Primary Safety Analyses
The incidence of TEAEs over the entire MP of up to 360 days was 10 (33.3%) for the INCO 20U group (N=30), 23 (38.3%) for the 50U group (N=60), 26 (42.6%) for the 75U group (N=61), and 59 (39.1%) in total (n=151). No serious TEAEs occurred (Table 2). One TEAE, a pregnancy, led to premature discontinuation of the study. The outcome was a healthy baby.
The incidence of treatment-related TEAEs was 2 (6.7%), 6 (10.0%) and 8 (13.1%) for the 20, 50 and 75U groups, respectively, and 16 (10.6%) in total (n=151). All treatment-related TEAEs were transient and mild to moderate in severity. In the entire SES, incidence of >1% was reported for only 4 Preferred Terms (Med- DRA version 22.1): nodule (2[1.3%]), hypoaesthesia (2[1.3%]), headache (6[4.0%]), and eyelid ptosis (2[1.3%]). Over all three dose groups, only 3 subjects (2.0%) reported TEAESIs: eyelid ptosis (2[1.3%]; both related to treatment) and constipation (1[0.7%]; unrelated to treatment). The incidence rates of related TEAEs and of TEAESIs on Preferred Term level are very low and thus not reported by dose group to avoid unblinding of investigators prior to completion of Stage 2.
The results of this study demonstrate a dose effect of at least 6 months duration with higher doses for the majority of GFL subjects as assessed by ≥1-point improvement to baseline severity at maximum frown on the FWS. Of note is the high proportion of subjects in this study with GFL rated “severe” at baseline (83–85% of subjects in all dose groups), indicating that such long duration can be achieved with INCO, even for difficult-to-treat patients with severe GFL. In similar studies investigating duration of effect for other neuromodulators, only 35%–41% of subjects per active treatment group had severe GFL at baseline.12-14
Preclinical studies demonstrate higher doses result in a longer duration of effect because more BoNT binds to motor endplates, allowing more light chain molecules can reach the cytosol of the neuron.15 The degradation of more light chain molecules takes a longer time, consequently, the duration is prolonged.16 Clinical studies with other commercially available neuromodulators have also demonstrated longer duration of effect with increasing dose in the treatment of GFL as described in Table 3. It is important to note that dosing should be based on the clinical data for each product. In an open-label, investigatorinitiated study, 30 subjects treated with 120U ABO exhibited a median duration of response of 150 days (21.4 weeks; 95% CI: 120, 180) compared to the 85 days (12.1 weeks) reported in pivotal studies for 50U ABO.14 A recent pharmacology (Phase 1b) study investigating duration for 40, 60, and 80U vs 20U ONA determined a median duration of response of 19.7 weeks (137.9 days; 95% CI: 16.1, 20.3) for the 20U group and 24 weeks (168 days; 95% CI: 20.1, 24.4) for the 40U group.17 Duration of response for investigational drug DAXI was explored for the 20, 40, and 60U doses compared to 20U ONA and placebo in a Phase 2 dose-ranging study.18 A statistically significant difference in median duration of response was observed for 40U DAXI vs 20U ONA, but not for 20U DAXI vs 20U ONA in this Phase 2 trial. Two subsequent Phase 3 studies investigated duration of response for the 40U dose vs placebo and confirmed the Phase 2 median of 24 weeks (168 days).19