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Botulinum Toxins: 2019 Update.

Botulinum toxins have an increasing number of approved indications and off-label uses, not only in aesthetic medicine and neuromuscular disorders, but also in ophthalmologic, urologic, gastrointestinal, hypersecretory, and pain disorders. (1) Several important pharmacological properties contribute to their utility: they are very potent and neurospecific toxins; when injected locally, their diffusion is limited; and their action reverses over time. (2) When used to minimize glabellar frown lines and other facial wrinkles, the full effect develops in about 1 to 2 weeks. Benefit lasts about 4 months, or longer in some cases. (3)

Approved Toxins

Conversion Factor

The first botulinum A toxin (onabotulinumtoxinA) was approved in the United States for cosmetic use in 2002. Three more toxins have been introduced since that time, including 1 in February 2019 (Table). (4-10) The dose of incobotulinumtoxinA is equivalent to that of onabotulinumtoxinA in published studies, (11,12) although some clinicians disagree. Multiple studies (12) have reported a dose conversion factor from onabotulinumtoxinA or incobotulinumtoxinA to abobotulinumtoxinA of 1:3; many clinicians use a conversion factor of 1:2.5. Relative potency of the investigational toxin daxibotulinumtoxinA compared with onabotulinumtoxinA has not been established. (13)

Response Rates

The newest agent approved by the US Food and Drug Administration (FDA), prabotulinumtoxinA-xvfs, demonstrated response rates of 68% and 70% at 30 days after a single injection in two phase 3 studies of patients with glabellar lines. Response was defined as at least a 2-point improvement on the 4-point Glabellar Line Scale (GLS) at 30 days. (14) Previous studies of onabotulinumtoxinA reported an 80% response rate at 30 days. (7)

The definition of response varies across clinical trials of these medications, complicating comparisons. Some head-to-head efficacy studies have been performed, however. IncobotulinumtoxinA (6) and prabotulinumtoxinA (9) each has demonstrated noninferiority to onabotulinumtoxinA for the treatment of glabellar lines in separate phase 3 trials. More than half of patients receiving prabotulinumtoxinA or onabotulinumtoxinA demonstrated response at day 2 (54% and 57%, respectively). The agents demonstrated a similar safety profile. (9)

A comparison of incobotulinumtoxinA and onabotulinumtoxinA revealed response rates at 4 weeks of 96% with each product. Response was defined as improvement of at least 1 point on a 4-point facial wrinkle scale at weeks 4 and 12. (6)

Response rates with prabotulinumtoxinA and onabotulinumtoxinA were 87% and 83%, respectively, in a noninferiority trial, in which response was defined as subjects with a GLS score of no lines or mild lines (0 or 1) by investigator assessment at 30 days postinjection. (9)

Investigational Toxins

Several investigational botulinum toxins are expected to be approved by the FDA soon. Injectable daxibotulinumtoxinA, which has completed phase 2 trials, demonstrated greater efficacy and a longer duration of response than onabotulinumtoxinA due to the presence of a stabilizing peptide. (13) In a 24-week dose-ranging study (N=268), 40 U daxibotulinumtoxinA had a significantly greater response rate and longer response duration (24 vs 19 weeks) in the treatment of glabellar lines compared with 20 U onabotulinumtoxinA (P=.03). (13) A phase 3, longterm safety study of daxibotulinumtoxinA for glabellar lines has been completed but results have not been reported (https:// clinicaltrials.gov, NCT03004248).

A botulinum toxin serotype E in the pipeline for treatment of glabellar lines has a rapid onset of action--within 24 hours--yet a response duration of only 2 to 4 weeks. (15) One potential use for such a short-acting toxin may be to reduce scarring after Mohs surgery to achieve better cosmesis. Rapid, short-acting toxins may also be desirable in patients who are toxin-naive or in individuals who have mild facial asymmetry, such as an elevated eyebrow. (15) The serotype E toxin will be sold in liquid form, so reconstitution will be unnecessary. (15) A liquid form of abobotulinumtoxinA is under study. (16)

Summary

Four toxins are available for facial rejuvenation and contouring beyond the glabellar lines. Pipeline toxins include a toxin A with longer duration than those currently available and a toxin E product with faster onset of action than the serotype A agents.

References

(1.) Gart MS, Gutowski KA. Overview of botulinum toxins for aesthetic uses. Clin Plast Surg. 2016;43(3):459-471.

(2.) Pirazzini M, Rossetto O, Eleopra R, Montecucco C. Botulinum neurotoxins: biology, pharmacology, and toxicology. Pharmacol Rev. 2017;69(2):200-235.

(3.) Small R. Botulinum toxin injection for facial wrinkles. Am Fam Physician. 2014;90(3): 168-175.

(4.) Dysport [package insert]. Fort Worth, TX: Galderma Laboratories, L.P.: July 2016.

(5.) Xeomin [package insert]. Raleigh, NC; Merz Pharmaceuticals, LLC; July 2018.

(6.) Sattler G, Callander MJ, Grablowitz D, et al. Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A in the treatment of glabellar frown lines. Dermatol Surg. 2010;36(suppl 4):2146-2154.

(7.) Botox Cosmetic [package insert]. Madison, NJ: Allergan USA, Inc; May 2018.

(8.) Jetiveau [package insert], Santa Barbara, CA: Evolus Inc; February 2019.

(9.) Rzany BJ, Ascher B, Avelar RL, et al. A multicenter, randomized, double-blind, placebo-controlled, single-dose, phase III, non-inferiority study comparing prabotulinumtoxinA and onabotulinumtoxinA for the treatment of moderate to severe glabellar lines in adult subjects. Aesthet Surg J. 2019 April 5 [Epub ahead of print].

(10.) Benedetto AV. What's new in cosmetic dermatology. Dermatol Clin. 2019;37(1):117-128.

(11.) Jandhyala R. Relative potency of incobotulinumtoxinA vs onabotulinumtoxinA a meta-analysis of key evidence. J Drugs Dermatol. 2012;11(6):731-736.

(12.) Samizadeh S, De Boulle K. Botulinum neurotoxin formulations: overcoming the confusion. Clin Cosmet Invest ig Dermatol. 2018; 11:273-287.

(13.) Carruthers J, Solish N, Humphrey S, et al. Injectable daxibotulinumtoxinA for the treatment of glabellar lines: a phase 2, randomized, dose-ranging, double-blind, multicenter comparison with onabotulinumtoxinA and placebo. Dermatol Surg. 2017;43(11): 1321-1331.

(14.) Beer KR, Shamban AT, Avelar RL, Gross JE, Jonker A. Efficacy and safety of prabotulinumtoxinA for the treatment of glabellar lines in adult subjects: results from 2 identical phase III studies. Dermatol Surg. 2019 March 18 [Epub ahead of print].

(15.) Yoelin SG, Dhawan SS, Vitarella D, Ahmad W, Hasan F, Abushakra S. Safety and efficacy of EB-001, a novel type E botulinum toxin, in subjects with glabellar frown lines: results of a phase 2, randomized, placebo-controlled, ascending-dose study. Plast Reconstr Surg. 2018;142(6):847e-855e.

(16.) Ascher B, Rzany B, Kestemont P, et al. Liquid formulation of abobotulinumtoxinA: a 6-month, phase 3, double-blind, randomized, placebo-controlled study of a single treatment, ready-to-use toxin for moderate-to-severe glabellar lines. Aesthet Surg J. 2019 March 20 [Epub ahead of print].
TABLE. FDA-Approved Botulinum Toxins for Aesthetic Use

Agent                  Bacterial     Units/Vial       Noninferiority
                       Production     (Product           Studies
                         Strain     Specific) (a)

AbobotulinumtoxinA     Hall NCTC     125/300/350            --
(4)                       2916

IncobotulinumtoxinA    Hall ATCC     50/100/200       Noninferior to
(5)                       3502                      onabotulinumtoxinA
                                                           (6)

OnabotulinumtoxinA     Hall-hyper    50/100/200             --
(7)

Prabotu1inumtoxin          --            100          Noninferior to
A-xvfs (8)                                          onabotulinumtoxinA
                                                           (9)

(a) The potency units of each product are specific to that product
and are not interchangeable with those for other products. ATCC,
American Type Culture Collection; FDA, US Food and Drug
Administration; NCTC, National Collection of Type Cultures. Adapted
from; Benedetto AV. Dermatol Clin. 2019;37(1):117-128. (10)
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Author:Kaminer, Michael S.
Publication:Dermatology News
Date:Aug 1, 2019
Words:1168
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