Ability of Nuedexta to Improve Bulbar Function in Swallowing and Speech in ALS

James Wymer, MD, FAAN

At the 2022 Annual Northeast Amyotrophic Lateral Sclerosis (NEALS) Consortium Meeting, held November 1-3, in Clearwater Beach, Florida, James Wymer, MD, FAAN, and colleagues presented an up-to-date investigation assessing combination dextromethorphan and quinidine (Nuedexta; Otsuka Pharmaceuticals) as a way to improve swallowing and speech, as well as bulbar functions in patients with amyotrophic lateral sclerosis (ALS).¹

The prospective, multicenter, pilot trial, conducted between August 2019 and August 2021included 28 patients with a confirmed ALS diagnosis (El-Escorial Criteria), ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subscale score less than or 10, speaking rate less than or 140 wpm, and were naïve to Nuedexta treatment. Of them, 25 completed the 30-day protocol.

Following treatment with Neudexta, the ALSFRS-R bulbar subscore improved (7.47 [±0.38] vs. 8.39 [±0.37]; mean difference, 0.92; 95% CI, 0.46-1.36; P <.0004). The results also showed a greater duration of uninterrupted speech based on the improved speech event duration (2.62 vs. 2.96 s, P = .035). Furthemore, the binary swallowing severity grades in Neudexta-treated patients improved, with reductions in the proportion of unsafe (75% vs. 44%, P =.003) and inefficient (67% vs. 58%, P =.002) swallowers.

Following the meeting, Wymer, neurologist, professor, The University of Florida, sat down with NeurologyLive^® and spoke about his study. He discussed the key points from the research, as well as the complexities of understanding and assessing the bulbar function in patients with ALS.

NeurologyLive^®: Can you discuss some of the top points from your study on Neudexta?

We were involved in a study that looked at Neudexta, which is dextromethorphan and quinidine sulfate, a formulation that is currently FDA approved for treatment of what's called pseudobulbar affect. In the clinical trials working out there were these background symptoms that we were seeing, with a little bit of signs that it [Neudexta] may be providing some benefit of in speech and swallowing for patients with ALS, but nothing we could clearly quantify. What we did in this study was we gave the medication for a period of 4 weeks to patients, looked at what impact it would have on their speech and their swallowing. Over the course of the four weeks, the patients with ALS that were placed on the Neudexta, we found there was some slight improvement in their speech. They were able to talk with less pauses, and we saw some improvement in their swallow. There was improvement in both of those with that we know what occurred during those first four weeks. We don't know if it occurs longer than that afterwards, it needs a longer study to do that. But we know at least the medication has what we have been seeing in the other times, we put it on patients where we were reporting improvement. We now have a clinical trial that documents what that improvement is, and in what areas it's in.

This drug was approved for treatment of pseudo bulbar affect in 2011, has it been used in patients with ALS before?

This medication was initially started in clinical trials in the early 2000s and it took about five to 10 years to get through all the FDA approval process to go from just an initial thought of a medication to something that we could quantify the results and show benefit. Again, this is FDA-approved for something called pseudobulbar affect. It's not approved for correcting swallowing in patients with ALS.. Pseudobulbar affect which is a lack of emotionality control. This is somebody who can have sudden outbursts of laughing and crying that we will see in a lot of different neurologic diseases. We can see this in patients with multiple sclerosis, patients with stroke, patients with ALS, traumatic brain injury, we can see across a spectrum. This is a medication, the only medication, that's FDA-approved to treat that disease. But it was during treatment of those patients and assessing that we started seeing this bulbar effect that prompted us to do, what we call an open-label study. There was no placebo in this study, everybody got the medication. We need to go back and do the next level study, which is where part of the people get the medications, part of the people get placebo. We could see if it really makes that benefit and how long that benefit lasts.

Are there any complexities with understanding and assessing the bulbar function and improvement in patients with ALS?

Well, we have two ways of assessing the bulbar function. We have patient reported outcomes, which are basically questionnaires about “are you better” or “are you worse”, “what has changed.” In those, when we did the studies on one of the questionnaires, they did better. On the other two, there wasn't much of a change. For some patients, it did no benefit. When we went in with the other more sophisticated testing, which is using video fluoroscopy—where you X ray while somebody's swallowing, or we did other speech testing and quantitative, how fast they were talking—we saw a more significant benefit from all of this, but some of these patients may not have noted the benefit. Some of them had a fairly significant benefit when they went on the medication. The testing that we use is much more sophisticated, picking up subtler things, finding very objective changes and while patients may or may not have noticed how much benefit they have.

If there needs to be additional research to validate these findings, what would that entail?

The best way to expand this would be a larger, placebo-controlled trial. We're certainly in discussions to figure out the best way to design that trial, and to do this most efficiently. We are also in discussion with the NEALS community about other centers that are interested in looking further into this data, and getting the outreach to other patients with ALS, and outreach to the community. But the first step we need to do is to validate the data in a more controlled setting with other options. We'd like to do that and other centers within the bulbar subcommittee of the northeastern ALS consortium or other groups that are interested in looking at this.

Aside from this study, what types of ways are we trying to improve the bulbar function in ALS?

Bulbar is one of the significant morbidities that can happen with patients with ALS. Losing the ability to swallow and losing the ability to talk is a huge disability that can happen with that. We have a lot of tools that we tried to do to improve that. Some of those tools can be as simple as can we position the headand we do certain exercises that may help. But as far as medications and other options to treat this, this is the first medication to have shown any benefit for that. The other medications that are available are slowing the rate of decline. This one in this small trial provided benefit. But again, I want to be cautious on saying provided benefit because we need to validate the results. We need a larger study, we need to look more into it. I don't want to jump too quickly into this result.

Transcript edited for clarity. Click here for more coverage of NEALS 2022.

REFERENCES
1. Gray T. L, Vasilopoulos T, DiBiase L, et al. Improving Speech and Swallowing in pALS: Preliminary Efficacy of Nuedexta Treatment. Presented at: 2022 Annual NEALS Meeting; November 1-3; Clearwater Beach, FL. Abstract 3