efficacy results were seen in the 100U group. Sustained efficacy at the 20U labeled INCO dose was also notable, including a median duration of effect for none or mild of 113 days.
Preclinical studies have demonstrated that increased INCO doses result in more BoNT binding to motor endplates, allowing more light chain molecules to reach the cytosol of the neuron.17 It takes longer to degrade additional light chain molecules, and hence, the duration of effect is prolonged. Clinical studies with increased doses of other BoNT products have demonstrated the same effect for treatment of GFL (Table 4).18–22
The duration of effect of INCO achieved in this study is especially notable because a large proportion of subjects (85.9%) were rated as severe by the investigator on the FWS at maximum frown at baseline. For secondary variables assessing duration of effect and response rates for effect defined by a score of none or mild, these subjects had to achieve at least a 2-point improvement, indicating that a greater duration of effect with INCO can be achieved even in these difficult to treat patients. The large proportion of severe subjects makes it difficult to compare these results to other trials involving large doses of BoNT/A products because these typically have included much lower proportions of subjects with severe GFL (31%–53%) per treatment group.18–20
In pairwise comparison of INCO dose groups, the increase in dose may not have been large enough to induce a statistically significant difference in duration of effect since the pharmacodynamics of BoNT/A are not dose-proportional. Differences in median time to return to baseline between dose groups might also be limited due to the predefined interval period between visits. Return to baseline could only be recorded at visits, which were performed every 30 days according to the clinical study protocol.
The safety analysis results were in line with the previous stage 1 findings that doses of INCO greater than 20U do not pose an increased risk of AEs and are as safe as 20U. Notably, the incidence of eyelid ptosis (N=4) in the total SES (N=241) was 1.7% (20U:0[0%], 50U:0[0%], 75U:2[3.3%], and 100U:2[3.4%]). The ptosis incidence was low and both the incidence and duration (44–108 days) were within the range for the approved 20U dose and comparable to other BoNT/A products.
The use of higher doses in aesthetic treatment is becoming more common. These results support the safety of using INCO in such an approach (eg, for large areas that require multiple injections up to 75 or 100U INCO, such as the full face), particularly in the context of the potentially lower immunogenicity of INCO.4–9 OnabotulinumtoxinA (Botox®/Vistabel®, Allergan Inc.), prabotulinumtoxinA (Nabota®, Daewong Therapeutics, Korea/ Jeuveau®, Evolus Inc., USA/Nuceiva®, Evolus Inc., Canada, Europe), and abobotulinumtoxinA (Dysport®/Azzalure®, Ipsen Pharma, Wrexham, UK) contain complexing proteins and/ or denatured BoNT protein that may induce the production of neutralizing antibodies that can lead to a decreased effect over time or treatment non-response.10,24 DaxibotulinumtoxinA (Revance Therapeutics, Inc., Nashville, TN, USA), which contains a virally-derived protein transduction domain (PTD), has been shown to induce detectable antibody titers in monkeys, but no real-world evidence in humans is available at this time.25,26
There is also an increasing desire from clinicians for more flexibility in BoNT dosing and intervals between treatments.27 These results support an increased flexibility with INCO (eg, a lower dose more often or a higher dose less often) to achieve different patient needs and preferences, which are paramount in determining treatment approach.
Limitations of the study include the large proportion of subjects with severe grade GFL, which may not be representative of a clinician's patient population. Additionally, although this phase 2 study was not designed for confirmatory comparisons between dose groups, the Kaplan-Meier plot (Figure 2) revealed clear differences in duration of effect between all pairs of dose groups when looking at different time intervals between day 90 and day 300. Few subjects in any dose group returned to baseline severity by day 90 (month 3), and nearly all subjects had returned to baseline by day 300 (month 10). Interpretation of results should focus on overall trends in the Kaplan-Meier plot, which clearly shows that time to return to baseline severity increases with increasing the INCO dose. While a clear doseresponse was demonstrated in our study, the dilution ratio may also play a role when it comes to duration of effect; however, further research would be required to confirm the role that the amount of diluent/injection volume plays.
Preclinical studies have demonstrated that increased INCO doses result in more BoNT binding to motor endplates, allowing more light chain molecules to reach the cytosol of the neuron.17 It takes longer to degrade additional light chain molecules, and hence, the duration of effect is prolonged. Clinical studies with increased doses of other BoNT products have demonstrated the same effect for treatment of GFL (Table 4).18–22
The duration of effect of INCO achieved in this study is especially notable because a large proportion of subjects (85.9%) were rated as severe by the investigator on the FWS at maximum frown at baseline. For secondary variables assessing duration of effect and response rates for effect defined by a score of none or mild, these subjects had to achieve at least a 2-point improvement, indicating that a greater duration of effect with INCO can be achieved even in these difficult to treat patients. The large proportion of severe subjects makes it difficult to compare these results to other trials involving large doses of BoNT/A products because these typically have included much lower proportions of subjects with severe GFL (31%–53%) per treatment group.18–20
In pairwise comparison of INCO dose groups, the increase in dose may not have been large enough to induce a statistically significant difference in duration of effect since the pharmacodynamics of BoNT/A are not dose-proportional. Differences in median time to return to baseline between dose groups might also be limited due to the predefined interval period between visits. Return to baseline could only be recorded at visits, which were performed every 30 days according to the clinical study protocol.
The safety analysis results were in line with the previous stage 1 findings that doses of INCO greater than 20U do not pose an increased risk of AEs and are as safe as 20U. Notably, the incidence of eyelid ptosis (N=4) in the total SES (N=241) was 1.7% (20U:0[0%], 50U:0[0%], 75U:2[3.3%], and 100U:2[3.4%]). The ptosis incidence was low and both the incidence and duration (44–108 days) were within the range for the approved 20U dose and comparable to other BoNT/A products.
The use of higher doses in aesthetic treatment is becoming more common. These results support the safety of using INCO in such an approach (eg, for large areas that require multiple injections up to 75 or 100U INCO, such as the full face), particularly in the context of the potentially lower immunogenicity of INCO.4–9 OnabotulinumtoxinA (Botox®/Vistabel®, Allergan Inc.), prabotulinumtoxinA (Nabota®, Daewong Therapeutics, Korea/ Jeuveau®, Evolus Inc., USA/Nuceiva®, Evolus Inc., Canada, Europe), and abobotulinumtoxinA (Dysport®/Azzalure®, Ipsen Pharma, Wrexham, UK) contain complexing proteins and/ or denatured BoNT protein that may induce the production of neutralizing antibodies that can lead to a decreased effect over time or treatment non-response.10,24 DaxibotulinumtoxinA (Revance Therapeutics, Inc., Nashville, TN, USA), which contains a virally-derived protein transduction domain (PTD), has been shown to induce detectable antibody titers in monkeys, but no real-world evidence in humans is available at this time.25,26
There is also an increasing desire from clinicians for more flexibility in BoNT dosing and intervals between treatments.27 These results support an increased flexibility with INCO (eg, a lower dose more often or a higher dose less often) to achieve different patient needs and preferences, which are paramount in determining treatment approach.
Limitations of the study include the large proportion of subjects with severe grade GFL, which may not be representative of a clinician's patient population. Additionally, although this phase 2 study was not designed for confirmatory comparisons between dose groups, the Kaplan-Meier plot (Figure 2) revealed clear differences in duration of effect between all pairs of dose groups when looking at different time intervals between day 90 and day 300. Few subjects in any dose group returned to baseline severity by day 90 (month 3), and nearly all subjects had returned to baseline by day 300 (month 10). Interpretation of results should focus on overall trends in the Kaplan-Meier plot, which clearly shows that time to return to baseline severity increases with increasing the INCO dose. While a clear doseresponse was demonstrated in our study, the dilution ratio may also play a role when it comes to duration of effect; however, further research would be required to confirm the role that the amount of diluent/injection volume plays.
CONCLUSION
These results clearly demonstrate that doses of INCO up to 100U
are well tolerated, consistent with the known safety profile of a
20U dose, and increasing doses of INCO prolong the duration
of effect for GFL.
DISCLOSURES
All authors except SR and GK have been consultants and/or
investigators for Merz Pharmaceuticals GmbH and Merz North
America, Inc. SR and GK are employees of Merz Pharmaceuticals
GmbH. This study and publication were sponsored by Merz
Aesthetics.
ACKNOWLEDGMENT
We wish to thank all study investigators and the R&D team for
conducting the study. Medical writing support was provided
for the first draft by Steve Mitchell, Merz North America, Inc., in
accordance with Good Publication Practice (GPP3) guidelines.
