Fighting Cancer, Easing Pain... Dr. Lorin Johnson, CSO, Glycyx Therapeutics
On average, over half of cancer patients suffer with significant pain, and for that pain, they are primarily prescribed opioids. But now there is scientific evidence that opioids may in fact interfere with the very immunotherapy they are taking for their cancer. Today's interview is about one company's big idea now beginning clinical trials to enable both the immunotherapy and the opioids to be effective. Doctor. Lorin Johnson is the Chief Scientific Officer of Glycyx Therapeutics.
Dr. Moira Gunn:Doctor. Johnson, welcome to the program.
Dr. Lorin Johnson:Thank you, Moira.
Dr. Moira Gunn:Now I remember when immunotherapy for cancer came on the scene and it's been basically a decade now and there was so much hope for it. In reality, the response rate has been about fifteen to twenty percent. And if that works for you, that's fantastic, but that leaves a lot of people out. Now with all that tremendous hope in the beginning, we've all wondered, you know, why doesn't it work better? And then I see a paper from late last fall, last November, in a well respected peer reviewed British medical journal, the Journal for Immunotherapy in Cancer.
Dr. Moira Gunn:And doctor Johnson, your name was one of the some dozen scientists who together authored that paper. How does morphine that a cancer patient takes for pain work against the immunotherapy that same cancer patient is taking?
Dr. Lorin Johnson:-Well, that has been a puzzle, and as you know, a lot of cancer patients take opioids for pain, up to fifty percent, and in studies on checkpoint inhibitors now, immunotherapy, in over one thousand patients, Patients taking opioids have been shown to not respond as well and to actually die about twice as fast as patients not taking opioids. So we wanted to test this in an animal model, and that's what the paper's about.
Dr. Moira Gunn:So we knew it in humans already, and we went back to test it in I think it was mice. I think he went back and tested it in mice. It usually goes the other way. We see it in mice, let's test it in humans. But you said, We're seeing this in humans, let's see if we can reproduce it.
Dr. Lorin Johnson:-Yes, and this was very key. Our collaborators at UPMC had already published on head and neck cancer, and they had found that in their head and neck cancer patients on immunotherapy and opioids, the immune cells did not invade the tumor. So we thought maybe we could reproduce this in an animal model and see what the mechanism is.
Dr. Moira Gunn:And it did. It worked, or it didn't work, as the case may be.
Dr. Lorin Johnson:-We reproduced the clinical effect the animal model, yes.
Dr. Moira Gunn:Wouldn't it be terrific if we already had a pain pill among so many that we have that didn't interfere with the immunotherapy, or at least be close on a pain pill, and that's where Glycic comes in.
Dr. Lorin Johnson:Well, that's right. As you know, opioids work in the brain, but what a lot of people don't know is they work all over the body also. So they suppress pain in the brain, but they have multiple effects outside of the brain, on the immune system, on the GI system, and some of these are very deleterious. In fact, what we know is they suppress the immune system. So what Glysix has is a drug that antagonizes, that stops opioids from working outside of the brain.
Dr. Lorin Johnson:Our drug does not go into the brain, and it blocks opioid actions outside of the brain. And it turns out this is the way to block the opioid effect on the immune system.
Dr. Moira Gunn:Okay, so now, of course, this isn't easy or we would have done it yesterday or years ago. This has to be tested. But you said to me a while back that our bodies produce natural opioids, endorphins, that can interfere with immunotherapy, and that the tumors themselves can produce opioids. Wouldn't this have an adverse reaction anyway?
Dr. Lorin Johnson:-Yes. In fact, the tumors that produce opioids, and melanoma is one that's well known to do so, suppress the immune system from attacking them. And this is one of the reasons why they are able to thrive in the body.
Dr. Moira Gunn:-We know that we're taking the opioids to suppress the pain, but why do they suppress the immune system?
Dr. Lorin Johnson:-Well, Moira, the whole opioid system evolved as part of essentially a wound healing process. So back in evolution, our genes encoded what we know as endorphin. When we have a wound, we have a tiger bite in the Serengeti, we have to deal with that, and opioids help produce the growth of new blood vessels into the wound, the, new connective tissue, and it keeps the immune system from overreacting to the wound. So it's a mechanism of wound healing. And cancer cells Cancer has figured out that's just a way to bypass everything and stay under detection of the immune system.
Dr. Moira Gunn:So actually, natural opioids have a really sophisticated and very positive function. It's just that the synthetic ones we take for pain have really That is a bad turn here.
Dr. Lorin Johnson:Yes, yes. The natural opioids are produced every night in your body. It's a wave that comes through in the middle of the night, but they don't stay constant. They come, they go, they come, they go. But when we take medicinal opioids, they're active the whole time, and that just pushes the system into the complete immunosuppressive side.
Dr. Moira Gunn:We can block what the opioids you're taking are doing. Can it also block the naturally occurring opioids and the ones that the tumor is producing?
Dr. Lorin Johnson:In fact, we do. In fact, some of the first preclinical studies we performed were in animal models where there were no opioids given, no medicinal opioids given, and in fact, we showed that we could enhance the effect of immunotherapy even in the absence of medicinal opioids. We were blocking the natural opioids.
Dr. Moira Gunn:-Okay, so this is very good news. And I think some people out there are saying, Well, why don't you just tell these cancer patients not to take the pain pills?
Dr. Lorin Johnson:-Well, unfortunately, pain is a very specific kind of pain. It has input at the tumor site, it has input at the metastasis sites, bone metastasis are quite painful, and it's a combination of central pain, neuropathic pain, and there are no alternatives to opioid therapy for cancer pain, yet. Obviously that would be a great place for research. But until there's a way to do that, our best approach is to block the effects of opioids outside of the brain.
Dr. Moira Gunn:So the idea is take your immunotherapy, which is our standard of care, take your opioids for the pain that originates in the brain, and block it in the rest of the body. Correct. Got it. That's a tall order, but I understand that you've got well, you've got four different cancers that you're working on. You know, head and neck, lung cancer, melanoma, and you've got pancreatic cancer.
Dr. Moira Gunn:And in the the first three that I mentioned, you've got a phase two b. That's an advanced study that you're just about ready to get going on here. Tell us about that. Who are the cancer patients? What do they do?
Dr. Moira Gunn:How long will it last?
Dr. Lorin Johnson:So the combination therapy of our drug with immunotherapy will be looked at in head and neck cancer, lung cancer, as you said, and melanoma. The head and neck cancer study will take a couple of years to complete, lung and melanoma, probably three years. And again, that's with the combination therapy. The pancreatic cancer study that you referred to is actually in end stage patients, end stage cancer patients, including pancreatic cancer patients, that are taking opioids to survive to the end of their life. And we know that the side effects of opioids on the immune system and other actions in the body are contributing to their shortened survival.
Dr. Lorin Johnson:That study is gonna start in August. We're ready to go with that.
Dr. Moira Gunn:What we're talking about there is getting that up and running. How long will that study take?
Dr. Lorin Johnson:That study will dose patients for about a year. It'll probably take about eighteen months to fully recruit.
Dr. Moira Gunn:So that's what they do there. Now, let me ask you about the other ones. How different in terms of pain are people with head and neck cancer, lung cancer, and melanoma?
Dr. Lorin Johnson:Well, that's a really enlightening question, because head and neck is very painful. You can imagine patients with cancers in their mouth or their throat, where they can't swallow, they can't eat. And so up to seventy percent and greater of head and neck cancer patients take opioids, exogenous opioids for pain, medicinal opioids. Lung cancer is about fifty percent, so it's in the middle. And melanoma is lower, maybe twenty to thirty percent, but melanoma patients in those cancers, those are the ones that are producing high amounts of endorphin themselves.
Dr. Lorin Johnson:So that's why melanoma is still a really strong target for us.
Dr. Moira Gunn:Well, this is really interesting in the melanoma case because their melanoma is producing these natural opioids, it's not as painful. And it's like, Wait a minute, we really need to get to you. We really need to do this.
Dr. Lorin Johnson:That's correct. Most of melanoma pain comes when there are metastases. So they've gone to other tissues. Melanoma does this because the gene in the human body that makes melanocytes stimulating hormone is in a big complex gene that also includes beta endorphin, so it's all in one big gene product, and melanoma cells are driven by melanocyte stimulating hormone, that's their normal feel good hormone, and it happens to end up producing endorphin at the same time and suppressing the immune system. So it's evolved for melanoma as a way to thrive and get around the immune system.
Dr. Lorin Johnson:It's quite remarkable, actually.
Dr. Moira Gunn:I know you guys wanna start all of these trials tomorrow afternoon, if not tomorrow morning. You know? It's like, I really wanna get on this. And there are all of these, you know, reasons to to go go deliberately here. And so there's a there's a lot to be it's going to get pushed by by what's available and resources available and people available.
Dr. Moira Gunn:But there's a real commonality besides the treatment that you have, the once daily pill that you have. And that is that you've gotta figure out what are you gonna measure with these patients when they're taking this drug? What are you going to measure? -:
Dr. Lorin Johnson:We have to abide by what FDA uses for approval of cancer drugs, and those endpoints are progression of the tumor. So does the tumor grow? Does it stay the same or does it shrink? And then ultimately, survival. And this is why cancer studies take a long time, because just getting a tumor to stop growing doesn't mean that it ultimately saves the patient's life.
Dr. Lorin Johnson:So the first phase of all of these studies is always to ask, what did we do to the tumor? Did we cause it to stop growing? That's great. That shows that our response rate has gone up. But ultimately, we keep the patients on the drug all the way out the end of their life, and that's where we get final approval.
Dr. Lorin Johnson:We also look at quality of life in these patients. There are other opioid side effects that are very troublesome for these patients, including commonly known, like constipation. We know this drug alleviates those issues. We know we will produce a benefit for quality of life, but unfortunately, cancer drugs aren't approved just for quality of life measures. We hopefully will see a survival benefit.
Dr. Lorin Johnson:Earlier, I talked about tumor progression, but I should also say that part of what will get measured are the appearance of new metastases, And from our previous animal studies, we know we have an effect on the ability of cancers to metastasize, and that is also driven by opioids. We mentioned previously that opioids cause the growth of new blood vessels, and tumor cells use this aspect to metastasize and grow new tumors at new sites. So we expect that as part of the suppression of the immune system and the slowing of tumor progression, we should also be able to see an effect on tumor metastasis.
Dr. Moira Gunn:Well, I have to say, this is very unusual to have four clinical trials all ready to go. Usually, it's like, well, we we'll go to another indication and get the go ahead to start studying that. You're all ready to go. You pick pancreatic cancer first, and that's gonna start in August. So good luck to you.
Dr. Moira Gunn:This is very exciting to not only to see this be a real possibility of hope for the immunotherapy drugs, but also that we're not asking people to be in pain.
Dr. Lorin Johnson:That's correct. So ultimately, it is all about quality of life. They can take the opioid, they can have their pain reduced, and they can live longer.
Dr. Moira Gunn:Well, thank you, Doctor. Johnson. Please come back, keep us updated.
Dr. Lorin Johnson:I will, and Moira, thank you for bringing science to everybody.
Dr. Moira Gunn:Doctor. Lorin Johnson is the Chief Scientific Officer of Glycyx Therapeutics. More information is available at glycyx.com. That's glycyx, glycyx Com.
