Commentary on: Safety, Pharmacodynamic Response, and Treatment Satisfaction With Onabotulinumtoxin A 40 U, 60 U and 80 U in Subjects With Moderate to Severe Dynamic Glabellar Lines

See the Original Article here.

Joseph et al present a well-thought-out Phase 1b dose-ranging, safety, and efficacy study of the effects of escalating doses of onabotulinumtoxin A (ONA) in reduced injection volume in mostly white female subjects with moderate to severe dynamic glabellar rhytides.¹ Subject evaluation was garnered with the Facial Line Satisfaction Questionnaire (FLSQ). Cleverly, the authors performed an open-label study in which 80 U of ONA was administered to a subset of 7 women to inform the decision about whether to include this dose in the larger subsequent double-blind study.

The study is very well done, and the results compare remarkably exactly with previous high-dose studies. My only question is the lack of any mention of the recovery time for 2 subjects (1 with brow ptosis and 1 with lid ptosis) because there is an unfounded fear that longer duration of effect also correlates with longer-lasting complications.

The clinical interest in higher dosing was sparked by the 6-month longevity of daxibotulinumtoxin A (Revance, Nashville, TN) seen in clinical trials.² Investigators sought to see if increasing dosage in already approved botulinum neurotoxin A (BoNT-A) products would also confer increased longevity and answer the question about natural vs “overdone” results.

DOSE-RANGING REVIEW

The objective of our 2005 dose-ranging studies was to compare the degree and duration of effect of various doses of ONA for the treatment of glabellar lines.^3,4 We treated females with 10, 20, 30, and 40 U of ONA, and males with 20, 40, 60, and 80 U. In the female study we found that although there was a significant difference in response rates between the 10-U dose and each of the top 3 doses at Months 1, 2, and 3 (P < 0.0294), no differences in duration or response rates were observed between the top 3 doses (20, 30, and 40 U) of ONA at any of the time points observed.³

It is interesting that 17 years later the 40-U dose seems to be separating out as giving at least another month of effect with complete subject satisfaction as demonstrated by the FLSQ. Our 2017 study compared placebo to 20 U of ONA and to 20, 40 and 60 U of daxibotulinumtoxin A.² The Kaplan-Meier graph showed ONA to have a median response duration of ≥1-point improvement of 18.8%, more than the 16% 24-week response to 20 U ONA observed in the current study.¹ Joseph et al’s 40-U ONA group showed a 32% ≥1-grade improvement at 24 weeks, an exact correspondence with our previous work. The 60- and 80-U groups in Joseph et al’s paper also did not lift the female dose-response curve.

DILUTION

In our 2005 female dose-ranging study, injection volume for all doses was kept constant to preserve masking.^3,4 The total injected volume was 0.4 mL in all groups (procerus, 0.08 mL; corrugator and medial orbicularis, 0.06 mL each on both sides; and midpupillary orbicularis, 0.04 mL on each side). In our 2017 study, the ONA dilution volume was on-label at 2.5 mL per 100 U or 4 U per 0.1 mL.² The injection volume in the current study was reduced from the on-label 0.1 mL per injection to 0.05 mL per injection and the same 5-point injection pattern was followed.

In a recent publication on high doses discussing all FDA-approved BoNT-A products, the effect of injection volume was also addressed: “Of note, for BoNT-A products, the registration dose, when administered in a smaller total volume, appears to give rise to more durable results than those observed in pivotal trials, implicating product concentration as an important consideration. Importantly, at higher doses, extended duration of effect does not appear to be at the expense of natural-looking results.” ⁵

We are all aware that there is no standardized comparative neuromodulator unit because all approved neuromodulators are produced by proprietary manufacturing processes. However, we certainly can compare dilution volumes. This excellent paper shows that at 50% dilution, the 20-U ONA group achieved 16% ≥1-point improvement at 24 weeks. This is an unexpected contrast to our 2017 study, in which 20 U achieved 18.8% >1-point improvement at 24 weeks with on-label dilution!

This excellent paper promotes the concept of higher dosing being aesthetically acceptable and safe. It also shows the need for a multicenter study evaluating dilution which would have important implications for us all from the perspectives of patient results and satisfaction, economics, and practice management. I thank the Editor for the opportunity to comment on this superb paper.

Disclosures

Dr Carruthers is a consultant and principal investigator for Alastin (Carlsbad, CA), Allergan (Irvine, CA), Alphaeon (Irvine, CA), Appiell (Los Altos, CA), Avari (Vancouver, BC, Canada), Bonti (Lake Bluff, IL), Evolus (Newport Beach, CA), Fount Bio (Cambridge, MA), InMode (Lake Forest, CA), Jeune Aesthetics (Pittsburgh, PA), Merz (Frankfurt, Germany), and Revance (Nashville, TN); is an author and editor for Elsevier (Amsterdam, the Netherlands); is an assistant editor for Dermatologic Surgery; and is a stockholder in Revance BioPharma.

Funding

The author received no financial support for the research, authorship, and publication of this article.

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