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

Abstract

Background: Recently reported clinical data provides evidence that increasing the dose of botulinum toxin A increases the duration of efficacy. A 2-stage Phase 2, randomized, double-blind study investigated the duration of effect and safety of IncobotulinumtoxinA (INCO; Xeomin ® , Bocouture ® ; Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) at doses higher than the approved 20 units (U) for glabellar frown lines (GFL). Primary safety and efficacy endpoints of Stage 1 are reported here. Methods: 151 subjects with moderate-to-severe GFL were randomized 1:2:2 to receive a single treatment with 20U, 50U, or 75U INCO. The primary efficacy endpoint was median duration of at least 1-point improvement from baseline as assessed by investigator at maximum frown on the Facial Wrinkle Scale. Results: The median duration of effect was 185 days for the 50U dose group (95% CI:[182, 205]) and 210 days for the 75U dose group (95% CI:[182, 217]). Duration of effect was significantly longer for 75U vs 50U (P=0.0400) and 20U (P=0.0166) despite the study not being powered for confirmatory statistical significance testing between the dose groups. Duration of effect was also longer for 50U vs 20U, however; statistical significance was not reached (P=0.4349). The incidence of treatment-related adverse events was low across all doses (20U:2[6.7%], 50U:6[10.0%] and 75U:8[13.1%]). Conclusions: These results demonstrate a dose effect of at least 6 months duration with higher doses in the majority of GFL subjects. All doses were well tolerated and safety was consistent with the known safety profile of 20U INCO for GFL.

Botulinum Toxin Type A for Glabellar Frown Lines: What Impact of Higher Doses on Outcomes?

“…Two INCO studies were found in the literature review; neither was a placebo-controlled trial. A Phase 2, randomized, double-blind trial investigated INCO 20, 50 and 75 U (up to 3.75-fold the on-label dose) in 151 subjects, of whom 87% were female and 85% had severe glabellar lines at maximum frown at baseline, on a 4-point facial wrinkle scale (FWS) [ 20 ]. Subjects were required to remain in the study for at least 180 ± 7 days (25.7 ± 1 weeks) ( Table 2 ).…”

“…For ONA, increasing the dose by 2–4 times was associated with greater responder rates and longer duration of response than the standard 20 U dose [ 19 ]. A 4-fold increase in the ONA on-label dose (from 20 to 80 U) increased the median duration to around 6 months [ 19 ], although the same duration of response was observed at 40 and 80 U. Dose-ranging studies of INCO also suggest a trend toward increased duration of response with escalating doses; increasing the on-label dose by 3.75-fold (from 20 to 75 U) increased the median duration of response to 7 months [ 20 ] and a 5-fold increase of the on-label dose (to 100 U) increased the median duration to 9 months [ 21 ]. Another BoNT-A product, daxibotulinumtoxinA, under development for the treatment of glabellar lines, has been shown in Phase 3 studies using a dose of 40 U (planned registration dose) to achieve a median duration of response (time to return to baseline from a none or mild response) of 26.0–27.7 weeks (6.1–6.5 months) [ 33 ], which is in the same range as shown for 2.5-fold the on-label dose of INCO [ 21 ] and the on-label dose of ABO reported in Joseph et al [ 18 ] ( Table 2 ).…”

“…Furthermore, it has been shown that there are notably greater amounts of active neurotoxin 150 kDa molecule in the standard on-label dose of ABO than in on-label doses of ONA or INCO [ 16 ]. Indeed, this may in part explain the lesser fold-increase in on-label dose needed to extend duration of effect with ABO than ONA or INCO [ 18 , 19 , 20 ]. A standardization of the dose units or establishment of a conversion ratio between toxin products would facilitate comparison, but no consensus has been reached [ 35 ].…”

“…In contrast, a prior study of ONA (before 2015) using the same dose range in men showed no plateau in efficacy with doses ≥2-fold the on-label dose, and greatest benefits with a 4-fold higher dose (80 U) [ 39 ]. For INCO, the data on duration of response in the two reviewed high-dose studies did not reveal a ceiling dose within the studied dose range (up to 5-fold the on-label dose) [ 20 , 21 ]. Altogether, this suggests that ceiling doses may exist, but are likely different for men and women.…”

“…In the recent high-dose studies reviewed, all BoNT-A preparations were well tolerated over a range of doses, with no apparent dose-dependent increase in AEs compared with the standard dose, and no new safety concerns identified with doses higher than on-label, for all doses tested of ABO, ONA and INCO [ 17 , 18 , 19 , 20 , 21 ]. Of note, the doses in these studies were raised by decreasing the dilution volume of BoNT-A, thereby injecting a more concentrated solution.…”