CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`209637Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`NDA
`
`CLINICAL PHARMACOLOGY REVIEW ADDENDUM
`209637
`
`Link to EDR:
`
`Submission Date:
`
`\\CDSESUB1\EVSPROD\NDA209637\209637.enx
`
`5th December, 2016
`
`Submission Type; Code:
`
`NDA 505(b)(1); Standard
`
`Brand Name:
`
`Generic Name:
`
`Dosage Form and Strength:
`
`Ozempic
`
`Semaglutide
`
`1.34 mg/mL of semaglutide in a pre-filled disposable
`pen injector that delivers 0.25 mg, 0.5 mg, or 1 mg per
`injection
`
`1.34 mg/mL of semaglutide in a pre-filled disposable
`pen injector that delivers 1 mg per injection
`
`Route of Administration:
`
`Subcutaneous
`
`Proposed Indication:
`
`Applicant:
`
`Associated IND:
`
`OCP Review Team:
`
`As an adjunct to diet and exercise to improve glycemic
`control in adults with Type 2 diabetes mellitus
`
`Novo Nordisk Inc.
`
`IND 079754
`
`Shalini Wickramaratne Senarath Yapa, Ph.D., Justin
`Earp, Ph.D., Lian Ma Ph.D., Manoj Khurana, Ph.D.
`
`OCP Final Signatory:
`
`Chandrahas G Sahajwalla, Ph.D.
`
`Reference ID: 4189532
`
`1
`
`

`

`1. Executive Summary
`This addendum will serve to provide the clinical pharmacology conclusions regarding the
`proposed dosing regimen considering the advisory committee’s feedback on the observed
`retinopathies in the cardiovascular outcomes trial.
`
`The clinical pharmacology review was placed in DARRTs on 8/22/2017 by Dr. Shalini
`Wickramaratne Senarath Yapa. In this review two quantitative analyses supported the hypothesis
`that rapid changes to glucodynamics in conjunction with semaglutide administration in patients
`with diabetes led to an increased risk of retinopathy:
`
`1) The reviewer’s multivariate time-to-event analysis of the adverse events dataset for the
`cardiovascular outcomes trial 3744 suggested that retinopathies increased with increasing
`dose as well as with increasing baseline HbA1c and decreased with baseline body-mass
`index.
`2) The results of the applicant’s analysis that evaluated whether EAC-confirmed diabetic
`retinopathies could be attributed to the initial rapid decline in blood glucose. The applicant
`concluded that:
`
`“The effect of the change in HbA1c at week 16 was found to be statistically significant
`with a HR of 1.26 for a 1%-point reduction in HbA1c at week 16. This supports the
`theory that a rapid decline in blood glucose contributed to the mechanisms underlying
`the development of diabetic retinopathy complications in those with a prior history of
`diabetic retinopathy.”
`(Source: Applicant’s Summary of Clinical Safety, page 160-163)
`
`Regarding the first point, the review team decided to use results from a separate analysis because
`the “retinopathy NEC” events (used in the Clin Pharm review) were not adjudicated for retinopathy
`specifically and included a larger grouping of events related to the eye. The results of a similar
`multivariate time-to-event analysis on the adjudicated retinopathies are presented in the statistical
`review by Dr. Ya-Hui Hsueh on 8/29/2017. The adjudicated events had an equal number of events
`in each semaglutide arm (n=25 per arm) reducing the overall evidence of dose response. However,
`the fact remains that the rate of adjudicated retinopathies in the semaglutide arm (50/1648) was
`76% higher than that for the placebo arm (29/1649).
`
`Regarding the second point, the applicant’s analysis demonstrates an appearance of increased risk
`of retinopathy for patients that have a rapid initial decline in baseline HbA1c. Their analysis also
`indicated that prior retinopathy history was an important factor for increased risk of retinopathy.
`This was briefly discussed by the advisory committee, and dismissed as “exploratory”. It appeared
`that the consensus regarding these events is that they are attributed to the disease.
`
`Additional data are required to evaluate the hypothesis that slower changes in glucodynamics can
`limit the occurrence of retinopathies. In the current diabetes environment where diabetic
`2
`
`Reference ID: 4189532
`
`

`

`retinopathy is a standard complication, with the paucity of data, it is not possible to conclude that
`this is associated with semaglutide induced changes to glucodynamics. As such, no changes can
`be recommended to the applicant’s dosing regimen.
`
`1.1 Recommendations
`The Office of Clinical Pharmacology has reviewed submission NDA 209637 for semaglutide and
`found the applicant’s proposed dosing regimen acceptable.
`
`Reference ID: 4189532
`
`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JUSTIN C EARP
`12/03/2017
`
`LIAN MA
`12/03/2017
`
`MANOJ KHURANA
`12/04/2017
`
`CHANDRAHAS G SAHAJWALLA
`12/04/2017
`
`Reference ID: 4189532
`
`

`

`NDA
`
`Link to EDR:
`
`Submission Date:
`
`CLINICAL PHARMACOLOGY REVIEW
`209637
`
`\\CDSESUB1\EVSPROD\NDA209637\209637.enx
`
`5th December, 2016
`
`Submission Type; Code:
`
`NDA 505(b)(1); Standard
`
`Brand Name:
`
`Generic Name:
`
`Dosage Form and Strength:
`
`Ozempic
`
`Semaglutide
`
`1.34 mg/mL of semaglutide in a pre-filled disposable
`pen injector that delivers 0.25 mg, 0.5 mg, or 1 mg per
`injection
`
`1.34 mg/mL of semaglutide in a pre-filled disposable
`pen injector that delivers 1 mg per injection
`
`Route of Administration:
`
`Subcutaneous
`
`Proposed Indication:
`
`Applicant:
`
`Associated IND:
`
`OCP Review Team:
`
`
`
`As an adjunct to diet and exercise to improve glycemic
`control in adults with Type 2 diabetes mellitus
`
`Novo Nordisk Inc.
`
`IND 079754
`
`Shalini Wickramaratne Senarath Yapa, Ph.D., Justin
`Earp, Ph.D., Lian Ma Ph.D., Manoj Khurana, Ph.D.
`
`OCP Final Signatory:
`
`Chandrahas G Sahajwalla, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4142722
`
`1
`
`

`

`Table of Contents
`1. Executive Summary .............................................................................................................................. 4
`
`1.1 Recommendations ............................................................................................................................... 4
`
`1.2 Post-Marketing Requirements and Commitments .............................................................................. 6
`
`2. Summary of Clinical Pharmacology Assessment ..................................................................................... 6
`
`2.1 Pharmacology and Clinical Pharmacokinetics .................................................................................... 6
`
`2.2 Dosing and Therapeutic Individualization .................................................................................... 13
`
`2.2.1 General dosing ........................................................................................................................... 13
`
`2.2.2 Therapeutic individualization .................................................................................................... 13
`
`2.3 Outstanding Issues ............................................................................................................................ 13
`
`2.4 Summary of Labeling Recommendations ......................................................................................... 13
`
`3. Comprehensive Clinical Pharmacology Review ..................................................................................... 14
`
`3.1 Overview of the Product and Regulatory Background ..................................................................... 14
`
`3.1.1 What pertinent regulatory background or history contributed to the current assessment of the
`clinical pharmacology of this drug? .................................................................................................... 14
`
`3.1.2 What are the highlights of the chemistry and physical-chemical properties of the drug
`substance and the formulation of the drug product? ........................................................................... 15
`
`3.1.3 What are the proposed mechanism of action and therapeutic indication of semaglutide? ......... 17
`
`3.1.4 What are the proposed dosages and routes of administration? .................................................. 17
`
`3.2 General Pharmacology and Pharmacokinetic Characteristics ........................................................... 17
`
`3.2.1 Pharmacokinetics ....................................................................................................................... 17
`
`3.2.2 Pharmacodynamics .................................................................................................................... 33
`
`3.2.3 Body weight ............................................................................................................................... 45
`
`3.2.4 QTc prolongation ....................................................................................................................... 48
`
`3.3 Clinical Pharmacology Questions ..................................................................................................... 48
`
`3.3.1 To what extent does the available clinical pharmacology information provide pivotal or
`supportive evidence of effectiveness? ................................................................................................. 48
`
`2
`
`
`
`Reference ID: 4142722
`
`

`

`3.3.2 Is the proposed dosing regimen appropriate for the general patient population for which the
`indication is being sought? .................................................................................................................. 52
`
`3.3.3 Is an alternative dosing regimen and/or management strategy required for subpopulations based
`on intrinsic factors? ............................................................................................................................. 55
`
`3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate
`management strategy? ......................................................................................................................... 62
`
`3.3.5 Is the clinical formulation of semaglutide used in the clinical pharmacology program similar to
`the to-be-marketed formulation? ......................................................................................................... 80
`
`4. Labeling Recommendations .................................................................................................................... 84
`
`5. Appendices .............................................................................................................................................. 91
`
`5.1 Key Highlights of Clinical Pharmacology Studies Cited in the QBR............................................... 91
`
`5.2 Summary of Bioanalytical Method Validation ................................................................................. 94
`
`5.2.1 Semaglutide ................................................................................................................................ 94
`
`5.2.2 Concomitantly Administered Drugs in Drug Interaction Studies ............................................ 107
`
`5.3 Population PK Analysis .................................................................................................................. 109
`
`5.4 Study NN9535-3616: Renal impairment study: Original Analysis ................................................ 123
`
`5.5 Applicant’s Analysis of Retinopathies with regards to change from baseline HbA1c ................... 126
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4142722
`
`
`
`3
`
`

`

`1. Executive Summary
`This is an original NDA submitted by Novo Nordisk Inc. on December 5th, 2016, seeking
`marketing approval for semaglutide as an adjunct to diet and exercise to improve glycemic
`control in adult patients with Type 2 diabetes mellitus (T2DM). Semaglutide is proposed to be
`marketed under the tradename of Ozempic.
`
` long-acting analogue of human glucagon-like peptide-1 (GLP-1),
`Semaglutide is a
`with a 94% sequence homology to human GLP-1. Semaglutide is a GLP-1 receptor agonist that
`selectively binds to and activates the GLP-1 receptor, a target receptor for native GLP-1. GLP-1
`is an endogenous incretin hormone that stimulates insulin secretion and inhibits glucagon
`secretion from the pancreatic islets in a glucose-dependent manner.
`
`Following subcutaneous (SC) administration, semaglutide has a relatively long terminal half-life
`(t1/2) which allows for once weekly dosing. The Applicant claimed that the prolonged action
`profile of semaglutide is due to the following mechanisms: delayed absorption from the subcutis,
`increase binding to albumin (decrease in renal clearance and protection from metabolic
`degradation), and an increase in enzymatic stability (against dipeptidyl peptidase 4 (DPP-4)
`enzymes).
`
`Semaglutide formulation is a clear and colorless 1.34 mg/mL solution for injection available in a
`pre-filled disposable pen injector.
`
`The clinical pharmacology development program conducted to characterize the pharmacokinetic
`(PK) and pharmacodynamic (PD) properties of semaglutide included 16 clinical pharmacology
`studies. Majority of the clinical pharmacology Phase 1 studies were conducted in healthy
`subjects (including first in human study, bioequivalence studies, metabolism study, QTc study,
`renal and hepatic impairment studies, drug-drug interaction studies, and studies in Japanese
`subjects) and the remaining studies were in patients with T2DM (PD studies, and 1 drug-drug
`interaction study). A Phase 1 PD study was conducted in obese, non-diabetic subjects. The Phase
`2 dose-finding study was conducted in patients with T2DM. Pharmacokinetic data from 5 Phase
`3a studies was used to perform population PK and exposure-response analyses. The program was
`supported by results from 9 in vitro human biomaterial studies.
`
`1.1 Recommendations
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP-2) has
`reviewed the clinical pharmacology data submitted in support of NDA 209637 for semaglutide
`and found it acceptable to support approval. OCP has the following recommendations and
`comments:
`
`
`
`
`
`Reference ID: 4142722
`
`4
`
`(b) (4)
`
`

`

`Pivotal or supportive evidence HbAlc reduction from Phase 33 studies provides primary
`
`Recommendations and Comments
`
`of effectiveness
`
`evidence of effectiveness for the proposed dosing regimen.
`
`The PK and PD (an increase in insulin secretion and a
`
`decrease in glucagon secretion in a glucose-dependent manner
`
`after treatment with semaglutide) of semaglutide in patients
`
`with T2DM provided supportive evidence for effectiveness.
`
`General dosing instructions
`
`Semaglutide is to be administered once weekly, at any time of
`
`the day, with or without meals, and injected subcutaneously in
`
`the abdomen, in the thigh, or in the upper arm.
`
`
`
`The starting dose of semaglutide is 0.25 mg once weekly,
`
`after 4 weeks the dose should be increased to 0.5 mg once
`
`weekly. If further improvement in glycemic control is needed,
`
`after 4 weeks, the dose of semaglutide may be increased to 1
`
`mg once weekly. The maximum recommended dose is 1 mg
`
`once weekly.
`
`The
`
`clinical pharmacology review identified a dose-
`
`retinopathy relationship for a higher incidence of retinopathies
`
`with the 1.0 mg dose compared to the 0.5 mg dose. The
`
`incidence of retinopathies is a concern and will be discussed
`
`at the upcoming advisory committee meeting for semaglutide
`
`in October 2017. The applicant conducted an analysis that
`
`suggests that patients with a faster drop in HbAlc were more
`
`prone to retinopathy, particularly in patients with prior
`
`retinopathy history and longer duration of prior diabetes
`
`history.
`
`Given the continuing discussion regarding the
`
`occurrence of retinopathies with increasing dose the final
`
`dosing recommendation will be made in an addendum to this
`
`review following the advisory committee meeting in October
`2017.
`
`Dosing inpatient subgroups
`
`No separate dose/dosing regimen is recommended in any
`
`patient subgroups due to intrinsic (age, sex, race, etlmicity,
`
`body weight,
`
`renal
`
`impairment, hepatic impairment) and
`
`extrinsic factors. Semaglutide does delay gastric emptying;
`therefore caution should be exercised when oral medications
`
`Reference ID: 4142722
`
`

`

`are concomitantly administered with semaglutide.
`
`Labeling
`
`No major labelling issues. Refer to Section 4.
`
`the
`Bridge between
`marketed and clinical
`formulations
`
`to-be-
`trial
`
`The to-be-marketed drug product formulation (1.34 mg/mL)
`was used in all pivotal Phase 3a studies and in the majority of
`the clinical pharmacology studies.
`
`During the clinical pharmacology development program,
`despite no changes to the formulation of semaglutide drug
`product, different concentrations of drug substance (1, 3, 10
`mg/mL) and a change to the drug substance manufacturing
`processes
` was
`implemented.
`Bioequivalence was established (based on
`the primary
`pharmacokinetic endpoints) between the 2 drug product
`formulations
` drug
`substance and between drug product strengths of 1 mg/mL, 3
`mg/mL, and 10 mg/mL.
`
`A faster absorption of semaglutide was observed with the
`highest drug product strength (10 mg/mL).
`
`
`
`1.2 Post-Marketing Requirements and Commitments
`None.
`
`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.
`
`Pharmacokinetics of semaglutide
`
`Semaglutide demonstrated dose independent pharmacokinetic characteristics from 0.5 mg and
`1.0 mg subcutaneous doses. Some of the key pharmacokinetic parameters of 1.0 mg SC
`semaglutide at steady-state in patients with T2DM are presented in the Table below.
`
`
`
`
`
`
`
`Reference ID: 4142722
`
`6
`
`(b) (4)
`
`(b) (4)
`
`

`

`We MmW
`
`
`
`Median
`
`The estimated terminal
`
`t1/2,ss of semaglutide indicates that steady-state will be achieved
`
`following 4-5 weeks of once weekly dosing in patients with T2DM.
`
`In healthy subjects, the absolute bioavailability of semaglutide was estimated to be 89% afier SC
`
`administration of 0.5 mg single dose of semaglutide.
`
`Protein binding of semaglutide
`
`In in vitro studies,
`
`the fraction unbound (f..) of semaglutide in human plasma was <1%.
`
`Therefore the plasma protein binding of semaglutide in human plasma was >99%, and similar
`
`across the species tested (rabbit, monkey, minipig, mouse, rat). In plasma, albumin was the
`
`primary protein for binding of semaglutide.
`
`Metabolism and excretion of semaglutide
`
`In an in vitro study, following incubation of semaglutide with human neutral endopeptidase
`
`24.11 (NEP), a total of 19 metabolites were structurally characterized. These metabolites are
`
`proposed to be products of initial NEP cleavage sites in the peptide backbone of semaglutide (4
`metabolites were products from 1 proteolytic cleavage at one of the following sites: Serls-Tyrw,
`Tyrlg-Leuzo, Glu27-Phe73, and T1p31- u”) and smaller peptides formed after additional
`proteolytic degradation.
`
`In an in vivo mass balance study, following administration of a single SC dose of 0.5 mg [3H]-
`
`semaglutide to healthy subjects, 7, 22, and 7 components were detected in plasma, urine, and
`
`feces, respectively, of which components P4 in plasma and U22 in urine was identified as intact
`
`semaglutide. In plasma, metabolite P3B was identified as a peptide metabolite formed after
`proteolytic cleavage in semaglutide between Tyr19 and Leu20 and products P3C-I, P3C-II, and
`
`P3C-III were characterized as semaglutide isomers.
`
`In urine, metabolite U6 and U7 was identified as the free Lys26 amino acid bound to the ADO—
`linker with di-butyric (C4) and di-hexanoic (C6) acid side chains, respectively, and are most
`
`Reference ID: 4142722
`
`

`

`likely formed after several proteolytic cleavages of the semaglutide peptide backbone and
`sequential beta-oxidation of the di-fatty acid side chain.
`
`The major excretion route of semaglutide-related materials was via the urinary (53% of
`administered dose) and fecal (18.6% of administered dose) routes. Approximately 3% of the
`dose was excreted as intact semaglutide in urine.
`
`Pharmacodynamics of semaglutide in patients with T2DM
`
`Pharmacodynamic effects of 1 mg semaglutide at steady-state on glycodynamics were
`demonstrated as follows:
`
`An improvement in insulin secretion, during both the first (0-10 min) and second (10-120 min)
`phase insulin secretion, was observed following treatment with semaglutide when compared to
`placebo in patients with T2DM.
`
`Following a meal stimulation test, there was a reduction in fasting glucose (22%), in AUC0-5 hr
`postprandial glucose (20-29%), and in the overall 24 hr glucose profile (22%) in patients with
`T2DM treated with semaglutide compared to placebo. Likewise, a reduction in fasting (8%),
`AUC0-5 hr postprandial (14-15%), and overall 24 hr profile (12%) glucagon was observed in
`patients with T2DM following semaglutide treatment compared to placebo. For insulin, an
`increase in fasting insulin was observed (30%) in patients treated with semaglutide compared to
`placebo, however no treatment effect of semaglutide when compared to placebo was evident for
`AUC0-5 hr postprandial insulin.
`
`For overall 24 hour insulin profile, the primary analysis revealed no treatment difference of
`semaglutide compared to placebo, however in a sensitivity analysis, which excluded patients
`who were non-compliant with meals, an 8-15% increase in insulin was observed after
`semaglutide treatment compared to placebo. Such observations for overall (primary analysis) and
`postprandial insulin are likely to be attributed to the lower postprandial demand for insulin in
`patients treated with semaglutide as a result of lower glucose concentrations and an increase in
`insulin sensitivity. In the Phase 3a studies, semaglutide treatment overall decreased insulin
`resistance (HOMA-IR indices) from baseline and throughout the trial.
`
`Under hyperglycemic conditions, following a IV injection of arginine, an increase in insulin
`levels was observed during 0-10 min and 0-30 min periods following treatment with semaglutide
`compared to placebo (at end-of-treatment). The estimated treatment ratio (semaglutide/placebo)
`for mean change from baseline to end-of-treatment was 2.82 and 4.42 (significant) for the 0-10
`min and 0-30 min time periods, respectively. The results suggest an improvement in maximal
`insulin secretory capacity in patients with T2DM treated with semaglutide when compared to
`placebo.
`
`8
`
`
`
`Reference ID: 4142722
`
`

`

`In patients with T2DM, an increase in insulin secretion rate with increasing plasma glucose
`levels (5-12 mmol/L) in a glucose-dependent manner was observed following treatment with
`semaglutide compared to placebo. For glucagon, a more pronounced glucose-dependent decrease
`in glucagon concentration was observed with increasing plasma glucose levels after treatment
`with semaglutide compared to placebo in patients with T2DM. Thereby, semaglutide improves
`insulin secretory response (β-cell responsiveness) and lowers glucagon secretion to elevated
`glucose concentrations in a glucose-dependent manner.
`
`The insulin secretion rate-glucose concentration profile after semaglutide treatment in patients
`with T2DM was similar to that observed in healthy subjects (no treatment). The glucagon
`concentration-time profile for patients with T2DM was more similar to that of healthy subjects
`(no treatment) as compared to patients with T2DM treated with placebo.
`
`Treatment with semaglutide (1 mg SC semaglutide at steady-state) did not compromise the
`overall counter-regulation of plasma glucose levels during hypoglycemia in patients with T2DM
`when compared to placebo. Semaglutide treatment compared to placebo did not alter the counter-
`regulatory responses of increased glucagon and did not impair the reduction in C-peptide levels
`in patients with T2DM.
`
`Body weight
`
`A body weight reduction of ~4-5 kg was evident in patients with T2DM and in obese, non-
`diabetic subjects following 12 weeks of treatment with semaglutide. In obese, non-diabetic
`subjects the reduction in body weight was likely attributed to appetite and energy intake rather
`than due to energy expenditure.
`
`The PK of semaglutide appears to be correlated with body weight. There was a 0.73- and 1.4-
`fold increase compared to the population estimate over the 95% confidence interval of body
`weights in the population. No dose adjustments are recommended based on this covariate, due to
`the nature of the dosing regimen, starting low and increasing dose based on glycemic response.
`
`QT/QTc
`
`No significant QTc prolongation effect of semaglutide (0.5 mg, 1.0 mg, and 1.5 mg) was detected
`in the TQT study. The largest upper bounds of the 2-sided 90% confidence interval (CI) for the
`mean difference between semaglutide (0.5 mg, 1.0 mg, and 1.5 mg) and placebo were below 10
`ms, the threshold for regulatory concern as described in the ICH E14 guideline.
`
`Age, sex, race, ethnicity
`
`Age, sex, race, and ethnicity did not alter the PK of semaglutide sufficiently to warrant a dose
`adjustment based on any of these factors. The range of effect on the estimate of AUC was 2 –
`
`9
`
`
`
`Reference ID: 4142722
`
`

`

`6% different for these 4 factors. See Appendix 5.3 for technical details of the population PK
`analysis.
`
`Renal and hepatic impairment
`
`No dose adjustment of semaglutide is proposed for patients with T2DM with renal (mild,
`moderate, severe, end-stage) and hepatic (mild, moderate, severe) impairment.
`
`In subjects with renal impairment (moderate, severe, end-stage), following adjustment for
`imbalances in age, sex, and body weight, the overall exposure of semaglutide, AUC0-∞, was 10-
`16% higher when compared to subjects with normal renal function. For subjects with mild renal
`impairment, AUC0-∞ was comparable (adjusted for imbalances) to that of subjects with normal
`renal function. On average, maximum concentrations of semaglutide were 11-20% lower
`(adjusted for imbalances) in subjects with renal impairment compared to subjects with normal
`renal function. In subjects with end-stage renal impairment, hemodialysis did not appear to affect
`the exposure of semaglutide. Results from the population PK analysis of the Phase 3 studies
`(NN9535-3623, NN9535-3626, NN9535-3624, NN9535-3744 and NN9535-4091) indicate little
`difference between patients with mild (1.06-fold increase in AUC), moderate (1.05-fold increase
`in AUC), and severe renal impairment (1.09-fold increase in AUC) and patients with normal
`renal function
`
`In subjects with hepatic impairment (mild, moderate, severe), the overall exposure of
`semaglutide (AUC0-∞) was comparable to subjects with normal hepatic function (estimated ratio
`of mean AUC0-∞ was close to 1). On average, subjects with severe hepatic impairment had a 15%
`higher maximum concentration of semaglutide compared to subjects with normal hepatic
`function; however these results are likely to have been driven by an extreme Cmax value from a
`single subject. Maximum concentrations of semaglutide were comparable for subjects with mild
`and moderate hepatic impairment compared to subjects with normal hepatic function (estimated
`ratio of mean Cmax was close to 1).
`
`Relative bioavailability from different injection sites
`
`The population PK analysis suggested that BA decreased approximately 3% for injection into the
`thigh compared to the abdominal skin and that BA decreased approximately 8% for injection into
`the upper arm compared to in the abdominal skin.
`
`Drug-drug interactions
`
`No clinically relevant drug-drug interactions were observed between semaglutide and any of the
`evaluated co-administered drugs, therefore no dose adjustments are proposed when co-
`administered with semaglutide.
`
`10
`
`
`
`Reference ID: 4142722
`
`

`

`In vitro studies showed semaglutide to have a very low potential to inhibit or induce cytochrome
`P450 enzymes, and to inhibit drug transporters (P-gp, BCRP, OCT2, OAT1, OAT3).
`Semaglutide did partially inhibit OATP1B1 and OATP1B3, however the potential for clinically
`relevant interactions between semaglutide and OATP1B1/1B3 transporters is considered to be
`low.
`
`Several drug-drug interactions were evaluated to assess to what extent the delay in gastric
`emptying by semaglutide would impact the PK profiles of concomitantly administered drugs.
`Drugs commonly used by patients with T2DM with different solubility and permeability
`properties and/or narrow therapeutic indices were selected; warfarin (Biopharmaceutics
`Classification System (BCS) Class I/II, narrow therapeutic index), atorvastatin (Class II),
`metformin (Class III), digoxin (Class II/IV, narrow therapeutic index).
`
`In addition, the impact on the PK profiles of a low dose combination oral contraceptive,
`ethinylestradiol (EE) and levonorgestrel (LN), was also assessed. The impact of semaglutide on
`the exposure (AUC and Cmax) of concomitantly administered drugs is presented in the Table
`below.
`
`Geometric mean maximum concentration (Cmax) of atorvastatin was approximately 38% lower
`when co-administered under semaglutide steady-state conditions compared to administration
`alone. The Applicant reports that the observed decrease in Cmax is unlikely to be of clinical
`relevance as the efficacy of atorvastatin has been shown to be poorly correlated with peak
`concentrations.
`
`For both EE and LN, a higher exposure, 11% and 20%, respectively, was observed when co-
`administered with semaglutide compared to administration alone. The Applicant overall
`concludes that no clinically relevant changes in the overall exposure of EE and LN was
`observed. The drug-drug interaction assessment for warfarin also showed no major changes in
`the overall or maximum anticoagulant effect of warfarin when co-administered with semaglutide.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4142722
`
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`

`

`Atorvastatin
`
`(40 mg. SD)
`
`Digoxin
`
`(0.5 mg, SD)
`
`Metformin
`
`(MD, 500 mg twice a day
`
`for 3.5 days)
`
`Warfarin
`(25 mg. SD):
`
`_
`
`daily for 8 days)
`
`0.25 mg. 0.5 mg. 1
`
`mg. Each dose
`administered once
`weekly for 4
`
`weeks. One or two
`
`additional doses of
`
`at Steady-State
`
`Before semaglutide
`dosing and at steady-state
`
`of 1 mg semaglutide
`
`Ethinylestradiol
`
`(MD. 0.03 mg once
`
`daily for 8 days)
`
`Levonorgestrel
`
`(MD. 0.15 mg once
`
`
`
`H No change: 2-5% change
`SD: Single-dose: MD: Multiple-dose
`
`To—be—marketed formulation vs. clinical trial formulations
`
`The proposed to-be—marketed formulation of
`
`semaglutide,
`
`1.34 mg/mL
`
`m“)
`
`, was used in all Phase 3a studies and in a majority of Phase 1 studies. Despite no
`
`changes in the formulation of semaglutide drug product, different concentrations of drug
`
`substance (1, 3, 10 mg/mL) and changes in the drug substance manufacturing processes
`m“) occurred during the development program.
`
`Bioequivalence (BE) was established between drug product strengths 1 mg/mL, 3 mg/mL, 10
`mg/mL based on the primary PK endpoint (AUColp) and between
`M“)
`semaglutide based on the primary PK endpoints (AUCMast, Cm). For drug product strength, a
`
`faster absorption of semaglutide was evident with increase in product strengths. For the key
`
`12
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`Reference ID: 4142722
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`

`

`supportive secondary PK endpoint of Cmax, only comparison of 1 mg/mL vs. 3 mg/mL product
`strengths met the pre-defined acceptance criteria.
`
`The drug product strength of 10 mg/mL was used in 3 Phase 1 studies, and the Applicant reports
`that overall the efficacy and safety of semaglutide in this program is based on the pivotal Phase
`3a studies which used the to-be-marketed formulation of semaglutide. No formal BE assessment
`was conducted with the to-be-marketed formulation (1.34 mg/mL); the Applicant reports that the
`results generated for product strengths 1 mg/mL and 3 mg/mL is representative of the to-be-
`marketed formulation of semaglutide.
`
`2.2 Dosing and Therapeutic Individualization
`
`2.2.1 General dosing
`Semaglutide is proposed to be administered once weekly, at any time of the day, with or without
`meals, and can be injected subcutaneously in the abdomen, thigh, or upper arm. The proposed
`dosing regimen for semaglutide is 0.25 mg once weekly via SC administration as a starting dose,
`after 4 weeks the dose should be increased to 0.5 mg once weekly. If further improvement in
`glycemic control is require