CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022472Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) CLINICAL PHARMACOLOGY REVIEW NDA 22-472 Submission Date(s) October 13, 2013 Brand Name AFREZZA Inhaler Generic Name Insulin human [rDNA origin] inhalation powder Reviewers* Sang M. Chung, Ph.D. Manoj Khurana, Ph.D. Team Leader Lokesh Jain, Ph.D. OCP Division Clinical Pharmacology 2 OND Division Metabolism and Endocrinology Products Sponsor MannKind Corporation Submission Type Resubmission: Response to the Complete Response Letter dated January 18, 2011 Formulation AFREZZA is available as single-use cartridges Strength(s) of: 10 and 20 U strength** Indication To improve glycemic control in adults with type 1 or type 2 diabetes mellitus Dosage & Administration AFREZZA is administered via oral inhalation using the AFREZZA Inhaler. * Dr. Sang Chung is the primary reviewer for this application and Dr. Manoj Khurana performed the PK/PD analyses and simulations ** Afrezza dosing units as reported in the clinical pharmacology studies. Cartridge units that will be reported in the label have not been finalized. 1 Reference ID: 3509366 Table of Contents 1 Executive Summary............................................................................................. 5 1.1 Recommendation ................................................................................................. 5 1.2 Phase IV Commitments ....................................................................................... 6 2 Summary of Clinical Pharmacology Findings and Review Issues ...................... 6 2.1 Background.......................................................................................................... 6 2.2 Dosing Regimen................................................................................................... 7 2.3 Assessment of Dosing Regimen Based on Clinical Pharmacology Data ............ 8 2.4 Assessment of Dose-Proportionality in PD Response in Healthy Subjects and its Potential Impact on Titration ............................................................................. 10 2.5 Assessment of PK Dose-Proportionality and Relative Bioavailability for Gen2 Delivered Afrezza Insulin in Healthy Subjects.................................................. 12 2.6 PK and PD for Gen2 Delivered Afrezza Insulin in Type 1 Diabetes ................ 13 2.7 Clinical Pharmacology Findings from Previous Submissions........................... 14 2.7.1 Comparability (1) between Gen2 and MedTone Model C, and (2) between two cartridges of 10 U and one cartridge of 20 U for Gen2 (from the amendment dated 6/29/2010) ..................................................................... 14 2.7.2 Insulin Exposure Following Multiple Doses (from the original submission) .................................................................................................................... 15 2.7.3 Intrinsic and Extrinsic Factors (from the original submission) .................. 16 2.8 Exploratory Simulations for Dose-Response Relationship of Afrezza vs. Subcutaneously Administered RHI.................................................................... 19 3 Individual Study Review.................................................................................... 25 3.1 Dose-Response in healthy subjects following AFREZZA using Gen2 inhaler (MKC-TI-176) ................................................................................................... 25 3.2 Insulin PK and PD in T1DM following AFREZZA using Gen2 inhaler (MKC- TI-177) ............................................................................................................... 32 3.3 Interim analysis of Study MKC-TI-118............................................................. 36 3.4 Bioanalytical Studies ......................................................................................... 37 4 Attachment......................................................................................................... 38 4.1 Complete Response Letter 1 Dated 3/12/2010 .................................................. 38 4.2 Complete Response Letter 1 Dated 6/29/2010 .................................................. 45 4.3 Tables of Studies/Clinical Trials........................................................................ 53 4.4 Study synopsis ................................................................................................... 63 4.4.1 MKC-TI-176............................................................................................... 63 4.4.2 MKC-TI-177............................................................................................... 70 2 Reference ID: 3509366 List of tables Table 1: Summary of Key Background .............................................................................. 6 Table 2: AFREZZA Dosage Chart (Study MKC-TI-171) .............................................. 7 Table 3: Comparison of dosing conversion factors - estimation based on AUCGIR comparison vs. the proposed labeling............................................................. 10 Table 4: Summary of Dose- GIRAUC0-240 (Geometric mean) (data source: Study MKC-TI-176).................................................................................................. 11 Table 5: Summary of between-subject variability (BSV, %CV) following Afrezza in healthy subjects (data source: Study MKC-TI-176) ....................................... 11 Table 6: Summary of PK and PD parameters in T1DM................................................... 14 Table 7: Least square geometric mean ratios (90% confidence interval) of AUC and Cmax comparing Gen2 (20U) versus Model C (30 U) inhaler (n=46).......... 15 Table 8: Least square geometric mean ratios (90% confidence interval) of AUC and Cmax comparing 2 x 10 U versus 1 x 20 U dose of Gen2 delivered insulin (n=46).............................................................................................................. 15 Table 9: Insulin PK parameters (geometric mean) in T2DM following multiple doses (Baseline-correction using previous concentrations)...................................... 15 Table 10: Summary of insulin and FDKP AUC in control and with disease or smoking 18 Table 11: Geometric mean ratio of insulin pharmacokinetic parameters in healthy volunteers (Study TI-114)............................................................................... 19 Table 12: PD model parameters for Afrezza vs. SC insulin............................................. 21 Table 13: Summary of insulin PK parameters in healthy subjects (C-peptide corrected) 27 Table 14: Insulin Relative BA following AFREZZA referencing SC in healthy subjects 28 Table 15: Summary of GIR data in healthy subjects ...................................................... 28 Table 16: Relative effect of AFREZZA to RHI in healthy subjects............................... 28 Table 17: Insulin PK parameters related to the exposure time following Afrezza........... 31 Table 18: Summary of PK parameters following AFREZZA and RAA SC in T1DM .. 34 Table 19: Summary of 5-minute average GIR PD parameters following AFREZZA and RAA SC in T1DM .......................................................................................... 35 3 Reference ID: 3509366 List of figures Figure 1: Afrezza dosage chart from the proposed label .................................................... 7 Figure 2: Summary of application’s justification for the proposed dosing conversion ... 8 Figure 3: Insulin concentration (upper) and GIR (lower) – time profiles in healthy subjects from study MKC-T1-176 (data source: \\CDSESUB1\evsprod\NDA022472\0074\m5\datasets\mkc-ti- 176\analysis\adam\datasets).............................................................................. 9 Figure 4: Relationship between insulin AUC0-180 and GIRAUC0-240: Each quartile of AUC0-180 represents 12.5% interval (data source: Study MKC-TI-176) ........ 11 Figure 5: Scatter plot for insulin AUC0-180 vs.GIRAUC0-240. (line: Loess fit, data source: Study MKC-TI-176) ....................................................................................... 12 Figure 6: Insulin concentration (upper) and GIR (lower) – time profiles (TI – Gen2 delivered Afrezza, RAA –rapid acting analog insulin lispro; data source - \\CDSESUB1\evsprod\NDA022472\0074\m5\datasets\mkc-ti-177) ............. 13 Figure 7: Schematic summary for the modeling and simulation................................... 21 Figure 8: Observed vs. Model Predicted insulin concentration vs. time and GIR vs. time profiles for Afrezza insulin ............................................................................. 22 Figure 9: Observed vs. Model Predicted insulin concentration vs. time and GIR vs. time profiles for SC insulin..................................................................................... 23 Figure 10: Simulated dose-response curve for Afrezza insulin vs. SC RHI. Top panel covers the extended range, the bottom panel focuses on the clinically relevant dose range ....................................................................................................... 24 Figure 11: Mean (SE) FDKP concentration-time profiles (upper panel) and its proportionality with doses (lower panel) following Afrezza in healthy subjects 29 Figure 12: Mean glucose (blue symbols and line) and natural insulin (red symbols and line) concentrations following the breakfast, lunch and dinner in healthy subjects (n=14, redrawn from Figure 1, Polonsky et