CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-341
`
`MEDICAL REVIEWg S}
`
`

`

`Addendum to Clinical Safety Review
`NDA 22341 (Victoza®, liraglutide injection)
`Submission Received from Applicant 26 Oct 2009
`Additional Calcitonin Shift Tables
`
`Karen Murry Mahoney, MD, Clinical Reviewer
`Division of Metabolism and Endocrinology Products
`27 Oct 2009
`
`On 26 Oct 2009, Novo Nordisk, the applicant for NDA 22341, submitted additional
`calcitonin analyses in response to a request from Dr. Hylton Joffe, Team Leader for
`Diabetes Products Team I in the Division of Metabolism and Endocrinology Products.
`These analyses include the five major Phase 3 diabetes trials which were included in the
`original NDA submission, and add data from two Phase 2 Japanese diabetes trials,
`preliminary data from a diabetes treatment trial versus exenatide, and preliminary data
`from a Phase 2 obesity treatment trial. Similarly to previous data presentations, the
`submitted shift tables show that the highest percentage of upward shifters occurs in the
`1.8 mg liraglutide dose group, which is the highest proposed dose for marketing.
`
`The following table summarizes the submitted data.
`
`
`
`Summary of Specified Upward Shifts in Calcitonin (LOCF); Phase 3 Diabetes
`
`Trials, Two Phase 2 Japanese Diabetes Trials, Preliminary Data from Diabetes
`
`Treatment Trial vs Exenatide, and Preliminary Data from Phase 2 Obesity Trial
`
`
`
`
`LGT LGT LGT PBO AC TC
`0.6
`1.1
`
`23.2
`
`
`
`
`
`
`
`
`
`
`Percentage of patients with shift from below the
`upper limit of normal to persistentlyl above the
`
`upper limit of normal, from baseline to Weeks
`20/24/26/282
`
`
`Rate per 1000 patient-years of patients with shift
`from below the upper limit of normal to
`
`persistentlyl above the upper limit of normal,
`
`
`from baseline to Weeks 20/24/26/282
`Percentage of patients with shift from below the
`0
`
`upper limit of normal to persistentlyl above the
`upper limit of normal, from baseline to Week 523
`
`(volunta
`unblinded extension data included)
`Rate per 1000 patient-years of patients with shift
`from below the upper limit of normal to
`persistentlyl above the upper limit of normal,
`from baseline to Week 523 (voluntary unblinded
`
`extension data included)
`Percentage of patients with shift from below the
`upper limit of normal to persistently1 above the
`upper limit of normal, from baseline to Week 1044
`(all voluntarflnblinded extension data)
`
`
`
`
`
`0
`
`0
`
`

`

` Summary of Specified Upward Shifts in Calcitonin (LOCF); Phase 3 Diabetes
`Trials, Two Phase 2 Japanese Diabetes Trials, Preliminary Data from Diabetes
`Treatment Trial vs Exenatide, and Preliminary Data from Phase 2 Obesity Trial
`
`
`
`
`
`
`
`
`LGT LGT LGT PBO AC TC
`0.6
`1.2
`
`
`
`
`
`
`
`
`
`
`Rate per 1000 PY of patients with shift from below
`the upper limit of normal to persistentlyl above
`the upper limit of normal, from baseline to Week
`1044 all voluntar unblinded extension data
`
`
`
`
`
`
`Percentage of patients who shifted from below the
`upper limit of normal to persistently above the
`
`upper limit of normal, all post-baseline
`observations
`‘
`
`
`
`
`Percentage of patients who began with serum
`calcitonin <20 ng/L and who shifted to a serum
`
`calcitonin 2 20 ng/L at Week 20/24/26/28
`
`
`Rate per 1000 FY of patients who began with
`serum calcitonin <20 ng/L and who shifted to a
`
`
`serum calcitonin 2 20 ng/L at Week 20/24/26/28
`
`
`
`Percentage of patients who began with serum
`
`calcitonin <20 ng/L and who shifted to a serum
`
`calcitonin 2 20 ng/L at Week 52 (voluntary
`
`
`unblinded extension data included)
`
`
`Rate per 1000 PY of patients who began with
`
`serum calcitonin <20 ng/L and who shifted to a
`
`serum calcitonin Z 20 ng/L at Week 52 (voluntary
`
`unblinded extension data included
`
`
`
`
`Percentage of patients who began with serum
`
`calcitonin <20 ng/L and who shifted to a serum
`
`calcitonin 2 20 ng/L at Week 104 (all voluntary
`
`unblinded extension data)
`
`Rate per 1000 FY of patients who began with
`
`serum calcitonin <20 ng/L and who shifted to a
`
`serum calcitonin 2 20 ng/L at Week 104 (all
`
`
`voluntary unblinded extension data
`
`
`
`Percentage of patients who began with serum
`calcitonin <20 ng/L and who shifted to a serum
`
`calcitonin 2 20 ng/L, all post—baseline observations
`
`
`
`

`

`
`Summary of Specified Upward Shifts in Calcitonin (LOCF); Phase 3 Diabetes
`Trials, Two Phase 2 Japanese Diabetes Trials, Preliminary Data from Diabetes
`
`Treatment Trial vs Exenatide, and Preliminary Data from Phase 2 Obesity Trial
`
`
`
`
`
`
`
`
`
`
`
`LGT LGT PBO AC
`1.2
`1.8
`
`Source: Applicant’s Table 2-3, NDA 22341 submission stamp date 26 Oct 2009, serial'pg 9; and Table 2-4, serial pg 10.
`1 “Persistently” is defined as having elevation in all calcitonin values obtained after baseline, up to the specified week
`2 Includes measurements at Weeks 20/24/26/28 for the Phase 3 diabetes trials, two Phase 2 Japanese diabetes trials,
`preliminary data from a Phase 2 obesity trial and preliminary data from a diabetes trial vs exenatide
`3 Includes data from a Phase 3 monotherapy diabetes trial; and voluntary unblinded extension data from a Phase 3 diabetes
`trial as add-on to metformin, two Phase 2 Japanese diabetes trials and preliminary data from a Phase 2 obesity trial. These
`data should be interpreted with caution, because the drop-out rate in extensions was high and differed between treatment
`groups.
`
`
`
`
`
`
`
`
`
`
`
`
`
`4 Voluntary unblinded extension data from a Phase 3 monotherapy diabetes trial and a Phase 3 diabetes trial as add-on to
`metformin. These data should be interpreted with caution, because the drop-out rate in extensions was high and differed
`between treatment _rou us.
`
`In a previous submission (25 Jun 2009), the applicant had stated that there were two
`liraglutide-treated patients (both treated with 1.8 mg/day) who began with a serum
`calcitonin <50 ng/L and shifted to >50 ng/L during study, and one comparator-treated
`patient. In the 26 Oct 2009, submission, the applicant states that there was only one
`liraglutide-treated patient (1.8 mg group) who exhibited this shift, and no comparator-
`treated patients. The 26 Oct 2009 submission did not discuss this discrepancy. In
`response (11 Nov 2009) to an inquiry regarding the difference, the applicant stated that
`the 25 Jun 2009 submission “contained an error”.
`
`Data provided for Weeks 52 and 104 should be interpreted with caution; most data at 52
`weeks, and all data at 104 weeks, are from voluntary unblinded extensions. The drop-out
`rate in extensions was high, and differed between treatment groups, as discussed in the
`original clinical safety review (DARRTS 8 Aug 2009). The applicant has not submitted
`study reports for the diabetes trial versus exenatide and for the Phase 2 obesity trial, and
`therefore these datalare preliminary. As in previous submissions, the mean and median
`changes in serum calcitonin are not large. Also as in previous submissions, the highest
`percentage of upward shifters occurs in the 1.8 mg liraglutide dose group, which is the
`highest proposed dose for marketing.
`
`As discussed in the original clinical safety review, the clinical safety reviewer remains
`concerned about the strong animal carcinogenicity signal for liraglutide, and feels that the
`duration of blinded controlled human study has been inadequate to recommend marketing
`at this time. The clinical reviewer continues to recommend a long-term (23 year) double-
`blinded controlled study, which would include multiple biomarkers to further
`characterize liraglutide’s effect on C-cells, prior to marketing.
`
`

`

`Application
`Type/Number
`
`Submission
`Type/Number
`
`Submitter Name
`
`Product Name
`
`NDA-22341
`
`ORIG-1
`
`‘
`
`NOVO NORDlSK
`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.
`
`KAREN M MAHONEY
`
`11/17/2009
`
`HYLTON V JOFFE
`
`11/17/2009
`
`See CDTL memorandum and addendum
`
`

`

`Consult, NDA 22341, Liraglutide, Novo Nordisk, 11/3/09
`
`H/B/O?
`
`DIVISION OF PULMONARY AND ALLERGY PRODUCTS
`
`MEDICAL OFFICER CONSULTATION
`
`Date:
`To:
`
`_
`
`From:
`Through:
`Through:
`Subject:
`
`November 3, 2009
`.
`John Bishai, Regulatory Project Manager, Division of Metabolic and
`Endocrine Products (DMEP)
`Brian Oscar Porter, M.D., Ph.D., M.P.H., Medical Reviewer
`Susan Limb, M.D., Medical Team Leader
`Badrul Chowdhury, M.D., Ph.D., Division Director
`Anti—drug antibody formation to liraglutide
`
`m G
`
`eneral Information
`
`NDA/IND#:
`
`NDA 22341
`
`Novo Nordisk
`Sponsor:
`Liraglutide (Victoza®)
`Drug Product:
`John Bishai, Regulatory Project Manager, DMEP
`Request From:
`Date of Request: October 28, 2009
`Date Received:
`October 29, 2009
`Date Due:
`ASAP
`
`Primary review of NDA 22341 by Clinical Review team; sections of
`Materials
`NDA 22341 related to immunogenicity of drug product
`‘ Reviewed:
`
`
`Executive Summary
`
`This is a Medical Officer Consultation Review requested by the Division of Metabolic and
`Endocrine Products (DMEP) from the Division of Pulmonary and Allergy Products (DPAP) for
`the drug liraglutide (NDA 22341). Liraglutide is an analogue of the glucoSe—dependent insulin
`secretagogue human glucagon—like—peptide-l (GLP-l), which is engineered to resist degradation
`by endogenous peptidases and thus contribute to long-term glycemic control with a decreased
`risk of hypoglycemia. The NDA was submitted on May 23, 2008. The proposed indication is as
`an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes
`mellitus. The target age group is adults aged 18 years and older.
`
`In pooled Phase III clinical trials, nearly 10% of liraglutide recipients formed anti-drug
`antibodies (ADA), of which ~50% cross-reacted with native GLP—1 and ~10% demonstrated
`neutralizing activity in a cell-based assay. Although an efficacy analysis of the treatment effect
`of ADA formation, , GLP-l cross-reactivity, and the presence of neutralizing ADA on
`glycosylated hemoglobin levels demonstrated no statistical impact of these factors on long—term
`glycemic control, the assay used to detect liraglutide-specific ADA is directly inhibited by the
`drug product itself. Although immunogenicity samples were drawn 25 days following last study
`drug administration, sampling was not done uniformly for all subjects in the Phase III
`
`

`

`Calm/ll, ”DA! 2234/, [lkug/Zz/z’a’e, /Vovo M/wk/é, l/fl/flfl
`
`development program, resulting in an incomplete dataset, which may be biased toward false
`negative misclassification, potentially resulting in regression of group values toward the mean in
`both efficacy and safety analyses.
`Thus, we recommend further evaluation of immunogenicity in the postrnarketing stage.
`Potentially,
`the Sponsor could add ADA sampling to the already planned 9000 subject
`postmarketing trial for long-term cardiovascular outcomes. Alternatively,
`the Sponsor can
`conduct a designated clinical trial to assess adverse events associated with immunogenicity.
`While antibody levels may be obtained on a subset of patients from the proposed large Phase IV
`trial, we recommend sampling subjects following a liraglutide-free period of uniform and
`sufficient duration. This may necessitate periodic drug-withholding periods within the trial
`design in order to screen for ADA with maximal sensitivity. In addition, outcome measures in
`this
`trial
`should also include assessments relevant
`to the potential
`immunopathogenic
`mechanisms of ADA, not only in terms of reduced drug efficacy, but also in terms of organ-
`specific adverse events common to drug hypersensitivity reactions.
`'
`
`Background
`
`Drug Product. Liraghitide is an analogue of human glucagon-like-peptide-l (GLP-l), which is
`currently under review (NDA 22341; Sponsor: Novo Nordisk) for approval as a subcutaneously
`injected, once daily treatment for diabetes mellitus type 2. Native GLP-1 is a gut incretin
`hormone that induces glucose-dependent insulin secretion but has an extremely short half~life,
`due to rapid degradation by endogenous dipeptidyl-peptidase—4. As an analogue to GLP—l,
`liraglutide has an altered structure, which makes it more resistant to degradation, resulting in a
`longer half—life. As the insulin-secreting activity of liraglutide is glucose—dependent, the drug is
`designed to facilitate glycemic control with a decreased risk of hypoglycemia due to insulin
`over-secretion, as compared to other insulin secretagogues, such as sulfonylurea drugs.
`
`,
`
`Anti—drug Antibody Formation. A review of the information submitted by the Sponsor for
`NDA 22341 reveals that anti—drug antibodies (ADA) to liraglutide developed in nearly 10% of
`study drug recipients in four major Phase III clinical trials (Trials 1572, 1436, 1574, and 1697).
`Of these, approximately half displayed cross-reactivity with native GLP—l
`(i.e., ~5% of
`liraglutide recipients tested), while roughly 10% (or 1-2% of the total sample) developed
`antibodies with neutralizing activity against liraglutide.
`In contrast to these liraglutide-specific
`ADA, antibodies formed against another GLP-l analogue, exenatide (the only FDA-approved
`drug product in this class: NDA 21773), demonstrated no significant treatment-emergent cross-
`reactivity with either GLP—l or glucagon. Liraglutide—specific ADA were detected using a
`radioimmune assay in which patient serum was adsorbed with radiolabeled liraglutide and then
`protein-extracted with polyethylene glycol. In turn, the amount of precipitated radioactivity (i.e.,
`liraglutide bound-antibody) was expressed as a percentage of the total amount of radioactivity
`applied to the sample and could be used to quantify the level of ADA present in the sample.
`Assessment of GLP—1 cross—reactivity was done by taking patient serum bound with radiolabeled
`liraglutide and subsequently incubating it with excess unlabeled native GLP-l protein to
`determine the extent to which GLP—l competed off bound, radiolabeled liraglutide. Neutralizing
`activity of ADA was assessed using a cell-based assay in which a luciferase reporter gene
`construct was created using the human GLP—1 receptor and transfected into a rodent cell line.
`This construct allowed for the quantification of cyclic adenosine monophosphate (CAMP) in
`
`

`

`Comm/t, fVDA 2234/, [lfogu/zI/IZ/e, Mm Wom’lkk, ll/J/flfl
`
`response to binding by GLP-l or an agonist, such as liraglutide. Thus, by incubating patient
`serum with a known amount of liraglutide prior to application to the cell line, the neutralizing
`activity of ADA could be measured as a function of their inhibitory activity against liraglutide-
`induced CAMP production.
`
`-Antibody Detection Assays and Efficacy Assessment. A primary concern with the assays
`described above is that the ADA detection assay is directly inhibited by the presence of drug
`product
`in patient serum.
`In other words, sensitivity of the detection assay is markedly
`diminished if sampling is done while levels of liraglutide are still detectable in the circulation,
`potentially resulting in false negative results. To address this concern, immunogenicity samples
`tested in the four Phase III trials were draWn 25 days following the last liraglutide dose. Of note,
`however, nonclinical animal studies in cynomolgus monkeys suggested ADA may interfere with
`liraglutide clearance and result in prolonged drug exposure. Thus, it is unclear whether a 5-day
`drug-free window is adequate to minimize misclassification bias in terms of ADA detection.
`With regard to drug efficacy, the treatment effects of ADA formation, GLP-l cross-reactivity,
`and neutralizing antibody formation on glycosylated hemoglobin (HgbAlc,
`i.e.,
`long—term
`glycemic control) were evaluated in separate ANCOVA models and found to have no statistical
`impact.
`Interestingly, mean HgbAlc levels were actually lower inthe small group of patients
`with detectable neutralizing ADA (n=12). However, properly timed samples were not universally
`available for all subjects in these studies. Moreover,
`the number of liraglutide-recipients
`evaluated in the HgbAlc efficacy analysis (n=1 174; ADA-positive=101) was lower than the total
`number of
`liraglutide-recipients
`included in ADA detection studies
`(n=2501; ADA-
`positive=160). Thus,
`the immunogenicity dataset gleaned from the Phase III trials appears
`incomplete. Moreover, a propensity for false negative misclassification in this dataset with
`regard to ADA detection would result in regression toward the mean in group values, potentially
`masking the impact of ADA on long-term drug effectiveness.
`
`Safety Assessment. Although no serious adverse events emerged in relation to ADA formatiOn,
`a comparison of adverse event profiles between subjects who developed anti—liraglutide '
`antibodies versus seronegative patients revealed trends toward an increased incidence in several
`categories of adverse events in the ADA-positive group, including infections (especially of the
`upper and lower respiratory tract), injection site reactions, and musculoskeletal disorders (e.g.,
`arthralgias). Again, false negative misclassifications would tend to regress these group values
`toward the mean and obscure actual underlying differences in adverse event rates associated with
`ADA formation. Thus, although there does not appear to be a significant safety signal among
`subjects who developed ADA, it remains concerning that over half of them displayed cross-
`reactivity to native GLP—l . and that the assays used for ADA detection have questionable
`accuracy, particularly at only 5 days following last study drug administration.
`
`Recommendations
`
`DMEP requests input from our Division regarding the potential impact of ADA on the approval
`of liraglutide and whether any additional studies should be required of the Sponsor to further
`explore safety and/or clinical efficacy issues of this drug, with respect to immunogenicity.
`
`

`

`Comm/z: NDXZZJWA [frag/Mink, /VOV0 Mini/£96 /[/1709
`
`Given concerns over the accuracy of the ADA detection assay used, particularly as it relates to
`decreased sensitivity in the presence of circulating study drug, as well as the incomplete nature
`of the Phase III clinical trial immunogenicity dataset as reflected in both partial testing and a
`propensity for false negative misclassification, we recommend conducting a postmarketing trial
`of liraglutide recipients to more reliably delineate the incidence and implications of liraglutide-
`specific ADA formation. At present,
`the Sponsor plans to conduct a randomized, blinded,
`placebo-controlled postmarketing trial of 9000 type 2 diabetic patients at risk for cardiovascular
`complications, in order to discern the impact of study drug on cardiovascular related mortality
`and morbidity. Clinical immunogenicity could be evaluated in a subset of liraglutide recipients in
`this large Phase IV trial. Alternatively, potential adverse events associated with immunogenicity
`could be assessed in a separate postmarketing trial.
`
`We note that antibody sampling in the Phase III trials after a 5-day drug-free period was only
`done after 6 months on study drug, while ADA formation against a similar drug product,
`exenatide, peaked at 6 weeks following drug initiation. Thus, assessing for antibody formation
`at more than one time point in the proposed study, including timepoints earlier than 6 months,
`would provide information on the kinetics of ADA formation. However,
`immunogeniCity
`sampling must be sufficiently separated in time from last study drug receipt, as supported by the
`Sponsor’s pharmacokinetic data. Given that liraglutide is administered as a once daily injection,
`this may necessitate recurrent periods of drug withholding at pre-planned points in the study, in
`order to draw immunogenicity samples only after a sufficient drug—free period, after which, study
`drug may be re—started for the purposes of completing the long-term cardiovascular outcomes
`study. A planned and uniformly executed immunogenicity evaluation would allow the Sponsor
`to robustly determine the effects of ADA formation on both the efficacy and safety profile of
`liraglutide, as such a study would capture immunogenicity data on the fiill dataset.
`
`As mentioned in the Clinical Safety Review of NDA 22341, the DMEP Clinical Review Team
`already recommended that an assessment of immune-related adverse events also be done for the
`entire sample of the proposed cardiovascular outcomes postmarketing study, with which we
`concur. To facilitate correlation of observed immune-related adverse events to seroconversion,
`
`antibody levels could be obtained from a subset of patients in this trial. The number of patients
`sampled Should take into account the overall rate of seroconversion (~10%), as well as the rates
`of seroconversion for neutralizing antibodies (~1—2%) and cross-reactive antibodies (~5%)
`observed in the Phase III clinical development program..
`
`Although no major safety signals emerged in this dataset related to IgE-mediated immediate
`hypersensitivity events other than urticaria, ADA formation with documented cross-reactivity to
`an endogenous protein carries a potential risk not only of inactivation of the native protein, but
`also of antigen—antibody complex mediated disease,
`including immune complex deposition,
`serum sickness, or other systemic hypersensitivity syndromes. Thus, outcome measures in this
`postmarketing immunogenicity study should also address these immune mechanisms, including
`appropriate historical and physical assessments of target body systems (e.g., cutaneous and
`musculoskeletal manifestations), measuring complement levels as an index of immune complex
`'mediated disease, and screening hepatic transaminases and renal function tests in the setting of
`systemic inflammatory findings.
`
`

`

`Application
`Type/Number.
`
`SmeiSSiO"
`Type/Number
`
`Submitter Name
`
`Product Name
`
`NBA-22341
`
`ORlG-1
`
`NOVO NORDISK
`NC
`
`VICTOZA (LlRAGLUTlDE)
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`BRIAN PORTER
`
`1 1/03/2009
`
`SUSAN L LlMB
`
`11/03/2009
`
`SALLY M SEYMOUR
`
`‘1/03/2009
`
`r'or Badrul Chowdhury
`
`

`

`ADDENDUM TO CLINICAL SAFETY REVIEW
`
`NDA 22341 (Victoza®, liraglutide injection)
`14 Aug 2009
`Karen Murry Mahoney, MD, FACE
`
`At the time of the original clinical safety review of liraglutide (DARRTS 7 Aug 2009),
`information from the applicant was pending regarding a patient who was treated with
`liraglutide and who had an event of “jaundice”. On 12 Aug 2009, the applicant submitted
`the requested information.
`
`Patient 212002 was a 45 year old woman who had a nonserious event of “jaundice”
`reported after 98 days of treatment with liraglutide. No further clinical history was
`available. However, the applicant provided laboratory data which suggests that this event
`was not clinically significant and may not have represented actual jaundice. Prior to the
`event, the patient had three separate sets of normal laboratory for serum alanine
`aminotransferase, aspartate aminotransferase and bilirubin, including normal values 4
`days prior to the reported date of the event. At that time, her bilirubin was 0.16 mg/dL
`(upper limit of normal 1.28). Subsequent to the date of the event of “jaundice”, all
`bilirubin levels and transaminase levels were normal on all seven subsequent collections
`over an additional 20 months. The closest post-event values were from samples collected
`3 months after the event; there is a small possibility that the patient had an event of
`jaundice that rapidly resolved. However, liraglutide had not been discontinued, and
`despite its continued use for 20 months, multiple subsequent measures of liver function
`were normal, suggesting that liraglutide was not causative in a significant liver injury.
`
`

`

`Linked Applications
`
`Submission
`Type/Number
`
`Sponsor Name
`
`Drug Name / Subject
`
`NDA 22341
`
`ORlG 1
`
`VICTOZA (LIRAGLUTIDE)
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`KAREN M MAHONEY
`
`08/14/2009
`
`HYLTON V JOFFE
`
`08/14/2009
`
`

`

`Clinical Review
`Lisa B. Yanoff, M.D.
`NDA 22,341 (Submission 000)
`Victoza® (liraglutide)
`
`CLINICAL REVIEW
`
`Application Type NDA
`Submission Number
`022341
`
`Submission Code N000
`
`Letter Date
`Stamp Date
`PDUFA Goal Date
`
`23 May 08
`23 May 08
`23 Mar 09
`
`Reviewer‘Name Lisa B. Yanoff, M.D.
`
`Review Completion Date
`
`22 Jul 09
`
`Established Name Liraglutide
`(Proposed) Trade Name Victoza
`Therapeutic Class GLP—l analogue
`Applicant Novo Nordisk
`
`Priority Designation
`
`S
`
`Formulation Subcutaneous injection
`Dosing Regimen
`0.6, 1.2, and 1.8 mg daily
`Indication Treatment of type 2 diabetes
`Intended Population Adults
`
`16
`
`

`

`Clinical Review
`
`Lisa B. Yanoff, M.D.
`NDA 22,341 (Submission 000)
`Victoza® (liraglutide)
`
`Table of Contents ,
`
`1
`
`EXECUTIVE SUMMARY.............................................................................. 5
`
`1.1
`1.2
`
`1.3
`
`RECOMMENDATION ON REGULATORY ACTION ........................................................................................... 5
`RECOMMENDATION ON POSTMARKETING ACTIONS .............................................................................. 5
`
`Risk Management Activity .............................................................................................................. 5
`Required Phase 4 Commitments ............................................................................................................ 5
`Other Phase 4 Requests .......................................................................................................................... 6
`SUMMARY OF CLINICAL FINDINGS .............................................................................................................. 6
`Brief Overview of Clinical Program ...................................................................................................... 6
`Efficacy .................................................................................................................................................. 6
`
`Safety ..............................
`
`Dosing Regimen and Administration...
`Drug-Drug Interactions .......................'................................................................................................ 9
`Special Populations ............................................................................................................................. 9
`
`1.2.1
`1.2.2
`1.2.3
`
`1.3.1
`1.3.2
`1.3.3
`1.3.4
`1.3.5
`1.3.6
`
`INTRODUCTION AND BACKGROUND .................................................................................................... 10
`
`
`....................................................................... 10
`PRODUCT INFORMATION .........................................
`p
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS .......................................................................... 1 1
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES .......................................... 14
`
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ................................................... 14
`PRESUBMISSION REGULATORY ACTIVITY .................................................................................................. 1 4
`OTHER RELEVANT BACKGROUND INFORMATION ...................................................................................... 16
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES .................................................... 17
`
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ........................................................................... 17
`ANIMAL PHARMACOLOGY/TOXICOLOGY
`........................................................................ 17
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`3.1
`3.2
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY..................................................... 17
`
`4.1
`4.2
`4.3
`
`4.4
`4.5
`4.6
`
`SOURCES OF CLINICAL DATA .................................................................................................................... 17
`TABLES OF CLINICAL STUDIES .................................................................................................................. 18
`REVIEW STRATEGY ...................................................................................................................................25
`
`DATA QUALITY AND INTEGRITY ............................................................................................................... 25
`COMPLIANCE WITH GOOD CLINICAL PRACTICES .......................................................................................26
`FINANCIAL DISCLOSURES ..........................................................................................................................26
`
`CLINICAL PHARMACOLOGY ...................................................................................................................27
`
`5.1 PHARMACOKINETICS ........................27
`5.2
`PHARMACODYNAMICS ............................................................................................................................... 31
`5 .3
`EXPOSURE-RESPONSE RELATIONSHIPS ..................................................................................................... 31
`
`INTEGRATED REVIEW OF EFFICACY ...................................................................................................32
`
`6.1
`
`INDICATION ............................................................................................................................................... 32
`6.1.1 Methods ............................................................................................................................................... 33
`
`6.1.2
`6.1.3
`6.1.4
`6.1.5
`6.1.6
`
`General Discussion of Endpoints ......................................................................................................... 34
`Study Design ........................................................................................................................................40
`Efficacy Findings ................................................................................................................................. 56
`Clinical Microbiology ........................................................................................................................ 121
`Efficacy Conclusions ......................................................................................................................... 121
`
`INTEGRATED REVIEW OF SAFETY ...................................................................................................... 121
`METHODS AND FINDINGS .................................................................... ERROR! BOOKMARK NOT DEFINED.
`
`7.1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`

`

`Clinical Review
`
`Lisa B. Yanoff, M.D.
`NDA 22,341 (Submission 000)
`Victoza® (liraglutide)
`
`7.1.1
`7.1.2
`
`7.1.3
`7.1.4
`7.1.5
`7.1.6
`
`7.1.7
`7.1.8
`7.1.9
`7.1.10
`7.1.11
`7.1.12
`7.1.13
`7.1.14
`7.1.15
`
`Deaths .................................................................................................. Error! Bookmark not defined.
`Other Serious Adverse Events ............................................................. Error! Bookmark not defined.
`
`Dropouts and Other Significant Adverse Events ................................. Error! Bookmark not defined.
`Other Search Strategies ........................................................................ Error! Bookmark not defined.
`Common Adverse Events .................................................................... Error! Bookmark not defined.
`Less Common Adverse Events ............................................................ Error! Bookmark not defined.
`
`Laboratory Findings ............................................................................. Error! Bookmark not defined.
`Vital Signs ........................................................................................... Error! Bookmark not defined.
`Electrocardiograms (ECGs) ................................................................. Error! Bookmark not defined.
`Immunogenicity .............................................................................. Error! Bookmark not defined.
`Human Carcinogenicity .................................................................. Error! Bookmark not defined.
`Special Safety Studies ..................................................................... Error! Bookmark not defined.
`Withdrawal Phenomena and/or Abuse Potential ............................. Error! Bookmark not defined.-
`Human Reproduction and Pregnancy Data ..................................... Error! Bookmark not defined.
`Assessment of Effect on Growth ..................................................... Error! Bookmark not defined.
`
`7.2
`
`Overdose Experience ...................................................................... Error! Bookmark not defined.
`7.1.16
`Postmarketing Exper