Botulinum toxin type E associated with reduced itch and pain during wound healing and acute scar formation following excision and linear repair on the forehead: A randomized controlled trial

To the Editor: Muscle relaxation using botulinum neurotoxin serotype A (BoNT/A) has been reported to lessen postoperative scar formation,1Honeybrook A. Lee W. Woodward J. Woodard C. Botulinum toxin-A and scar reduction: a review.Am J Cosmet Surg. 2018; 35: 165-176Crossref Google Scholar presumably by reducing tension on healing wounds by weakening the underlying muscle. However, injection at the time of surgery may not reduce muscle motion for 2-3 days, during which time a fresh wound is under tension. Botulinum neurotoxin serotype E (BoNT/E) affects the same molecular target as BoNT/A but with onset within 1 day and a duration of approximately 3-4 weeks, potentially just long enough to stabilize the acute wound.2Flynn T.C. Use of intraoperative botulinum toxin in facial reconstruction.Dermatol Surg. 2009; 35: 182-188Crossref PubMed Scopus (24) Google Scholar,3Yoelin S.G. Dhawan S.S. Vitarella D. et al.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: 847e-855eCrossref PubMed Scopus (23) Google Scholar EB-001 (now AGN-151,568) is currently in Phase 3 development as a rapid onset neuromodulator (NCT05248880, NCT0524886). This study evaluated the safety and efficacy of a single treatment of BoNT/E (EB-001; Bonti, Inc, an AbbVie Company; not yet marketed) for improving wound healing and reducing scar formation in patients undergoing excisions with linear repairs of the forehead. Adult patients receiving Mohs surgery and bilayered linear repair of ≥2 cm including deep absorbable and superficial nonabsorbable sutures were randomly assigned (2:1) to receive BoNT/E injections or saline (placebo) immediately following repair. A volume of 0.5 mL of product, reconstituted using sterile, non-preserved saline solution of 0.9% sodium chloride, containing 2.8 ng BoNT/E (a value from initial stages of development, to be transitioned to unit measurement), was evenly distributed among 5 points and injected into the frontalis muscles (Fig 1). Blinded personnel assessed healing and scar formation at days 1 (2 hours post-injection), 2, 8, 30, and 90 post-treatment using the Visual Analog Scale (VAS), Scar Cosmesis Assessment and Rating (SCAR) scale,4Kantor J. The SCAR (scar cosmesis assessment and rating) scale: development and validation of a new outcome measure for postoperative scar assessment.Br J Dermatol. 2016; 175: 1394-1396Crossref PubMed Scopus (33) Google Scholar Patient and Observer Scar Assessment Scale (POSAS),5Draaijers L.J. Tempelman F.R.H. Botman Y.A.M. et al.The patient and observer scar assessment scale: a reliable and feasible tool for scar evaluation.Plast Reconstr Surg. 2004; 113 (discussion 1966-1967): 1960-1965Crossref PubMed Scopus (525) Google Scholar and Facial Wrinkle Scale by Investigator Assessment (FWS-IA) (Table I). Treatment-emergent adverse events (TEAEs) were monitored.Table IEfficacy assessmentsScaleDescriptionVASEvaluates scar appearance from worst (0) to best (10) using a 10-cm horizontal line.SCAR scaleMeasures postoperative scar cosmesis based on 6 observer-scored items (scar spread, erythema, dyspigmentation, track marks or suture marks, hypertrophy/atrophy, overall impression) and 2 patient-scored items (itch and pain), with higher scores indicating greater severity and total scores ranging from 0 (best possible scar) to 15 (worst possible scar).POSASIncludes 5 observer-assessed items of vascularity, pigmentation, thickness, relief, and pliability, and 6 patient assessments of pain, itching, color, stiffness, thickness, and irregularity, with each item scored from 0 to 10, with higher scores indicating greater severity; total scores range from 0 to 110.FWS-IAInvestigator assessment of the severity of forehead lines as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), evaluated at rest and then at maximum eyebrow elevation.FWS-IA, Facial wrinkle scale by investigator assessment; POSAS, patient and observer scar assessment scale; SCAR, scar cosmesis assessment and rating; VAS, visual analog scale. Open table in a new tab FWS-IA, Facial wrinkle scale by investigator assessment; POSAS, patient and observer scar assessment scale; SCAR, scar cosmesis assessment and rating; VAS, visual analog scale. Among 13 participants, 9 received BoNT/E and 4 received saline. One participant randomized to BoNT/E was excluded from efficacy analyses due to wound dehiscence associated with high tension closure but included in safety analyses (n = 9). Participants analyzed for efficacy (BoNT/E, n = 8; placebo, n = 4) were 58.3% (7/12) male and 100% White (not Hispanic); mean (SD) age was 61.8 (11.39) years. There were no differences in improvement over time between 2.8 ng BoNT/E and placebo on primary measures. However, SCAR subscale items for “itch” and “pain” were favorable for BoNT/E. No participants in the BoNT/E group reported itch, compared with 75% and 50% at days 2 and 8 in the placebo group, respectively. Similarly, 75% of participants in the BoNT/E group versus 100% in the placebo group reported pain on day 2; 25% of participants in the BoNT/E group versus 50% in the placebo group reported pain on day 8. One (1/9, 11.1%) participant who received BoNT/E experienced facial asymmetry due to intraoperative temporal nerve injury before BoNT/E injection. Compared with placebo, a single dose of 2.8 ng BoNT/E was safe and nominally improved itch and pain but not other aspects of wound healing or scar formation. Future studies may assess larger or less well-approximated repairs. This study was limited by the small sample, variability in surgical wound size, fixed dose, and fixed injection paradigm. As a rapid onset neurotoxin, BoNT/E may help improve patient comfort during the acute phase of scar formation. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information- sharing/data-and-information-sharing-with-qualified-researchers.html. Disclosures including pharmaceutical and device product(s): Murad Alam has no financial interests to declare in relation to the content of this article, and has not received payment or stock from Bonti, AbbVie, or any related organization. Domenico Vitarella, at the time of study conduct, was an employee of Bonti Inc and held Bonti stock prior to its acquisition by Allergan, an AbbVie Company. Wajdie Ahmad, at the time of study conduct, was a cofounder and chief operating officer of Bonti Inc and held Bonti stock prior to its acquisition by Allergan, an AbbVie Company. Susan Abushakra, at the time of study conduct, was a cofounder and chief medical officer of Bonti Inc, was co-inventor on several BoNT/E (EB-001) patents, and held Bonti stock prior to its acquisition by Allergan, an AbbVie Company. Cheri Mao is a former employee of AbbVie. Mitchell F. Brin is an employee of, and owns stock/stock options in, AbbVie. This product (BoNT/E; EB-001) is not labeled for the use under discussion.