CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-341
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW(S)
`
`

`

`Office of Clinical Pharmacology
`
`Memo to File
`
`22—341
`
`05/23/08
`
`Victoza (Liraglutide) 6 mg/mL
`
`September 29, 2009
`Manoj Khurana, Ph.D.
`
`.
`
`Sally Choe, Ph.D.
`
`Novo Nordisk
`
`Clinical Site Deficiencies cited by The Division of
`Scientific Investigations
`(DSI) on the Pivotal
`Bioequivalence Trial.
`
`NDA
`
`Submission Date ,
`
`Drug
`
`Memo Date
`Reviewer
`
`Team Leader
`
`Sponsor
`
`Subject
`
`Background Information:-
`
`The Division of Scientific Investigations (DSI) audited and issued the Form 483s to the
`analytical and clinical sites of the following pivotal bioequivalence trial, IMP NN2211-
`1692: “A Randomized, Double-Blind, Single—Center, Two—Period, Cross—Over Trial in
`Healthy Subjects Investigating the Bioequivalence Between the Phase 3a Formulating of
`Liraglutide (Formulation 4) and the Planned Phase 3b Formulation (Final Formulation
`4)”. The response to analytical site deficiencies of the trial was found acceptable by both
`Office of Clinical Pharmacology (see QBR Memo Dated 07/10/09) and DSI (See review
`dated 08/31/09 in DAARTS) reviewers.
`
`DSI Findings:
`
`DSI mentioned in their review (dated 02/25/2009) that following the inspection of the
`clinical site, Lund University Hospital, Lund, Sweden (January 26 — 29, 2009), a 2-item
`Form 483 was issued. DSI reported their evaluation of the significant findings, reported
`in form 483 and the clinical site’s response letter (February 18, 2009) to the deficiencies,
`as follows:
`
`“1) Failure of the clinical site tomaintain the blinding code to identify that the study
`formulations administered to the individual subjects followed the randomization code.
`The site was unable to provide assurance that the individual test articles administered to
`subjects or retained for reserve samples contained a specific formulation.
`2) Source data were not signed and dated by the individual collecting the data. For
`example; collection time points for
`the pharmacokinetic blood samples were not
`attributable to either of the two study staff present at the time of collection, corrections to
`the raw data in 3 of 4 occurrences were performed approximately 3 months after the date
`of collection and cannot be verified, and those corrections were not performed by the
`staff present during the collection.”
`
`

`

`The Sponsor’s Response:
`1) The firm’5 response letter stated that the sealed codes were handled according to the
`ICH GCP guideline, section 8.4. 6. However, in DSI reviewer s opinion this was not in
`accordance with Agency’s Final Rule and mentioned that the “Guidance for Industry:
`Handling and Retention ofBA and BE Testing Samples” clearly addresses this issue. DSI
`also noted that during the inspection, the sponsor emailed a document, which meant to
`represent the blinding code, but this document was generated on 05/22/07, which is after
`the conduct of the study. There was no assurance that this code was identical to that
`provided to the site at the time of randomization for the trial. Therefore, this document
`does not assure the identity of the drug products administered to subjects or the reserve
`samples.
`2) The firm’s response letter stated they agreed that the design of the Case Report Forms
`(CRFs) used to capture the source data was not optimal, as it did not allow the staff
`collecting the samples to date and sign the collection time. However, they had created a
`schedule for blood collection time points and that the staff had been instructed to follow
`that schedule. They stated that the investigator and research coordinator, who had not
`performed the blood collection task, had evaluated and corrected the source data after
`receiving a Date Correction Form (DCF) from the sponsor monitor. No corrective actions
`were purposed by the firm for the significant observation.
`
`Reviewer’s Comments and Conclusions:
`
`Based on the review of the responses provided by the sponsor and DSI’s review, the,
`following were noted:
`0 The site’s handling of codes was in accordance to the ICH guidance document E6
`item 8.4.6 that states that randomization codes should be retained by the Sponsor
`after the study ends. However, the sponsor failed in appropriately directing the
`site to ensure compliance with the FDA guidance and later did not provide
`adequate responses to the D81 during inspection.
`0 Even though the randomization codes were not handled as per the FDA guidance,
`this reviewer considers that site did demonstrate adherence to the ICH guidance
`document E6: Good Clinical Practice item 8.4.6, and considers it to be rather a
`procedural failure at the sponsor’s part. The trial results are acceptable based on
`this fact and the totality of study results.
`
`Recommendation:
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology—H (OCP/DCP-
`II) has reviewed the results of the Division of Scientific Investigations (DSI) audit
`conducted on a pivotal bioequivalence trial for NDA 22-341 (liraglutide) and found the
`trial results to be acceptable.
`
`

`

`Application
`Type/Number
`
`Submission
`Type/Number ,
`
`Submitter Name
`
`Product Name
`
`NBA-22341
`
`ORlG—1
`
`NOVO NORDISK
`INC
`
`VICTOZA (LIRAGLUTIDE)
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`MAN OJ KHURANA
`
`1 1/04/2009
`
`SALLY Y CHOE
`
`11/05/2009
`
`

`

`Office of Clinical Pharmacology
`
`Memo to File
`
`22-341
`
`05/23/08
`
`Victoza (Liraglutide) 6 mg/mL
`
`July 10, 2009
`
`NDA
`
`Submission Date
`
`Brand Name
`
`Memo Date
`
`Clinical Pharmacology
`Reviewer
`
`Manoj Khurana, PhD.
`'
`
`Clinical Pharmacology Team
`Leader
`
`Sally Choe, Ph.D.
`
`Sponsor
`
`Subject
`
`Novo Nordisk
`
`Sponsor’s response to FDA letter (dated 04/ 17/09)
`requesting information on a summary of the pivotal
`bioequivalence and other clinical pharmacology studies
`including a by—study summary of the percentage of
`duplicate values in the analytical standards.
`
`Background Information:
`In a letter dated March 5, 2009, the Agency requested Novo Nordisk (hereafter referred as
`sponsor) for responses to deficiencies cited during the January 2009 analytical site inspections
`
`conducted at
`The sponsor provided their response in
`March 27, 2009 with revised clinical pharmacology assessments, which were incorporated in the
`final QBR. However, in another letter dated 04/17/09 Agency asked the sponsor for further
`clarification in this regard:
`
`“In Agency’s opinion, your approach of (1) accepting one of duplicate determinations when the
`mean of the duplicates are outside +/—30% and %CV >30% and excluding single determination
`that deviates most from the nominal value, and (2) exclusion of one of the duplicates for both
`calibrators and QCs due to technical errors (reported after generation of results),
`is not
`completely objective and may introduce bias. Please provide us your justification for using these
`criteria. ”
`'
`
`.
`
`to evaluate the impact of this approach on the overall clinical pharmacology
`Additionally,
`program the following request was made:
`“We also request you to provide us a summary for the pivotal BE and other clinical
`pharmacology studies, covered in the responses submitted on March 27th and March 30th, 2009,
`and which should include the following:
`(a) A by-study summary ofthe percentage ofduplicate values in the analytical standards
`(Calibration and QC) as well as test samples thatfall into above mentioned criteria (i.e.
`where single values were reported instead of means) and the percent of analytical runs
`affected.
`(b) Listing ofsubject IDs for each studyfor which these criteria were used. ”
`
`

`

`Current Submission:
`
`The sponsor provided their response in May 08, 2009 submission. The sponsor mentioned that
`for the review of raw data, they prospectively decided to consistently adhere to the assay
`run acceptance criteria set by ' ’F“ at the time of sample analysis. In addition, they
`supplemented the acceptance criteria with CV requirements for duplicate determinations,
`in order to be able to reject single determinations objectively. All analytical runs not
`meeting the criteria were rejected, unless a reason for
`the data evaluation was
`documented in the raw data. Thus, the approach of accepting one of duplicate calibrator
`determinations when the mean accuracy of the duplicates are outside +/—30% and CV
`>30%, and excluding the single determination that deviated most from the nominal value
`was adopted.
`
`Further, the sponsor elaborated that “The rationalefor keeping calibrator points as single
`determinations, instead of excluding the calibrator level if the mean did not fulfill the
`criteria, relates to the fact that the calibration curve has been split and validated in two
`parts in the liraglutide bioanalytical assay performed at ~r---~. . Thus, exclusion of
`central calibrator levels could affect the whole calibration curve. The rationale for
`keeping the single determination that is closest to the nominal value is that this value
`most likely will result in the best fitfor the calibration curve.”
`
`Sponsor also provided re-analysis results for the pivotal BE study analysis after excluding all
`runs accepted based on single determinations of calibrators or QCs (20% runs; 18%
`samples). The result of the updated analysis is presented in summary in Table 1.
`
`to
`
`HIM
`
`Table iml
`
`Comparison between Formulations (Final Permutation 4 / Formulation 4) m
`
`Primary Endpoints — Trial 1692
`
`
`
`Based on the review of the responses provided by the sponsor, the following were noted:
`0
`In this reviewer ’s opinion, overall, the use of uniform criteria for data review is a
`
`better approach over the inconsistent approach followed by the
`and
`the revised analysis did not impact the interpretation of clinical pharmacology
`studies.
`(See the Clinical Pharmacology NDA review in DAARTS dated
`04/24/09).
`In this reviewer ’s opinion, the justification in support of retaining single values is
`not clear as to how the retention of central calibrator is related to the splitting of
`standard curve during validation, when the context is the calibration standards
`used during the analysis of study samples.
`If the objective of keeping a value
`
`0
`
`W)
`
`

`

`then this
`close to nominal value is to get the best fit for the calibration curve,
`objective is not bias free. Though one can argue that this will not impact the back
`calculation of unknown concentrations in test samples, one should not deviate
`from the objective of calibration standards and QCs. The objective of calibration
`standards and QCs is to capture the analytical performance ofassay on any given
`day using the known concentrations.
`This reviewer agrees with the conclusion that the results of the pivotal BE study
`were not afiected by the further exclusion of data based on single determinations
`in the calibration/QC standards. For other clinical pharmacology studies 6—] 7%
`of samples were aflected by this issue and do not impact the interpretation of
`results.
`
`0
`
`Recommendation:
`
`Overall, from Clinical Pharmacology perspective, the sponsor still did not provide adequate
`justification regarding the-bias-free nature of the approach they followed in retaining single
`determinations. However, we agree that the impact of this approach is minimal and does not
`affect the interpretation of clinical pharmacology data. No further action is recommended with
`respect to the data integrity issues.
`
`Nevertheless, in future submissions, the sponsor is strongly advised to proactively undertake the
`responsibility of providing the assurance of analytical data integrity. Since the analytical data
`from one vendor supported the pivotal clinical pharmacology program in this submission, the
`sponsor should have been considerate of the associated impact of the vendor’s performance on
`quality of the data submitted for regulatory approval. This recommendation should be sent to the
`sponsor as appropriate.
`
`

`

`Submission
`Linked Applications Type/Number
`
`Sponsor Name
`
`Drug Name / Subject
`
`NDA 22341
`
`NDA 22341
`
`ORIG 1
`
`ORIG 1
`
`.
`
`VICTOZA (LIRAGLUTlDE)
`
`VICTOZA (LIRAGLUTlDE)
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`MANOJ ,KHURANA
`
`08/13/2009
`
`SALLY Y CHOE
`
`08/13/2009
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`NDA: 22-341
`
`Brand Name
`
`Generic Name
`
`Submission Date(s): 05/30/2008
`
`VictozaTM
`
`Liraglutide
`
`Clinical Pharmacology Reviewer
`
`Manoj Khurana, Ph.D.
`
`Clinical Pharmacology Co-Reviewer
`
`Ritesh Jain, Ph.D.
`
`Clinical Pharmacology Team Leader (Acting)
`
`Wei Qiu, Ph.D.
`
`Primary Pharmacometrics Reviewer
`
`. Manoj Khurana, Ph.D.
`
`Secondary Pharmacometrics Reviewer
`
`Rajanikanth Madabushi, Ph.D.
`
`Pharmacometrics Team Leader
`
`Christoffer Tornoe, Ph.D.
`
`OCP Division
`
`0ND division
`
`Sponsor
`
`Submission Type; Code
`
`Formulation; Strength(s)
`
`Clinical Pharmacology —2
`
`Metabolic and Endocrine Products
`
`Novo—Nordisk
`
`NDA 505(b)(1); Standard
`
`Solution for SC Injection
`
`Proposed Indication
`
`An adjunct therapy to diet and exercise to
`improve glycemic control
`in subjects with
`type 2 diabetes.
`
`
`LIST OF FIGURES AND TABLES
`
`......................................
`
`.....................
`
`..... 3
`
`1
`
`EXECUTIVE SUMMARY ....................................................
`
`............................
`
`............ 5
`
`1.1
`1.2
`1.3
`
`RECOMMENDATION ....................................................................................................................... 5
`PHASE IV COMMITMENTS ............................................................................................................. 5
`SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY FINDINGS ............................................. 5
`
`2
`
`QUESTION-BASED REVIEW (QBR) ...........................................
`
`...........................
`
`....... 10
`
`GENERAL ATTRIBUTES ................................................................................................................ 10
`2.1
`2.1.1 What are the highlights ofthe Liraglutide drug product as they relate to clinical pharmacology review?
`
`2.1.2 Whatis the composition ofto be marketed formulation of Liraglutide? .........
`
`GENERAL CLINICAL PHARMACOLOGY ....................................................................................... 13
`2.2
`2.2.1 What are the PK characteristics of Iiraglutide after subcutaneous administration and how do they relate to the
`dose? ...........................................................................................................................
`
`2.2.2 What are the pharmacodynamic characteristics of liraglutide after subcutaneous a ministration and how do they
`relate to the dose? ......................................................................................................
`
`2.2.3 Is major route of elimination identified? ..........
`2.2.4 Does this drug prolong the QT or QTc Interval? .......................................................
`
`2.2.5 What are the characteristics of the exposure-response relations ips (dose-response, concentra ion--response) with
`regards to efficacy? ......................................................................................................................................................................... 28
`2.2.6 What are the characteristics of the exposure-calcitonin relationships (dose—response, concentration-response) with
`
`regards to thyroid safety? ................................... 30
`2.3
`INTRINSIC FACTORS ...............................................................................
`......................... 32
`
`NDA 22—341 (Liraglutide) OCP Review
`
`1
`
`

`

`3
`
`4
`
`2.3.l What intrinsic factors (e.g., age, gender, race, weight, height, disease, genetic polymorphism, pregnancy, and organ
`dysfunction) influence exposure (PK usually) and/or response, and what is the impact of any differences in exposure on
`efficacy or safety responses? ...............................................................................................................
`
`2.3.2 Does the renal function affect Liraglutide pharmacokinetics ? .....................................
`
`2.3.3 Does the hepatic function affect Liraglutide pharmacokinetics pharmacokinetics ? .
`
`2.4
`EXTRINSIC FACTORS ...................................
`2.4.1 What is the effect of different injection sites on the bioavaIlability of Liraglutide? .....................
`
`2.4.2 Drug-Drug Interactions ...........................................................................................
`2.4.2.] What is the CYP inhibition potential of Liraglutide
`2.4.2.2 What is the effect of Liraglutide co-administration on the pharmacokinetics of other drugs? 40
`GENERAL BIOPHARMACEUTICS ...................................
`.
`................................................... 48
`2.5
`
`2.6.1 What is absolute bioavailability and disposition of Liraglutide? .........................................
`2.6.2 Is bioequivalence established between the to-be-marketed formulation and the Phase 3 trial formulation and how
`does it relate to the overall product development?
`................................................................................ 49
`2.6
`ANALYTICAL ....................................................................................................... 52
`
`2.7.1 ls the analytical method for Liraglutide appropriately validated? ................................................................................. 52
`
`LABELING COMMENTS (PRELIMINARY) ......
`
`...............
`
`.................
`
`53
`
`APPENDIX
`
`.....................
`
`...............
`
`..........
`
`........................ 55
`
`4.]
`PROPOSED LABEL ............................................................................'....................... 55
`
`4.2
`INDIVIDUAL STUDY REVIEWS ............................................. 80
`4.2.] Initial PK and Tolerability Study in Healthy Subjects
`
`4.2.2 Mass—Balance Study (NN221 1-1699) ...........................
`
`4.2.3 Single-Dose PD Study (NN2211-2063)..
`4.2.4 Multiple—Dose PD Study (NN2211-1332) ........................................................................................
`
`4.2.5 Single—Dose PD Study (NN2211-1224) .................................................................................
`
`4.2.6 Multiple—Dose PD Study Appetite Suppression (NN2211-1589)...
`
`4.2.7 BE—Evaluations (NN2211-l331, 1636, 1692, 1693) .......
`
`4.2.8 Relative Bioavailability Study (NN2211-1745) ......
`
`4.2.9 DDl Study (NN2211-1330) .........................
`
`4.2.10
`DDI Study (NN2211-1608) ..............
`
`Pharmacokinetics in Elderly (NN2211-1327)........................................................
`4.2.11
`Renal Impairment Study (NN2211-1329)..............................................................
`4.2.12
`
`.215
`4.2.13
`Hepatic Impairment Study (NN2211-1328) ............
`Single-Dose PK Study in Healthy Japanese (NN2211-1326)..
`..22]
`4.2.14
`
`Multiple-Dose PK Study in Healthy Japanese (NN2211-1551) ............................................................................ 227
`4.2.15
`4.2.16
`Multiple-Dose PKPD Study in Type 2 Japanese (NN221 1-1591) ........................................................................ 233
`4.3
`PHARMACOMETRICS REVIEW ................................................................................................... 239
`4.4
`OCP FILING MEMO ................................................................................................................... 261
`
`NDA 22-341 (Liraglutide) OCP Review
`
`2
`
`

`

`
`List of Figures and Tables
`
`GLP-I RECEPTOR ACTIVATED SIGNALING PATHWAYS IN PANCREATIC BETA-CELLS .................. 1 1
`FIGURE 1
`CHEMICAL STRUCTURE OF LIRAGLUTIDE. ................................................................................. 12
`FIGURE 2
`FIGURE 3 MEAN PLASMA CONCENTRATION TIME PROFILE OF LIRAGLUTIDE AFTER SINGLE RISING S.C.
`
`DOSES (1.25 TO 20 LIG/KG) ..................................................................................................................... 13
`FIGURE 4
`DOSE PROPORTIONAL INCREASE IN LIRAGLUTIDE CMAX AND AUC(HNF ...................................... 14
`FIGURE 5
`PLASMA CONCENTRATION-TIME PROFILE OF LIRAGLUTIDE AFTER ORAL ADMINISTRATION ....... 15
`FIGURE 6 MEAN PLASMA GLUCOSE PROFILE FOR PLACEBO TREATED, LIRAGLUTIDE TREATED AND
`HEALTHY SUBJECTS (CONTROL). ........................................................................................................... 18
`FIGURE 7 MEAN INSULIN SECRETION RATE VERSUS PLASMA GLUCOSE PROFILE FOR PLACEBO TREATED,
`LIRAGLUTIDE (NNC 90-1 170) TREATED AND HEALTHY SUBJECTS (CONTROL) ................. . .................... 18
`FIGURE 8 MEAN 24 HOUR PROFILES FOR PLASMA GLUCOSE (A) AND INSULIN (B). ................................... 20
`FIGURE 9
`(A) MEAN 24 HOUR PROFILES FOR PLASMA GLUCAGON ON DAY 1 AND (B) MEAN FIRST-PHASE
`INSULIN ASSESSED DURING THE HYPERGLYCEMIC CLAMP 0N DAY 2 ..................................................... 21
`FIGURE 10
`LIRAGLUTIDE DOES NOT IMPAIR THE GLUCAGON RESPONSE TO HYPOGLYCEMIC COUNTER-
`REGULATION ......................................................................................................................................... 24
`
`FIGURE 1 1
`FIGURE 12
`0.75 MG.
`
`LOCATION OF TRITIUM LABEL IN [3H]-LIRAGLUTIDE ............................................................. 25
`MEAN PLASMA CONCENTRATIONS 0F [3H]-LIRAGLUTIDE FOLLOWING A SINGLE SC DOSE OF
`.............................................................................................................................................. 26
`
`AA QTCI VS. LIRAGLUTIDE CONCENTRATION ....................................................................... 27
`FIGURE 13
`(A) TIME COURSE OF CHANGE FROM BASELINE IN HBAIC FROM THE 52-WEEK PHASE 3
`FIGURE 14
`CONFIRMATORY TRIAL (1573) AND, (B) DOSE DEPENDENT INCREASE IN EFFECTIVENESS OF LIRAGLUTIDE
`BASED ON MEAN(:I:SE) %CHANGE FROM BASELINE IN HBAIC FROM 12-WEEK PHASE 2 TRIAL (1310),
`14-WEEK PHASE 2 TRIAL (1571 ), AND 12-WEEK DATA FROM THE 52—WEEK PHASE 3 CONFIRMATORY
`TRIAL (1573). ........................................................................................................................................ 29
`FIGURE 15
`EXPOSURE—RESPONSE RELATIONSHIP OF LIRAGLUTIDE IN (A) PHASE 2 EXPLORATORY AND (B)
`PHASE 3 CONFIRMATORY TRIAL. ....................................................................................................... 30
`
`TIME COURSE OF CALCITONIN FROM (A) 52-WEEK PHASE 3 CONFIRMATORY TRIAL 1573 AND
`FIGURE 16
`(B) ADD-ON TO METFORMIN PHASE 3 TRIAL 1572 ................................................................................. 31
`FIGURE 17
`FLAT LIRAGLUTIDE EXPOSURE—CHANGE FROM BASELINE IN CALCITONIN RELATIONSHIP AT
`WEEK 26 FROM THE 52-WEEK PHASE 3 CONFIRMATORY TRIAL (1573). ................................................. 32
`FIGURE 1 8
`EFFECT OF BODY WEIGHT ON LIRAGLUTIDE CLEARANCE PHARMACOKINETICS ...................... 33
`FIGURE 19
`NO EFFECT OF AGE AND BMI ON LIRAGLUTIDE CLEARANCE ................................................. 33
`FIGURE 20
`EFFECT OF GENDER AND RACE ON FENOFIBRIC ACID PHARMACOKINETICS. ........................... 34
`FIGURE 2]
`LIRAGLUTIDE PHARMACOKINETIC PROFILE 1N HEALTHY AND RENAL IMPAIRMENT SUBJECTS 36
`FIGURE 22
`LIRAGLUTIDE PHARMACOKINETIC PROFILE IN HEALTHY AND HEPATIC IMPAIRMENT SUBJECTS
`
`AFTER SINGLE 0.75 MG DOSE .................................................................................................................. 37
`FIGURE 23
`MEAN LIRAGLUTIDE PLASMA CONCENTRATIONS FROM DIFFERENT INJECTION SITES.
`39
`FIGURE 24
`MEAN CONCENTRATION-TIME PROFILES FOR THE CO-ADMINISTERED DRUGS ........................ 41
`FIGURE 25
`EFFECTS OF LIRAGLUTIDE ON THE GASTRIC PH ..................................................................... 43
`FIGURE 26
`EFFECTS OF LIRAGLUTIDE ON THE PHARMACOKINETICS OF PARACETAMOL ......................... 44
`
`MEAN PLASMA ETHINYLESTRADIOL (A) AND LEVONORGESTREL (B) FOLLOWING SINGLE DOSE
`FIGURE 27
`ADMINISTRATION OF ORAL CONTRACEPTIVE (NEOVLETTA; 0.03MG ETHINYLESTRADIOL, 0.15 MG
`LEVONORGESTREL) ............................................................................................................................... 47
`FIGURE 28
`MEAN PLASMA LIRAGLUTIDE PROFILES AFTER 5 [JG/KG LIRAGLUTIDE GIVEN AS 1 HOUR IV
`INFUSION AND AS SINGLE SC ADMINISTRATION .................................................................................... 49
`
`NDA 22-341 (Liraglutide) OCP Review
`
`3
`
`

`

`QUANTITATIVE COMPOSITION OF TO-BE-MARKETED LIRAGLUTIDE 6.0 MG/ML, 3 ML
`TABLE I
`CARTRIDGE ........................................................................................................................................... 13
`TABLE 2
`PHARMACOKINETIC PARAMETERS OF LIRAGLUTIDE AFTER SINGLE RISING SUBCUTANEOUS DOSES
`
`FROM 1.25 To 20 LIG/KG ......................................................................................................................... 14
`TABLE 3
`PHARMACOKINETIC PARAMETERS OF LIRAGLUTIDE AFTER SINGLE 0.7 MG S.C. DOSE IN PIVOTAL
`
`BE STUDY USING FORMULATION 4 (PHASE 3) AND FINAL FORMULATION 4 (TO-BE-MARKETED) .......... 15
`TABLE 4
`MEAN LIRAGLUTIDE PHARMACOKINETIC PARAMETERS AFTER SINGLE DOSE (ON DAY 1) AND
`MULTIPLE ONCE DAILY S.C. DOSE .......................................................................................................... 16
`
`AUC(40-220)OF INSULIN SECRETION RATE (ISR) VALUES IN T2DM BY TREATMENT, VERSUS
`TABLE 5
`HEALTHYSUBJECTS .............................. 19
`TABLE 6
`STATISTICAL ANALYSIS OF 24-HOUR PLASMA GLUCOSE
`TABLE 7
`STATISTICAL ANALYSIS OF 24—HOUR PLASMA GLUCAGON
`22
`TABLE 8
`STATISTICAL ANALYSIS OF FIRST-PHASE INSULIN DURING HYPERGLYCEMIC CLAMP ............... 22
`TABLE 9
`POINT ESTIMATES AND THE 90% C15 CORRESPONDING TO THE LARGEST UPPER BOUNDS FOR
`
`LIRAGLUTIDE (1.8 MG AND 1.2 MG) AND THE LARGEST LOWER BOUND FOR MOXIFLOXACIN .............. 27
`TABLE 10
`THE CLASSIFICATIONS OF RENAL IMPAIRMENT GROUPS ........................................................ 34
`TABLE 1 1
`PHARMACOKINETIC PARAMETERS OF LIRAGLUTIDE IN HEALTHY AND RENALLY IMPAIRED
`SUBJECTS .............................................................................................................................................. 35
`TABLE 12 THE CLASSIFICATIONS OF HEPATIC IMPAIRMENT GROUPS ............................................................. 36
`TABLE 13
`STATISTICAL COMPARISON OF AUCOW OF LIRAGLUTIDE IN HEALTHY AND HEPATIC
`IMPAIRMENT SUBJECTS .......................................................................................................................... 38
`
`EFFECT OF INJECTION SITE ON LIRAGLUTIDE PHARMACOKINETICS AFTER SINGLE 0.6 MG SC
`TABLE 14
`ADMINISTRATION IN THIGH, ABDOMEN, AND UPPER ARM USING FORMULATION 4 ................................. 39
`TABLE 15
`IN VITRO CYP ENZYME INHIBITION POTENTIAL OF LIRAGLUTIDE .......................................... 40
`TABLE 16
`SUMMARY OF PHARMACOKINETIC DRUG INTERACTION STUDY DESIGN ............................... 41
`
`EFFECTS OF LIRAGLUTIDE ON PHARMACOKINETIC PARAMETERS OF ATORVASTATIN,
`TABLE 17
`LISINOPRIL, GRISEOFULVIN, AND DIGOXIN ........................................................................................... 42
`TABLE 18
`SUMMARY OF PARACETAMOL PHARMACOKINETIC DRUG INTERACTION STUDY DESIGN ...... 43
`TABLE 19
`SUMMARY OF PRIMARY AND SECONDARY PHARMACOKINETIC PARAMETERS OF
`PARACETAMOL ...................................................................................................................................... 44
`TABLE 20
`EXPECTED AND OBSERVED EFFECTS OF LIRAGLUTIDE CO-ADMINISTRATION ON FOUR
`REPRESENTATIVE BCS CLASS DRUGS .................................................................................................... 45
`TABLE 21
`SUMMARY OF ORAL CONTRACEPTIVE PHARMACOKINETIC DRUG INTERACTION STUDY
`DESIGN
`
`46
`
`STATISTICAL COMPARISON BETWEEN TREATMENTS (LIRAGLUTIDE/PLACEBO) FOR
`TABLE 22
`ETHINYLESTRADIOL AND LEVONORGESTREL ........................................................................................ 47
`TABLE 23
`PHARMACOKINETIC PARAMETERS OF LIRAGLUTIDE AFTER INTRAVENOUS ADMINISTRATION 48
`
`TABLE 24
`
`ABSOLUTE BIOAVAILABILITY (%) OF LIRAGLUTIDE AFTER SUBCUTANEOUS ADMINISTRATION .
`.............................................................................................................................................. 48
`RESULTS OF BIOEQUIVALENCE ANALYSIS FROM MILESTONE BE EVALUATIONS INCLUDING THE
`TABLE 25
`PIVOTAL STUDY (STUDY NNZZI 1-1692) FROM ORIGINAL SUBMISSION ................................................. 50
`TABLE 26
`SUMMARY OF BIOEQUIVALENCE ANALYSIS FOR PIVOTAL BE STUDY I692 ............................ SI
`TABLE 27
`SUMMARY OF ANALYTICAL METHOD USED FOR THE CPB STUDIES ....................................... 52
`
`NBA 22-341 (Liraglutide) OCP Review
`
`4
`
`

`

`1
`
`1.]
`
`Executive Summary
`
`Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP-Z) has
`reviewed the clinical pharmacology data submitted in support of NDA 22-341 for liraglutide and
`found it acceptable, pending an acceptable resolution of the deficiencies found in the Division of
`Scientific Investigation with regards to the bio-analytical method.
`
`Required Office Level OCP briefing was held on 25m March, 2009. Attendees included Dr.
`Chandrahas Sahajwalla, Dr. lsam Zineh, Dr. Kellie S Reynolds, Dr. Nam Atiqur Rahman, Dr.
`Hae Young Ahn, Dr. Sally Y Choe,
`, Dr. Christoffer Tornoe, Dr. Rajanikanth Madabushi, Dr.
`Partha Roy from Office of Clinical Pharmacology and Dr. Mary H Parks, Dr. Hylton Joffe from
`Office ofNew Drugs.
`
`1.2
`
`Phase IV Commitments
`
`None
`
`1.3
`
`Summary oflmportant Clinical Pharmacology Findings
`
`Novo Nordisk is seeking an approval of VictozaTM (Liraglutide) for the indication of improving
`glycemic control in patients with type 2 diabetes mellitus (T2DM). Liraglutide is intended as an
`adjunct to diet and exercise to achieve glycaemic control
`in T2DM patients. Liraglutide is
`developed for once-daily administration as:
`0 Monotherapy
`(metformin,
`drugs
`antidiabetic
`oral
`or more
`one
`- Combination therapy with
`sulphonylureas or a thiazolidinedione) when previous therapy does not achieve adequate
`glycaemic control.
`
`Liraglutide is a human Glucagon—Like Peptide—l (GLP-l) analog with 97% homology to human
`GLP-l that binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native
`GLP-l, which is an endogenous incretin hormone that potentiates the glucose—dependent insulin
`secretion from the pancreatic beta cells. Unlike GLP-l, liraglutide has a pharmacokinetic and
`pharmacodynamic profile
`in human suitable
`for once daily administration. Following
`subcutaneous administration, the protracted action profile is based on three mechanisms: self—
`association, which results in slow absorption, and binding to albumin and enzymatic stability
`towards the DPP—IV enzyme both resulting in a long plasma half—life.
`
`The liraglutide formulation is a clear, colorless solution (6 mg/mL) for subcutaneous injection,
`provided in a multi-dose, disposable pre-filled pen. The proposed dosing regimen is that
`liraglutide is administered once daily at any time, independent of meals, and can be injected
`subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site and timing can
`be changed without dose adjustment. For all patients liraglutide should be initiated with a dose of
`0.6 mg for at least one week, after which the dose should be increased to 1.2 mg. Based on
`clinical response and after at least one week the dose can be increased to 1.8 mg to achieve
`maximum efficacy. No dose adjustment is recommended by the sponsor either based on age,
`race, body weight and body mass index, or for elderly subjects, subjects with renal impairment,
`and subjects with hepatic impairment.
`
`NDA 22-341 (Liraglutide) OCP Review
`
`5
`
`

`

`Overall, the liraglutide clinical development program comprised 38 completed trials that were
`conducted world-wide, with the majority being conducted in Europe.
`The therapeutic
`confirmatory trial program investigated the benefits of liraglutide as a:
`- monotherapy (Trial 1573)
`0
`combination with metformin (Trial 1572)
`0
`combination with an SU (glimepiride) (Trial 1436)
`o
`combination with a TZD (rosiglitazone) and metforrnin (Trial 1574)
`0
`combination with an SU (glirnepiride) and rnetforrnin (Trial 1697)
`
`The five long-term therapeutic confirmatory trials were all randomized, double-blind, double-
`dumrny (including liraglutide and/0r OAD placebo) trials, providing long-term efficacy and
`safety data.
`
`and
`the pharmacokinetic
`evaluate
`program performed to
`clinical pharmacology
`The
`pharmacodynamic properties of liraglutide included 26 clinical pharmacology trials. These
`comprised 19 trials in healthy subjects (including bioequivalence trials, trials in elder