Terrance Ocheltree, PhDa, Janet Wittes, PhDb, Jessica Case, MPHb, Michael Tuley, PhDc, Irina Krause, MSc, Elizabeth I.O. Garner, MD, MPHd, Joseph Chiodo III, PharmDd aPharmTree Consultants, LLC, Libertyville, IL, USA; bStatistics Collaborative, Inc., Washington, DC, USA; cTKL Research Inc., Fair Lawn, NJ, USA; Columbia University Irving Medical Center, 622 West 168th Street, New York, NY 10032, USA; dAgile Therapeutics, 101 Poor Farm Road, Princeton, NJ 08540, USA. Table 1. Adhesion Scale Table 8. ATI-CL26 Adverse Events ATI-CL26 • AG200-15 (Twirla®) is a transdermal contraceptive delivery system (TCDS) under investigation as a once-weekly prescription contraceptive patch (Figure 1) • • • For ATI-CL26 the overall mean score for all 30 subjects was 0.08 (SD 0.26) (Table 4) Overall, 96.7% of subjects had a mean adhesion score < 1 (i.e., > 90% adhesion) and 100% of subjects had a mean adhesion score < 2 (i.e., > 75% adhesion) (Table 5) There were no complete detachments; 2 subjects had an adhesion score > 2 at any time point, these occurred on Day 6 and Day 7 of the study Figure 1. Schematic of the AG200-15 Contraceptive Patch (Not drawn to scale) Table 4. ATI-CL26 Adhesion Scores • Subjects could conduct activities of daily living and could not re-adhere patches that were partially detached or use overlays, tape or other coverings The primary objective of ATI-CL26 was to evaluate the adhesion of AG200-15 over 7 days; descriptive statistics, including mean patch adhesion scores and number and percent of subjects with scores > 90% and > 75% were assessed The primary objective of ATI-CL25 was to evaluate the adhesion of AG200-15 patch over 7 days/168 hours compared to the 7-day adhesion of the Xulane TCDS; AG200-15 would be considered statistically non-inferior to Xulane if the upper 95% confidence limit (95% CL) of the mean difference in adhesion scores was below +0.15 All analyses used the worst score carried forward method, such that the highest adhesion score for a subject using the five-point scale assessed at any time point after baseline is used for the subsequent time points until a higher score is assessed for that subject • Table 5. ATI-CL26 Adhesion > 90% and > 75% • • • AG200-15 delivers 120 g of levonorgestrel and 30 g of ethinyl estradiol daily A 28-day cycle consists of consecutive administration of three 7-day patches followed by 7 days off-treatment We report two Phase 1 in-vivo, single center wear studies: a single-arm study (ATI-CL26) and a crossover study (ATI-CL25) comparing AG200-15 to Xulane®, a marketed generic TCDS hormonal contraceptive containing norelgestromin and ethinyl estradiol (Figure 2) Note: Adverse events are coded using MedDRA and are sorted by decreasing SOC frequency. Subjects are counted once for each system organ class. A TEAE is an adverse event with an onset date on or after the first patch application through Day 8 (day of final study visit). ATI-CL25 • ATI-CL25 • • Overall, 49/83 (59.0%) of the subjects experienced at least one TEAE, 32/81 (39.5%) and 36/81 (44.4%) of subjects for the AG200-15 and Xulane treatment periods, respectively (Table 9) There were no TEAEs that led to study-drug discontinuation, no SAEs, and no deaths during the course of the study • For ATI-CL25, the overall mean score for AG200-15 subjects was 0.14 (SD 0.28) and for Xulane was 0.39 (SD 0.40). Results for all time points are presented in (Table 6) The study met the non-inferiority criterion by demonstrating a mean difference of -0.24 and upper 95% confidence limit of -0.16 (Table 7 and Figure 3) • • Subject Disposition & Demographics Figure 2. Schematic of the AG200-15 Contraceptive Patch (Not drawn to scale) • ATI-CL26 screened 54 subjects, 30 subjects were randomized into the study and received study drug; all subjects completed the study. Demographics are summarized in Table 2 Table 6. ATI-CL25 Mean Adhesion Scores Table 9. ATI-CL25 Adverse Events (occurring in over 2% of subjects in either treatment period) Table 2. ATI-CL26 Demographics * One subject is excluded from the primary endpoint mean calculation because her data cannot be analyzed using a paired t-test Figure 3. Non-inferiority Scale • ATI-CL26 was a 7-day, single-arm pilot study of AG200-15 ATI-CL25 subjects were randomized to wear AG200-15 or Xulane for Week 1; they then switched to the patch not initially worn for Week 2 Both studies enrolled 18 - 35 year-old women with BMI < 35 kg/m2 who remained in the clinic for the duration of the studies Patch adhesion was assessed daily by trained study site personnel using a five-point scale (Table 1) • • ATI-CL25 screened 135 subjects; 83 subjects were randomized into the study and received study drug; 79 subjects completed the study; 77 subjects were included in the per protocol analysis population (two subjects were excluded from the analysis for a protocol violation). Demographics are summarized in Table 3 Table 7. ATI-CL25 Adhesion > 90% and > 75% Note: Adverse events are coded using MedDRA and are sorted by decreasing SOC frequency. Subjects are counted once for each system organ class. Adverse events are analyzed based on the treatment last applied prior to the onset of the AE. • Table 3. ATI-CL25 Demographics • • Overall, the ATI-CL26 and ATI-CL25 studies support an acceptable in-vivo adhesion profile of AG200-15 In ATI-CL25, AG200-15 demonstrated non-inferiority compared to Xulane since the upper 95% CL was -0.16 which was below the prespecified +0.15 non-inferiority criterion. Both TCDS were generally well-tolerated Patch tracers held a transparent diagram over the o patch and lifted areas were marked permanent marker Patchgraders(separatefromthe using a Safety ATI-CL26 • tracers) o provided grading for the percentage of patch lifting Each tracer and grader were blinded to any previous assessments • • Overall, 14/30 (46.7%) of the subjects experienced at least one TEAE (Table 8) All adverse events were mild except one subject reported an event that was considered moderate in severity (fatigue) Two adverse events were considered unrelated to study drug (skin discoloration and acne), the remainder were considered possibly related by the investigator There were no TEAEs that led to study-drug discontinuation, no SAEs, and no deaths during the course of the study • o • • Presented at VCU Women’s Health 2019, June 28-30, 2019, in Norfolk, VA CONCLUSIONS Parameter Subjects (N=83) Age (years), mean (SD) 27.3 (4.8) Weight (kg), mean (SD) 68.3 (10.8) Height (cm), mean (SD) 161.4 (5.9) BMI (kg/m2), mean (SD) 26.2 (3.9) Race, n (%) White Black or African American Other 26 (31.3%) 52 (62.7%) 5 (6.0%) Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino 22 (26.5%) 61 (73.5%) AG200-15 (N=78) n (%) Subjects with mean adhesion score < 1 (>90% adhesion) 58 (74.4) Subjects with mean adhesion score < 2 (>75% adhesion) 77 (98.8) STUDY DESIGN, MATERIAL, & METHODS Parameter AG200-15 (N=30) Age (years), mean (SD) 28.3 (5.2) Weight (kg), mean (SD) 69.0 (10.1) Height (cm), mean (SD) 160.8 (4.6) BMI (kg/m2), mean (SD) 26.7 (3.9) Race, n (%) White Black or African American Other 10 (33.3%) 18 (60.0%) 2 (6.7%) Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino 13 (43.3%) 17 (56.7%) System Organ Class AG200-15 (N=81) Xulane (N=81) Any adverse events 32 (39.5%) 36 (44.4%) Skin and subcutaneous tissue disorders Eczema Pruritus Rash 11 (13.6%) 3 (3.7%) 3 (3.7%) 4 (4.9%) 8 (9.9%) 2 (2.5%) 2 (2.5%) 1 (1.2%) Reproductive system and breast disorders Breast tenderness Metrorrhagia 8 (9.9%) 4 (4.9%) 3 (3.7%) 8 (9.9%) 3 (3.7%) 3 (3.7%) Respiratory, thoracic and mediastinal disorders Nasal congestion 0 0 5 (6.2%) 2 (2.5%) General disorders and administration site conditions Administration site rash 2 (2.5%) 2 (2.5%) 3 (3.7%) 1 (1.2%) AG200-15 (N = 77*) Xulane (N = 77) Difference (AG200-15 – Xulane) Mean (SD) Mean (SD) Mean (SD) One-sided upper 95% CI Non-inferiority Criteria Met Per Protocol population 0.14 (0.28) 0.39 (0.40) - 0.24 (0.46) - 0.16 YES AG200-15 (N=30) n (%) Subjects with mean adhesion score < 1 (>90% adhesion) 29 (96.7) Subjects with mean adhesion score < 2 (>75% adhesion) 30 (100) N Mean (SD) Overall 30 0.08 (0.26) System Organ Class AG200-15 (N=30) Any adverse events 14 (46.7%) Nervous system disorders Headache 8 (26.7%) 8 (26.7%) Gastrointestinal disorders Vomiting Abdominal pain Nausea 5 (16.7%) 3 (10.0%) 2 (6.7%) 1 (3.3%) Skin and subcutaneous tissue disorders Acne Hives Skin discoloration 3 (10.0%) 1 (3.3%) 1 (3.3%) 1 (3.3%) Reproductive system and breast disorders Menstrual cramps 2 (6.7%) 2 (6.7%) General disorders and administration site conditions Fatigue 1 (3.3%) 1 (3.3%) Score Adhesion 0 > 90% adhered (essentially no lift off the skin) 1 > 75% to < 90% adhered (some edges only lifting off the skin) 2 > 50% to < 75% adhered (less than one-half of the patch lifting off the skin) 3 > 0% to < 50% adhered (not detached, but greater than one-half of the patch lifting off the skin without falling off) 4 0 % adhered (patch detached; completely off the skin) RESULTS INTRODUCTION