CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`206321Orig1s000
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`SUMMARY REVIEW
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`Summary Review for Regulatory Action
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`l0 November 20] 4
`
`James P. Smith, MD, MS
`Summar Review for Reulator Action
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`20632]
`NDA#
`
`
`
`Applicant
`Date of Submission
`PDUFA Goal Date
`
`Novo Nordisk
`20 December 2013
`20 October 2014
`
`——
`Proprietary Name /
`.
`.
`Established (USAN) names
`SAXENDA / Ilraglutlde
`Iniectable solution, 6 mg/mL, to be administered
`subcutaneously at a maintenance dose of 3 mg daily via a
`ore-filled PDS290 oen in'ector
`
`Proposed Indication
`Chronic weight management
`Recommended:
`A . . roval
`
`Dosage forms / Strength
`
`Material Reviewed/Consulted & Primary Roviowor(s)
`Medical Officer Review
`l8 Oct 20l 4
`Statistical Review (Efficacy)
`l5 Sep 20l 4
`Statistical Review Addendum (Efficacy)
`lb Oct 20l 4
`Statistical Review (CV Safety)
`12 Sep 2014
`Clinical Pharmacology Review
`l9 Sep 20] 4
`QT-IRT Consult
`2] Oct 20l I
`
`Julie Golden, MD
`Bradley McEvoy, DrPH
`Bradley McEvoy, DrPH
`Rongmei Zhang, PhD
`Jayabharathi Vaidyanathan, PhD
`Zhu Hao
`
`Study Endpoints Review
`Epidemiology: Review of Clinical Trials
`Epidemiology: Review of Interim Study Report
`Division of Oncology Drug Products I Consult
`Division of Neurology Products Consult
`Pharmacovigilance Review
`
`03 Oct 20l 4
`l8 Aug 2014
`30 Jun 20] 4
`03 Jul 20l4
`2] Oct 2014
`l3 Aug 20l 4
`
`Sarrit Kovacs, PhD
`Christian Hampp, PhD
`Christian Hampp, PhD
`Jonathan P. Jarow, MD
`Ronald Farkas, MD, PhD
`Debra L Ryan, PharmD, MBA &
`Carolyn J. Tabak, MD, MPH
`26 Sep 2014 Marina Zemskova, MD
`l4 May 20l 4
`Joseph Leginus, PhD
`lb Jan 20l 4
`Bryan S. Riley, PhD
`15 Sep 2014
`Anthony L Parola, PhD
`26 Sep 20l 4
`Amarilys Vega, MD, MPH & Kate Oswell, MA
`lb Oct 20l 4
`Amarilys Vega, MD, MPH & Kate Oswell, MA
`02 Sep 2014
`Cynthia F. Kleppinger, MD
`22 Aug 20l 4
`QuynhNhu Nguyen
`lb Apr 20l 4
`Saiiad H. Syed
`30 Apr 20l 4
`LCDR John W. Diehl
`22 Jul 20l4
`Sarah K. Vee, PharmD
`Ol Apr 20l 4
`Sarah K. Vee, PharmD
`l4 Aug 20l 4
`Kendra Y. Jones
`I5 Oct 2014
`Sharon W. Williams, MSN, BSN, RN (DMPP) &
`Kendra Y. Jones )OPDP)
`QT-IRT: QT Interdisciplinary Review Team; MTC: Medullary thyroid cancer; CMC: Chemistry, Manufacturing, and Controls;
`REMS: Risk Evaluation and Mitigation Strategy; OSI: Office of Scientific Investigations; CDRH: Center for Devices and
`Radiological Health; OSE: Office of Surveillance and Epidemiology; DMEPA: Division of Medication Error Prevention and
`Analysis; OPDP: Office of Prescription Drug Promotion; DMPP: Division of Medical Policy Programs
`
`Clinical Review of Post-marketing MTC Cases
`CMC Review
`Microbiology Review
`Pharmacology/Toxicology Review
`REMS Modification Review #l
`REMS Modification Review #2
`Clinical Inspection Summary/OSI
`CDRH Human Factors Review
`CDRH Device Review
`CDRH Office of Compliance
`OSE/DMEPA Human Factors & Labeling Rev.
`OSE/DMEPA Proprietary Name Review
`OPDP Labeling Consult
`DMPP/OPDP Patient Labeling Review
`
`Reference ID: 36561 37
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 2 of 35
`
`1. INTRODUCTION
`In the present application, the applicant has proposed that “Saxenda is indicated as an adjunct to a
`reduced calorie diet and increased physical activity for chronic weight management in adult patients
`with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater
`(overweight) in the presence of one weight related comorbidity such as hypertension, dysglycemia
`(prediabetes and type 2 diabetes mellitus), dyslipidemia or obstructive sleep apnea.”
`This review summarizes the conclusions and regulatory recommendations of the review disciplines
`assigned to review the safety and efficacy of Saxenda (liraglutide 3 mg for injection) for chronic weight
`management. I am not aware of any disagreements within or between the review disciplines regarding
`final regulatory recommendations; all disciplines have recommended approval.
`
`2. BACKGROUND
`During the past two decades, there has been a dramatic increase in obesity in the United States. More
`than one-third (nearly 79 million) of U.S. adults and approximately 17% of children and adolescents
`have obesity according to the Centers for Disease Control and Prevention (CDC). Obesity is associated
`with increased risk for all-cause and cardiovascular mortality, and having obesity raises the risk of
`morbidity from hypertension, dyslipidemia, type 2 diabetes mellitus, cardiovascular disease,
`gallbladder disease, osteoarthritis, and sleep apnea. Although a comprehensive program of dietary
`strategies and lifestyle intervention/counseling is of paramount importance for affected individuals,1 it
`is well recognized that these efforts are often insufficient to achieve health outcome goals.
`Despite the extraordinarily adverse impact of overweight and obesity on patients and the healthcare
`system, there is a paucity of approved pharmacologic interventions to aid the treatment of obesity. The
`currently available FDA-approved medications for chronic weight management are Xenical (orlistat;
`approved in 1999), Belviq (lorcaserin HCl; 2012), Qsymia (phentermine/topiramate XR; 2012), and
`Contrave (naltrexone HCl/bupropion HCl; 2014).
`Liraglutide is a human glucagon-like peptide 1 (GLP-1) analog that was approved 25 January 2010,
`under the tradename Victoza at a maximum dosage of 1.8 mg daily, for the treatment of type 2 diabetes
`mellitus (T2DM). During clinical trials designed to support approval for T2DM, it was noted that
`liraglutide appeared to reduce body weight, and the sponsor held a pre-IND/end-of-phase 2 meeting
`with the Division in March 2008 to discuss the development of liraglutide for weight management. It
`bears mention that the target population with overweight/obesity far surpasses the estimated 29
`million people in the United States with diabetes.
`Victoza was approved with a boxed warning to notify prescribers that the drug causes thyroid C-cell
`tumors at clinically relevant exposures in both rats and mice; the human relevance of this observation
`had not, and has still not, been determined by clinical or nonclinical studies. Given the strength of this
`nonclinical signal, however, it was determined that the benefit/risk of Victoza for the treatment of
`T2DM could only be favorable if approved with a Risk Evaluation and Mitigation Strategy (REMS),
`which comprises a communication plan and a timetable of assessments. The REMS also aimed to
`inform patients and providers about the risk of acute pancreatitis (including necrotizing pancreatitis).
`
`
`1 Jensen MD, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the
`American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
`Circulation 2014 Jun 24; 129(25 Suppl 2):S102-38.
`
`Reference ID: 3656137
`
`
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 3 of 35
`
`3. CMC / DEVICE
`CMC
`Dr. Leginus conducted the CMC review for Saxenda. The drug products of the current NDA (Saxenda)
`and the previously approved Victoza (liraglutide [rDNA] injection; NDA 22341) have the same drug
`substance,
`. Both NDAs use an identical 3-
`mL glass cartridge as the primary container closure system, although the glass cartridge for Saxenda
`will be provided in a different pen injector (PDS290).
`Dr. Leginus recommends approval from a CMC perspective. He has no recommendations for post-
`marketing commitments, agreements, or risk management steps. I concur with his assessment.
`
`Microbiology
`Dr. Riley noted that the proposed drug product is identical to an approved drug product from a
`product quality microbiology perspective and, therefore, no additional product quality microbiology
`assessment is necessary.
`
`Facilities Review/Inspection
`The facilities report from the Office of Compliance states that the overall recommendation is
`acceptable.
`
`Device Review
`The primary packaging for Saxenda is the same as that approved for Victoza under NDA 22341, i.e., a
`3-mL cartridge,
` The secondary packaging is an assembled
`PDS290 pen injector, which is a pre-filled, multiple-dose, disposable, delivery device that contains the
`3-mL cartridge. The PDS290 liraglutide 3 mg pen injector is based on the approved FlexTouch® pen
`injector.
`Device-related requests for information were conveyed to the applicant in the filing communication
`dated 04 March 2014. The applicant’s responses, received 21 March 2014, were reviewed by Sajjad Syed
`(Electrical Engineer, CDRH General Hospital Devices Branch) and LCDR John W. Diehl (Regulatory
`Operations Officer, CDRH Office of Compliance, Division of Manufacturing and Quality) and found to
`be adequate. Dr. Patricia Beaston, an endocrinologist with CDRH’s General Hospital Devices Branch,
`reviewed dose accuracy for the device as well (referenced in S. Syed’s memo). CDRH indicated that
`there were no additional questions regarding device biocompatibility, safety, or performance.
`
`Human Factors
`QuynhNhu Nguyen reviewed a 129-subject human factors validation study from the CDRH
`perspective and identified concerns regarding needle stick injury and use errors that could result in
`mis-dosing.
`Dr. Vee also reviewed this study from the DMEPA perspective. She noted that although some
`untrained users encountered difficulties while administering this product, the same difficulties “have
`also been reported with the use of other prefilled injection pen devices and have been managed
`reasonably well through labeling.” She states that failure to perform these tasks would result in
`underdoses in most instances and would not be expected to cause serious harm acutely. This same
`pen-injector platform (PDS290) has been approved for Novolog and Levemir. Recommendations to
`improve labeling were provided.
`
`Reference ID: 3656137
`
`
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`(b) (4)
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`(b) (4)
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`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 4 of 35
`
`I do not believe that there are outstanding issues related to human factors that would preclude
`approval with appropriate labeling.
`
`4. NONCLINICAL PHARMACOLOGY/TOXICOLOGY
`Dr. Anthony Parola reviewed the nonclinical data supporting this application, which cross-referenced
`pivotal nonclinical studies that were previously reviewed (by Dr. Parola) under Victoza NDA 22341.
`See Dr. Parola’s review for a thorough discussion of the nonclinical data.
`The proposed dosage for Saxenda is 3 mg/day, compared with the recommended maximum dosage of
`1.8 mg/day for Victoza for the treatment of type 2 diabetes mellitus (T2DM). Because systemic
`clearance of subcutaneously injected liraglutide increases with body weight in humans, however,
`systemic exposure at steady state in obese adults administered 3 mg/day was only slightly higher than
`that in healthy adults administered 1.8 mg/day (AUC0-24h 854 vs. 809 nM·h) despite the 1.7-fold higher
`dose. Thus, Dr. Parola notes that “human exposure multiples based on systemic exposure for findings
`in nonclinical safety studies of liraglutide, including carcinogenicity and reproductive and
`developmental toxicity studies, are similar for 3.0 mg/day liraglutide in obese adults and 1.8 mg/day
`liraglutide in healthy adults.”
`Safety and toxicity of liraglutide were evaluated in safety pharmacology studies, single- and repeat-
`dose toxicity studies, genetic toxicity studies, 2-year carcinogenicity studies in rats and mice,
`reproductive and developmental toxicity studies, local tolerance studies, and mechanistic studies of
`liraglutide-induced thyroid C-cell tumors in rodents. All pivotal nonclinical safety studies were
`reviewed under Victoza NDA 22341. Dr. Parola summarizes that liraglutide toxicity occurred in
`thyroid (mice and rats) and at injection sites (mice, pigs, and monkeys), and included a mild anemia
`(mice, rats, and monkeys).
`
`Carcinogenicity
`Two-year lifetime carcinogenicity studies in mice and rats showed that liraglutide causes thyroid C-cell
`tumors at clinically relevant exposures in male and female mice and rats, as well as fibrosarcomas on
`the dorsal skin and subcutis of male mice. Thyroid C-cell tumors are rare findings during
`carcinogenicity testing in mice and rats. The nonclinical data regarding thyroid C-cell tumors, as
`summarized in the FDA briefing document for the 11 September 2014 meeting of the Endocrinologic
`and Metabolic Drugs Advisory Committee (EMDAC), are presented below. Note that the no observed
`adverse effect level (NOAEL) for thyroid C-cell tumors in mice was 0.2 mg/kg/day liraglutide (1.8-
`times human exposure based on AUC comparison); a NOAEL was not established in the rat
`carcinogenicity study. These nonclinical data regarding thyroid C-cell tumors formed the basis for a
`boxed warning and Risk Evaluation and Mitigation Strategy (REMS) for Victoza. The approved
`labeling for Victoza and the proposed labeling for Saxenda state that it is unknown whether liraglutide
`will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) in humans, as the
`human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by
`clinical or nonclinical studies.
`
`Reference ID: 3656137
`
`
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 5 of 35
`
`Source: FDA briefing document for 11 Sept 2014 EMDAC, p. 335.
`
`
`
`
`
`Source: FDA briefing document for 11 Sept 2014 EMDAC, p. 336.
`Approval of Victoza included 2 post-marketing requirements (PMRs) to evaluate the effects of
`liraglutide on proliferative C-cell lesions in mice. In the first study, intended to satisfy Victoza PMR
`1583-3, liraglutide was subcutaneously administered to CD-1 mice for 26 weeks (25% of their total
`lifespan) followed by a 78-week recovery period to determine if transient exposure to liraglutide
`increases the lifetime risk of developing proliferative C-cell lesions. Dr. Parola notes that mice treated
`with 3.0 mg/kg/day appeared to be at an increased risk for developing proliferative thyroid C-cell
`lesions (preneoplastic focal C-cell hyperplasia in males and benign C-cell adenoma in females) for up
`to 78 weeks after treatment was stopped. However, as a result of a low incidence of proliferative C-cell
`lesions in concurrent control group male mice as well, a clear relationship to liraglutide treatment was
`not established. Thus, whether or not transient exposure to liraglutide increases the lifetime risk of
`proliferative C-cell lesions in mice was not adequately addressed by this study.
`The second study, intended to satisfy Victoza PMR 1583-5, was a 13-week repeat-dose study of
`liraglutide in wild-type and GLP1R-deficient mice that demonstrated liraglutide-induced thyroid C-
`
`Reference ID: 3656137
`
`
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 6 of 35
`
`cell hyperplasia and activation of ribosomal protein S6, in both normal and hyperplastic C-cells, are
`both GLP1R-dependent in mice. Liraglutide did not activate the rearranged during transfection (RET)
`proto-oncogene.
`As stated in Victoza labeling, in the 2-year carcinogenicity study in mice, a treatment-related increase
`in fibrosarcomas occurred on the dorsal skin and subcutis in males in the 3 mg/kg/day group.
`Fibrosarcomas at or near the injection site were attributed to the high local concentration of drug; the
`concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration
`administered to mice (0.6 mg/mL).
`
`Pancreatitis
`Pancreatitis is a safety concern of special interest for liraglutide as well as other members of the GLP1-
`agonist class. Review of repeat-dose toxicity studies of liraglutide submitted to Victoza NDA 22341,
`including chronic toxicity studies in rats and monkeys and carcinogenicity studies in mice and rats, did
`not show any substantive evidence of pancreatitis (or pancreatic cancer). Dr. Parola reviewed
`additional nonclinical data (summarized on pp. 150-151 of his review) that did not support a causal
`role for GLP-1 agonists and pancreas injury. Approval of Victoza included a post-marketing
`requirement to determine the effects of liraglutide on the exocrine pancreas in a rodent model of
`insulin-resistant T2DM (NDA 22341; PMR 1583-4). In this study, up to 1.0 mg/kg/day liraglutide for 3
`months had no adverse effects on the exocrine pancreas of male or female hyperglycemic Zucker
`Diabetic Fatty (ZDF) fa/fa rats.
`
`Cholelithiasis and Cholecystitis
`As described in the Clinical Safety portion of this memo, treatment with liraglutide was associated
`with an increased incidence of adverse events related to the gallbladder in clinical trials for weight
`management; this was not observed in clinical trials employing ≤1.8 mg/day for the treatment of
`T2DM. In repeat-dose toxicity studies, up to 5 mg/kg/day liraglutide had no effect on gallbladder in
`mice treated for up to 13 weeks or cynomolgus monkeys treated for up to 52 weeks. In the 2-year
`carcinogenicity study of liraglutide in mice, liraglutide increased the incidence of macroscopic
`pathology findings involving the gallbladder (i.e., abnormal contents, dilation/distension, enlargement)
`but these findings were not dose-related and did not correlate with microscopic pathology.
`
`Reproductive and Developmental Toxicity
`The approved Victoza labeling and the proposed Saxenda labeling note that liraglutide was teratogenic
`in rats and rabbits at clinically relevant exposures. No additional relevant data were submitted to the
`Saxenda NDA. Victoza is labeled as pregnancy category C based on these data, but Saxenda will be
`labeled as pregnancy category X, since weight loss offers no potential benefit to a pregnant woman and
`may result in fetal harm.
`
`Nonclinical Recommendation
`Dr. Parola concludes, “Based on prior approval of up to 1.8 mg/day liraglutide for the treatment of
`type 2 diabetes mellitus, the approval of other long-acting GLP-1 receptor agonists that are known or
`suspected to induce rodent thyroid C-cell tumors of unknown human relevance, similar steady state
`systemic exposure to liraglutide in obese adults administered 3.0 mg/day liraglutide compared to
`healthy adults administered 1.8 mg/day, and no new safety concerns from nonclinical studies for the
`proposed indication for weight management in obese adults or overweight adults with at least [one]
`weight-related comorbidity, I recommend approval of up to 3.0 mg/day liraglutide for the proposed
`
`Reference ID: 3656137
`
`
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 7 of 35
`
`weight management indication” (p. 6). I agree that there are not any nonclinical deficiencies that would
`preclude approval.
`
`5. CLINICAL PHARMACOLOGY
`Dr. Jayabharathi Vaidyanathan reviewed this application from the clinical pharmacology and
`pharmacometrics perspective. The Office of Clinical Pharmacology recommends approval. I agree that
`there are no deficiencies related to clinical pharmacology that would preclude approval.
`General pharmacology information for liraglutide was reviewed under Victoza NDA 22341 and
`appears in the Victoza package insert and Dr. Vaidyanathan’s review.
`
`Intrinsic Factors
`Baseline body weight was the most significant covariate affecting the clearance (CL/F) of liraglutide as
`determined by the population PK analysis conducted for both programs, with an increase in liraglutide
`clearance as body weight increases. Using data from phase 3 trials 1839 (non-diabetics) and 1922 (type
`2 diabetics), the effects of other covariates on the clearance of liraglutide were considered as well: age,
`sex, race, ethnicity, dose, and glycemic status at baseline (normoglycemia, pre-diabetes, and T2DM).
`Among these, sex was the other significant covariate, with males having 24% lower liraglutide
`exposure than females, after accounting for body weight differences. In addition, in trial 1922, obese
`diabetic subjects had ~16% lower exposure than obese normoglycemic or prediabetic subjects. Dr.
`Vaidyanathan concluded, however, that no dose adjustments are recommended based on sex or
`diabetic status. Furthermore, she determined that there does not appear to be a need for different
`dosing regimens for patients with lower body weight or patients who lose weight during treatment.
`The following figures show the correlation of body weight to AUC for subjects receiving the 3 mg dose
`in the obesity trials (Figure 2) and the distribution of AUC in the Victoza and obesity programs (Figure
`3). Dr. Vaidyanathan notes that although overlap in AUCs was observed in the two programs, the
`proportion of subjects in the obesity program having higher AUC was greater in the obesity program
`(3 mg dose) than in the Victoza program (1.8 mg dose). Approximately 16% of subjects in the obesity
`trials receiving liraglutide 3 mg/day had exposures higher than the maximum AUC observed with the
`1.8 mg/day dose in the Victoza trials.
`
`Source: Dr. Vaidyanathan’s review, p. 7.
`
`
`
`Reference ID: 3656137
`
`
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 8 of 35
`
`
`
`Source: Dr. Vaidyanathan’s review, p. 7.
`Regarding Cmax, the sponsor compared the observed liraglutide Cmax from the cardiac electrophysiology
`(TQTc) trial (i.e., NN211-1644; NDA 22341) and trials 1839, 1807 (a dose-ranging trial), and 3630. There
`was substantial overlap in the observed liraglutide Cmax following administration of either the 1.8 mg
`or 3.0 mg dose. In part, this observation led the QT-IRT to agree that the thorough QTc study
`conducted for the Victoza development program was sufficient to support the current NDA as well.
`
`Dose-Response/Exposure-Response for Efficacy
`Trial 1807 evaluated daily doses of liraglutide 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg compared with
`placebo (and open-label orlistat). The results from this trial, which had a primary endpoint of change in
`body weight from baseline to Week 20, supported the choice of 3 mg/day for phase 3 trials. Consistent
`with the observed dose-response relationship, Dr. Vaidyanathan states that there was a clear
`relationship between liraglutide exposure (data from trials 1807, 1839, and 1922) and weight loss, with
`increasing exposure leading to greater weight loss. The weight loss appeared to reach plateau at the
`highest exposure.
`
`6. CLINICAL/STATISTICAL- EFFICACY
`Dr. Julie Golden and Dr. Brad McEvoy reviewed the efficacy of Saxenda for chronic weight
`management from a clinical and statistical standpoint, respectively. Both reviewers conclude that
`Saxenda is more effective than placebo with regard to weight loss, and Dr. Golden adds that the
`treatment difference is clinically meaningful.
`The efficacy of Saxenda for a weight-related indication was evaluated in a single phase 2 dose-ranging
`trial (trial 1807) and four phase 3 trials: a 56-week trial in patients without T2DM (1839); a 56-week trial
`in patients with T2DM (1922); a 56-week trial in patients without T2DM who were able to lose ≥5%
`body weight during a 4-12-week run-in period by following a low-calorie diet (1923); and a 32-week
`trial in patients with moderate to severe obstructive sleep apnea (3970), in which the primary endpoint
`was the apnea-hypopnea index (AHI). All trials included a 4-week titration period at the onset of
`dosing. For details regarding the individual trial designs, see the thorough reviews of Dr. Golden and
`Dr. McEvoy.
`In the trials conducted in patients without T2DM or sleep apnea (i.e., 1839, 1923, and 1807), most
`participants (76-81%) were women; in the trial of patients with T2DM (1922), there was a similar
`proportion of men and women; and in the trial with patients with obstructive sleep apnea (3970), most
`participants (72%) were men. Across these trials, mean BMI ranged from 34 to 39 kg/m2. The mean age
`
`Reference ID: 3656137
`
`
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 9 of 35
`
`in most trials was approximately 46 years, except for trial 1922 where the mean age was 55 years. The
`majority of patients were white (85% overall). Regarding comorbidities, more patients in trial 1922 had
`hypertension (69%) or dyslipidemia (67%) than those in trial 1839 (35% and 29%, respectively), as one
`would expect in the diabetic and non-diabetic populations, respectively. Overall, 9% of patients had a
`history of cardiovascular disease as assessed by MedDRA queries of past medical history.
`
`Effects on Body Weight
`In trial 1807, 564 obese patients without T2DM were randomly assigned to receive liraglutide 1.2, 1.8,
`2.4, or 3 mg once daily, liraglutide placebo once daily, or open-label orlistat 120 mg three times daily,
`with equal allocation. Patients could continue into an optional extension period for an additional 84
`weeks, with the patients and investigators (but not the sponsor) remaining blind to treatment
`allocation from week 20 to 52. Beyond week 52, all liraglutide- or placebo-treated patients were
`switched to open-label liraglutide (initially 2.4 mg daily, later changed to 3 mg daily). As shown in the
`figure below, excerpted from Dr. Golden’s review, this trial supported a dose-response relationship for
`liraglutide with weight loss, and guided the sponsor’s decision to develop a dose of 3 mg daily for a
`weight management indication. Dr. McEvoy cautions that data beyond week 20 should be interpreted
`“extremely cautiously due to the likely bias resulting from a sizable number of subjects not consenting
`to the 84 week extension period.”2
`Figure 7. Change in Body Weight (kg), LOCF, Trial 1807 52-Week Interim Analysis
`
`
`
`Source: NN8022-1807-ext Clinical Trial Report, Figure 11-1
`In trial 1839, the largest phase 3 trial in this development program, 3,731 patients without T2DM but
`with obesity or overweight with at least one other weight-related comorbid condition were randomly
`assigned 2:1 to daily doses of liraglutide 3 mg or placebo. Patients with pre-diabetes at baseline (one of
`the stratification factors) were assigned to 160 weeks of treatment, but data after week 56 were not
`included in the submission. Patients without pre-diabetes were randomized to 56 weeks of treatment,
`which was followed by a 12-week placebo-controlled randomized withdrawal (1:1) for those initially
`
`
`2 Dr. McEvoy points out that 472 (84%) of the 564 randomized patients completed the 20-week main treatment period, with
`74 (16%) of these 472 subjects not enrolling into the extension period. Furthermore, he notes that the decision not to continue
`follow-up appears to be associated with the degree of weight loss at week 20, with the patients that enrolled into the
`extension having more favorable average weight reductions than those that did not (p. 16 of statistical review).
`
`Reference ID: 3656137
`
`
`
`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 10 of 35
`
`assigned to liraglutide. The pre-specified primary efficacy endpoints included (1) % change in fasting
`body weight from baseline; (2) proportion of patients losing ≥5% of fasting baseline body weight; (3)
`proportion of subjects losing ≥10% of fasting baseline body weight; and (4) onset of T2DM in subjects
`with pre-diabetes at week 160 (not submitted with NDA). In this trial, the proportions of subjects who
`discontinued study drug prior to the primary endpoint assessment (at week 56) were 28% and 36% for
`liraglutide and placebo, respectively.
`In trial 1922, 846 patients with T2DM and either obesity or overweight were randomly assigned 2:1:1 to
`daily doses of liraglutide 1.8 mg, 3 mg, or placebo for 56 weeks. Subjects treated with sulfonylureas
`were asked to reduce the dose of the sulfonylurea by 50% to reduce the risk for hypoglycemia. If
`fasting plasma glucose exceeded pre-specified limits, the investigator could provide glycemic rescue by
`adding an antidiabetic medication or increasing the dose of an existing medication. The co-primary
`endpoints were the same as the weight-related endpoints in trial 1839. In this trial, the proportions of
`subjects who discontinued study drug prior to the primary endpoint assessment were 22%, 23%, and
`34% for liraglutide 1.8 mg, 3 mg, and placebo, respectively.
`In trial 1923, 422 subjects without T2DM but with obesity or overweight with at least one other weight-
`related comorbid condition first entered a low-calorie-diet (1200-1400 kcal/day) run-in period. Those
`who successfully lost ≥5% of their body weight within 12 weeks of dietary/lifestyle intervention were
`then randomly assigned 1:1 to daily doses of liraglutide 3 mg or placebo for 56 weeks. The co-primary
`endpoints were (1) % change in fasting body weight from baseline; (2) proportion of subjects that
`maintained the ≥5% reduction in initial fasting body weight achieved during the low-calorie-diet run-
`in period; and (3) the proportion of subjects losing at least 5% of of fasting baseline body weight. In this
`trial, the proportions of subjects who discontinued study drug prior to the primary endpoint
`assessment were 25% and 30% for liraglutide and placebo, respectively. A similar proportion of
`randomized subjects discontinued because of adverse events (~9% in each group).
`In trial 3970, 359 subjects with obesity and moderate or severe obstructive sleep apnea, but not T2DM,
`were randomly assigned 1:1 to daily doses of liraglutide 3 mg or placebo for 32 weeks. The primary
`endpoint was the change in AHI rate (events/hour). In this trial, the proportions of subjects who
`discontinued study drug prior to the primary endpoint assessment were 26% and 21% for liraglutide
`and placebo, respectively. Weight-related endpoints were secondary endpoints for this trial, so I have
`not described them in this summary review.
`With the exception of the sleep apnea trial, the primary efficacy endpoints were designed to follow the
`2007 FDA Draft Guidance for Industry, Developing Products for Weight Management. As outlined in this
`guidance, efficacy can be established by satisfying at least one of two criteria after one year of
`treatment:
`• The difference in mean weight loss between the active-product and placebo-treated groups is
`at least 5% and the difference is statistically significant; and
`• The proportion of subjects who lose ≥5% of baseline weight in the active-product group is at
`least 35%, is approximately double the proportion in the placebo-treated group, and the
`difference between groups is statistically significant.
`The guidance also suggests that the analysis should be applied to the last observation carried forward
`(LOCF) on treatment in the modified ITT population, defined as subjects who received at least one
`dose of study drug and have at least one post-baseline assessment of body weight. Since the
`publication of this draft guidance in 2007, however, the Division’s view on handling of missing data
`has evolved. The Division has reconsidered the use of LOCF following the 2010 publication of the
`
`Reference ID: 3656137
`
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`

`

`
`Summary Review for Regulatory Action
`NDA 206321 / SAXENDA (liraglutide [rDNA origin] injection)
`
`James P. Smith, MD, MS
`p. 11 of 35
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`FDA-commissioned report on missing data by the National Academy of Sciences, the Prevention and
`Treatment of Missing Data in Clinical Trials.3 Thus, during the review of this application, the statistical
`reviewers conducted a detailed review of the results with an emphasis on the impact of missing data.
`Concentrating on trials 1839, 1922, and 1923, Dr. McEvoy noted that a sizable proportion of subjects
`did not have a weight assessment at week 56, with missing data occurring more frequently in the
`placebo groups (19% to 26%) than in the liraglutide 3 mg groups (17% to 20%). Because off-treatment
`values were excluded from the sponsor’s primary analysis, even if measured, it is notable that the
`proportion of randomized subjects that lacked an on-treatment assessment at week 56 ranged from
`31% to 45% for the placebo groups and 25% to 27% for the liraglutide 3 mg groups. (The majority of
`subjects that discont