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.
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.