Neuromodulators in Clinical Practice: An Update

The toxin market is growing for aesthetic indications, and patient interest continues to soar. But in addition to a growing market, there are other trends to watch. Ahead, I discuss new research into different doses for varying duration of effect, more indications approved for use, as well as trends surrounding micro injections to treat not only fine lines and wrinkles but also improving the texture of the skin and reducing sebum for certain dermatologic conditions.

MArket OvervIew

Cosmetically, toxins are still changing. We’re now thinking about—and companies are investigating—duration of effect. The concept of onabotulinumtoxinA (Botox Cosmetic) 20 years ago was how little could we inject to see an effect for a decent duration of time without causing any adverse events. That led to the original treatment parameter of 20 units of Botox Cosmetic in the glabella with a duration of effect of three to four months. That became the standard. We were dealing with a toxin and people were nervous. Now, 20+ years later, the question is becoming, “What happens if we inject more than 20 units in the glabella?”

Data show that higher doses do last longer. Revance Therapeutics’ long-acting neuromodulator daxibotulinumtoxinA for Injection (RT002) delivered positive top-line results in alleviating moderate to severe glabellar lines in the SAKURA 3 Phase 3 open-label, long-term safety study. Based on investigator assessment, more than 95 percent of patients achieved a score of none or mild glabellar lines at maximum frown at Week 4 after each of three treatments and the median time to return to baseline glabellar line severity was 28 weeks. The median time to loss of none or mild wrinkle severity was 24 weeks. We anticipate FDA approval of this new toxin in the near future; COVID-related restrictions delayed a site visit and hence a decision on the biologics license application. In addition, Revance has also been evaluating its new toxin in the forehead and in crow’s feet in pilot studies.

Now that 40 units of daxibotulinumtoxinA has been shown to last longer, other companies have started preliminary investigation into the safety, efficacy, and duration of effect of higher doses of their toxins. Allergan, Galderma, and Merz Aesthetics have been studying their toxins, onabotulinumtoxinA (Botox Cosmetic), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin), respectively, in higher doses in the glabella with very successful results in preliminary reports and presentations. As well, Merz is studying treatment of the glabella, forehead, and crow’s feet, looking at safety and efficacy for treating the upper face.

PrabotulinumtoxinA (Jeuveau, Evolus) was the last neurotoxin approved for a cosmetic indication in the US (the temporary improvement in the appearance of moderate to severe glabellar lines). Clinical studies show that its efficacy and duration are equivalent to Botox Cosmetic. Availability of the agent may be hindered due to ongoing litigation.

Allergan’s EB-001A toxin appears to have some very interesting characteristics. It is a Type E botulinum toxin serotype, and Phase 2 clinical trials indicate that EB-001A appears to have a rapid onset of action and short duration of effect relative to other available toxins. This may be very interesting to patients still unsure of wanting to have a neurotoxin injection, or for those needing a toxin with a fast onset of action for an event or social occasion, when that becomes “normal” again.

Several years ago, Austria-based Croma had an agreement to bring Hugel’s South Korean botulinum toxin A, Botulax, to North America. Clinical trials in the US and in Europe are now finished. Through a new agreement with Bain Capital, Hugel now controls the US toxin trials and the Croma US dermal fillers trials. So what we thought would be a Croma-run US presence now will be a Hugel-run US company. The compound has been submitted to European authorities for review. A specific target date for US submission has not been announced but we expect this in 2021 or 2022.

TOXIN TRENDS

A trend that we’re continuing to investigate in the US is the concept of micro botulimun toxin injection, commonly referred to as mesobotox outside the US. Most of us in the US are not using the term mesobotox, as there have been negative connotations to the term mesotherapy in the past in this country. The technique, which can be used with any of our available toxins, has been widely investigated in Asia, and some formal investigation has started in the US.

In Asia, they perform a lot of microbotox—much more than we do here. I learned how to do this in Asia, where I first heard this talked about at a meeting. I had never seen injecting like it: putting one unit of toxin into multiple injection sites in each cheek and in the forehead. Microbotox is performed by injecting a dilute amount of botulinum toxin into the dermis with a very fine gauge needle. Injectors must use extreme caution and be well skilled; placement too deep may lead to adverse events, including drooping in half of the patient’s face, which can last up to three months, or difficulty in smiling, both of which I have seen with improper techniques. When done well, fine lines smooth out, the texture of the skin improves, there is improvement in the appearance of pores, and sebum production is reduced, making it useful in those suffering from acne and from rosacea and associated blushing.

Microbotox has also been used as a way to make other cosmetic procedures work better. If you do IPL treatments or fractional lasers, microbotox can be done in combination, and it seems to make the procedures last longer and even lead to a little bit more beneficial of an outcome.

It’s also being used as a treatment to improve the appearance of scars and, again, as an additional treatment to make the scars respond better to other treatments. This has been something that has become very important and its use in helping improve scars and scarring is gaining in popularity.

We await large clinical trials to demonstrate the benefit of any of these approaches. While we have positive case series reported, it is important to confirm benefit through rigorous study and determine the most effective treatment protocols.We will await the current evaluations that are now underway for fine lines. For the other indications for microbotox, we will await randomized clinical trials to show their true efficacy, but preliminary work is very promising.

Based on my experience and study to date, I believe microbotox can be used to effectively enhance other procedures I do for acne, aesthetic procedures, and scar treatments. I do not think it will replace what I do each and every day, but, for sure, will enhance everything I do, leading to better outcomes. We are always striving to offer cutting edge treatments to our patients based on science, and the science for microbotox is increasing day by day.

Study and Learn

We have more toxins and more indications for our toxins coming into our market and into our armamentarium. This is all good for our patients. But remember: there are still potentials for adverse events, so learning from the clinical trials that I am thankful to be part of helps us to determine the best treatment options and enhancements for us to offer our patients with our toxins. One must study and learn; cookie-cutter approaches will not work with some of these newer indications. The toxins we have and the new ones we are going to see are not interchangeable from one to the other, so learn them well, and become the best injector you can be.