METHODS
Study Designs and Participants
The Phase 1 study was an open-label, proof-of-concept, singlecenter study in adults (aged ≥18 years) with clinically typical AK on the forearm. Participants were enrolled into 4 sequential cohorts: Cohort 1 received tirbanibulin ointment 1% 50 mg/day once daily for 3 days over 25 cm2 treatment area with 4–8 AK lesions; Cohort 2 received 200 mg/day once daily for 3 days over 100 cm2 treatment area with 8–16 AK lesions; Cohort 3 and Cohort 4 were similar to Cohort 1 and Cohort 2, respectively, but treatment was for 5 days. The Follow-up period was through day 45.
The Phase 2 study was an open-label, uncontrolled, doseregimen- finding, multicenter study in adults (aged ≥18 years) with clinically typical AK on the face or scalp. Participants were sequentially enrolled and received tirbanibulin ointment 1% once daily for 3 or 5 days over 25 cm2 treatment area with 4–8 AK lesions; approximately 50 mg/day per application. Response assessment was through day 57 and the Recurrence Follow-up Period was up to 12 months after day 57 for participants who achieved complete (100%) AK clearance in the treatment area at day 57. In both studies, tirbanibulin ointment 1% was formulated in a base ointment containing propylene glycol and glycerol monostearate.
These studies were conducted in accordance with the Declaration of Helsinki, 2013, the US Code of Federal Regulation, and Good Clinical Practice guidelines. The protocols, informed consent forms, and all other appropriate related documents were submitted and approved by the central Institutional Review Board, Quorum Review IRB, Seattle, WA, USA.
Assessments and Statistical Analyses
To assess activity in the Phase 1 study, AK lesion numbers at baseline, days 10, 17, 31, and 45 were summarized by cohort. Complete (100%) and partial (≥75%) AK clearance rates (defined as the proportion of participants who had 100% and ≥75% reduction in AK lesion counts, respectively, in the treatment area at day 45 compared with baseline) were evaluated for each cohort. No statistical inference was made. Participants missing an AK lesion count at day 45 were considered non-responders.
In the Phase 2 study, AK lesions at days 1 (baseline), 8, 15, 29, and 57 were summarized by cohort at each visit. Based on the number of participants who achieved 100% clearance at day 57, the complete response rate and its corresponding 95% Clopper–Pearson Exact confidence interval (CI) were estimated. AK lesion numbers at each timepoint and change from baseline were summarized by cohort at each visit and in subgroups (age, sex, AK lesion count, weight, skin type, and treatment location). The proportion of participants with partial clearance (≥75%) at day 57 were also analyzed. No statistical inference was made.
Recurrence rates and associated 95% CIs were estimated with the Kaplan-Meier method at each post-day 57 visit (at 3, 6, 9, and 12 months post-day 57) and presented by cohort for participants who achieved 100% clearance at day 57.
For both studies, safety was assessed by recording treatmentemergent adverse events (TEAEs) and their relationship to study drug; serious AEs (SAEs); laboratory evaluation of blood chemistry, hematology, and urine analysis; vital signs and electrocardiograms; and physical examinations at predetermined visits according to study protocols.
For both studies, signs of local skin reactions (LSRs; erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration) were assessed by investigators on a 5-point scale (0 [not present], 1 [minimal], 2 [mild], 3 [moderate], or 4 [severe]) at predetermined visits according to protocol.
Blood samples were collected to measure plasma concentrations of tirbanibulin pre-dose and at predetermined timepoints for both cohorts in the Phase 2 study. Plasma concentrations were analyzed using validated liquid chromatography/tandem mass spectrometry (LC-MS/MS, lower limit of detection of 0.1 ng/mL).
The Phase 1 study was an open-label, proof-of-concept, singlecenter study in adults (aged ≥18 years) with clinically typical AK on the forearm. Participants were enrolled into 4 sequential cohorts: Cohort 1 received tirbanibulin ointment 1% 50 mg/day once daily for 3 days over 25 cm2 treatment area with 4–8 AK lesions; Cohort 2 received 200 mg/day once daily for 3 days over 100 cm2 treatment area with 8–16 AK lesions; Cohort 3 and Cohort 4 were similar to Cohort 1 and Cohort 2, respectively, but treatment was for 5 days. The Follow-up period was through day 45.
The Phase 2 study was an open-label, uncontrolled, doseregimen- finding, multicenter study in adults (aged ≥18 years) with clinically typical AK on the face or scalp. Participants were sequentially enrolled and received tirbanibulin ointment 1% once daily for 3 or 5 days over 25 cm2 treatment area with 4–8 AK lesions; approximately 50 mg/day per application. Response assessment was through day 57 and the Recurrence Follow-up Period was up to 12 months after day 57 for participants who achieved complete (100%) AK clearance in the treatment area at day 57. In both studies, tirbanibulin ointment 1% was formulated in a base ointment containing propylene glycol and glycerol monostearate.
These studies were conducted in accordance with the Declaration of Helsinki, 2013, the US Code of Federal Regulation, and Good Clinical Practice guidelines. The protocols, informed consent forms, and all other appropriate related documents were submitted and approved by the central Institutional Review Board, Quorum Review IRB, Seattle, WA, USA.
Assessments and Statistical Analyses
To assess activity in the Phase 1 study, AK lesion numbers at baseline, days 10, 17, 31, and 45 were summarized by cohort. Complete (100%) and partial (≥75%) AK clearance rates (defined as the proportion of participants who had 100% and ≥75% reduction in AK lesion counts, respectively, in the treatment area at day 45 compared with baseline) were evaluated for each cohort. No statistical inference was made. Participants missing an AK lesion count at day 45 were considered non-responders.
In the Phase 2 study, AK lesions at days 1 (baseline), 8, 15, 29, and 57 were summarized by cohort at each visit. Based on the number of participants who achieved 100% clearance at day 57, the complete response rate and its corresponding 95% Clopper–Pearson Exact confidence interval (CI) were estimated. AK lesion numbers at each timepoint and change from baseline were summarized by cohort at each visit and in subgroups (age, sex, AK lesion count, weight, skin type, and treatment location). The proportion of participants with partial clearance (≥75%) at day 57 were also analyzed. No statistical inference was made.
Recurrence rates and associated 95% CIs were estimated with the Kaplan-Meier method at each post-day 57 visit (at 3, 6, 9, and 12 months post-day 57) and presented by cohort for participants who achieved 100% clearance at day 57.
For both studies, safety was assessed by recording treatmentemergent adverse events (TEAEs) and their relationship to study drug; serious AEs (SAEs); laboratory evaluation of blood chemistry, hematology, and urine analysis; vital signs and electrocardiograms; and physical examinations at predetermined visits according to study protocols.
For both studies, signs of local skin reactions (LSRs; erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration) were assessed by investigators on a 5-point scale (0 [not present], 1 [minimal], 2 [mild], 3 [moderate], or 4 [severe]) at predetermined visits according to protocol.
Blood samples were collected to measure plasma concentrations of tirbanibulin pre-dose and at predetermined timepoints for both cohorts in the Phase 2 study. Plasma concentrations were analyzed using validated liquid chromatography/tandem mass spectrometry (LC-MS/MS, lower limit of detection of 0.1 ng/mL).
RESULTS
Participant Populations
In the Phase 1 study, 30 participants were enrolled in one US site. Twenty-nine completed the study and one participant (Cohort 2) withdrew consent on day 2. All 168 participants (n=84 in each cohort) enrolled in the Phase 2 study, from 16 sites across the US, completed the treatment (100% compliance) and follow-up until day 57. Baseline characteristics of all participants met with protocol requirements and were comparable across treatment cohorts, except there were more participants with face than scalp AK lesions in the 3-day vs 5-day cohort in the Phase 2 study. The majority of participants in both studies were White, mean age >60 years, and of non-Hispanic ethnicity with Fitzpatrick skin type I–III (Table 1).
Activity
In the Phase 1 study, reductions in lesion counts from day 1 to 45 were observed in all cohorts (Figure 1). By day 45, 25%, 0%, 50%, and 12.5% of participants demonstrated 100% AK clearance in the treatment area in Cohorts 1–4, respectively (Table 2).
In the Phase 2 study, substantial overall AK clearance on the face or scalp was demonstrated in both cohorts. More participants had 100% clearance at day 57 in the 5-day vs the 3-day cohort (43% vs 32%) (Table 2). Partial clearance rates were also slightly higher in the 5-day vs the 3-day cohort (56% vs 52%) (Table 2). There was a consistent decrease in lesion counts across all visits from baseline to day 57, for both cohorts. A substantial overall mean (standard deviation) decrease from baseline in lesion
In the Phase 1 study, 30 participants were enrolled in one US site. Twenty-nine completed the study and one participant (Cohort 2) withdrew consent on day 2. All 168 participants (n=84 in each cohort) enrolled in the Phase 2 study, from 16 sites across the US, completed the treatment (100% compliance) and follow-up until day 57. Baseline characteristics of all participants met with protocol requirements and were comparable across treatment cohorts, except there were more participants with face than scalp AK lesions in the 3-day vs 5-day cohort in the Phase 2 study. The majority of participants in both studies were White, mean age >60 years, and of non-Hispanic ethnicity with Fitzpatrick skin type I–III (Table 1).
Activity
In the Phase 1 study, reductions in lesion counts from day 1 to 45 were observed in all cohorts (Figure 1). By day 45, 25%, 0%, 50%, and 12.5% of participants demonstrated 100% AK clearance in the treatment area in Cohorts 1–4, respectively (Table 2).
In the Phase 2 study, substantial overall AK clearance on the face or scalp was demonstrated in both cohorts. More participants had 100% clearance at day 57 in the 5-day vs the 3-day cohort (43% vs 32%) (Table 2). Partial clearance rates were also slightly higher in the 5-day vs the 3-day cohort (56% vs 52%) (Table 2). There was a consistent decrease in lesion counts across all visits from baseline to day 57, for both cohorts. A substantial overall mean (standard deviation) decrease from baseline in lesion
