DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring MD 20993

NDA 208471
NDA APPROVAL
Sanofi US Services Inc.
Attention: David Faunce
Director, Global Regulatory Affairs
55 Corporate Drive
Mail Stop: 55D-225A
Bridgewater, NJ 08807
Dear Mr. Faunce:
Please refer to your New Drug Application (NDA) dated and received July 27, 2015, and your
amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
(FDCA) for Adlyxin (lixisenatide) injection 0.05 mg/mL and 0.1 mg/mL.
This new drug application provides for the use of Adlyxin (lixisenatide) injection as an adjunct
to diet and exercise to improve glycemic control in the treatment of adults with type 2 diabetes
mellitus.
We have completed our review of this application, as amended. It is approved, effective on the
date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
CONTENT OF LABELING
As soon as possible, but no later than 14 days from the date of this letter, submit the content of
labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
automated drug registration and listing system (eLIST), as described at
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
of labeling must be identical to the enclosed labeling (text for the package insert, text for the
IFUs, Medication Guide). Information on submitting SPL files using eLIST may be found in the
guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM072392.pdf.
The SPL will be accessible via publicly available labeling repositories.
CARTON AND IMMEDIATE CONTAINER LABELS
Submit final printed carton and immediate container labels that are identical to the enclosed
carton and immediate container labels, as soon as they are available, but no more than 30 days

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after they are printed. Please submit these labels electronically according to the guidance for
industry Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical
Product Applications and Related Submissions Using the eCTD Specifications (June 2008).
Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
heavy-weight paper or similar material. For administrative purposes, designate this submission
“Final Printed Carton and Container Labels for approved NDA 208471.” Approval of this
submission by FDA is not required before the labeling is used.
Marketing the product(s) with FPL that is not identical to the approved labeling text may render
the product misbranded and an unapproved new drug.
DATING PERIOD
The dating period for Adlyxin is 24 months from the date of manufacture when stored at 5±3°C.
The in-use period is 14 days when stored at 30°C.
REQUIRED PEDIATRIC ASSESSMENTS
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
administration are required to contain an assessment of the safety and effectiveness of the
product for the claimed indication(s) in pediatric patients unless this requirement is waived,
deferred, or inapplicable.
We are waiving the pediatric studies requirement for ages 0 to less than 10 years because
necessary studies are impossible or highly impracticable. This is because type 2 diabetes
mellitus is extremely rare in children younger than 10 years of age.
We are deferring submission of your pediatric studies for ages 10 to 17 years (inclusive) for this
application because this product is ready for approval for use in adults and the pediatric studies
have not been completed.
Your deferred pediatric studies required by section 505B(a) of the FDCA are required
postmarketing studies. The status of these postmarketing studies must be reported annually
according to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. These required studies are
listed below.
3102-1  

Conduct a repeat dose, pharmacokinetic/pharmacodynamics (PK/PD) study
evaluating Adlyxin (lixisenatide) in patients with type 2 diabetes ages 10 to
17 years (inclusive) that are insufficiently controlled with metformin and/or basal
insulin. Subjects will be randomized to lixisenatide or placebo. Titration will
occur every 2 weeks increasing the dose from 5 mcg to 10 mcg then to 20 mcg.
Study Completion:
Final Report Submission:

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March 2018
 
September 2018
 

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3102-2  

Conduct a 24-week, randomized, controlled efficacy and safety study comparing
Adlyxin (lixisenatide) with placebo in patients with type 2 diabetes ages 10 to
17 years (inclusive), followed by a 28-week double-blind controlled extension.
Subjects will be on a background of metformin and/or basal insulin at a stable
dose. This trial should not be initiated until the results of the pediatric PK/PD
study (PMR 3102-1) have been submitted to and reviewed by the Agency.
Final Protocol Submission:
Study Completion:
Final Report Submission:

March 2019
March 2024
September 2024

Submit the protocols to your IND 062724, with a cross-reference letter to this NDA.
Reports of these required pediatric postmarketing studies must be submitted as a new drug
application (NDA) or as a supplement to your approved NDA with the proposed labeling
changes you believe are warranted based on the data derived from these studies. When
submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
the submission.
POSTMARKETING REQUIREMENTS UNDER 505(o)
Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
biological product applications to conduct postmarketing studies and clinical trials for certain
purposes, if FDA makes certain findings required by the statute.
We have determined that an analysis of spontaneous postmarketing adverse events reported
under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk
of the development of anti-drug antibodies (ADA) that could potentially neutralize the function
of Adlyxin (i.e., neutralizing antibodies [Nab]) or cross-react with endogenous GLP-1 or
glucagon and adversely impact regulation of glucose metabolism.
Furthermore, the new pharmacovigilance system that FDA is required to establish under section
505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
Therefore, based on appropriate scientific data, FDA has determined that you are required to
conduct the following:
3102-3  

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Perform immunogenicity testing on anti-drug antibody (ADA)-positive samples
from clinical studies of type 2 diabetes patients treated with lixisenatide to
determine the incidence of neutralizing antibodies (NAb) and anti-lixisenatide
antibodies that are cross-reactive with endogenous GLP-1 and glucagon peptides
and are capable of neutralizing these endogenous peptides. Assessments should
be performed using assays demonstrated to be suitable for their intended purposes
through formal validation studies that have been reviewed by the Agency prior to
their use in clinical sample analysis. Samples used for these assessments should

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be archived under suitable conditions until testing, and should include sufficient
quantity to allow for completion of required immunogenicity assessments. Study
report(s) submitted to the Agency will include evaluation of the impact of NAb
and cross-reactive antibodies on patient safety as well as PK, PD, and efficacy of
lixisenatide.
The timetable you submitted on July 19, 2016, states that you will conduct this study according
to the following schedule:
Interim Milestone 1
(Final Report –Assay Validation):
Interim Milestone 2 (Studies EFC12404
and EFC12405 Completion):
Interim Milestone 3 (Studies EFC12404
and EFC12405 Final Report Submission):
Study Completion (EFC13794):
Final Study Report Submission (EFC13794):

September 2017
June 2018
December 2018
January 2019
June 2019

You may choose to conduct this evaluation using appropriately scheduled samples collected
from Phase 3 studies evaluating insulin glargine/lixisenatide injection; however, the adequacy of
these data will depend on the demonstration of comparable anti-lixisenatide immunogenicity
rates between the monotherapy and combination product trials.
Submit the protocols to your IND 062724, with a cross-reference letter to this NDA. Submit all
final reports to your NDA. Prominently identify the submission with the following wording in
bold capital letters at the top of the first page of the submission, as appropriate: “Required
Postmarketing Protocol Under 505(o),” “Required Postmarketing Final Report Under
505(o),” “Required Postmarketing Correspondence Under 505(o).”
Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
study or clinical trial required under this section. This section also requires you to periodically
report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
report annually on the status of any postmarketing commitments or required studies or clinical
trials.
FDA will consider the submission of your annual report under section 506B and 21 CFR
314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
remind you that to comply with 505(o), your annual report must also include a report on the
status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
submit an annual report for studies or clinical trials required under 505(o) on the date required
will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
action.

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PROMOTIONAL MATERIALS
You may request advisory comments on proposed introductory advertising and promotional
labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
proposed materials in draft or mock-up form with annotated references, and the package insert,
Medication Guide, and patient PI (as applicable) to:
OPDP Regulatory Project Manager
 
Food and Drug Administration 

Center for Drug Evaluation and Research
 
Office of Prescription Drug Promotion 

5901-B Ammendale Road
 
Beltsville, MD 20705-1266 

Alternatively, you may submit a request for advisory comments electronically in eCTD format.
For more information about submitting promotional materials in eCTD format, see the draft
Guidance for Industry (available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM443702.pdf ).
As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
2253. Form FDA 2253 is available at
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
Information and Instructions for completing the form can be found at
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
more information about submission of promotional materials to the Office of Prescription Drug
Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
REPORTING REQUIREMENTS
We remind you that you must comply with reporting requirements for an approved NDA
(21 CFR 314.80 and 314.81).
We request that for a period of two years, you submit all cases of serious hypersensitivity
reactions reported with Adlyxin (lixisenatide) injection as 15-day alert reports, and that you
provide detailed analyses of serious hypersensitivity reactions reported from clinical study and
post-marketing reports as adverse events of special interest in your periodic safety report (i.e.,
the Periodic Adverse Drug Experience Report [PADER] required under 21 CFR 314.80(c)(2) or
the ICH E2C Periodic Benefit-Risk Evaluation Report [PBRER] format). These analyses should
show cumulative data relative to the date of approval of Adlyxin (lixisenatide) injection as well
as relative to prior periodic safety reports. Medical literature reviews for case reports/case series
of serious hypersensitivity reactions reported with Adlyxin (lixisenatide) injection should also be
provided in the periodic safety report.

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MEDWATCH-TO-MANUFACTURER PROGRAM
The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
event reports that are received directly by the FDA. New molecular entities and important new
biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
copies of reports for this product. To participate in the program, please see the enrollment
instructions and program description details at
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
POST APPROVAL FEEDBACK MEETING
New molecular entities and new biologics qualify for a post approval feedback meeting. Such
meetings are used to discuss the quality of the application and to evaluate the communication
process during drug development and marketing application review. The purpose is to learn
from successful aspects of the review process and to identify areas that could benefit from
improvement. If you would like to have such a meeting with us, call the Regulatory Project
Manager for this application.
PDUFA V APPLICANT INTERVIEW
FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
and final assessment of the Program for Enhanced Review Transparency and Communication for
NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
Letter states that these assessments will include interviews with applicants following FDA action
on applications reviewed in the Program. For this purpose, first-cycle actions include approvals,
complete responses, and withdrawals after filing. The purpose of the interview is to better
understand applicant experiences with the Program and its ability to improve transparency and
communication during FDA review.
ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about
the interview process. Your responses during the interview will be confidential with respect to
the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
identifying information to anyone outside their project team. They will report only anonymized
results and findings in the interim and final assessments. Members of the FDA review team will
be interviewed by ERG separately. While your participation in the interview is voluntary, your
feedback will be helpful to these assessments.
FDA BENEFIT-RISK FRAMEWORK APPLICANT INTERVIEW
FDA has also contracted with Eastern Research Group, Inc. (ERG) to conduct an assessment of
FDA’s initial phase implementation of the Benefit-Risk Framework (BRF) in human drug
review. A key element of this evaluation includes interviews with applicants following FDA
approval of New Molecular Entity (NME) New Drug Applications (NDAs) and original Biologic
License Applications (BLAs). The purpose of the interview is to assess the extent to which the
BRF provides applicants with a clear understanding of the reasoning behind FDA’s regulatory
decisions for NME NDAs and original BLAs.

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ERG will contact you to schedule a BRF applicant interview and provide specifics about the
interview process. Your responses during the interview will be confidential with respect to the
FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
identifying information to anyone outside their project team. They will report only anonymized
results and findings in the interim and final reports. Members of the FDA review team will be
interviewed by ERG separately. While your participation in the interview is voluntary, your
feedback will be helpful to this evaluation.
If you have any questions, call Martin White, M.S., Regulatory Project Manager, at
(240) 402-6018.
Sincerely,
{See appended electronic signature page}

Mary Thanh Hai Parks, MD
Deputy Director
Office of Drug Evaluation II
Office of New Drugs
Center for Drug Evaluation and Research
Enclosures:
Content of Labeling
Carton and Container Labeling

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 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------MARY H PARKS
07/27/2016

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