Episode 34: Pain Management Science & Biotech Innovation with Key Opinion Leader James Zadina

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I'm James Zanewicz, the Chief Business Officer for the Tulane School of Medicine.

And I'm Dr. Elaine Hamm, the Executive in Residence for the Tulane School of Medicine.

And this is Bio from the Bayou.

Welcome back to Bio from the Bayou. I'm your host, Dr. Elaine Hamm, and I'm the executive in residence at Tulane School of Medicine. And today's guest is Dr. James Adena. He is a professor of medicine, pharmacology, and neuroscience at Tulane School of Medicine and the director of neuroscience laboratory at the VA. His research focuses on the neurobiology of certain peptides and their role in alleviating pain. So welcome to the show, Jim.

Thank you. Great to be here.

Well, wonderful. So, I mean, we have all heard about the many court cases that have impacted the pain management industry. Everything from traditional news media to television shows have, have really highlighted a lot of the opioid crisis. So before we dive into your specific scientific advances, could you talk a little bit about opioid dependence In general, and just sort of the problems that opioids can cause?

Sure. We have an opioid dilemma. More people suffer from chronic pain than cancer, diabetes, and heart disease combined. It's a huge problem. And opioids are the most effective painkillers, the gold standard, because their receptors are in all the right places to kill pain, and they act by several mechanisms to do that. But of course, they also have the well-known side effects like respiratory depression, tolerance, and rewarding effects, which can lead to addiction. So attempts to solve the pain problem have contributed to an epidemic, and more than 200 people will die in the US from opioid overdose just today alone. We definitely need better non-addictive pain medications.

I know this might seem like an obvious question. When people are addicted to opioid painkillers and die, what is it that causes their death? Is it that respiratory Depression that you mentioned, what are the—

Yes, that is what—

Let's dig into that.

That is the main cause of it is the respiratory depression, yes.

Okay. That makes sense. So now I'd like to talk about what you are doing in efforts to really rethink sort of how we think about pain management and dive into the novel peptide that you are working on, which we call Tuleva. What is it and exactly how does it work and how does it differ from what we've done previous in the pain management industry?

Right. We think that the opioid overdose epidemic is partly because of currently available opioids. Almost all of them are variations on actually World War I opioids like oxycodone.

Wow.

Drugs that are derived from or modifications of ingredients in opium from poppies. And we took a very different approach, starting with a peptide, which is a string of amino acids that we found in the brain that can produce analgesia. We modified that compound to make a stable drug. It acts at the mu-opiate receptor. That's the one named for morphine that produces most of the familiar effects of morphine. And we found that it is a very effective analgesic in animal models. And yet it showed absence of several side effects, including respiratory depression, tolerance, and rewarding effects. We think this is a good example of a new way of thinking about the mu-opioid receptor. Because we and others are finding that not all drugs that act at that receptor produce the same effects.

That seems like a big shift in the industry, 'cause it seems like we sort of have our opinion about the opioid receptor. So that seems like a, a different way of thinking about it, which is interesting. Are there challenges that you've seen in the industry to like push away from the opioid receptor because of that? Based on what your research is saying, it sounds like there just is a different way to attack it. Does that make sense?

Yes. There is a lot of resistance because of, again, And again, the reason we think this is a new way of thinking is because the old way of thinking is that if an agonist acts at that receptor, it's pretty much going to do the same thing in the cell and the rest of the body that morphine or anything else does. And we're finding that's not true. It's much more complicated than that. And that's good because maybe we can capitalize on that difference.

Yeah, that's great. Different way of looking at it. Well, so how is Taliva different from sort of the common pain management drugs like we think of, of morphine or oxycodone for treating chronic pain?

We've shown effectiveness of TULIVA in several animal models of pain, including acute, postoperative, visceral, inflammatory, and neuropathic pain. One of the most interesting tests we did was with inflammatory pain, where we found out that several days of treatment with morphine, while providing short-term relief, paradoxically prolonged the duration of the pain. TULIVA, by contrast, actually shortened the time to recovery from that pain. And we use this model to show also that morphine activates glial cells, which can increase pain because of the chemicals they produce. And TULIVA does not do that. So we think that glial activation appears to reflect a critical mechanistic difference between our compound and other opioids.

Is that when people are talking about rebound pain, they're talking about that effect of activated glial cells? Is that what rebound pain is, or is that different?

That's a little different. The glial activation is kind of more ongoing, so it builds up over time. Yeah.

So as we discussed before, the opioid dependence and abuse is a real issue for sufferers of chronic pain. They're having to sort of choose between pain management and living their life. And there's this concern, though, of the currently available drugs have such a negative impact. And so while TULIVA is technically an opioid, as we had talked about, it also doesn't generate those side effects. So how have you alleviated those concerns with the development of TULIVA?

Most important, there are 2 well-accepted animals— animal models of abuse liability. One where an animal will increase time spent in a chamber where he received drug. And then there's another model where the animal can press a bar to get the drug. And morphine and oxycodone increase responding in these tests, while Taliva does not cause that effect. These tests correlate very well with human responses, and they indicate low or absent abuse liability for Taliva.

So one common method to treat the disorders is a substitution with something that's a little less addictive, like methadone. But, you know, methadone also has a potential for abuse. So do you think that your drug could help in sort of the treatment of addiction?

Yes. As I just mentioned, we showed that Tuleva is not self-administered. This is also true in animals that were previously self-administering oxycodone. Tuleva doesn't sustain the responses. So an oxy addict, if you will, is unlikely to substitute Taliva for the oxy. The compound also inhibited oxycodone-seeking behavior. So if you withdraw the animal from oxycodone, it actually inhibits his trying to recover the responses. So these and other results that we worked out indicate promise as a treatment for addiction.

That's really interesting. So you'd have the ability for a patient that's on chronic pain management using oxycodone to treat their chronic pain. But have developed a physical dependence on them, but yet they're still suffering from chronic pain. In theory, they could begin taking to wean themselves off of oxycodone and still have that pain relief that they get from Taliva in that, in that situation. Is that true?

Theoretically, that's true. And that's what we hope to be the case. Yes.

That's fantastic. Yeah. Well, you're working on a couple of different generations of these peptides in tandem. You, you know, Taliva, what we're calling Taliva, is your second generation. But what are some of the improvements that you're seeing in your third generation of compounds?

For our 3rd generation, we're testing addition of sugars, which is technically glycosylation. We add that to the molecule with the idea that it could increase penetration into the brain. So far, this has worked pretty well because we do have improved analgesia. A lower dose can give longer pain relief. And our preliminary studies indicate also that it has low abuse liability using those animal models I just described.

So that leads me to my next question. So what stage is your research at? And, you know, when are you thinking about the clinical trial stage of things?

With Taliva, we have extensive preclinical data to support IND-enabling studies so that clinical trials can be planned and started.

So in addition to the efficacy data that you've mentioned with your animal models, you've also done an extensive amount of safety and pharmacology work as well, right?

We've done some, yes. We would like to do more, and we'd like partners to join in doing that.

Well, it sounds like you're open to partnerships or collaborations.

Yes.

Wonderful. And you've had those before in the past?

Yes.

Perfect. Well, if you have any other projects going on in the lab that we can chat about, and will you be at any conferences coming up?

We have a couple of other projects that probably not best to get into for time right now.

We'll save that for another podcast.

Yes, we'll do another podcast down the road. I will be presenting some of our results at the International Narcotics Research Conference, the INRC. That's in Ann Arbor. This is sort of the premier opioid researcher meeting in the world. And you always learn a lot there, and it's always good to present there to get the word around.

Well, and that'll be in July in Ann Arbor. So if you're looking to connect with Jim, he'll be there at that conference. Well, thank you so much for sharing your expertise with us, Jim, and, and thank you for, for taking on such a complicated but really important need in treating chronic pain, which is to find something that can be safe, efficacious, and non-addictive. Thank you for your time.

Thank you. Thank you for having me.

As always, we'll have Dr. Zanewicz's contact information and informational links posted in our show notes. Make sure you check them out to learn more. And thank you once again for joining us for Bio from the Bayou. Thanks for joining us for Bio from the Bayou, and we hope you'll join us again.

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