Dan Wagner (00:13):

Hi, and thank you for joining us. As you have no doubt seen on TV, in the news, and on social media, sadly, the opioid epidemic is not going away anytime soon. Here at Vital Spark, we're bringing together some of the brightest minds in opioid use disorder to share more innovative treatment options and a better path forward for both providers and the patients they serve.

(00:35):

I'm Dan Wagner, Chief Commercial Officer for Spark Biomedical, and your host for Vital Spark. Today I'm joined by two leading edge care providers and innovators in the neonatal space. They have joined forces to provide solutions for the most innocent victims of the opioid crisis. Let's get into our show to learn from our guests and how they're using bioelectric medicine to help infants overcome neonatal opioid withdrawal syndrome.

(01:03):

Well, welcome. My name is Dan Wagner. I'm the Chief Commercial Officer here at Spark Biomedical, and I'm just thrilled to be joined by two tremendous experts today, Dr. Jenkins and Dr. Badran. Thank you so much for being with us and talk about such an important topic.

(01:18):

To get us started and to tell our audience and those who are watching, I'd love to hear Dr. Jenkins please give us an introduction around your clinical and professional experience.

Dr. Jenkins (01:28):

I'm a clinical neonatologist who does research in translational therapies for babies with brain injury. We became interested in babies with neonatal opioid withdrawal years ago and started looking at their neuroinflammatory process in the brain and how we could help that. That's our background.

(01:48):

Dr. Badran and I have been collaborating on treating babies with neurostimulation with brain injury who are trying to learn oral motor skills. That's our collaboration. Bashar is just a great collaborator for that project and we've done some groundbreaking work there.

Dan Wagner (02:09):

Oh, that's awesome. Dr. Badran, great segue from Dr. Jenkins introduction. Can you tell us a little bit more about your professional experience and bringing together in that partnership?

Dr. Badran (02:20):

Yeah, of course. Thanks so much for having me. I'm a neuroscientist. I've been doing brain stimulation research or brain stimulation device development for about 12 years now. Currently, I serve as the director of the MUSC Neuro-X Lab and the director of the Computational Brain Imaging Core.

(02:39):

Essentially, what we do is develop new technologies and use neuroimaging to kind of help better understand how these technologies work. As I was developing some of this auricular neurostimulation work, really kind of the early trials in optimizing [inaudible 00:02:58] individuals, Dr. Jenkins approached me with this awesome idea of trying to use a regular neurostimulation to help babies who had difficulty feeding.

(03:10):

That's kind of how the collaboration was born about five years ago. Much credit to Dr. Jenkins, she was right. I mean, this technology has immense potential to help a lot of babies and impact a lifetime worth of development, and I'm happy to have been kind of on this journey with her. We're happy to be here.

Dan Wagner (03:30):

Awesome. Well, thank you so much. It's almost like you guys know what the script is because the next question I was going to ask you all is tell us a little bit about the problem that you're solving. Taking a little bit of a step back for our audience to kind of come on the journey with you, what is this problem specifically at MUSC that you're looking to solve with the patient population that you treat?

Dr. Jenkins (03:53):

Neonatal opioid withdrawal is a really common problem for us as neonatologists. Due to the opioid crisis, a lot of mothers during pregnancy are taking opioids either prescribed or in some cases not prescribed, and their babies are being exposed to morphine or some form of opioid during development.

(04:15):

This is bad for development, but it also causes an abrupt stopping of that opioid delivery after birth. Placenta is no longer delivering opioids to the baby, and they are used to having opioids. So they actually go through a withdrawal phase in many cases, which is significant and leads to really pretty adverse consequences for the baby.

(04:40):

We know this from brain imaging that these babies have this neuroinflammation, but clinically these babies are in distress and they are crying and irritable and they can't eat and their glucoses drop and just all kinds of things that prolong hospitalization and have to ultimately be treated with morphine and/or methadone. These therapies, we don't want to continue them, they're not good for the brain, but we don't have many alternatives.

Dan Wagner (05:10):

Speaking of those alternatives with morphine and methadone, what do we know about the effects to the kind of premature developing brain?

Dr. Jenkins (05:19):

We know that morphine or methadone or opioids in general cause neurons to die. That is unfortunately one of the consequences. We know that in the Petri dish, we know that in animal models, and we know that in babies. What we don't know is how we can fix that. The inflammation that goes on with opioid exposure is what leads to that cell death. We want to be able to decrease that inflammation and we want to be able to stop that cell death, and we certainly don't want to have to give opioids after birth, which may actually be aggravating everything.

Dan Wagner (05:59):

Oh, that makes great sense. Thank you so much. In defining the problem and looking at that, can you explain and expand, and Dr. Badran, maybe you can help us, what is the new solution that you're looking at now and what have you done as far as your first steps or first phase with that in the clinical trial?

Dr. Jenkins (06:19):

I mean, we want to decrease the oxidative stress in the brain, that's for sure. And we want to be able to get off morphine faster. Bashar was working on transcutaneous, so a non-invasive form of vagus nerve stimulation. He's going to expand more on this, but we know that vagus nerve stimulation decreases inflammation. It seems like a natural target, but there are other mechanisms that he'll go through that may actually help treat a baby with opioid withdrawal more effectively than just morphine alone.

Dan Wagner (06:50):

That's a great segue. So initially thinking anti-inflammation, but there are additional mechanisms of action. Dr. Badran?

Dr. Badran (06:57):

Yeah, I think that the jury is still out on exactly what the underlying mechanism is exactly, and I don't think that we'll ever definitively tell at least in the next couple years, but we're on track to kind of start better understanding reasonable high ranking hypotheses that may be the reason why we get such beneficial effects of auricular neurostimulation.

(07:20):

I think it's important to take a couple steps back and say, "Okay, well how does this stimulation work and what is it?" I think in the basic principle of this stimulation modality, what we're doing is placing adhesive electrodes, so they're kind of like stickers, on the ear. Those stickers have embedded circuitry in there to deliver electrical stimulation to nerves in the ear that activate the brain. The nerves in the ear really are twofold. One, there's the auricular branch of the vagus nerve and the trigeminal nerve.

(07:58):

And so there's kind of two ripe cranial nerves there that not only communicate directly to the brain but also have recursive projections out to the body. And so many of our early studies showed that stimulating the ear in these specific ways can not only activate parts of the brain that are mid-brain and cortex level brain structures, but also have these projections out to the body that cause a parasympathetic relaxation. So your classic rest and digest parasympathetic system is activated by stimulating these nerves in the ear.

(08:37):

There is a one, an efferent kind of hypothesis that suggests that this parasympathetic relaxation effect can help mitigate or counteract some of the withdrawal symptoms and help babies feel more comforted during the process, but there's also the central effects. One of the leading hypotheses outside of neuroinflammation and reduction of oxidative stress is this concept that perhaps this may be what I like to call an electro opioid.

(09:07):

If that is true, and the jury is still out, we may be activating parts of the brain that are involved in endogenous opioid release. And so if we can activate those parts of the brain, perhaps we can mitigate withdrawal symptoms by activating the release of endorphins, which makes people feel good, and also reduce withdrawal symptoms.

(09:30):

Those are kind of the overall hypotheses that we've been exploring. I can't say definitively exactly how this one works, especially in the newborn population. It's still a new study and we've only done a handful of babies to date, but it is really exciting technology that has multiple mechanisms that are probably all going on at a varying level of impact simultaneously. And so that's why there's this kind of robust behavioral effect that we're starting to see.

Dan Wagner (10:04):

That's awesome. Speaking on that and with the clinical work that you are doing, can you help to expand a little bit? I'm curious, as you've taken this technology into the baby population in the cohort, are the things that you've learned from the first phase of using this technology that you've applied into this second phase of your clinical work? What are the outcomes you're seeing, just anecdotally?

Dr. Jenkins (10:30):

We've treated eight babies in the phase one trial. These babies, some of them had been on opioids for quite some time. We looked at not only obviously safety to see if we had any adverse effects, which we did not see. Didn't see low heart rates, did not see a lot of skin irritation, really minimal effects acutely. We also looked at kind of how rapidly they would get off of morphine.

(10:59):

With this protocol, we're using a twice a day ween schedule, 15% of the control dose we call or the stable dose of morphine every 12 hours. That's 30% ween of morphine a day. Now, under standard protocols and without tAN, we frequently cannot get away with that. Standard protocol is 24 hours for a 15% ween, so it's twice as fast.

(11:27):

With this protocol, we were successful in getting all the babies off morphine. The mean time was seven days, and the median time after starting tan, of course, so they have been on morphine a bit before we started the auricular nerve stimulation, but after we started it, we got them off pretty fast. So six days for the median, seven days for the mean. Some babies took longer who'd been on longer, but it was really rapid compared to other published literature length of treatment numbers. So we were thrilled.

(12:03):

It doesn't mean that it's effective, because we haven't done the randomized trial yet. That's what we're doing now, but it's highly encouraging. We didn't see an increase in discomfort or pain with the method that we have for doing a sub threshold type of stimulation. We did do it four times a day. We didn't look at dosage effects. Four times a day is as much as we can do clinically now within a study format. Maybe eventually we'll do it eight times a day.

(12:35):

And we do it at the peak time when the baby is going to be withdrawing. So an hour before the morphine dose is scheduled, we start treatment for 30 minutes. That should capture the baby about the time that they're really getting hit with low morphine levels and they're starting to withdraw more.

(12:52):

That same protocol and that same approach, we're going to continue in this phase two trial, but Bashar may want to talk a little bit more about some of those aspects of the perceptual stimulation, et cetera.

Dr. Badran (13:06):

Of course. Again, I always go back before we go forward, and I think one of the reasons why we're all here doing this podcast is because of the early work that really Dr. Jenkins was pioneering in babies who had difficulty feeding. That is clearly the kind of first neurostimulation in the youngest population that I know of at least on the planet.

(13:33):

It's really easy to discuss what we've been doing now because we worked out a lot of these early details in the development and onset of that really cool technology that we developed. Actually, that's one of the reasons also why we're here because we met Dan Powell, Spark CEO, at a meeting where we're presenting this work. It is important to kind of reflect on the early work that we did that got us here.

(14:00):

What I like to say is that really we worked out a lot of the kinks that are kind of incorporated into this NOWS trial in our prior baby strong work. That involves everything from administering neurostimulation in the NICU, which was new, getting all the care team providers on the same page and on board with this neurostimulation, which in the beginning people were not super thrilled about. Putting in new technology onto newborns that's untested is scary for parents and for care team members. And so breaking down those walls and getting this technology into that space was really important.

(14:43):

And then figuring out a way to do this safely that doesn't involve any pain to the baby is also critical. What we worked on is kind of an opposite solution to what we normally do in adults, which is starting to deliver stimulation at a really low intensity and then working it up in small increments of current until we see what's called a perceptional threshold.

(15:11):

The perceptual threshold is when the baby has a visual motor reaction that's time synchronized to the delivery of stimulation. What does that mean? It really looks like kind of a shoulder shrug or a hand raise towards the ear where stimulation is being delivered. That's when we know that the baby can feel it.

(15:32):

Now, after we get that level, we actually turn down the stimulation .1 milliamps below that, which is essentially not painful or uncomfortable to the baby. We can't say if it's imperceptible, but what we can say is that there is no physical response that's time locked to stimulation that indicates that it's uncomfortable in any way.

(15:59):

Essentially, you can't really see what's going on, but the electrical stimulation is being delivered and that's kind of part of the process. In the NOWS trial that's ongoing and in the early work, we use a very straightforward 30-minute paradigm four times a day before morphine is administered. There is kind of a clockwork type schedule where we're delivering this stimulation throughout the course of a day over the treatment course. That's the overall intricacies of how we deliver it.

(16:31):

What's also really interesting is the wearable electrodes stay on for the whole day. I think that's one of the really cool things that happened between our phase one and our phase two now is the big leap in the technology that was made from the phase one device made by Spark to the phase two device, which had all of the improvements that we requested and needed after we learned what was needed in the phase one. That includes things like devices with screens and a better user interface and devices that were easier. I think at one point there was all these Bluetooth issues, and a lot of those got solved in the phase two.

(17:11):

And then ultimately creating ear electrodes are hard. The human ear is a tough place to create technology for. That's why big companies like Apple have millions in dollars of design budget to create these earbuds that fit really nicely that I could talk to you on. But without that kind of budget and doing it on small scales, not only are they expensive, it's really hard to figure out the human ergonomics.

(17:38):

And so from phase one to phase two now, there's these really beautiful electrodes that Spark's made. Alejandro and Navid have done an amazing job there. These electrodes can stick and stay on the ear for up to a day. So all you have to do is start plugging the electrode in and out of the device, which I think is a huge game changer for the kind of acceptance and adoption of the technology.

Dan Wagner (18:03):

Oh, that's awesome. I think just as you mentioned, the journey and understanding the process of how we got to this discussion today is really, really important. So I appreciate you taking us a step back to look at that.

(18:16):

Speaking of that same journey, Dr. Jenkins, you mentioned basically twice as fast a mean of seven days. What does that look like for you clinically in operating in the NICU? Where do you see that journey? I guess I'm asking what is the comparative scope to a typical NICU stay, and how does that change the operations for you as a clinician?

Dr. Jenkins (18:45):

A typical NICU stay for a NOWS baby who's on morphine or opioid replacement can be anywhere from 15 days to more than 30 days. Some of these have a terrible time getting off of opioids. That's not only very expensive for the hospital and perhaps for the parents depending on what kind of insurance or Medicaid they have or whatever, but it's also distressing for the baby.

(19:13):

We're constantly trying to have the baby do a controlled withdrawal. That's what you have to do to be able to get them off morphine. So this whole time will be pushing the baby from a brain standpoint to reduce opioid replacement. That really for the baby, decreases developmental time, decreases the time when they will actually go home and get better developmental stimulation than in the NICU.

(19:42):

It's just very concerning for families. These are vulnerable families in a lot of cases, and they're trying to establish a good family bond with the baby, and that makes it hard staying in the hospital that period of time. It's a multifactorial benefit to get them out sooner.

Dan Wagner (20:03):

Oh, that's tremendous. And thank you for that context. Dr. Badran, to you, as you think about that context and looking at that development time, how critical is that early stage neurological development for the baby and giving that time back?

Dr. Badran (20:20):

Yeah, I think that's a really good point and actually something that Dr. Jenkins got me behind because in the early days I was always saying... All my research has been in adults, whether they're healthy adults or adults with neuropsychiatric disorders, depression, anxiety, or even stroke. And moving into a baby population for me, my comments were, "This is going to be really hard. Why don't we do something a little easier?" Dr. Jenkins to her credit said, "If you impact babies now, they have a full life ahead of them. And so the impacts are even greater then."

(20:59):

I think that's what sold me is that when you intervene this early, you have a lifetime of development that you can save. And so that's really where the crux of these kind of treatments are going is that can we create technologies that can help create a more promising trajectory for these babies at the earliest stage, which then can lead to these amazing benefits down their life?

(21:28):

They're not going to remember the team that was delivering a auricular neurostimulation to them when they were that young, but it's clear that this will have an impact throughout their whole life and will be part of their life story.

Dr. Jenkins (21:43):

One of the particular things we're trying to impact is their behavioral outcomes. We know that these babies are at high risk when they get into pre-K and school for behavioral disorders, not just ADHD, but multiple other significant neuropsychiatric problems. And they're frequently a grade behind. If we can change this, then this study is not exactly designed to figure out the long-term consequences, but our hypothesis is if we improve the neuro inflammation early enough and decrease the length of time that they're getting morphine after birth, then that may be improved as well.

(22:24):

That would be a huge thing for these babies because ADHD makes it really hard to learn as anybody with ADHD can tell you, and it's not just those type of disorders. But if we can change that, that's really important for social functioning and for integration into an average classroom.

Dan Wagner (22:44):

No, absolutely. And giving each individual the best shot for their lives in that entire continuum is so important. What a valuable component. Speaking specifically on the ongoing study that you're executing right now, can you give us understanding around the size, scope, and parameters of what you're looking at?

Dr. Jenkins (23:07):

We're back to the primary outcome of trying to determine whether we can reduce the mean time or median time of staying in the hospital after you start tAN treatment. Remember, it's still an adjunct to morphine treatment. It is not a standalone treatment at this point. This trial is designed as a phase two trial with the randomization between just morphine alone and what we call sham stimulation or no stimulation and morphine with active stimulation.

(23:41):

It'll involve two sites. And we've already started enrolling in the other site. UT Southwestern is going to be enrolling we hope soon this fall. It's going to involve a total of 80 subjects. So that's very exciting. Will be probably enough to show that difference given our preliminary data from the eight babies. Now, you never know until you start if that eight babies is a representative sample, but the differences are significant enough that I think we will likely be able to show efficacy.

(24:14):

Of course, we're going to be looking at safety again. We always look at safety in clinical trial and babies, but I'm pretty excited that when we get through with this trial, we'll have an answer to does this basic treatment, which is both vagus and trigeminal nerve stimulation, improve the length of stay, i.e. decrease it for these babies?

Dan Wagner (24:39):

Now that's phenomenal. I think looking at a cohort of 80 subjects in that study, it's definitely a larger group and we'll hopefully see correlation and some data translate to the initial pilot study of eight babies that you took on initially. That's tremendous. Excellent.

(24:59):

Well, thinking about that study and the fact that you've gone through both the pilot, the phase one, and now moved into the phase two component, I'm curious for your staff and for the NICU you oversee, how's it you've seen integrating this technology within the workplace for your staff, the attendees, the other clinicians? How have you seen them interact with the technology and work with their patients using it?

Dr. Jenkins (25:26):

We've gotten really good acceptance, and part of that's from doing our due diligence. As Dr. Badran said, we met with everyone. We showed them how it worked, we did it on them so they would get some understanding of what it felt like. And we've had really good acceptance from staff as well as from care providers. They now look for babies to refer to us because they're excited about it.

Dan Wagner (25:52):

That's cool.

Dr. Jenkins (25:55):

Bedside nurses are the ones who have to suffer through this baby being in such distress. And sometimes parents are there a lot as well. It's distressing for us to see a baby in distress in withdrawal. And so anything we can do to improve that, that's not opioid, we're thrilled to do. We've gotten really good acceptance and we've had, I can say, no refusals for consent because parents see what their babies are going through and they don't like it and they want to help them.

Dan Wagner (26:25):

Oh, that's tremendous. That's absolutely tremendous. Thank you so much. Getting to the top of our podcast here, and so I'd like to go around as we close it and ask, what do you see in the future for these technologies and what are you hopeful for as we bring these things to market?

(26:45):

Dr. Badran, I'm really curious to hear your insights. As you mentioned, there are a number of open hypotheses as we look at these and other technologies, but what are you hopeful for as we bridge to the next generation of medical technologies?

Dr. Badran (27:01):

I see the future as being the next 20 years marked by the rise of the bioelectronic man. The bioelectronic man has all sorts of various technological assistance devices to interact with their environment and interact with their body. And so the rise of these wearable electronics that are safe, that are easy to self administer, whether they're administered by a care team provider in the NICU or at home in the home setting, these technologies are kind of growing in their advancement level and are really quite fascinating.

(27:42):

We're getting to the point where electronics can be screen printed, they're lightweight, the cost has come down, EPGs and various kind of circuitry that's involved in the administration of these stimulatory kind of interventions are features of other already existing devices. You can start to see a future where neurostimulation becomes part of a regular toolkit, very much similar to how Bluetooth wireless headphones have seen a rise or laptops or cell phones.

(28:15):

I see this technology as being another piece of technology in the medicine cabinet that you can access when you need. And so even though we are in the hospital now, and much of our work is either done in the laboratory or in the hospital setting, these technologies are now starting to show not only behavioral effects that are quite promising, but are showing that they're very safe and easy to use. And so there is no reason why they shouldn't see an expansion over the next 10 to 20 years in the home setting. In fact, many groups are already starting to do that.

(28:47):

That's what gets me really excited is the ability to start to have non-pharmacological interventions in the home setting. I think the technology that's being used in the Spark device is really on the forefront of that development. Really I haven't seen any electrodes like the ones that Spark has made, and I've seen a lot of electrodes in my career. Big steps in technology require big efforts. And I think Spark is really on the forefront of that. The future will be marked by these wearable technologies.

Dr. Jenkins (29:21):

I don't know, Dan or Bashar, if we are ready for a bioelectronic baby yet, but I do think-

Dan Wagner (29:27):

All right.

Dr. Jenkins (29:28):

... that we will be able to, at least for a short interval, improve outcomes for babies. We aren't going to measure a neurobehavioral scale in the NICU. We just don't know if that's going to translate later into more effective behavioral outcomes for the babies. But that's what I'm most excited about, is that.

(29:48):

But I also see perhaps we could start treating the mothers during pregnancy so that they can actually decrease their opioid consumption during pregnancy and help decrease these brain changes we know happen in these babies during pregnancy. That's preventative for the baby, and that would be really, really cool.

(30:09):

And then of course, we would love not to have to use opioids at all if the baby is withdrawing after birth and just use this type of stimulation instead of morphine. We're not doing that trial now, but that's where I hope we're going to go.

Dan Wagner (30:22):

Oh, well, that's a great recap, Dr. Jenkins, and thank you so much. Dr. Badran, I loved your points as well. I mean, bringing it full circle, it seems that we have these technologies which we know to be safe. And as you mentioned, now we're doing the studies to prove efficacy and look at the applications. And then as you aforementioned into the future, I think the components there are then now making them accessible into the daily lives of the patients that the devices, technologies, and ultimately the clinicians serve. So really exciting mission to be on together.

(30:59):

With that, I want to say thank you so much for your time today. Dr. Badran, Dr. Jenkins, thank you for joining us. Do you have any last words for our audience?

Dr. Jenkins (31:09):

No, I just hope that in a year or maybe two years we'll be able to have a different podcast where we say, "Hey, this works. It's great. Let's start using this."

Dr. Badran (31:21):

The only thing I want to add is that of all things, the most important aspect of creating new technology is having a strong team. I think the team here between Dr. Jenkins' leadership and the team we've assembled between our site and the collaboration with Spark and the collaboration with the University of Texas Southwestern is really at the core of what makes this technology amazing.

(31:44):

You can have infinite resources, and if you don't have a great team, you can't get anywhere. And so really, I want to take this time to give a big shout-out to Dr. Jenkins, who's really the pioneer in this space, and really someone who's been on a mission to change the way that babies start to receive new treatments. She's been doing it her whole career, and this is just a big step in the right direction. The team is really important, and thanks to Dr. Jenkins, otherwise this couldn't happen.

Dr. Jenkins (32:14):

Yeah, the team is really important and the collaboration is what makes it work. We're blessed to have, as Bashar said, have his expertise, have Spark's expertise, and everybody working towards improving these outcomes for babies.

Dan Wagner (32:29):

Oh, absolutely. The team is critical. Thank you both for being a part of that team, and thank you so much for taking the time out of your day to share the communication and message with, not just Spark, but with the entire world, because as we communicate these ideas and we share the information that we can make progress together as the larger team.

(32:50):

Thank you so much. Your time is very valuable and we're very grateful for you to share it with us and with the community. So thank you for what you do.

Dr. Jenkins (32:58):

Thank you.

Dan Wagner (32:59):

Have a great day.

Dr. Badran (33:01):

Thank you so much.