declined for the remainder of the study (Figure 2). Erythema, observed in the greatest number of patients at week 2, was the most prominent parameter impacting the mean LSR composite score.
Both patients with quantifiable hMAP3 concentrations on day 15 experienced LSRs. The 5-year-old patient’s LSR composite score on day 14 was 4 (highest possible score was 24), slightly above the overall safety population mean of 3.26 (SD, 3.33; range 0-11). On day 5, this patient experienced an AE of mild application-site pain (considered definitely related to berdazimer gel, 10.3%). No action was taken regarding application of berdazimer gel 10.3%, the mild application-site pain resolved, and no other TEAEs were reported. The patient completed all study visits for both treatment periods.
The 11-year-old patient's day 14 composite LSR score was 11 compared with the overall safety population mean day composite score of 3.26 (SD, 3.33; range 0-11), indicating she had the highest LSR composite score among all patients. On day 3, the patient experienced an AE of moderate applicationsite pain (considered definitely related to berdazimer gel 10.3%); on day 15, this patient experienced application-site erythema, application-site exfoliation, and application-site scab (all were moderate in severity, and all were considered definitely related to berdazimer gel, 10.3%). No action was taken regarding application of berdazimer gel, 10.3%, and all TEAEs had resolved by day 58. The composite LSR scores at Weeks 4, 8, and 12 were 3, 0, and 0, respectively. The patient completed all study visits for both treatment periods.
Other patients had composite LSR scores of ≥8 during the study; however, none of the patients had quantifiable hMAP3 concentrations. No patients had LSRs that were believed to be suggestive of allergic contact dermatitis.
Electrocardiogram Parameters
There were no clinically significant findings or meaningful changes in ECG parameters, including heart rate, PR interval, QRS duration, P-R-T axis, or RR interval. There were no confirmed cardiac AEs. A mild TEAE of prolonged QT interval was reported in the 11-year-old female patient with quantifiable hMAP3 levels on day 15; this AE was considered by the investigator unlikely to be related to berdazimer gel, 10.3%.
Effectiveness
Throughout both study periods, progressive decreases from baseline in molluscum lesion counts were observed. At week 12, the mean decrease from baseline was 68.4% (median decrease, 86.1%). Four patients achieved complete MC clearance at week 12, including the patient with 4 quantifiable hMAP3 levels on day 15.
Both patients with quantifiable hMAP3 concentrations on day 15 experienced LSRs. The 5-year-old patient’s LSR composite score on day 14 was 4 (highest possible score was 24), slightly above the overall safety population mean of 3.26 (SD, 3.33; range 0-11). On day 5, this patient experienced an AE of mild application-site pain (considered definitely related to berdazimer gel, 10.3%). No action was taken regarding application of berdazimer gel 10.3%, the mild application-site pain resolved, and no other TEAEs were reported. The patient completed all study visits for both treatment periods.
The 11-year-old patient's day 14 composite LSR score was 11 compared with the overall safety population mean day composite score of 3.26 (SD, 3.33; range 0-11), indicating she had the highest LSR composite score among all patients. On day 3, the patient experienced an AE of moderate applicationsite pain (considered definitely related to berdazimer gel 10.3%); on day 15, this patient experienced application-site erythema, application-site exfoliation, and application-site scab (all were moderate in severity, and all were considered definitely related to berdazimer gel, 10.3%). No action was taken regarding application of berdazimer gel, 10.3%, and all TEAEs had resolved by day 58. The composite LSR scores at Weeks 4, 8, and 12 were 3, 0, and 0, respectively. The patient completed all study visits for both treatment periods.
Other patients had composite LSR scores of ≥8 during the study; however, none of the patients had quantifiable hMAP3 concentrations. No patients had LSRs that were believed to be suggestive of allergic contact dermatitis.
Electrocardiogram Parameters
There were no clinically significant findings or meaningful changes in ECG parameters, including heart rate, PR interval, QRS duration, P-R-T axis, or RR interval. There were no confirmed cardiac AEs. A mild TEAE of prolonged QT interval was reported in the 11-year-old female patient with quantifiable hMAP3 levels on day 15; this AE was considered by the investigator unlikely to be related to berdazimer gel, 10.3%.
Effectiveness
Throughout both study periods, progressive decreases from baseline in molluscum lesion counts were observed. At week 12, the mean decrease from baseline was 68.4% (median decrease, 86.1%). Four patients achieved complete MC clearance at week 12, including the patient with 4 quantifiable hMAP3 levels on day 15.
DISCUSSION
Once-daily topical application of berdazimer, 10.3% gel demonstrated largely minimal systemic exposure to NO as measured by the metabolite of parent compound, hMAP3, with favorable safety and tolerability in patients 2 to 12 years of age with MC. Accurate assessment of berdazimer sodium PK parameters is best achieved by measurements of the polymeric silicon-based backbone via the monomer hMAP3, which is not endogenous, rather than nitrate, which is endogenous and largely impacted by diet. There is a theoretical risk of methemoglobinemia resulting from dermal application of NO (ie, through NO binding with systemic hemoglobin); therefore, methemoglobin levels were closely monitored throughout the study.
This study supports the safety of berdazimer gel 10.3% with respect to systemic exposure in children under maximal use conditions. The PK data herein demonstrate minimal systemic exposure under maximal use conditions in children as young as 2 years of age with MC. Only 2 patients showed quantifiable plasma hMAP3 concentrations on day 15; however, the maximum concentration (33.9 ng/mL) was >10-fold lower than the no observed adverse effect level (NOAEL) in an animal toxicology study. Plasma nitrate profiles remained relatively flat across the sampling interval for both patients, suggesting there was minimal, if any, systemic absorption of berdazimer sodium. Systemic AEs were not observed.
For the 11-year-old who experienced quantifiable hMAP3 plasma levels on day 15, the patient’s LSRs may have induced disruption of the skin barrier functions and increased skin penetration of topically applied berdazimer sodium, potentially contributing to the systemic exposure measured day 15. However, other patients who had composite LSR scores of 8 or greater during the study did not have quantifiable hMAP3 concentrations. In addition, 17 of the 34 enrolled patients had 6% or higher BSA treated and, of those, only the 5-year-old patient (6.05% BSA treated) had a single quantifiable hMAP3 concentration at any timepoint during the study. The 11-year-old patient had 3.69% BSA treated, below the overall mean of 5.96% BSA treated. Thus, there does not appear to be a correlation between systemic absorption of berdazimer sodium and either high composite LSR scores or % BSA treated based on these data. TEAEs were mostly mild or moderate, with application-site pain reported as the most frequent TEAE.
TEAEs were mostly mild or moderate and considered by investigators to be related to berdazimer gel, 10.3%. No TEAEs were serious, and none required a change in berdazimer dosing. Safety and tolerability data, coupled with PK data, support a favorable safety profile for berdazimer gel, 10.3%.
Berdazimer gel, 10.3% is in late-stage clinical development8 and,
This study supports the safety of berdazimer gel 10.3% with respect to systemic exposure in children under maximal use conditions. The PK data herein demonstrate minimal systemic exposure under maximal use conditions in children as young as 2 years of age with MC. Only 2 patients showed quantifiable plasma hMAP3 concentrations on day 15; however, the maximum concentration (33.9 ng/mL) was >10-fold lower than the no observed adverse effect level (NOAEL) in an animal toxicology study. Plasma nitrate profiles remained relatively flat across the sampling interval for both patients, suggesting there was minimal, if any, systemic absorption of berdazimer sodium. Systemic AEs were not observed.
For the 11-year-old who experienced quantifiable hMAP3 plasma levels on day 15, the patient’s LSRs may have induced disruption of the skin barrier functions and increased skin penetration of topically applied berdazimer sodium, potentially contributing to the systemic exposure measured day 15. However, other patients who had composite LSR scores of 8 or greater during the study did not have quantifiable hMAP3 concentrations. In addition, 17 of the 34 enrolled patients had 6% or higher BSA treated and, of those, only the 5-year-old patient (6.05% BSA treated) had a single quantifiable hMAP3 concentration at any timepoint during the study. The 11-year-old patient had 3.69% BSA treated, below the overall mean of 5.96% BSA treated. Thus, there does not appear to be a correlation between systemic absorption of berdazimer sodium and either high composite LSR scores or % BSA treated based on these data. TEAEs were mostly mild or moderate, with application-site pain reported as the most frequent TEAE.
TEAEs were mostly mild or moderate and considered by investigators to be related to berdazimer gel, 10.3%. No TEAEs were serious, and none required a change in berdazimer dosing. Safety and tolerability data, coupled with PK data, support a favorable safety profile for berdazimer gel, 10.3%.
Berdazimer gel, 10.3% is in late-stage clinical development8 and,
