Safety of AG200-15, an Investigational Transdermal Patch, in Three Phase 3 Studies Table 2. Phase 3 Studies Summary of Treatment Emergent Adverse Events Table 4. Phase 3 Studies Potentially Hormone-Related TEAEs and Application Site Disorder Adverse Events (> 2% of Subjects) (N=3481) Anita L. Nelson1, Andrew Kaunitz2, Robin Kroll3 James A. Simon4, Paula Castaño5, , Elizabeth I.O. Garner6 1 Western University of Health Sciences, Pomona, CA, David Geffen School of Medicine, Los Angeles, CA; 2 University of Florida College of Medicine-Jacksonville, Jacksonville, FL; 3 University of Washington, Seattle, WA; 4 George Washington University School of Medicine, and IntimMedicine Specialists, Washington, DC; 5 Columbia University Irving Medical Center, New York, NY 6 Agile Therapeutics, Princeton, NJ INTRODUCTION RESULTS • Across all three Phase 3 studies 6,556 subjects were screened and 3,611 were enrolled; ATI-CL23 accounted for over half of these subjects (Table 1) • Overall the mean age was 27.0, mean BMI was 27.9 (15.1 kg/m2 to 63.0 kg/m2), 35.1% were obese (BMI >30 kg/m2), 69.4% were White, 23% were Black or African American, and 18.3% were Hispanic or Latino • The safety population includes subjects who wore at least one patch for any length of time. Approximately half of the subjects who wore at least one patch completed the studies • AG200-15 (Twirla®) is alow-dose transdermal contraceptive delivery system under investigation as a once-weekly prescription contraceptive patch (Figure 1) • A 28-day cycle consists of consecutive administration of three 7-day patches followed by 7 days without treatment • We report the safety from three Phase 3 studies - SECURE (ATI-CL23) study, ATI-CL12, and ATI-CL13 the • Common TEAEs (i.e., those reported in at least 2% of subjects summarized in (Table 3) • Overall no individual TEAE was reported in > 6.0% of subjects are * A bundle of terms coded using MedDRA version 18.1 ** Application site disorder TEAE most frequently reported by subjects • Across all studies, 56 (1.6%) subjects reported SAEs • Hormone related SAEs occurring in 19 subjects included cholelithiasis (4), deep vein thrombosis/embolism venous (4), pulmonary embolism (3), cholecystitis (3), major depression (3), suicidal ideation (2), suicide attempt (1), necrotizing pancreatitis (1), vomiting (1) Figure 1. Schematic of the AG200-15 Contraceptive Patch (Not drawn to scale) • The most common reasons for discontinuation of study subject decision, lost to follow-up and adverse events drug were • In ATI-CL23, nasopharyngitis and upper respiratory tract infection were the two most frequently reported TEAEs; in ATI-CL12/13, nausea were the two TEAEs most frequently reported nasopharyngitis and • The percentage of subjects lost to follow-up was lower than in previous Phase 3 studies (ATI-CL12/13) combined Table 1. Phase 3 Studies Subject Disposition in ATI-CL23 • AmongtheobservedTEAEs,nausea, headache, considered cervicaldysplasia, dysmenorrhea, related TEAEs and increase weight were potentially hormone-- There were six women with venous thromboembolic events, five had baseline BMI > 30 kg/m2 and weight > 200 lbs There were six women with cholelithiasis or cholecystitis, all had baseline BMI > 35 kg/m2 and weight > 210 lbs Table 3. Phase 3 Studies Incidence of Most Common Treatment Emergent Adverse Events (> 2%) - AIM • To present the safety and tolerability profile of the investigational combined hormonal contraceptive AG200-15, in women of child bearing potential patch, CONCLUSION • AG200-15 was generally well-tolerated and had an overall favorable safety profile • The most-frequent hormone-related adverse events, none of which were experienced by more than 5% of subjects, were generally in line with adverse events observed in approved low dose combined hormonal products • Overall, patch-related skin irritation was infrequent and was mild in severity • Serious potentially hormone-related adverse events occurred in a population of women at higher baseline risk for these events (VTE and gallbladder disease) STUDY DESIGN, MATERIAL, & METHODS • SECURE(Study to EvaluateContraception Use, Reliability, and Effectiveness) was a single-arm, 13-cycle, open-label study conducted in 2014-2016 • ATI-CL12 (13-cycles) and ATI-CL13 (6-cycles) were open-label, randomized, active-controlled (approved oral contraceptives (OC)) safety and efficacy studies Note: Preferred terms are coded using MedDRA version 18.1 conducted in 2010-2011 • All study sites were in the U.S. • Treatment-emergentadverse Disclosures AN: Consultant/Advisor: Agile, AMAG Pharma, Bayer, ContraMed, Merck, Pharmanest; Honoraria/ Speaker: Bayer, Merck; Grants/Research Support: Agile, ContraMed, Estetra SPRL, Evofem Inc, FHI (MonaLisa), Mithra Pharma. • Overall 726 (Table 4) (20.9%) had TEAEs considered potentially hormone-related events (TEAEs) were • A total of 15.6% had a hormone-related TEAEs that were considered drug-evaluated and defined as adverse events that occurred from start of treatment to the day after the last patch was removed related, 1.6% had a hormone-related severe TEAEs, 0.6% had related SAEs, and 5.3% had a hormone-related TEAEs that discontinuation of the study drug a hormone resulted in AK: Consultant/Advisor: Bayer, Merck, Mithra;Consultant (institution): Medicines360; Research Support (institution): Agile, Allergan, Bayer, Evofem, Merck, Mithra. RK: Research Support: AbbVie, Agile, Allergan, Bayer, Chemo Group, Contramed, Merck, Mithra. JS: Consultant/Advisor: AbbVie, Allergan, AMAG, Amgen, Ascend, Azure, Millendo, Nuelle, Radius, Regeneron, Roivant, Sanofi, Sebela, Sermonix, Shionogi, Symbiotec, TherapeuticsMD, Valeant; Speaker: Novo Nordisk, Shionogi, Valeant; Research Support: AbbVie, Agile, • An overall summary of TEAEs for subjects who wore the AG200-15 patch in the three Phase 3 studies is provided in (Table 2) • There were no deaths among subjects who wore the patch • Fewer than 2% of subjects had an SAE, and approximately 11% had TEAEs that resulted in study drug discontinuation • The percentages of subjects with any TEAE, SAE, and TEAE resulting in study drug discontinuation in ATI-CL23 were comparable to those seen in the previous Phase 3 studies (ATI-CL12/13) • Hormone-related the investigators adverse reactions were evaluated by and defined as reactions likely caused • Application site skin irritation was the most frequently reported application site disorder and the application site disorder TEAE most frequently leading to discontinuation of study drug by combination hormonal contraception • Subjects rated patch site skin irritation on a 4-point scale 2 = moderate, 4 = severe) (0 = none, 1 = mild, Allergan, Bayer, New EnglandResearch Institute, Palatin, Symbio, TherapeuticsMD; Stock Ownership: Sermonix. PC: Consultant/Advisor: Bayer; Research Support: Bayer. EG: Employee/Stock Ownership: Agile Therapeutics. • Across the safety population, for Cycles 1-13 combined, the subject-reported mean skin irritation score was 1.3 ATI-CL12/13 ATI-CL23 Overall Cycles 1-6 (CL13) (N=1220) 1-13 (CL12) (N=1450) 1-13 (N=2031) All (N=3481) Nasopharyngitis 64 (5.3%) 83 (5.7%) 116 (5.7%) 199 (5.7%) Upper respiratory tract infection 43 (3.5%) 55 (3.8%) 100 (4.9%) 155 (4.5%) Nausea 50 (4.1%) 64 (4.4%) 84 (4.1%) 148 (4.3%) Headache 41 (3.4%) 52 (3.6%) 72 (3.6%) 124 (3.6%) Urinary tract infection 26 (2.1%) 48 (3.3%) 72 (3.6%) 120 (3.5%) Cervical dysplasia 28 (2.3%) 90 (6.2%) 17 (0.8%) 107 (3.1%) Sinusitis 35 (2.9%) 52 (3.6%) 54 (2.7%) 106 (3.1%) Dysmenorrhea 22 (1.8%) 26 (1.8%) 47 (2.3%) 73 (2.1%) Weight increased 23 (1.9%) 30 (2.0%) 41 (2.0%) 71 (2.0%) ATI-CL12/13 ATI-CL23 Overall Cycles 1-6 (CL13) 1-13 (CL12) 1-13 All Women Screened 2243 2523 4033 6556 Randomized/Enrolled 1330 1579 2032 3611 Safety Population 1220 1450 2031 3481 Completed Study 597 (48.9%) 747 (51.5%) 989 (48.7%) 1736 (49.9%) Reason for Discontinuation Any 623 (51.1%) 703 (48.5%) 1042 (51.3%) 1745 (50.1%) Subject Decision 176 (14.4%) 200 (13.8%) 310 (15.3%) 510 (14.7%) Lost to Follow-up 207 (17.0%) 229 (15.8%) 229 (11.3%) 458 (13.2%) Adverse Events 135 (11.1%) 151 (10.4%) 222 (10.9%) 373 (10.7%) Non-compliance 42 (3.4%) 47 (3.2%) 116 (5.7%) 163 (4.7%) Pregnancy 38 (3.1%) 46 (3.2%) 73 (3.6%) 119 (3.4%) Investigator's Decision 14 (1.1%) 16 (1.1%) 17 (0.8%) 33 (0.9%) Protocol Violation 4 (0.3%) 4 (0.3%) 14 (0.7%) 18 (0.5%) Sponsor Decision 0 0 18 (0.9%) 18 (0.5%) Sponsor Decision (Study Termination) 0 0 2 (0.1%) 2 (0.1%) Death 0 0 0 0 Other 8 (0.7%) 10 (0.7%) 41 (2.0%) 51 (1.5%) Preferred Term Any Hormone-Related TEAE Severe TEAE Drug Related TEAE SAE TEAE Resulting in Discontinuing Study Drug Any Hormone-Related AE 726 (20.9%) 55 (1.6%) 543 (15.6%) 19 (0.6%) 183 (5.3%) Nausea 148 (4.6%) 5 (0.1%) 103 (3.0%) 0 26 (0.8%) Headache 124 (3.6%) 12 (0.3%) 75 (2.2%) 0 12 (0.3%) / Dysmenorrhea 73 (2.1%) 6 (0.2%) 56 (1.6%) 0 10 (0.3%) Weight Increased 71 (2.0%) 2 (0.1%) 58 (1.7%) 0 9 (0.3%) Application Site Disorder* 197 (5.7%) 24 (0.7%) 193 (5.5%) 0 125 (3.6%) Application site irritation** 64 (1.8%) 6 (0.2%) 64 (1.8%) 0 52 (1.5%) ATI-CL12/13 ATI-CL23 Overall Cycles 1-6 (CL13) (N=1220) 1-13 (CL12) (N=1450) 1-13 (N=2031) All (N=3481) Subjects with Any TEAEs 580 (47.5%) 781 (53.4%) 1085 (53.4%) 1866 (53.6%) Subjects with Any Study Drug-Related TEAEs 261 (21.4%) 338 (23.3%) 552 (27.2%) 890 (25.6%) Subjects with Severe TEAEs 50 (4.1%) 73 (5.0%) 92 (4.5%) 165 (4.7%) Subjects with SAEs 14 (1.2%) 16 (1.1%) 40 (2.0%) 56 (1.6%) Subjects with Study Drug-Related SAEs 3 (0.3%) 3 (0.2%) 15 (0.7%) 18 (0.5%) Subjects with TEAEs Resulting in Study Drug Discontinuation 119 (9.8%) 151 (10.4%) 224 (11.0%) 375 (10.8%) Subjects Who Died 0 0 0 0