IncobotulinumtoxinA Demonstrates Safety and Prolonged Duration of Effect in a Dose-Ranging Study for Glabellar Lines

October 2020 | Volume 19 | Issue 10 | Original Article | 985 | Copyright © October 2020


Published online September 30, 2020

Martina Kerscher PhDa, Sabrina Fabi MDb, Tanja Fischer MDPhD, Michael Gold MDd, John Joseph MDe, Welf Prager MDf, Berthold Rzany MD ScMg, Steve Yoelin MDh, Susanna Roll Dr. med, Gudrun Klein PhDi, Corey Maas MD PhDj

aUniversität Hamburg, Hamburg, Germany bCosmetic Laser Dermatology, San Diego, CA cHaut- & Lasercentrum, Potsdam, Germany dGold Skin Care Center, Tennessee Clinical Research Center, Nashville, TN eJohn Joseph MD, Private Practice, Beverly Hills, CA fPrager and Partner Dermatologische Praxis, Hamburg, Germany gHautärzte RZANY&HUND, Berlin, Germany hMedical Associates, Inc., Newport Beach, CA iMerz Pharmaceuticals GmbH, Frankfurt am Main, Germany jThe Maas Clinic, San Francisco, CA

While a dose effect was demonstrated in our study, the amount of diluent/injection volume may also play a role when it comes to duration of effect. The combination of higher doses and low injection volumes resulted in a high degree of efficacy with sustained duration of effect while maintaining a favorable safety profile. Sustained efficacy beyond 4 months for the 20U dose group is notable for the majority of subjects in this first cohort of 30 subjects. Previous INCO studies have demonstrated efficacy up to 4 months for the majority of patients; however, these previous studies did not extend beyond day 120 or utilize a time to event study design to investigate longer duration.5,6,9,20

Safety
The results of this Phase 2, dose-ranging study demonstrate INCO doses of 50U and 75U are safe, well tolerated, and safety is consistent with the known safety profile of the 20U dose for GFL. Notably, the incidence of eyelid ptosis (N=2) in the total SES (N=151) was 1.3%, and no other TEAESIs related to treatment occurred. This favorable safety profile was not unexpected given a previous dose-escalation study in which patients with spasticity received 3 consecutive injection cycles of 400U, 600U, and 600–800U INCO, respectively, without emergence of new TEAESIs.21

INCO has demonstrated an excellent safety profile across all large, well-controlled clinical studies, as determined by a pooled safety analysis of 13 studies evaluating more than 6,000 INCO treatments in 2,547 aesthetic patients.22 Furthermore, INCO is the only BoNT/A with no subjects in clinical studies who have developed neutralizing antibodies and demonstrated a secondary lack of treatment response as outlined in recent updates to the INCO prescribing information.1 A recent pharmacovigilance analysis of the US FDA AE reporting system database assessed a total of 23,789 BoNT/A cases reported for therapeutic and aesthetic patients. The rate of AEs that involved decreased effect when on treatment for at least 1 year was 0% for INCO compared to other BoNT/As. Causal relationships cannot be established from pharmacovigilance analyses; however, an association was identified in this analysis of one of the largest BoNT/A safety data sets.23

By utilizing the only state-of-the-art manufacturing process that employs a 2-step chromatographic purification process to extract from the complexing proteins and leave just the active 150kDa molecule, INCO provides the lowest protein load available compared to other BoNT/A formulations.1,24-29 INCO contains 0.44ng 150kDa neurotoxin per 100U (0.088 ng/20U dose) and has a high specific activity of 227U/ng, consistent with no denaturing of the BoNT complex during the INCO chromatographic purification process.24-29 In contrast, ONA, ABO, and PRA all contain complexing proteins and/or denatured BoNT protein that may initiate an immune response, leading to production of neutralizing antibodies that can be associated with decreased effect over time or treatment non-response.24,31 Investigational drug DaxibotulinumtoxinA (DAXI; RT002, Revance Therapeutics Inc.) contains a virally-derived protein transduction domain (PTD), as part of an added excipient and stabilizer (RTP004). While PTDs have shown promise in pre-clinical efforts for transporting cargo across the cellular membrane, many PTDs have demonstrated immunogenic potential.29 In line with these findings, DAXI was shown to induce detectable antibody titers to RTP004 within 3 months of use in 30% of tested monkeys, but no long-term immunogenicity data in humans is available at this time.30,33

Limitations of our study include low sample size (n=30) in the 20U group for Stage 1, that results in limited power for statistical comparisons to the higher doses. Strengths of our study include a robust observation period of 360 days and high subject retention. Additional strengths include enrollment of males (12.6%), and >80% of subjects with GFL rated “severe” at baseline and across each dose group indicating that even difficult-to-treat patients can achieve long duration with INCO.

CONCLUSION

The results of this study demonstrate a dose effect of at least 6 months duration with higher doses in the majority of GFL subjects. Remarkably, this prolonged duration of effect with INCO was achieved even for difficult-to-treat patients with severe GFL. All doses were well tolerated, and safety was consistent with the known safety profile of 20U INCO for GFL.

ACKNOWLEDGMENT

Medical writing support was provided for the first draft by Emma Robertson, formerly of Merz Pharmaceuticals GmbH, in accordance with Good Publication Practice (GPP3) guidelines.

REFERENCES

1. Merz Pharmaceuticals GmbH. Xeomin - US Highlights of Prescribing Information. Available at: https://www.xeominaesthetic.com/wp-content/ uploads/2019/05/XEOMIN-Full-Prescribing-Information-including-MedGuide. pdf. Accessed April, 2020. Merz Pharmaceuticals GmbH. Bocouture - Summary of Product Characteristics. Available at: https://www.medicines. org.uk/emc/product/7418/smpc. Accessed April, 2020.
2. Allergan Inc. Highlights of prescribing information - Botox®. 2017. Available from:https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/ 103000s5302lbl.pdf. Accessed 2 October 2018
3. Jeuveau Highlights of prescribing information. 2019. Availablefrom:https:// www.accessdata.fda.gov/drugsatfda_docs/label/2019/761085s000lbl.pdf. Accessed 1 July 2020
4. Galderma (U.K.) Ltd. Azzalure® Summary of Product Characteristics. 2018. Available from:https://www.medicines.org.uk/emc/product/6584/smpc. Accessed 2 October 2018.