Where Are We in 2023? A Q&A on Botulinum Toxins

The aesthetic applications of botulinum toxins have grown significantly in the 20-plus years since their introduction to the cosmetic dermatology space.¹ Research findings suggest high levels of patient and physician satisfaction with these popular products, with ratings approaching 100% in some studies.² In addition to the range of current cosmetic indications approved by the US Food and Drug Administration (FDA), multiple trials are underway that will likely lead to several new on-label indications for botulinum toxins.

To explore the landscape of treatment and ongoing development in this area, Modern Aesthetics talked with Sue Ellen Cox, MD, founder and medical director of Aesthetic Solutions in Chapel Hill, North Carolina. Dr. Cox has served as an investigator in various trials focused on novel products and indications in the realm of neuromodulators for facial rejuvenation.

Modern Aesthetics: How would you characterize the overall landscape of current applications for botulinum toxins in cosmetic dermatology?

Dr. Cox: Botulinum toxins have a broad range of applications in dermatology because of their high safety profile and incredibly predictable results, with a reported 97% patient satisfaction when used for cosmetic indications.² Some of the applications are FDA-approved and others are used off-label.

As of December 2023, the landscape of FDA-approved neuromodulators in the USA includes Botox (onabotulinumtoxinA), Dysport (abobotulinumtoxinA), Xeomin (incobotulinumtoxinA), Jeuveau (prabotulinumtoxinA), and Daxxify (daxibotulinumtoxinA).^3,4 The most common approved cosmetic indications are for treating moderate-to-severe glabellar lines, lateral canthal lines, and forehead lines, approved in 2002, 2013, and 2017, respectively.¹

Off-label use in cosmetic dermatology includes bunny lines, gummy smile, lip flip, downturned mouth, platysmal bands, and facial shaping with the treatment of the masseter muscles. Some newer off-label cosmetic treatments include scar reduction, décolleté wrinkles, facial asymmetries, leg contouring, trapezius muscle injections for shoulder shaping, and microdroplet botulinum toxin for sebum control, face lifting, and pore size reduction.

In medical dermatology, these products received FDA approval for on-label use for axillary hyperhidrosis in 2004.¹ Off-label medical dermatology uses include facial hyperhidrosis, bromhidrosis, chromhidrosis, Frey’s syndrome, Hailey-Hailey disease, post-herpetic neuralgia, and psoriasis. Migraine treatment became an approved use in 2010.¹ Clearly, the landscape for botulinum toxin treatments is incredibly broad.

MA: What do you consider the most exciting recent innovations in this area, and how have these treatments been received in your practice so far?

Dr. Cox: The latest buzz is high-dose treatment to prolong duration. Daxxify was the first to receive approval for a longer duration with a 40-unit glabellar line dose, and now other companies are performing studies to try and achieve similar durations by increasing the dose of their on-label approvals and hyper-concentrating the dilution. Frequent retreatment every three or four months can be inconvenient for patients, so there’s interest in products that will last longer.

I was a clinical investigator for Daxxify in the SAKURA 1 registration trial, so I knew the product and was excited to introduce it to my patients during the early launch program.⁴ I found the commercial launch to be a bit challenging, as it was priced at a premium and extended duration was not always predictable. The studies showed a median duration of six months, but that means 50% of those who are treated will not get that duration. It’s difficult to know who will achieve the duration of 24 weeks.

There is a subset of patients who were early adopters and excited to try this product. Other patients for whom neuromodulators only last two to three months were also happy to try a potentially longer-lasting product. Some have continued with it while others have gone back to their previous treatments.

MA: What are some of the most notable advances that may emerge in the near future with botulinum toxins for cosmetic dermatology?

Dr. Cox: I’ve been fortunate to be involved in clinical trials for several developments in the pipeline, including the new indication of platysmal bands with onabotulinumtoxinA (ClinicalTrials.gov Identifier: NCT04994535).⁵ Although we have been using it in this location for years, it would nice to finally have the indication so that direct-to-consumer marketing can help drive patients with that interest to our offices.

Another study I’m involved in is a phase 3 trial for trenibotulinumtoxinE (ClinicalTrials.gov Identifiers: NCT05248867 and NCT05248880). This is a first-in-class, short-acting neurotoxin which has the potential to bring true innovation to the aesthetic industry. A recent press release noted that the pivotal phase 3 studies demonstrated statistical significance for improvement of glabellar lines vs placebo. The onset of efficacy (2-grade improvement from baseline) was demonstrated at eight hours after administration, and the efficacy duration was observed for two to three weeks.⁶

In practice, this type of “starter toxin” will be nice for new patients or those who have hesitancy to try a neuromodulator. This differentiating factor will help grow the toxin experience for the new patient population.

A third trial I participated in was for the new liquid toxin relabotulinumtoxinA (ClinicalTrials.gov Identifiers: NCT04249583 and NCT04249687). This will be a unique product with a quick onset of action starting at one day in both glabellar lines and lateral canthal lines. The duration was excellent at six months, and it had very high patient satisfaction with consistent results and very natural-looking effects.⁷ These are just a few of the exciting developments for the near future.

In your view, what key developments would patients and physicians most like to see in this area?

Dr. Cox: Patients would like to see longer durations that are predictable, and they would love it if no needles were involved. Both patients and physicians would like an agent that could completely reverse the effects if there were an untoward event. Physicians would also benefit if more off-label uses received approval so that direct-to-consumer education could more comprehensively present the benefits of treatment to these areas.

Which topics should be the focus of future research regarding the use of botulinum toxins for cosmetic indications?

Dr. Cox: Aside from new indications for current off-label use, I would like to see research focused on evidence and not mythology. There are a lot of teachings that have been perpetuated over the past 20 years that aren’t scientifically proven. An example of this is injection points in the glabellar area: Many physicians continue to use the 5-point injection patterns used in the clinical trials, but this may not optimize individual patient results because those injection points are not based on individualized anatomy. Some studies suggest that other points and locations produce better results.⁸

Another area in need of controlled trials would be the improvement of skin quality with neuromodulators. Many companies tout their product as offering the advantages of improved skin tone and quality. However, no one has conducted a randomized trial looking at the five cohorts of currently available products to assess whether there is a statistically significant difference between them for these outcomes.

There are so many topics that would be interesting for future research, but we don’t have the time to delve deeper. A few that come to mind are: What is the optimum dosing for muscle mass considering racial and ethnic and gender variation? What is the ideal outcome metric? Is it weeks, months, or years? How should we be comparing units if they are not interchangeable? How does dilution affect results? There’s so much to talk about in this area!

Disclosure: Dr Cox reported that she serves as principal investigator, consultant, and advisory board member for Allergan, Evolus, Galderma, Revance, and Zeltiq; consultant and advisory board member for Merz and Solta Medical; principal investigator and consultant for Croma-Pharma; principal investigator for Caliway; and advisory board member for Hugel and Suneva.

1. Bach K, Simman R. The multispecialty toxin: A literature review of botulinum toxin. Plast Reconstr Surg Glob Open. 2022;10(4):e4228. doi:10.1097/GOX.0000000000004228

2. Smit R, Gubanova E, Kaufman J, et al. Patient satisfaction with abobotulinumtoxinA for aesthetic use in the upper face: A systematic literature review and post-hoc analysis of the APPEAL study. J Clin Aesthet Dermatol. 2021;14(2):E69-E88. PMID:34221231

3. Kaufman-Janette J, Cox SE, Dayan S, Joseph J. Botulinum toxin type A for glabellar frown lines: What impact of higher doses on outcomes? Toxins (Basel). 2021;13(7):494. doi:10.3390/toxins13070494

4. Carruthers JD, Fagien S, Joseph JH, et al; SAKURA 1 and SAKURA 2 Investigator Group; SAKURA 1 and SAKURA 2 Investigator Group. DaxibotulinumtoxinA for injection for the treatment of glabellar lines: Results from each of two multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2). Plast Reconstr Surg. 2020;145(1):45-58. doi:10.1097/PRS.0000000000006327

5. PR Newswire. Allergan Aesthetics announces positive topline results from second phase 3 study of onabotulinumtoxinA (BOTOX® Cosmetic) for the treatment of platysma prominence. Published September 18, 2023. Accessed November 20, 2023.

6. PR Newswire. Allergan Aesthetics announces positive topline results from two pivotal phase 3 studies of trenibotulinumtoxinE (BoNT/E) for the treatment of glabellar lines. Published October 24, 2023. Accessed November 20, 2023.

7. Galderma. Galderma announces positive results in two phase III studies for a novel liquid formulation botulinumtoxinA (RelabotulinumtoxinA) for the treatment of glabellar lines (frown) and lateral canthal lines (crow’s feet). Published June 10, 2022. Accessed November 20, 2023.

8. Kaminer MS, Cox SE, Fagien S, Kaufman J, Lupo MP, Shamban A. Re-examining the optimal use of neuromodulators and the changing landscape: A consensus panel update. J Drugs Dermatol. 2020;19(4):s5-15.