Long-Acting Injectable Formulations Targeting Opioid Overdose With Elysium's Tom Jenkins

Not only do opioid overdose sufferers need urgent, rescue treatments but they often remain vulnerable to symptom rebound and continued opioid use disorder (OUD). In this episode of Sit and Deliver, Tom Jenkins, Chief Scientific Officer of biopharmaceutical company Elysium Therapeutics, talks with videocast host Tom von Gunden about mitigating recurrence by using long-acting, intramuscular injectables (LAIs) to deliver the rescue drug naloxone in a rapid onset, slow-off formulation. 

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series. Today I am joined by Chief Scientific Officer Tom Jenkins from Elysium Therapeutics, which is a biopharmaceutical company working on preventative and rescue therapies targeting opioid overdose.

Welcome, Tom.

Tom Jenkins, Chief Scientific Officer, Elysium Therapeutics:

Thank you for the opportunity to share our progress on our exciting programs at Elysium Therapeutics. It's much appreciated.

Well, it's my pleasure. Thanks for joining.

So, let's go ahead — and, just before we dive in, I want to remind our audience that there is an episode of Sit and Deliver that I did a while back with CEO Greg Sturmer, also from Elysium. And, in that episode, we talked about formulations targeting overdose from oral prescription opioids and preventative medicines there.

So today, we're going to shift and talk about rescue agents targeting overdose of synthetic opioids such as fentanyl. And so, my first question for you, Tom, is: Tell us a little bit about that landscape out there of folks who suffer from overdose scenarios. What typically happens? What is typically administered? And to what effect?

Sure. Just a quick biochemical background that's important to understand is that opioids like heroin and fentanyl and common prescription opioids are actually classified as opioid agonists. So, they actually bind to the human opioid receptors in the brain. Most of their activities are exerted centrally. And the way that we reverse those effects, especially when someone is suffering from a frank overdose that has basically stopped breathing, is the intervention with an opioid antagonist. And the most commonly understood example of that is the intranasal Narcan, which is widely available and is actually helping. And what the opioid antagonist does is, it basically blocks the receptor from the agonist and the subsequent signaling that the agonist induces at the receptor. So, it's a way to displace quickly an opioid agonist and mitigate or stop the effects almost immediately upon administration. So, that's really the common tool that we have.

There are other things that people are working on that are early stage and maybe not as relevant to overdoses in the field with highly potent opioids like fentanyl. And these would include things like vaccines. You've probably heard of the fentanyl vaccine. And there are also what are termed agnostic respiratory stimulants, which actually work by a different mechanism to stimulate breathing in someone who is suffering from opioid-induced respiratory depression.

So, what commonly happens is, someone gets into trouble. A loved one or a first responder arrives on scene and administers Narcan. This is usually an effective way to restore breathing — spontaneous respiration, if you will. That person is then subsequently transported to get medical care at usually an emergency room and then discharged after being monitored and stabilized. In some cases, however, in  states like New Jersey and some places in the Northeast, people can refuse transport to the hospital. So, they're revived in the field with Narcan, and they're basically left there with maybe one or two doses of Narcan.

Even if it [an overdose] is mitigated and the patient revives in the moment, I understand that there's a possibility that the symptoms can actually recur, or what sometimes is referred to as fentanyl rebound. So, can you tell us a little bit about what allows that to happen and why that is of continuing concern?

Yes, absolutely. So, the fentanyl rebound also medically is referred to as renarcotizaton. This is what happens when you've ingested a potentially lethal dose of fentanyl. And, following oral ingestion, the absorption of the fentanyl into the system occurs over a fairly long period of time. And this is basically slow onset. So, for a period of up to six hours, you could have increasing plasma concentrations of fentanyl. The problem is that drugs like Narcan and most of the opioid antagonists we have available today are relatively short-acting. They were designed originally for intravenous heroin overdose, where the drug has a fast-on, fast-off profile. So, the fast-on, fast-off profile of Narcan really complemented that.

But the cartels aren't stupid, and they understand that they can attract more customers by offering an oral version of fentanyl because there's a lot more people who are willing to take pills than are willing to inject or inhale opioids.

So, this actual mismatch between the pharmacokinetics of Narcan and the pharmacokinetics of ingested oral fentanyl overdose is what allows for this renarcotization to occur. In other words, the Narcan wears off, and there's still enough fentanyl in the system to reassert respiratory depression. And that's bad.

Another point that's often overlooked is, intranasal Narcan, while it's perceived to have a very rapid onset, can sometimes take several doses or up to 5 minutes or 10 minutes to basically restore respiration. So, intramuscular-injected Narcan is much more effective. And usually, a single dose can reverse respiratory depression quite effectively.

So, there are problems both with the onset and the offset. But people have realized for a while that drugs like Narcan are too short-acting. And what they've decided to do, which is kind of like the low-hanging fruit strategy, is just make higher dose strengths. So, you could have it last marginally longer.

But the problem with doing that is, when you add higher dose strengths, you have a much higher maximum concentration in the plasma. And this precipitates rapid and severe withdrawal symptoms. And this is basically due to the fact that you go from 100% occupancy of your central opioid receptors with an agonist like fentanyl, and you quickly switch that out to have a 100% receptor occupancy with an antagonist. And that person basically gets slammed into a very severe withdrawal state.

And you don't really need to do that. What we're finding out — and there have been some studies that have been conducted recently — is you really only need to occupy about 40% of the central opioid receptors to restore spontaneous respiration. So, there is an opportunity to have a drug with a much more targeted PK profile that can actually, quickly reverse an overdose, restore spontaneous breathing while mitigating that risk of severe withdrawal.

And the final point I think is worth mentioning: A lot of these people that overdose are people who have a very severe opioid use disorder, and they've been using opioids chronically for quite some time. And an overdose to some of these folks is an inconvenience. And what they'll do is they'll be rescued with Narcan and then wait for the Narcan to wear off and then just keep reusing and same day reuse is kind of an issue.

Tell us a bit about in terms of both addressing the overdose scenario in its moment and also trying to mitigate against the return or recurrence of symptoms. And tell us about the formulation, the route of administration, the mechanism of action — help us understand what you're working on and how it should work when it works.

Sure. We actually saw an opportunity to deal with these issues with actually a fairly well-precedented technology. It's been out there for quite some time. And this is a technology that's called LAI technology, which stands for long-acting injection. And this was originally developed for, mostly for, psych drugs,  where the patient had some sort of derangement where they couldn't really adhere to a dosing regimen, but they needed a constant exposure of a therapeutic to help manage their symptoms.

And what they would do is, they would take a drug and they would make a prodrug out of it by making a fatty ester. So, they would attach a fatty acid molecule to the drug, and basically that would make the drug fairly greasy or, as we say as chemists, lipophilic. This drug then would be formulated in an oleaginous vehicle or an oil, like soybean oil or peanut oil, and then injected subq [subcutaneously] or intramuscularly. And that would form a depot and, inside that depot, that fatty ester drug would sit and slowly diffuse out. And the moment it would diffuse out of the oil depot and be exposed to certain tissues or plasma enzymes, the drug itself would hydrolyze and release the parent molecule.

So, you'd have almost like an infusion of a drug from a single injection. And some of these drugs, if you make a really fatty ester, highly lipophilic, you can actually have a once-a-month dosing.

But what was novel about what we did is: Inherent in that strategy is a slow-on, slow-off profile. And we can't have that, right? We can't have a rescue medication — someone's lying on the sidewalk, not breathing — we can't have slow onset. So, what we figured out — and the novelty which we were able to file IP on — is we figured out a way of making a combination of ester prodrugs so that we would have very rapid onset. In fact, we were surprised to see in our animal studies that the onset of naloxone from our formulation was actually, significantly faster than that of intramuscular naloxone, which I already discussed is actually faster than the current intranasal naloxone or Narcan.

So, we've been able to produce a drug that has immediate rapid onset, probably faster than anything that's out there, and the ability to tune the duration of action. So, we're currently shooting for about a 12 hour, maybe up to a day of protection. And also, the ability to target a plasma level so that we can add enough drug and have enough drug on board to restore spontaneous breathing while mitigating the withdrawal symptoms.

And the technology is actually amenable to other therapies for opioid use disorder. There's an option here for once or twice monthly injection. And similarly, opioid antagonists have been used for alcohol use disorder, and so we're thinking about extending the technology to that area as well.

So, Tom, as the work continues there, tell us about any of the additional challenges to be addressed or problems to be solved or questions to be answered as the work proceeds.

Sure. I think it's worth mentioning that we're just on the cusp of having our pre-IND meeting with the FDA. And this is actually for our SOOPR program, which stands for Synthetic Opioid Overdose Prevention and Rescue. So, if you look into Elysium, and you see the SOOPR program, that's currently what we're talking about. And it benefits from a prodrug approach. What it does is deliver naloxone, but it delivers it in a way that's [different from] any other opioid antagonist product out there.

So, we're taking advantage of the very well understood safety and efficacy of naloxone and using a very low risk, well-precedented, prodrug approach using this long-acting injection technology. The underlying components of what we're doing are all safe. Our metabolites from our prodrugs are actually endogenous compounds that are found already in the body. So, we feel we have a pretty low-risk approach from a safety and efficacy perspective by virtue of the prodrug and the safety of the intended metabolites.

We also are benefiting from a well-defined development path that's been established at the FDA through its recent approval of OPVEE®, which is a nalmefene-, not naloxone-, based opioid antagonist  intranasal formulation. That was approved in May of 2023. So, there's a very recent path that's been adjudicated for approval of a molecule in this space.

So, really, I guess to answer your question: Like everybody else right now in this space, financing is really our major barrier. And we feel we have a really excellent opportunity for potential investors or partners. I mean, one partner that would be perfect for us would be someone who already manufactures an autoinjector for emergency use because we're doing IM [intramuscular] delivery. And there are multiple potential partners for that.

How do you envision the scenario to be different for folks — whether it's the overdose sufferer, whether it's caregivers and providers, whether that's trained professionals, or family members or whomever might be around in the scenario — how will that look different?

Oh, that's a great question. So, what we envision is better rescues. And, just to remind you: With Narcan, it can take multiple doses to transport someone to the hospital because the drug wears off so quickly. We've talked to first responders where they've given four, six, up to 10 doses of Narcan just to get someone to the hospital. And this constant cycling of respiratory depression or renarcotization or fentanyl rebound carries with it a high risk for brain injury — hypoxic brain injury — where your brain is deprived of oxygen for a significant period. Cardiovascular toxicity. And also, these continued doses where you're spiking multiple Cmaxes and adding them on top of each other can cause severe and rapid withdrawal symptoms.

So, we think we could deal with all of these things. We think we can have almost like a one-and-done intervention where the drug has a very rapid and predictable onset. It produces a plasma concentration that's sufficient to restore and maintain spontaneous breathing without risk of withdrawal and also last long enough to prevent these cycles of renarcotization or fentanyl rebound so that the risk of brain injury and CB toxicity and other things are minimized.

What it also does is then, once someone is at the emergency room, they can engage in something called hallway monitoring, where the person has this long-acting antagonist on board. There's very low chance that they're going to renarcotize. So, they'll just monitor their O2 saturation and basically put them in the hallway and check in on them occasionally. So, it reduces the burden on the healthcare staff, reduces the monitoring, reduces the risk of same-day reuse.

And it also provides a window of time. Once someone has an overdose, their best chance at survival is, subsequent to that overdose where they have this sort of life-changing event, to go into treatment and get treatment with medical-assisted therapy with buprenorphine or part of a program — or ideally both — to treat their opioid use disorder. And this drug will provide a window of time that will establish that bridge to buprenorphine. And the buprenorphine can be used both to mitigate withdrawal symptoms and also to treat their opioid use disorder and get them help.

Great, great.

So, just one last question for you today, Tom, and that is: Are there any other patient needs or therapeutic targets that are potentially something you'll look out on the horizon and work to address?

Yes, there are. What we want to do with this program is sell a higher dose strength version for the military and first responders as protection against potentially weaponized fentanyl. Fentanyl is widely available. And we have drones now and other things, and it can be aerosolized and there could easily be a mass casualty event with fentanyl that's probably less expensive for whoever's doing it than a conventional nerve gas or other type of deployment. So, what we want to do is offer the military an injector they can carry that will provide 24 hours of protection against weaponized opioids.

We also think that we can make OUD [opioid use disorder] treatments using naltrexone, for example, which are cheaper and easier to administer than what's currently available for the treatment of OUDs. So, currently now, you get sort of a polymer bead implant that releases naltrexone for a month. We could do the same thing, but it could be patient-administered and much less expensive.

Tom, I want to thank you for joining me and updating us on the work there in the new program. Also, I want to thank our audience for joining us for another episode of Sit and Deliver. And we'll see you next time.