the way
10:49
Speaker 2: at the relevant molecules and informed of drug development.
10:54
Speaker 1: So it's basically like, if there's some family of people
10:56
Speaker 1: that has a strange version of a common malady, let's
11:00
Speaker 1: look at their genes and maybe that'll point to a
11:02
Speaker 1: way to treat that malady in people without the mutation.
11:05
Speaker 1: That's the basic hypothesis.
11:07
Speaker 2: That's exactly right. You just did it.
11:09
Speaker 1: Yeah, so you want that, but for ion channels, that's
11:13
Speaker 1: what you're looking for as you're doing your lab work.
11:15
Speaker 1: You want this sort of genetic mutation that might show
11:19
Speaker 1: a clinical application.
11:20
Speaker 2: That's correct. So we launched a worldwide search for families
11:24
Speaker 2: with inherited neuropathic pain pain due to inappropriate firing of
11:29
Speaker 2: peripheral nerves. Neurologists see patients with neuropathic pain all the time,
11:33
Speaker 2: our clinics are filled, but we never see families.
11:37
Speaker 1: So it's typically not a genetic problem. Right, It's like
11:40
Speaker 1: you have diabetes or something. It's not you inherited it
11:43
Speaker 1: from your mother.
11:44
Speaker 2: That's correct. So we launched this search and what happened
11:48
Speaker 2: was interesting. In the beginning of two thousand and three,
11:52
Speaker 2: February or March, a colleague member of my team brought
11:56
Speaker 2: me the latest issue of the Journal of Human Genetics.
12:00
Speaker 2: There was an article out of Beijing, China on two
12:05
Speaker 2: families with men on fire syndrome inherited from lalgia, each
12:10
Speaker 2: with a mutation of navy one point seven. The man
12:15
Speaker 2: on fire syndrome inherited erythrommelalgia is a really interesting disease.
12:19
Speaker 2: Most physicians have never seen a case, never will, but
12:23
Speaker 2: if you see it, you remember it because it's so striking.
12:27
Speaker 2: These people feel that they're on fire. They describe searing, scalding,
12:32
Speaker 2: burning pain that's triggered by mild warmth, putting on shoes,
12:37
Speaker 2: wearing a sweater, going outside when it's seventy two degrees fahrenheit.
12:41
Speaker 2: The pain is so bad some patients ask for limbs
12:44
Speaker 2: to be surgically amputated, which does not help. But it's
12:49
Speaker 2: excruciating pain. So here was an article out of Beijing
12:53
Speaker 2: by a very good group of academic dermatologists and geneticists saying,
12:58
Speaker 2: we have two families with the man on fire syndrome,
13:01
Speaker 2: each with a mutation of Navy one point seven. And
13:04
Speaker 2: my initial response to my colleagues my research team was
13:08
Speaker 2: to say, think, gee, we've been scooped. This is not
13:11
Speaker 2: a good day. And I said to my colleagues, stay
13:14
Speaker 2: away from me.
13:16
Speaker 1: It's a good day for humanity, but not a good
13:18
Speaker 1: day for your lab because somebody beats you.
13:21
Speaker 2: Yeah, exactly. And my initial response was stay away from me.
13:26
Speaker 2: I'm going to be pretty grumbly.
13:27
Speaker 1: And just as a reminder any of you one point seven,
13:30
Speaker 1: that's the that's the ion channel that you had identified
13:33
Speaker 1: as associated with pain in the lab. And here's a
13:36
Speaker 1: kind of clinical validation of that, but coming not from
13:40
Speaker 1: you but from some other scientists.
13:42
Speaker 2: Yeah, from Beijing, China. But when I closed the door
13:46
Speaker 2: and read the paper over a cup of coffee, I
13:49
Speaker 2: realized they had not told the full story. They had
13:52
Speaker 2: told just the first chapter. And the reason is this.
13:56
Speaker 2: When you when a neuroscientist finds a or an ion channel,
14:01
Speaker 2: biologist finds a mutation of an ion channel, that's just
14:05
Speaker 2: the beginning of the story. Because the presence of the
14:08
Speaker 2: mutation doesn't necessarily establish that the mutation is causing disease.
14:14
Speaker 2: What you need to do and what's industry standard is
14:17
Speaker 2: you make the mutant channel, you put it in cells,
14:20
Speaker 2: and you find out does the mutation cause a change
14:23
Speaker 2: in activity of the mutant channel, and then hopefully you
14:27
Speaker 2: can then take the mutant channel, put it in cells
14:29
Speaker 2: where it normally is expressed, and ask does it change
14:32
Speaker 2: their behavior. They hadn't done any of this stuff.
14:35
Speaker 1: So essentially they had identified a correlation, but they had
14:38
Speaker 1: not demonstrated that causation.
14:41
Speaker 2: Right, yeah, and they hadn't done it. These were very,
14:44
Speaker 2: very fine academic dermatologists. We've subsequently become friends. One of
14:49
Speaker 2: them spent the sabbatical in my lab. But so what
14:52
Speaker 2: needed to be done was what I just said, to
14:54
Speaker 2: make the channel and study its physiology. And we had
14:58
Speaker 2: the channel in our freezer because we had done all
15:01
Speaker 2: the work on the normal channel. So what would have
15:03
Speaker 2: taken anyone else a year took us a few months.
15:06
Speaker 2: We made the mutant channel, we found that in the
15:10
Speaker 2: mutation causes the channel to be overactive, and at that
15:14
Speaker 2: point we published it and shortly thereafter got a call
15:18
Speaker 2: or an email from the Erythrum Lalgia Association. This is
15:23
Speaker 2: a small group of patients with erythrumlalgia.
15:26
Speaker 1: Which is man on fire syndrome.
15:28
Speaker 2: Yeah, and the large family is in Alabama, Okay, and
15:33
Speaker 2: I sent the team down to Alabamas. We spent a
15:37
Speaker 2: week examining these patients, getting detailed histories, and most importantly,
15:41
Speaker 2: getting blood for DNA analysis. The Erhythmologia Association gave us
15:46
Speaker 2: a gift to support our research, but much more important
15:49
Speaker 2: than the funding gift, the monetary gift was the gift
15:53
Speaker 2: of DNA and these precious histories for correlation with it.
15:58
Speaker 2: And it's been a very, very a warm relationship. It's
16:02
Speaker 2: taught me a lot about how patients really are, are
16:05
Speaker 2: more than patients their partners in our research.
16:09
Speaker 1: What did you learn from those patients in Alabama that
16:14
Speaker 1: you didn't know already?
16:17
Speaker 2: What we learned was now we had a pedigree of
16:21
Speaker 2: around sixty individuals in five generations. Half of them had
16:26
Speaker 2: the mutation. That's what you expect for a mutation of
16:28
Speaker 2: this sort. Every patient you had the mutation had the
16:32
Speaker 2: man on fire syndrome. None of the patients without the
16:35
Speaker 2: mutation had it. And now putting it together, this was
16:38
Speaker 2: rock solid. This is as good as it gets in
16:41
Speaker 2: terms of genetic validations.
16:44
Speaker 1: So this mutation that all of these people have effects
16:49
Speaker 1: the sodium channel in AV one point seven, right, one
16:53
Speaker 1: of the ones you had identified, and is it right
16:56
Speaker 1: that that inspires you or other researchers to think reasonably, Okay,
17:02
Speaker 1: let's try and make a drug that blocks that channel
17:05
Speaker 1: and see if it will treat pain or Jacob.
17:08
Speaker 2: This is really interesting and it speaks to sort of
17:12
Speaker 2: the sociology of science and the way science moves forward
17:17
Speaker 2: given the fact that it's very expensive. So we had
17:20
Speaker 2: mechanistic validation from studies in a dish for a strong
17:25
Speaker 2: strong role of both NAV one point seven and NAV
17:29
Speaker 2: one point eight in pain, and we argued that both
17:33
Speaker 2: were good targets. In some ways NAV one point eight
17:37
Speaker 2: could have been regarded as a stronger target, but what
17:39
Speaker 2: we had for NAV one point seven was this very
17:44
Speaker 2: very remarkable picture of genetic validation. And in addition to
17:48
Speaker 2: our patients with men on fire syndrome, there were other
17:52
Speaker 2: families found a few years later with loss of function
17:55
Speaker 2: of NAV one point seven. These families don't make NAV
17:58
Speaker 2: one point seven, and those people don't feel any pain,
18:02
Speaker 2: painless childbirth, painless tooth extractions, painless bone fractures.
18:07
Speaker 1: We basically, if you have two much action in NAV
18:10
Speaker 1: one point seven, you have a lot of pain, and
18:11
Speaker 1: if you have no action there, you have no pain.
18:15
Speaker 1: That's correct, very compelling set of evidence.
18:18
Speaker 2: It is compelling, and most of the biopharma industry followed
18:22
Speaker 2: that evidence and studied one point seven or tried to
18:26
Speaker 2: develop drugs that block NAV one point seven. It was
18:30
Speaker 2: harder to convince biopharma to study NAV one point eight.
18:35
Speaker 2: The physiological evidence was there, but the genetic validation wasn't.
18:43
Speaker 1: We'll be back in just a minute. Back in the aughts,
18:55
Speaker 1: Pfizer and other pharmaceutical companies started trying to develop drugs
18:59
Speaker 1: to treat pain by blocking NAV one point seven, that
19:03
Speaker 1: key channel that Stephen and other researchers had identified both
19:07
Speaker 1: in the lab and in pall with man on fire syndrome.
19:11
Speaker 1: The preliminary results were promising, but kind of shockingly, in
19:15
Speaker 1: larger trials, the drugs targeting NAV one point seven did
19:19
Speaker 1: not seem to be effective in treating pain. It's not
19:22
Speaker 1: entirely clear why the drugs didn't work, but this kind
19:26
Speaker 1: of thing in fact happens all the time. Drugs that
19:28
Speaker 1: seem perfectly designed just don't end up panning out in
19:31
Speaker 1: the real world. But remember NAV one point seven wasn't
19:36
Speaker 1: the only key channel involved in pain. There's also NAV
19:40
Speaker 1: one point eight, and one drug company decided to bet
19:43
Speaker 1: on one point eight.
19:45
Speaker 2: The company that's taken this across the goal line as
19:47
Speaker 2: a company called Vertex. I'm now advising them. They looked
19:52
Speaker 2: at one seven, and they looked at one eight. They
19:56
Speaker 2: had a number of failures, and they kept going. They
20:00
Speaker 2: invested an immense amount of money when we worked with Pfizer.
20:05
Speaker 2: My estimate is that they invested well over two hundred
20:08
Speaker 2: and fifty million dollars in their one seven blocker before
20:11
Speaker 2: abandoning it. Vertex has studied many compounds, they have very
20:17
Speaker 2: gifted scientists, and they made the decision to stay with it.
20:21
Speaker 2: They invested much more than that, and they stayed with
20:24
Speaker 2: it over over twenty plus years. So I don't know
20:29
Speaker 2: who the decision makers were, but they made the right decision.
20:33
Speaker 1: So they decided to work on compounds that blocked this
20:39
Speaker 1: channel one point eight, another one that you had identified.
20:44
Speaker 1: I know you weren't involved in all of it, but
20:46
Speaker 1: more or less, what is the story of developing that drug.
20:51
Speaker 2: So what this company did and others did is they
20:55
Speaker 2: had their target molecule. The question is can you identify
20:59
Speaker 2: a molecule potential drug that blocks it, and you can
21:03
Speaker 2: put those molecules into a cell. There are robots that
21:07
Speaker 2: will look as you screen hundreds of thousands of compounds,
21:11
Speaker 2: asking is there something that silences that molecular battery one
21:15
Speaker 2: seven or one.
21:16
Speaker 1: Eight and you wanted to silence that and nothing else, right,
21:20
Speaker 1: that's correct part of that and not have some weirdo
21:23
Speaker 1: side effect that's gonna make people sick.
21:25
Speaker 2: That's absolutely crucial. But with using these robotic technologies, it's
21:31
Speaker 2: possible to find one or two that work. And then
21:34
Speaker 2: you say to your chemists, Okay, this is our lead compound,
21:37
Speaker 2: make it better, make it orally available, give it the
21:41
Speaker 2: right absorption and excretion compounds properties, et cetera, et cetera.
21:46
Speaker 2: And so that's how it goes. And then you still
21:49
Speaker 2: have a lot of work because you need to demonstrate
21:51
Speaker 2: in a dish that the compound silence is the activity
21:55
Speaker 2: of pain signaling neurons. Then usually go to rodent models,
22:00
Speaker 2: sometimes non human primates, and then the human trials. It's
22:03
Speaker 2: a long, long process and they.
22:06
Speaker 1: Managed to get through this process, right. So there is
22:08
Speaker 1: this drug suzetragene. Yeah, it got FDA approval for at
22:15
Speaker 1: least some indications this year, correct.
22:18
Speaker 2: Yeah, I think there were a couple of milestones.
22:20
Speaker 1: Yeah.
22:21
Speaker 2: One was the demonstration even prior to FDA approval that
22:24
Speaker 2: it produced a statistically significant reduction in pain in humans.
22:30
Speaker 1: So let's talk about that moment. So, you know, it's
22:33
Speaker 1: this incredible long road and they have to find the
22:35
Speaker 1: compound in testing animals, and they do phase one and
22:37
Speaker 1: face two, and then finally there's the giant phase three trial. Right,
22:40
Speaker 1: so you're a phase three trial with hundreds of patients
22:43
Speaker 1: and then the results come out, Like when did you
22:46
Speaker 1: learn the results of this pivotal trial.
22:52
Speaker 2: I learned of the results of this pivotal trial when
22:56
Speaker 2: a medical journal, the New England Journal of Medicine, said, Steve,
23:00
Speaker 2: there's been this pivotal trial. You've done all the work
23:04
Speaker 2: on one eight identifying it as a target, and when
23:07
Speaker 2: we published the results of the trial, will you write
23:11
Speaker 2: an accompanying article. We have a series of articles on
23:15
Speaker 2: the science behind the clinical trial and they asked me
23:19
Speaker 2: to do that.
23:19
Speaker 1: You really didn't know until the New England Journal asked
23:23
Speaker 1: you to write an editorial.
23:25
Speaker 2: I didn't And what did you think when you saw
23:27
Speaker 2: the results?
23:29
Speaker 1: I thought, my.
23:30
Speaker 2: God, we're getting there. We're not there, but we're getting there.
23:34
Speaker 2: If this can be repeated, it's a very important step forward.
23:38
Speaker 1: Tell me about both pieces of that. That's like two things, like,
23:41
Speaker 1: we're getting there is something, but we're not there is
23:44
Speaker 1: also something, So what is the we're getting there piece?
23:47
Speaker 2: We're getting there was why I regard their study as
23:52
Speaker 2: a milestone. It was proof of concept that by targeting
23:56
Speaker 2: a peripheral sodium channel, which is a step toward non addictive,
24:02
Speaker 2: non opiate pain therapy, one can reduce pain in humans.
24:05
Speaker 2: That in itself is a real milestone.
24:08
Speaker 1: And just to be clear, what was the finding specifically
24:10
Speaker 1: of this trial, what was the outcome?
24:13
Speaker 2: These were two groups of patients with abdominoplasty that's tummy
24:18
Speaker 2: tuck surgery and bunyan ectomy, and the reduction in pain
24:23
Speaker 2: was statistically significant, about as large as was seen with opiates.
24:29
Speaker 1: It was vicd in right, it was some fairly standard
24:32
Speaker 1: h yep. So it's like this basically is like for
24:34
Speaker 1: these patients, this is about as good as vicotin, which
24:37
Speaker 1: is actually great because as we know, opioids are addictive
24:42
Speaker 1: and it's a huge problem. And so if you can
24:46
Speaker 1: reduce pain in a non addictive way, that seems like
24:49
Speaker 1: quite a happy finding.
24:50
Speaker 2: So that is a happy finding. It's a contribution to
24:53
Speaker 2: clinical medicine. But for me, as a researcher, it's also,
24:57
Speaker 2: as I said, proof of concept, and it raises the question, Okay,
25:01
Speaker 2: we have proof of concept. Now we build on it
25:03
Speaker 2: and build even better drugs. And that gets to the
25:06
Speaker 2: issue of that you asked, why still more work to do?
25:11
Speaker 2: And the point is that the drug was as good
25:14
Speaker 2: as vicodin. It reduced pain by two points on the
25:17
Speaker 2: ten point scale, but it did not totally abolish pain,
25:22
Speaker 2: and so why did it not work better? So we're
25:26
Speaker 2: working and I'm assuming that within the biopharma industry there
25:31
Speaker 2: is great effort to We're working on the question of
25:34
Speaker 2: can you do better? And if so, how would you
25:37
Speaker 2: do it? So the first question is when you see
25:40
Speaker 2: less than full pain relief, is it because the drug
25:44
Speaker 2: to in this particular drug is less than optimally designed
25:49
Speaker 2: in terms of its pharmacokinetics, pharmacodynamics, distribution through the body.
25:54
Speaker 2: And if so, then it should be possible to build
25:58
Speaker 2: a better drug, or is there a biological ceiling. This
26:03
Speaker 2: is the best you can do by targeting that particular
26:07
Speaker 2: molecule at a one point eight. So we're looking at
26:11
Speaker 2: that right now in the lab.
26:12
Speaker 1: Right now, is there a notion that there are other
26:15
Speaker 1: channels that might be complementary. If you target more than
26:19
Speaker 1: one channel at once, you might get improved outcomes. So
26:23
Speaker 1: anybody trying one point seven and one point eight, that's
26:26
Speaker 1: an obvious question, would you like a job?
26:30
Speaker 2: So we're going through the exercise of doing that in
26:35
Speaker 2: a dish in a very quantitative way. Let's block one
26:38
Speaker 2: point eight plus one point seven. We could do it
26:41
Speaker 2: with one point nine. There's a channel of interest. It's
26:45
Speaker 2: a break on the firing of these sales called kV seven.
26:48
Speaker 2: These are very, very challenging experiments, but we're doing it
26:52
Speaker 2: very systematically, and so in a year I hope we
26:55
Speaker 2: have an answer for that. My prediction is number one,
26:59
Speaker 2: there will be next generation drugs that are more effective.
27:04
Speaker 2: But my caveat to it is they may involve a
27:07
Speaker 2: combinatorial approach, blocking several channels or modulating several channels, and
27:13
Speaker 2: we have a lot of work to do to get there.
27:15
Speaker 1: If you think about that future, whenever it is five
27:18
Speaker 1: years from now, ten years from now, twenty years from now, like,
27:22
Speaker 1: what's that world look like?
27:26
Speaker 2: What's that world look like?
27:28
Speaker 1: You know?
27:30
Speaker 2: Weekly daily, I receive letters more frequently emails from patients,
27:37
Speaker 2: or more frequently from their loved ones, particularly parents, concerned doctors.
27:42
Speaker 2: I have a patient with whatever, and their pain is untreatable.
27:48
Speaker 2: There's just nothing for them. And I envisioned a world
27:53
Speaker 2: where we can treat these people. It's an important goal.
27:57
Speaker 2: It's hard to quantitate it. I certainly can't put a
28:00
Speaker 2: timescale on it, but there's an immense need and I'm encouraged.
28:05
Speaker 2: I tend to use my words very conservatively and cautiously.
28:10
Speaker 2: And there's one particular teenager whose father periodically emails me,
28:15
Speaker 2: is there anything for my daughter? I used to tell
28:18
Speaker 2: him that I hoped we would have a non addictive
28:22
Speaker 2: treatment for chronic pain for people like his daughter. I
28:26
Speaker 2: now can write back confidently and say I can't say
28:29
Speaker 2: how long it's going to take, but there will be.
28:32
Speaker 2: And so that's the way I look at things. And
28:35
Speaker 2: we've come a long way.
28:40
Speaker 1: We'll be back in a minute with the lightning round. Okay,
28:54
Speaker 1: now we're going to finish with the lightning ground it's
28:56
Speaker 1: going to be a little bit more random, but still
28:59
Speaker 1: more or less on point. Is it possible to learn
29:02
Speaker 1: to be more resilient to pain? Oh?
29:04
Speaker 2: Absolutely, Look we send marines to Tampa June to toughen
29:10
Speaker 2: them up, and they learn to be resilient to pain.
29:13
Speaker 2: There are various types of monks who manage their pain beautifully.
29:18
Speaker 2: Cognitive and behavioral therapy work. So there's no question that
29:23
Speaker 2: there are psychological aspects to pain, and that provides an
29:27
Speaker 2: important lever on pain. Having said that, here we are
29:31
Speaker 2: in the year twenty twenty five. Those techniques have been
29:35
Speaker 2: refined again and again, and we still have just a
29:39
Speaker 2: highway of patients who have unrelieved pain, and so we
29:44
Speaker 2: need pharmacological approaches.
29:46
Speaker 1: Is there something I can do to be less angry
29:49
Speaker 1: when I bang my head or stub my toe. It's remarkable.
29:52
Speaker 1: I'm not generally an angry person, but I get so
29:54
Speaker 1: angry for a moment when that happens. You know.
29:59
Speaker 2: I follow a family with a man on fire syndrome,
30:03
Speaker 2: and there are two children who have severe pain. They've
30:06
Speaker 2: had a hard time dealing with it. But their mother
30:10
Speaker 2: wrote to me some months ago and she said, one
30:13
Speaker 2: of the children is having a very hard time because
30:15
Speaker 2: he fights the pain, and her other child, through therapy,
30:20
Speaker 2: has learned to quote, go with it, and there's a
30:23
Speaker 2: lesson there go with it.
30:25
Speaker 1: When I'm taking away from that is go with it.
30:28
Speaker 2: Well, that's the word the mother used.
30:31
Speaker 1: What is something about pain that is currently poorly understood
30:37
Speaker 1: or entirely mysterious that you wish were better understood.
30:41
Speaker 2: Well, one major problem is how pain becomes chronic. So
30:47
Speaker 2: if you stub your toe or burn your finger, there
30:51
Speaker 2: is hyperactivity of those sensory neurons that is appropriate and protective.
30:56
Speaker 2: You withdraw your your finger.
30:58
Speaker 1: That's good pain, that's the pain we need.
31:00
Speaker 2: That's good pain. But if you have diabetic neuropathy and
31:04
Speaker 2: develop a painful neuropathy or chemotherapy and doce neuropathy, or
31:09
Speaker 2: if you have a nerve injury, those same nerve cells
31:13
Speaker 2: generate barrages of impulses in the absence of a painful stimulus,
31:20
Speaker 2: and the details of what drives cells to become chronically
31:25
Speaker 2: hyperactive are still unknown, So that's something we need to understand.
31:32
Speaker 2: We need to understand when that happens. Are their changes
31:35
Speaker 2: also in the spinal cord, lower brain, and higher brain.
31:38
Speaker 2: All these things are understudy, but they are important mysteries
31:42
Speaker 2: and they will be solved.
31:51
Speaker 1: Stephen Waxman is a professor of neurology, neuroscience, and pharmacology
31:56
Speaker 1: at Yale. Please email us at problem at pushkin dot fm.
32:01
Speaker 1: We are always looking for new guests for the show.
32:05
Speaker 1: Today's show was produced by Trinamnino and Gabriel Hunter Chang.
32:09
Speaker 1: It was edited by Alexander Garriton and engineered by Sarah Bruger.
32:13
Speaker 1: I'm Jacob Goldstein and we'll be back next week with
32:15
Speaker 1: another episode of What's Your prob