CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`210913Orig1s000
`
`
`CLINICAL PHARMACOLOGY
`
`REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`
`
` Office of Clinical Pharmacology Review
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 213051
`
`
`
` \\Cdsesub1\evsprod\NDA213051\213051.enx
`
` 20 Mar 2019
`
` 505 (b)(1)
` Rybelsus (Proposed)
`
` Semaglutide
` Tablet; 3 mg, 7 mg and 14 mg
`
`
`
`
`
`
`
`
`
`NDA or BLA
`
` Number
`
` Link to EDR
`
`
` Submission Date
`Submission Type
`
` Brand Name
` Generic Name
`
`Dosage Form and
`
` Strength
`
` Route of
` Administration
`
` Proposed
`Adjunct to diet and exercise to improve glycemic control in adults
`
` Indication
`
` with type 2 diabetes mellitus
`
` Applicant
`
` Novo Nordisk
` Associated IND
`
`
` IND-114464
` OCP Review Team Suryanarayana Sista, PhD; Mohammad (Abir) Absar, PhD; Justin
`
`
`
`
`
` Penzenstadler, PharmD, MS; Justin Earp, PhD; Manoj Khurana, PhD
`
`
`
`
`
` Oral
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 1
`
`

`

`
`
` Table of Contents
`
` 1.
`
`
`
`
`
` EXECUTIVE SUMMARY .......................................................................................................................... 7
`
`
`
`
`
`
` Recommendations ........................................................................................................................ 8
`
`
`
`
`
`
` Post-Marketing Requirements and Commitments....................................................................... 8
`
`
`
`
`
`
`
`
` 1.1
`
`
`
` 1.2
`
`
`
` 2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT......................................................................... 9
`
`
`
`
`
`
`
`
` Pharmacology and Clinical Pharmacokinetics............................................................................... 9
`
`
`
`
`
`
` Dosing and Therapeutic Individualization..................................................................................... 9
`
`
`
`
`
`
`
`
` General dosing ...................................................................................................................... 9
`
`
`
`
`
`
` Therapeutic individualization.............................................................................................. 10
`
`
`
`
`
`
`
`
` 2.2.1
`
`
`
` 2.2.2
`
`
`
` Outstanding Issues...................................................................................................................... 11
`
`
`
`
`
`
`
`
` 2.1
`
`
`
` 2.2
`
`
`
` 2.3
`
`
`
` 2.4
`
`
`
` Summary of Labeling Recommendations ................................................................................... 11
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW...................................................................... 12
`
`
`
`
`
`
` 3.1
`
` 3.2
`
`
`
` Overview of the Product and Regulatory Background ............................................................... 12
`
`
`
`
`
`
` General Pharmacological and Pharmacokinetic Characteristics ................................................ 14
`
`
`
`
`
`
`
`
` 3.2.1
`
`
`
` 3.2.2
`
`
`
` 3.2.3
`
`
`
` 3.2.4
`
`
`
` 3.2.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Mechanism of Action: ......................................................................................................... 14
`
`
`
`
`
`
` Pharmacokinetics:............................................................................................................... 15
`
`
`
`
`
`
`
`
` Pharmacodynamics:............................................................................................................ 22
`
`
`
`
`
`
`
`
`
`
`
`
` QT Prolongation: ................................................................................................................. 23
`
`
`
`
`
`
` Immunogenicity: ................................................................................................................. 24
`
`
`
`
`
`
`
`
` 3.3
`
`
`
` Clinical Pharmacology Questions................................................................................................ 26
`
`
`
`
`
`
` Does the clinical pharmacology information provide supportive evidence of
`
`
` 3.3.1
`
`
` effectiveness? ..................................................................................................................................... 26
`
`
`
`
`
`
`
`
`
`
`
`
` 3.3.2. Why was SNAC used in the tablet formulation?................................................................. 26
`
`
`
`
`
` Is the proposed general dosing regimen appropriate for the general patient population
`
` 3.3.3
`
` for which the indication is being sought?........................................................................................... 29
`
`
`
`
`
`
`
` Is an alternative dosing regimen and management strategy required for subpopulations
`
`
` 3.3.4
`
`
` based on intrinsic factors? .................................................................................................................. 33
`
`
`
`
`
`Are there clinically relevant food-drug or drug-drug interactions and what is the
`
` 3.3.5
`
` appropriate management strategy?................................................................................................... 42
`
`
`
`
`
`
`
`
`Is the to-be-marketed formulation the same as the clinical trial formulation, and if not,
`
` 3.3.6
`
`
` are there bioequivalence data to support the to-be-marketed formulation? ................................... 52
`
`
`
`
`
`
`
`
`
`
`
`
` 3.3.7 What were the immunogenicity findings?.......................................................................... 54
`
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 2
`
`
`

`

`
`
`
`
`
`
` 4. APPENDICES ........................................................................................................................................ 56
`
`
`
`
`
`
` 4.1
`
`
`
`
`
`
`
` Appendix - Summary of Bioanalytical Method Validation.......................................................... 59
`
`
`
`
`
`
`
` How are parent drug and relevant metabolites of semaglutide identified and what are the
`
` 4.1.1
`
` analytical methods used to measure them in plasma and other matrices? ...................................... 59
`
`
`
`
`
`
`
`
`
`
`
`
` 4.1.2 What was the performance of bioanalytical methods for Semaglutide?........................... 59
`
`
`
`
` 4.1.3. What analytical methods were used to measure the concentration of SNAC and its
`
`
`
`
` relevant metabolites? ......................................................................................................................... 63
`
`
`
`
`
`
`
`
` 4.2
`
`
`
` Pharmacometrics Assessment .................................................................................................... 65
`
`
`
`
`
`
`
`
` Executive Summary............................................................................................................. 65
`
`
`
`
`
`
`
`
`
`
`
`
` Population PK Analysis........................................................................................................ 66
`
`
`
`
`
`
` 4.2.1
`
`
`
` 4.2.2
`
`
`
` 4.2.3
`
`
`
` 4.2.4
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
` Dose- and Exposure- Response Analysis for Safety ............................................................ 79
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Exposure- Response Analysis for Efficacy ........................................................................... 84
`
`
`
`
`
`
` 3
`
`
`

`

`
`
`
`
` Parameter estimates for the dose-response model for effects of oral semaglutide on
`
`
`
`
` HbA1c ...........................................................................................................................................................10
`
`
`
` Compositions of drug products to be used in the phase 3 clinical trial expressed as
`
`
`
` "per tablet" .................................................................................................................................................14
`
`
`Drug-drug interaction: Rationale for victim drug selection − trials with oral
`
`
` semaglutide as potential perpetrator .............................................................................................18
`
`
`
`
` Statistical Analysis of PK Parameters for Semaglutide and SNAC in Hepatic Impaired
`
` Patients Compared to Healthy Matched Subjects ......................................................................35
`
`
`
`
`
` Statistical Analysis of PK Parameters for Semaglutide and SNAC in Renal Impaired
`
`
` Patients Compared to Healthy Matched Subjects ......................................................................37
`
`
`
`
` Statistical Analysis of PK Parameters for Semaglutide and SNAC in Patients with
`
`
`
`
`Upper Gastrointestinal Disease Compared to Patients without Upper Gastrointestinal
`
`
` Disease .........................................................................................................................................................39
`
`
`
` Statistical Analysis of PK Parameters for Semaglutide and SNAC in Japanese Subjects
`
`
`
` Compared to Caucasian Subjects ......................................................................................................40
`
`
`
`
` Summary of trials investigating drug-drug interactions.........................................................46
`
`
`
`
`
` Semaglutide as a Perpetrator on Commonly Administered Drugs.....................................48
`
`
`
`
` SNAC as a Perpetrator on Commonly Administered Drugs ...................................................49
`
`
`
`
`
` PK of semaglutide as victim drug and SNAC as victim excipient .........................................52
`
`
`
`
` Semaglutide Trial Products, Manufacturing Process and Associated Clinical Trials ..53
`
`
`
`
` Overview of Clinical Formulations – Late Phase 1 to Phase 3 and Commercial Scale 53
`
`
`
`
` Overview of Process Changes During Scale-Up ..........................................................................54
`
`
`
`
` Tabular Listing of Phase 1 studies Providing Clinical Pharmacology Data .....................56
`
`
`
`
` Summary of Semaglutide PK Assay Validation (LC-MS/MS) in Human Plasma............60
`
`
`
` Bioanalytical method validation summary for SNAC ...............................................................64
`
`
`
`
` Summary of phase 3a trials contributing data to population PK and exposure
`
`
` response of oral semaglutide..............................................................................................................66
`
`
`
`Number of subjects with PK sampling during treatment with oral semaglutide for
`
` PIONEER......................................................................................................................................................67
`
`
`
`
` Parameter Estimates for the Reduced Population Pharmacokinetic Model...................68
`
`
`
`
` Forest plot of covariate effects on the exposure of oral semaglutide. ...............................69
`
`
`
`
` Parameter estimates from the dose-response model of HbA1c change from baseline
`
`
` .........................................................................................................................................................................87
`
`
`
`
`
`
`
`
`
`
`
`Table 1
`
`
`Table 2
`
`
`Table 3
`
`
`Table 4
`
`
`Table 5
`
`
`Table 6
`
`
`Table 7
`
`
`Table 8
`
`Table 9
`
`Table 10
`
`Table 11
`
`Table 12
`
`Table 13
`
`Table 14
`
`Table 15
`
`Table 16
`
`Table 17
`
`Table 18
`
`
`Table 19
`
`
`Table 20
`
`Table 21
`
`Table 22
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` List of Tables
`
`
`
`
`
` 4
`
`
`

`

`
`
` List of Figures
`
`Figure 1
`
`Figure 2
`
`Figure 3
`
`Figure 4
`
`Figure 5
`
`Figure 6
`
`
`Figure 7
`
`
`Figure 8
`
`
`Figure 9
`
`Figure 10
`
`
`Figure 11
`
`
`Figure 12
`
`
`Figure 13
`
`
`Figure 14
`
`
`Figure 15
`
`
`Figure 16
`
`
`Figure 17
`
`
`Figure 18
`
`
`Figure 19
`
`
`Figure 20
`
`
`Figure 21
`
`Figure 22
`
`
`Figure 23
`
`Figure 24
`
`Figure 25
`
`
`Figure 26
`
`
`Figure 27
`
`
`
`
`
`
` HbA1c change from baseline versus oral maintenance dose of semaglutide.................10
`
`
`
`
` Drug-Drug Interactions Between Semaglutide and Concomitant Medications.............19
`
`
`
`
` Drug-drug interactions between SNAC and concomitant medications ............................20
`
`
`
`
` Mean and 90% CI ∆∆QTcF Time course.........................................................................................23
`
`
`
`
` Mean and 90% Unadjusted CI ΔΔQTcF Timecourse (SNAC and Moxifloxacin) .............24
`
`
`
`
`
`Comparative Exposures of Semaglutide from Subcutaneous Dosing in SUSTAIN and
`
`
` Oral Dosing in PIONEER .......................................................................................................................26
`
`
`
`Plasma concentration-time profile of oral semaglutide with varying amount of SNAC
`
`(Study 3691); (inset) plasma concentration time profile for 2 hr to demonstrate
`
` variability in semaglutide concentration.......................................................................................28
`
`
`
`
` Plasma semaglutide exposure following administration of 10 mg semaglutide
`
` formulated with 300 mg or 600 mg SNAC ....................................................................................28
`
`
`
`
`
` Observed mean semaglutide exposure versus time for oral and s.c. dosing groups...29
`
`
`
`Change from baseline versus oral maintenance dose of semaglutide for HbA1c (left
`
`
` panel) and body weight (right panel) .............................................................................................30
`
`
`
`Simulated effects on HbA1c change from baseline versus predicted average
`
`
` concentrations for phase 3a doses...................................................................................................31
`
`
`Effect of post-dose fasting time on AUC0-24h (A) and Cmax (B) of semaglutide (Study
`
`
`
`
`
` 3794) ............................................................................................................................................................32
`
`
`
`
` Plasma semaglutide concentration following administration with 50 mL and 240 mL
`
`
` of water (Study 3957) ...........................................................................................................................33
`
`
`
`
` Intrinsic factors: Covariate effects on the exposure of oral semaglutide –Phase 1 data
`
`
` .........................................................................................................................................................................34
`
`
`
`
`Intrinsic factors: Covariate effects on the exposure of oral semaglutide –population
`
` PK analysis of Phase 3 data .................................................................................................................34
`
`
`
`
`
` Scatter plots for Semaglutide Exposure as a Function of Creatinine Clearance in
`
` Subjects with Varying Degrees of Renal Function .....................................................................38
`
`
`
`
`Semaglutide AUC0-24 (top panel) and Cmax (bottom panel) at Steady-State Following
`
`
`
`
` Oral Dosing of 10, 20 and 40 mg Semaglutide in Japanese and Caucasian Subjects ...41
`
`
`
`
`
`Semaglutide AUC0-24 (top panel) and Cmax (bottom panel) at Steady-State Following
`
`
`
`
`
` Oral Dosing of Semaglutide Under Fasting (with 240 mL Water) and Reference (with
`
` 120 mL Water) Conditions ..................................................................................................................43
`
`
`
`
`SNAC AUC0-24 (top panel) and Cmax (bottom panel) at Steady-State Following Oral
`
`
`
`
`Dosing of Semaglutide Under Fasting (with 240 mL Water) and Reference (with 120
`
`
` mL Water) Conditions ...........................................................................................................................44
`
`
`
`General study design to investigate the effect of oral semaglutide/SNAC on other
`
` drugs: single victim drug (A); multiple victim drugs (B) ........................................................47
`
`
`
`
`
` Trial Designs for Semaglutide as Victim Drug and SNAC as Victim Excipient................51
`
`
`
`
`
` Spaghetti Plot of HbA1c Change from Baseline by Occurrence of Antibodies –Pioneer
`
`
` 1–5 And 9 – On-Treatment ..................................................................................................................55
`
`
`
`
`
` Residual Goodness of Fit Plots for the Reduced Model............................................................70
`
`
`
` Visual Predictive Check.........................................................................................................................71
`
`
`
`
` Empirical Cumulative Distribution Plots for PK Observations Vs. Time After Dosing
`
`
` and Time After Randomization..........................................................................................................72
`
`
`
`
` Simulated Concentration Versus Time Profiles for a Typical Patient at Steady State In
`
`
`
` Clinical Pharmacology Trials ..............................................................................................................73
`
`
`
`
` Correlation Matrix of Post-Hoc Average Plasma Concentration Estimates Between
`
`
` Different Models ......................................................................................................................................74
`
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 5
`
`
`
`
`

`

` Scatterplot of Average Plasma Level Versus Body Weight, with a Loess Overlay ........75
`
`
`
`
`
`Smoothed Density Plots of Predicted Average Patient Plasma Level At Steady State
`
` Treatment of 7mg Oral Semaglutide, Daily, Faceted by Dose ...............................................76
`
`
`
`
` Semaglutide Plasma Observations Vs. Time, Faceted by Dose and Study .......................77
`
`
`
`
` Model Prediction Error Versus Time after Randomization ...................................................78
`
`
`
`
` Exposure-Response Analysis for Nausea and Vomiting..........................................................80
`
`
`
`
`
`Kaplan-Mayer Plot of Cumulative Prevalence of Patients Reporting Nausea or
`
`
` Vomiting ......................................................................................................................................................81
`
`
`Kaplan-Mayer Plot of Cumulative Prevalence of Patients Reporting Nausea or
`
`
` Vomiting ......................................................................................................................................................82
`
`
`Forest Plot of Model Predicted Hazard Ratios Between 7mg Oral Semaglutide and
`
`
` Placebo.........................................................................................................................................................83
`
`
` Base Exposure-Response model of HbA1c Change from Baseline with Sensitivity
`
`
`
`
` Analyses Overlaid....................................................................................................................................85
`
`
` Model fit to observed data for HbA1c change from baseline by trial, dose, HbA1c
`
`
`
`baseline, body weight baseline, BMI, diabetes duration, sex, age group, race, ethnicity,
`
`
` renal function and presence of upper GI disease .......................................................................86
`
`
`
`HbA1c change from baseline versus semaglutide exposure stratified by trial (Left)
`
` and by population (Right)....................................................................................................................87
`
`
`
`
` Model Residual Error Versus Continuous Covariates ..............................................................88
`
`
`
`
` Model Residual Error Versus Discrete Covariate.......................................................................89
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 28
`
`Figure 29
`
`
`Figure 30
`
`Figure 31
`
`Figure 32
`
`Figure 33
`
`
`Figure 34
`
`
`Figure 35
`
`
`Figure 36
`
`
`Figure 37
`
`
`Figure 38
`
`
`Figure 39
`
`Figure 40
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 6
`
`
`

`

`
` 1. EXECUTIVE SUMMARY
`
`
`
`
`
`
`
`
`
`
`
`
` This is an original NDA submitted by Novo Nordisk Inc. on March 20th, 2019, seeking marketing approval
`
`
` for oral semaglutide tablets as an adjunct to diet and exercise to improve glycemic control in adult patients
`
`
`
`
` with Type 2 diabetes mellitus (T2DM). Oral semaglutide tablets are proposed to be marketed under the
`
`
`
`
`
`
`
`
` tradename of RYBELSUS.
`
`
`
`
`
`
`
`
` Semaglutide is a recombinant long-acting analogue of human glucagon-like peptide-1 (GLP-1) that
`
` selectively binds to and activates the GLP-1 receptor, a target receptor for native GLP-1. Semaglutide
`
`
`
`
` exhibits a 94% sequence homology to human GLP-1, an endogenous incretin hormone that stimulates
`
`
`
`
`
`
` insulin secretion and inhibits glucagon secretion from the pancreatic islets in a glucose-dependent manner.
`
`
`
`
`
`
`
`
` Semaglutide is co-formulated with salcaprozate sodium, a small fatty-acid-derivate absorption enhancer
`
` (also called SNAC) for the tablet formulation. SNAC transiently increases the transcellular permeability of
`
`
`
`
`
`
`
`
`
` the gastric epithelium to semaglutide to facilitate absorption after oral administration. Mechanistic studies
`
`
`
`
`
` indicate that the absorption of semaglutide predominantly occurs in the stomach. Once absorbed,
`
`
`
`
`
`
`
` semaglutide is distributed, metabolized and eliminated in the same way irrespective of the route of
`
`
`
`
`
`
`
`
`
` administration. The systemic effect of semaglutide is therefore independent of the route of administration.
`
`
`
`
`
`
`
`
`
`
` Through buffering actions, SNAC helps facilitate a high pH in the localized stomach environment beneath
`
` the tablet, thereby protecting semaglutide from degradation by gastric enzymes, whose action is most
`
`
`
`
`
` predominant at low pH. The presence of food results in greater dilution of SNAC and semaglutide and
`
`
`
`
`
`
`
`
`
`
` presents a barrier to establish a concentration gradient sufficient to permit enhanced absorption and
`
`
`
`
`
`
` protection against enzymatic degradation.
`
`
`
`
`
`
`
`
`
` SNAC reportedly interacts with the plasma membrane of the gastric epithelium to promote absorption of
`
` semaglutide via the transcellular route. SNAC gets incorporated in and fluidizes model lipid membranes.
`
`
`
`
`
`
`
` The Applicant opines that despite its effects on the cell membrane of gastric mucosa, SNAC had no
`
`
`
`
`
`
`
`
`
` appreciable effect on tight junction complexes at the apical surface. The absorption enhancing effects of
`
`
`
`
`
`
`
` SNAC were transient, size dependent, reversible and require co-formulation.
`
`
`
`
`
` In the phase 3a trials, oral semaglutide tablets were swallowed whole on an empty stomach with up to half
`
` a glass of water equivalent to 120 mL. At least 30 minutes had to lapse before the first meal or drink of the
`
`
`
`
`
`
`
`
`
`
`
`
`
` day and taking other oral medications.
`
`
`
`
` The key issues addressed during the review of clinical pharmacology of oral semaglutide are summarized
` below:
`
`
`• Acceptability of the Proposed Dosage Regimen from Dose and Exposure-Response
`
`
`
`
`
`
` Perspective
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` o The proposed dosage regimen utilizing oral doses of 3 mg, 7 mg, and 14 mg semaglutide once daily is
`
`
`
` adequately supported by dose-response and exposure-response relationship in change in HbA1c after 26
`
`
`
`
`
`
`
` weeks of treatment from safety/efficacy trials vis-à-vis the dose-response for safety. Further, with
`
`
`
`
`
`
`
`
`
`
`
`
` regards to the effect of body weight on apparent clearance, both 7 mg and 14 mg once-daily doses
`
`
`
`
`
`
`
`
`
`
`
`
`
` generated adequate systemic exposure over the typical body weight range of subjects with T2DM
`
`
`
`
`
`
`
`
`
` ensuring efficacy.
`
`
`
`• Optimal Dosing Conditions (time of fast prior to and after dosing, amount of water, meal)
`
`
`
`
`
` o The results from the clinical pharmacology studies and two clinical studies (trials 3794 and 3957),
`
`
`
`
`
`
`
`
` support a recommended use for oral semaglutide tablet to be taken on an empty stomach and be
`
`
`
`
`
`
`
`
`
`
`
` swallowed whole with up to half a glass of water equivalent to 120 mL without splitting, crushing
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` or chewing the tablet. After taking oral semaglutide, patients are recommended to wait at least 30
`
`
`
`
`
`
`
`
`
`
`
`
` minutes before the first meal or drink of the day and taking other oral medications.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 7
`
`

`

`
`
`
` 1.1 Recommendations
`
`
` The Office of Clinical Pharmacology has reviewed the information contained in NDA 213051 and found
` it acceptable to support approval of oral Semaglutide in the T2DM population. Key review issues with
`
`
`
`
` specific recommendations and comments are summarized below:
`
`
`
`
`
` Review Issues
`
`
`
` Recommendations and Comments
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` The primary evidence of effectiveness for the proposed dosing regimen
`
`
` were obtained from data from 10 efficacy trials, which showed that
`
`
`
`
`
`
` oral semaglutide produced clinically relevant reductions in HbA1c that
`
`
`
`
`
` were dose-dependent and lasted through the duration of the trials.
`
`
`
`
`
`
`
`
` Clinically relevant dose-dependent sustained reduction in body weight
`
`
`
`
`
` was also observed across all phase 3a trials.
`
`
`
`
`
`
`
`
` Semaglutide oral tablets must be taken on an empty stomach after first
`
`
`
`
`
` waking up in the morning. Semaglutide oral tablets should be taken at
`
`
`
`
`
`
`
` least 30 minutes before the first food, beverage or other oral
`
`
`
`
`
`
` medications of the day with no more than half a glass of water
`
`
`
`
`
`
`
`
`
`
` (approximately 4 ounces). The tablet should be swallowed whole.
`
`
`
`
`
` The recommended starting dose is 3 mg once daily for 1 month. After
`
`
`
`
`
`
`
`
`
`
` 1 month on 3 mg, the dose should be increased to 7 mg once daily. If
`
`
`
`
`
`
`
`
`
`
`
`
` additional benefits are needed after at least one month on 7 mg, the
`
`
`
`
`
`
`
`
` dose may be increased to 14 mg once daily.
`
`
`
`
`
`
`
`
`
`
` No separate dose/dosing regimen is recommended in any patient
`
`
`
`
`
` subgroups due to intrinsic (age, sex, race, ethnicity, body weight, renal
`
`
`
`
`
`
` impairment, hepatic impairment) and extrinsic factors. Semaglutide
`
`
`
` does delay gastric emptying; therefore, caution should be exercised
`
`
`
`
`
`
` when oral medications are concomitantly administered with
`
`
`
`
`
` semaglutide.
`
`
`
`
`
`
`
`
` The to-be-marketed drug product formulation (Process 3) was used in
`
` all pivotal Phase 3 studies and in all the clinical pharmacology studies
`
`
`
`
`
` that evaluated drug-drug interactions.
`
`
`
`
`
`
`
` Supportive evidence of
` effectiveness
`
`
`
`
`
`
`
` General dosing
` instructions
`
`
`
` Dosing in patient
`subgroups
`
`
`
`
`
`
`
` Bridge between the “to-be­
` marketed” and clinical trial
`
`
`
` formulations
`
`
`
`
`
`
` 1.2 Post-Marketing Requirements and Commitments
`
`
` None.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 8
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT
`
`
`
` 2.1 Pharmacology and Clinical Pharmacokinetics
`
` Semaglutide is a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor. A
`
`
` summary of the PK and PD characteristics of semaglutide is presented below.
`
` The following is a summary of the clinical pharmacokinetics of oral semaglutide:
`
`
`
`
`
`
`
`
`
` • Following oral administration, maximum concentration of semaglutide is reached 1-hour
`
`
`
`
` post-dose. Steady-state exposure is achieved following 4-5 weeks administration. In
`
`
`
`
`
` patients with type 2 diabetes, the mean population-PK estimated steady-state
`
`
`
`
`
` concentrations following once daily oral administration of 7 and 14 mg semaglutide were
`
`
`
`
`
`
`
`
`
`
`
` approximately 6.7 nmol/L and 14.6 nmol/L, respectively. Based on population
`
`
`
`
`
`
`
`
`
` pharmacokinetics (PK) estimates, semaglutide exposure increases in a dose-proportional
`
`
`
` manner. The Population-PK estimated absolute bioavailability of semaglutide to be
`
`
`
`
`
` approximately 0.4 - 1%, following oral administration.
`
`
`
`
`
`
`
` • Semaglutide is extensively bound to plasma albumin (>99%). The estimated volume of
`
`
`
`
`
`
`
` distribution of semaglutide following oral administration in healthy subjects is
`
`
`
`
`
`
` approximately 8 L.
`
`
`
`
`
`
`
`
`
` • The elimination half-life of semaglutide is approximately 1-week. The clearance of
`
`
`
`
`
` semaglutide following oral administration in healthy subjects is approximately 0.04 L/h.
`
`
`
`
`
`
`
` • The primary excretion routes of semaglutide-related material are via the urine and feces,
`
`
`
`
`
`
` with approximately 3% of the absorbed dose excreted in the urine as intact semaglutide.
`
`
`
`
`
`
`
` • The primary route of elimination for semaglutide is metabolism following proteolytic
`
`
`
`
`
`
`
`
` cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side
`
`
`
`
`
`
`
`
` chain.
`
`
`
`
`
`
`
` Absorption:
`
`
`
` Distribution:
`
`Elimination:
`
`
`
`
`
` Metabolism:
`
`
`
`
`
`
`
`
`
`
`
`
` 2.2 Dosing and Therapeutic Individualization
`
`
` 2.2.1 General dosing
`
`
`
` The proposed starting dose of RYBELSUS is as follows:
` The recommended starting dose is 3 mg once daily for 1 month. After 1 month on 3 mg, the dose should
`
`
`
`
`
` be increased to 7 mg once daily. If additional glycemic control is needed after at least one month on 7 mg,
` the dose may be increased to 14 mg once daily.
`
`
`
`
`
`
`
` Semaglutide oral tablets must be taken at least 30 minutes before the first food, beverage or other oral
` medications of the day with no more than half a glass of water (approximately 4 ounces). Other
`
`
`
`
` beverages (including mineral water), food, and some medications are likely to reduce the absorption of
` semaglutide. Waiting less than 30 minutes, or taking semaglutide with food, beverages (other than plain
`
`
` water) or other medications will lessen the effect of semaglutide by decreasing its absorption into the
`
`
` body. Remaining in a fast for more than 30 minutes after taking semaglutide is likely to increase the
`
`
`
` absorption. The tablet should be swallowed whole.
`
`
`
`
`
`
` The dose-response relationship for HbA1c change from baseline following 26 weeks of treatment showed
` a non-linear dose-response relationship with an ED50 value of approx. 6 mg with the steepest part of the
`
`
`
`
`
`
` curve ranging up to doses of 10 mg, following which the effect started to level off. The relationship was
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 9
`
`
`

`

`
`
`
`
` adequately described by an Emax model as indicated by the model shown as a line in Figure 1. The
`
` estimated model parameters for the dose-response model for HbA1c are provided in Table 1.
`
`
`
`
`
`
`
`
` Figure 1
`
` HbA1c change from baseline versus oral maintenance dose of semaglutide
` (Source: Modelling Report Population PK and Exposure-Response Analysis, Figure 7, Page 32)
`
`
`
`
`
`
`
`
`
`
`
`
` Table 1
`
`
`
`
`
` Parameter estimates for the dose-response model for effects of oral
`
`
` semaglutide on HbA1c
`
`
`
`
`
`
`
`
`
`
`
` (Source: Modelling Report Population PK and Exposure-Response Analysis, Table 15, Page 56)
`
`The proposed dosing regimen is supported by a dose-response analysis. For further details, see Section
`
` 4.2.3.
`
`
`
` 2.2.2 Therapeutic individualization
`
`
`
` No prospective dose adjustments based on patient factors are recommended. Semaglutide dosing should
` follow a titration scheme. Taking two 7 mg semaglutide tablets to achieve a 14 mg dose is not
`
`
`
` recommended. Patients treated with weekly 0.5 mg OZEMPIC (semaglutide) subcutaneous injection can
`
`
`
`
` be transitioned to 14 mg oral semaglutide by starting oral therapy 2 to -4 days following the last injection
`
`
`
`
` (see section 3.3.1, page 26). There is no equivalent dose of oral semaglutide for 1 mg OZEMPIC
`
`
`
`
`
` injection.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4478617Reference ID: 4497378
`
`
`
` 10
`
`
`

`

`
`
`
` 2.3 Outstanding Issues
`
`
` None.
`
`
` 2.4
`
` The Office of Clinical Pharmacology recommends the following preliminary labeling concepts be
`
`
`
` included in the final package insert:
`
`
`
`
`
` Summary of Labeling Recommendations
`
`
`
`
`
`
`
` Label Section
`
`
` 2. DOSAGE AND ADMINISTRATION
`
`
` 2.1 Important Administration
`
`
`
` Instructions
`
`
`
`
` 2.2 Recommended Dosage
`
`
`
`
`
`
`
` 2.3 Switching patients from
` OZEMPIC to TRADENAME
`
`
`
`
`
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
`
`
`
`
`
` 12.3 Pharmacokinetics
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recommendation
`
`
` • Take TRADENAME at least 30 minutes before the first food, beverage, or
`
`
`
`
`
`
`
`
`
`
`
`
`
` medication of th