DaxibotulinumtoxinA for cervical dystonia

Prof. Luxman Bahru: Thank you for having us. 

Dr. Todd Gross: Yes, thank you for having us. 

Dr. Sara Schaefer: So to start just a little bit of background here. Your study looked at a relatively new botulinum toxin, DaxibotulinumtoxinA or DAXI or [00:01:00] Daxxify for short for the treatment of cervical dystonia. We do have four other botulinum toxins that are used in regular clinical practice for the treatment of movement disorders, including Botox, Xeomin, BioBlock, and Dysport.

Can you explain first the unmet need for the treatment of cervical dystonia with chemodenervation, Dr. Bahroo?

Dr. Laxman Bahroo: Absolutely. As we have multiple preparations of botulinum toxins on the market, each of them has a cap at 12 weeks.

One cannot inject under 12 weeks. Even at that 12-week mark, we have individuals having a what's called a yo-yo effect, and depending on the literature, up to 80% of individuals will have a lag time from the time they get injected to the time they experience benefits of a few weeks. And prior to that 12-week mark, they'll have a drop-off, and as many folks have experienced, they'll get an eight to 10-week response of benefit even within that 12-week window.

Daxibotulinumtoxin has an unmet need that fixes by giving a longer duration response, and we're [00:02:00] gonna talk about that in that article and hopefully throughout this podcast. 

Dr. Sara Schaefer: Yeah. And maybe you'll get into this a little bit, Dr. Gross, with the next question, which is, in what way is DAXI chemically similar to or different from the other botulinum toxins in use?

Dr. Todd Gross: Yeah. So there are three components here. First of all, Daxxify is formulated using 150 kilodalton neurotoxin molecule which is free of accessory proteins. Among the, the botulinum toxins that are approved for use in cervical dystonia, there's a range. Some have 150 kilodalton molecule, some have a variable up to typically 500 kilodalton, and some have a 900 kilodalton.

 Above 150, you see the inclusion of accessory proteins. Second, Daxxify is formulated with a positively charged proprietary peptide, which is used for stabilization. And as we discussed in the paper, the peptide binds electrostatically to the core neurotoxin. This has been shown to enhance the binding of the [00:03:00] toxin to the neuronal surface, and it increases SNAP 25 cleavage in a dose-dependent manner.

And then finally, Daxxify does not use human serum albumin in its formulation, as do other approved bots. Eliminating the HSA avoids the risk of viral transmission that can accompany the use of HSA in the manufacturing process. It also results in a, something that is shelf life stable at room temperature.

Dr. Sara Schaefer: Oh, interesting. So that may be an option for Jehovah's Witnesses, for example, who are not able to use other botulinum toxins or choose not to because of their religious beliefs in terms of being injected with other human materials, correct? 

Dr. Todd Gross: Absolutely. 

Dr. Sara Schaefer: In 2023, Daxxify was approved by the FDA in the United States for the treatment of cervical dystonia after clinical trials demonstrated efficacy and prolonged benefit compared to durations reported for other toxins, as you mentioned, Dr. Bahroo. [00:04:00] Can you briefly touch on those previous trials that led to that FDA approval and just a brief overview of their protocols and what they found that led to the approval for background on your paper? 

Dr. Laxman Bahroo: Absolutely. So there were two trials that were phase three that led to the approval. The first one was ASPEN-1.

It was a randomized placebo-controlled trial, single injection following up, up to about 36 weeks, and the doses were basically placebo daxibotulinumtoxin 125 units and 250 units. And basically, the effect was to see the benefit versus placebo for both of those doses. Now, of course, the interesting thing was both of them showed benefit, relatively low adverse events in terms of dysphasia or muscle weakness, and then came the open label extension, which followed individuals out to about a year.

The dosage then was titrated up to about 300 units, and again, the safety portion of the data was seen again, was repeated as we saw what we saw with ASPEN-1 as well. And those are the two studies that led to the approval. Of course, the label per [00:05:00] the FDA, the max dosing is at 250 units based on the placebo control trial, not the open label 300 units.

Dr. Sara Schaefer: Yeah, we'll talk about that a little bit later. So we spoke about the US FDA and its approval. Can you touch on Daxxify's use and approval for use outside of the United States as it stands today, Dr. Gross? 

Dr. Todd Gross: Certainly. And as you mentioned, so Daxxify is approved for two indications in the United States.

It was approved for dermatological indication, glabellar lines, in 2022 and for cervical dystonia in 2023. Since then, it has been approved for both of those indications in China in 2024 and for both indications in Australia in 2024.

Dr. Sara Schaefer: And how did you conduct your study and what did you find in your study, Dr. Bahroo? 

Dr. Laxman Bahroo: So the preview experience program was basically a way for individuals to get real world experience with it outside of the setting of a trial, which was a phase three pivotal trial.

16 practices [00:06:00] were selected based on movement disorders practices, based on their experience with botulinum toxins. A total of 234 patients were enrolled, up to three cycles. Not everybody got all the way to three cycles, but three cycles. And of course, the main goal was to enroll patients that were having the issue of wearing off.

And approximately about 88% of the individuals were botulinum toxin experienced, 12% were naive. The great majority of that percentage of people that were previously experienced, about three quarters, were actually having breakthrough symptoms prior to 12 weeks. Approximately about 15% said they were happy with their previous treatment, but again, three quarters of the individuals were having breakthrough symptoms.

Prior to that, they were brought in, and for those individuals that were previously exposed to botulinum toxin, their average starting dose was about 244 units. So it was on the higher end of the Aspen data, but again, within that range. And then across each cycle, between cycle one and cycle two, they were titrated and titrated again.

And we got two different groups of [00:07:00] individuals who were treated for breakthrough symptoms versus individuals that were treated for stable maintenance of symptoms. The dosing range averages were 244 for the first cycle, 294 for the second, and approximately 315, with the median dose being about 300 units.

So that was in line with the Aspen open label study. Now, with that said, there were two groups, as I mentioned. The groups that were titrated a little bit more were titrated because they had breakthrough of symptoms prior to the next injection cycle. On the other hand, individuals that maintained their benefit had much less titration done. 

Dr. Sara Schaefer: And you mentioned the median doses in each cycle.

And I noted when I read your study that many of the Botox-experienced patients specifically had treatments that where the amounts exceeded the original studies and in some cases far exceeded it. Am I right that some of these patients got up to 800 units for an injection? And the original study, as you mentioned, was 125 or 250 [00:08:00] units, and then

up to 300 in the subsequent study. And - Medicare in the United States, their guidelines specify a maximum dose of 250. So can you speak to that, the real world experience versus, what's been approved and how that might impact care? 

Dr. Laxman Bahroo: Oh, absolutely. And I think there's two components of this.

One, this is what the data we get from a real world study. In these studies that are done that are pivotal phase three studies, you know, the doses are fixed, the number of injections are fixed so you have a lot less flexibility. As somebody once said to me very nicely, said, " the home that you live in is the home of the real world experience."

The studies are the home that they show you before you buy that home that where everything is neatly done. While it looks beautiful and clean, it doesn't necessarily apply to real life and real practice. Now, yes, we did have individuals that received higher doses. Very few, but nonetheless, some individuals did receive higher dose units, and they were of course being treated with from higher dose botulinum toxin prior experience as well.

Additionally, they were also having significant breakthrough [00:09:00] symptoms. So they started off from a higher baseline, went to a higher baseline as well. But that is the benefit we get from a real world experience, that there are outliers and individuals with severe cervical dystonia that oftentimes may need higher doses that exceed any product label. 

Dr. Todd Gross: And if I can expand maybe a little bit on the data that was found as you mentioned, the pivotal trial studied 125 and 250 units.

For regulatory purposes, those were designed to support approval, which they did quite well. And as Dr. Bahroo mentioned, when you move out into clinical practice, you might see different behavior. The findings within the preview program experience was, as, as you mentioned, a median of 300.

Many of the patients were within a fairly tight range around that. And we see in terms of the titration that many patients got to a stable dose by the second or third cycle. In fact, Dr. Bahroo mentioned the increases from the second to third cycle were much more modest than they were from the first to second.

This is obviously reflecting the individual needs of patients. Some [00:10:00] patients need more, some patients need less, and patients that are chosen because they're having breakthrough symptoms or who are on a higher prior toxin dose might end up needing higher doses of Daxxify. 

Dr. Sara Schaefer: Now getting to the side effects, which is of course important to talk about in any trial of a drug.

In both the registration studies and the clinical insights paper, you report rates of key adverse events such as dysphasia and muscle weakness that do appear to be low compared to reported rates for other approved neurotoxins. However, of course, if the toxin is sticking around for longer, there's the possibility of those side effects lasting longer for any given injection cycle.

What is your explanation for this, and how do you think this finding affects treatment decisions in clinical practice? 

Dr. Laxman Bahroo: I'll take that one first and maybe Dr. Gross can come back with a different version of this. So if you look at it, as you mentioned, the adverse events were less, what were our top preview adverse events, [00:11:00] weakness was seen at about a little over 2%, I think 2.4 to be exact.

Dysphasia was seen in .3 and as mentioned, doses in many cases were titrated above the doses of the ASPEN-1 and the Aspen OLE. I think this is what makes daxibotulinumtoxin unique in that sense because it has a peptide called RT004, which is a peptide that's designed to cover the botulinum toxin core neurotoxin, but also designed to approximate it close to the membrane, the negatively charged membrane with a positively charged peptide.

It allows for less diffusion outside of that site. I think that makes it unique in the sense that you have more neurotoxin getting absorbed in, less getting away from the site of injection into sites that we don't want to get into, and therefore you see less issues with regards to spread, such as weakness or dysphasia.

That's the explanation I've thought of in terms of why we saw that. With successive increasing in dosing, we didn't get a concomitant increase in side effects. 

Dr. Todd Gross: Yeah, I think that is a very very good answer. I would just add that what was observed in the preview [00:12:00] program was very consistent with what we observed in the pivotal trial and the open-label study that followed it, which was rates of dysphagia that were between 1.6 and 3.8%, depending on treatment group, and rates of muscle weakness of 4.8 and 2.3% across the two treatment groups.

And when we moved into actual clinical practice, we saw that those rates were pretty consistent. 

Dr. Sara Schaefer: Of course, these aren't head-to-head trials, so you have to add an asterisk to this a little bit. But it is interesting, especially with the kind of chemical explanation that you gave, Dr. Bahroo, for why it might be the case that side effects could be more limited with this particular botulinum toxin. So for those clinicians who might be listening to this and Daxxify curious who may be considering switching their patients what practical tips do you have for them in terms...

you mentioned in your paper some information about ratios and intervals. You mentioned Dr. Bahroo, that some [00:13:00] physicians that you studied in your study decided to treat patients before they started having a waning of their symptom benefit, whereas others retreated because of a waning of symptom benefit.

Knowing what you know, what are the logistics you would employ for a new patient in your own practice? 

Dr. Laxman Bahroo: There's a lot to unpack, and I think those are incredibly valid points. Let's say starting out, we started out almost one-to-one ratio between daxi and onabot.

Majority of our patients that were previously experienced were on onabot. So we started out one to one. Now, organically, I will tell you there are 16 different injectors with 16 different style dosing, but we pretty much huddled close to that. Now, naive patients, of course, were started at a lower dosage because there was no prior record of what their dosing was.

As you should be with naive patients to the class of drugs, we were more conservative. With patients who were more experienced, even though they were naive to DAXI, we were a little bit more freer with that dosing. And of course, titration made up for it. And over the course of titration, we went from one to one to closer [00:14:00] to 1.4 in that dosing interval.

Now, what it came down to this was the retreatment interval. Now, the retreatment interval is interesting because our prior experience with almost every other botulinum toxin was 12 weeks, and you're selecting out individuals, as I said, 80-plus percent of them who have a wearing off prior to coming into the next dose.

So where do we set the retreatment interval? This was a little bit of a guesswork on our part. Initially, we all set it roughly around 12, 13 week time period. Now, the problematic situation was that many patients were doing well, and this is a good problem to have, but they were doing well. Now, if a patient is sitting in front of you and they're looking to get their injections, if they made the effort to come in, more often than not, they're gonna not like going away and coming back two, three weeks later.

So many of those patients said, "Okay, I'll come in and get injected even though I'm maintaining my benefit that time." That was one aspect of it. Some of my patients and across the board of, from the 16 practices also did the same thing. They would call a week or two ahead and move the appointment a couple of weeks [00:15:00] later.

So there was a little bit of an unknown of how long this first cycle would last. We expected 14 weeks, 16 weeks time period, but patients were unsure because they are patients that are having breakthrough symptoms. We are used to having these patients have breakthrough symptoms, so it was a little bit of finding in that sense.

There was one other variable that we discovered. When the preview program started, it started late summer, early fall. When you look 12 to 13 weeks out, that is the holiday season. A handful of patients came in prior to the holiday season because they knew between provider schedules, their schedules, they might be out a whole month.

And their fear, and this is what several of them said to me and to other providers, is the fear was, "What if in the next two weeks I start to wear off and I can't come in for another four weeks? Then I'm going to be miserable." So individuals in the first cycle came in, even though they were stable on maintenance dosing, to get injected.

Now, the second cycle, as you can see, developed a little bit more longer time, and they were able to go in longer. One, they were used to getting the response and they were able to be more confident that they were going to get the longer [00:16:00] duration response. Plus we titrated the ones that had breakthrough symptoms over so they could get that longer duration response.

So there's nuances there. How I would convert in terms of practicality, I would start close to their dosing. If they're on Onabot, close to that dosing, knowing full well that I'm going to titrate. Set the expectations that our average dosing trial retreatment interval is about 16 weeks. And as to how patients prefer to come in that depends on the patient, the provider.

We believe that, the daxi dosing duration gives you flexibility. There might be individuals that might want less frequent injections because of cost or distance or just a preference to have less injections, and other individuals who may say, "No, I want perfect control, so therefore I'll be coming in as close to that interval so that I don't have breakthrough."

And that's the beauty of being an injector, in my opinion, is that you can have the same logic appeal to both patients depending on what they want to bring to it. It's seeing the glass half full and half empty. 

Dr. Sara Schaefer: Yeah, I c- I can think of specific patients in my own practice who would fall into every one of those categories.

Dr. Laxman Bahroo: Yeah. 

Dr. Sara Schaefer: [00:17:00] Any closing remarks from either of you? 

Dr. Todd Gross: Well, I'd like to just take this opportunity to thank you for the invitation to appear on the podcast and discuss the article. And I wanna thank the investigators who provided information to it. 

You know, as we prepared to move from approval into commercialization, it was exceptionally invaluable to get their input.

And, we believe that this is a very effective model for moving into commercialization and getting this early experience.

Dr. Laxman Bahroo: For my part my closing comment would be we really enjoyed the preview experience. We enjoyed looking at the ASPEN and the open-label extension data and seeing where the data really would...

was a kind of a manual or guide, and then putting that guidebook into practical use and really fine-tuning and honing our injection skills and dose titration. And I will tell you, many of us titrated and had slightly different ways of thinking about it, but ultimately, all injectors have coalesced around some basic ideas.

So it was great for us to talk to other injectors across the country, discuss tips of how we approach [00:18:00] something, learning from each other. And as any injector can tell you, one injector always learns from another injector and benefits from it. So I think ultimately, this benefited our learning of, longer duration botulinum toxin.

Our patients who were able to get botulinum toxins, whether that was a cost issue for them or duration issue, and benefited from a therapy that was both novel and as well as the fact that they were able to get several cycles of therapy to be able to titrate and fine-tune their control of cervical dystonia.

So thank you very much for having me on. 

Dr. Sara Schaefer: I like this closing remark. It basically we don't belong in silos. We have to talk to each other, right? 

Dr. Laxman Bahroo: Absolutely. 

Dr. Sara Schaefer: Wonderful. All right. Thank you for joining us today. 

Dr. Todd Gross: Thank you. 

Dr. Laxman Bahroo: Thank you very much. [00:19:00]