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Request Letter for PRE-IND Meeting

Valsartan ER Tablets

Corporate. EZRA Pharma DBA 4301 W. Markham Street #831 Littie Rock, AR, 72205 1
Courier 401 South Cedar Street Little Rock, AR, 72205
 March 4, 2013

Norman Stockbridge. M.D. Ph.D.

Director
Office of Drug Evaluation I
Division of Cardiovascular and Renal Products
10903 New Hampshire Avenue
Silver Spring, MD 20993

Subject: Request for Type BPRE-IND Meeting- Valsartan ER Tablets

Dear Dr. Stockbridge:
Section 119(a) of the FDA Modernization Act of 1997 (FDAMA) directs the Food and Drug
Administration (FDA) to meet with the sponsor of an investigation or the applicant for a
drug if the sponsor or applicant makes a "reasonable written request for a meeting for the
purpose of reaching agreement on the design and size of clinical trials intended to fom the
primary basis of an effectiveness claim." Pursuant to the implementation of section 119().
the FDA issued a guidance document titled "Formal Meetings With Sponsors and
Applicants for PDUFA Products," in which the agency describes the procedures a sponsor
or applicant should follow when filing a written request. With this letter, and in accordance
with both FDAMA section 119(a) and FDA's Guidance document, EZRA Pharma dba.,
Division of EZRA Innovations LLC (*EZRA") requests a Type B PRE-IND meeting with the
FDA for its product Valsartan ER Tablets for the treatment of Stage l and Stage Il
hypertension (HTN).

1.0 Product Name

Valsartan Extended Release Tablets 160 mg and 80 mg

Interchangeably referenced as Valsartan ER and Valsartan XL Tablets.

Cornor ate EZRA Pharma DBA 4301 W. Marknam Street #831 Little Rock, AR, 72205 2
Courier: 401 South Cedar Street Lttle Rock, AR 72205
2.0 Chemical Names and Structure

HsCCHs
HjC. COOH N=N
HN,N

Valsartan USP

Molecular Formula: CH,N,O, Molecular Weight: 435.51876

(S)-N-valery-N{2-(1H-Tetrazol-5-y) tbiphenyl-4-yl methyl}valine OR

N{p-(0-1H-Tetrazol-5-ylphenyl)benzyl-N-valery-L-valine (Valsartan USP)
IUPAC Name: (2S)-3-methyl-2-{pentanoyl-([4-(2-(2H-tetrazol-5-y)phenyl]phenyl]
methyllamino]butanoic acid
CAS: 0137862-53-4

3.0 Proposed Indication

Treatment of Hypertension (HTN)

4.0 Type of Meeting Requested

Type B PRE-IND meeting

Corporate [ZRA Pharma DBA 4301 W Markiham Street #831 Little Rock, AR, 72205 3
Courier 401 Soutih Cedar Street Littie Rock, AR. 72205
5.0 Statement Purpose of Meeting

1. Confirm that 505(b)(2) NDA is the appropriate filing mechanism.

2. Discuss the sponsor's plans to demonstrate safety and efficacy via existing
pharmacokinetics (PK) studies and literature.
3. Confirm that the existing scientific literature sufficient such that no additional
clinical safety or clinical safety/eficacy studies are required.
4. Review the requirements for the IND filing.
5. Discuss the Chemistry Manufacturing and Control (CMC) and Phase 1 clinical
protocol synopsis questions presernted in this meeting package and to
address any unresolved issues related the proposed IND.

EZRA is presenting a brief overview of the dosage form under development with a
summary of six pharmacokinetics (PK) studies conducted on the product. EZRA is
also providing a brief synopsis of the proposed Phase 1clinical study as Supporting
information to facilitate the meeting request. Supporting information on CMC and
Phase 1 clinical design is provided in the attachment1 of this request letter.

6.0 List of Specific Outcomes Expected from the Meeting

Agreement that 505(b) (2) NDA is the appropiate filing mechanism for
Valsartan ER Tablets.

Agreement that the sponsor's plan to demonstrate safety and efficacy via
existing PK studies and literature is sufficient.
Confirm that the existing scientific literature is sufficient such that no
additional clinical safety or clinical safety/efficacy studies are required.
Review the requirements for the IND filing.

Discuss the Chemistry Manufacturing and Control (CMC) and Phase 1

clinical protocolsynopsis questions presented in this Meeting Package and
to address any unresolved issues related in the proposed IND.

7.0 Proposed Agenda Items

1. Brief introductions (AlI) 5 minutes
2. Overview of the development of the product and rationale 10 minutes
3. Presentation of the Phase 1study design 20 minutes
4. Open discussion of Agency responses to list of questions
5. Unresolved issues
40 minutes
15 minutes

Corporate EZRA Pharma DBA 4 301 W Markham Street a831 Litte Rock, AR, 72205 4
Courner 401 South Cedar Street Little Rock, AR. 72 205
8.0 Draft List of
Questions
8.1 General/Regulatory
a. Does the Agency agree
for
Valsartan ER Tablets?that a 505(b)(2) is the
b. Does the Agency agree that appropriate filing mechanism
Pharmaceuticals Corporation Diovan® Tablets 160 mg of Novartis
drug (RLD) strength to use for ("Novartis") is an
appropriate reference listed
clinical studies. Phase I clinical and
C. Does the Agency agree that no subsequent Phase 3
required? additional pre-clinical safety studies will be
8.2 Non-clinical

The sponsor
proposes to
in the following support the safety of EZRA's Valsartan ER
manner: Tablets
a. The
approval of an NDA
(NDA 021283) approved for Diovan® brand of Valsartan Tablets 160 mg
on July 18, 2001 owned
by Novartis
b. Pharmaceuticals Corporation.
Available literature on safety and efficacy of
8.3 Clinical
Valsartan Tablets.

EZRA proposes to evaluate the superior therapeutic efficacy and

ER Tablets for the safety of Valsartan
treatment of HTN.
Phase I: A prospective, randomized, open label,
to blinded endpoint, crossover study
compare the safety, efficacy, and duration of action of Valsartan ER 160 mg
once-daily to Diovan® 160 mg once-daily on patients with Stage Iand Stage Ill
hypertension in approximately 30 patients.
Phase 3: Clinical trial design to be determined after the outcome of Phase 1
study.
a Does FDA agree with the endpoints identified in Phase 1 Protocol
that prove the product effective? Synopsys
b. Does FDA agree with the use of the initial Ambulatoy Blood
Pressure
Monitoring (ABPM) baseline as the baseline for the study?
C. Does Agency agree with the dosing strategy of Diovan® Tablets without food
and Valsartan ER Tablets with food, that is the dosing of each agent relative
to meals, based on PK summary data provided?
d. Does Agency agree with the selection of 160 mg as the principal dose?
e. Does Agency agree with the three weeks long for each treatment?
f. Does Agency agree with the 1- week washout period between treatments?
g. Does Agency agree with conducting Phase 3 clinical trial after successful
outcome of Phase 1 study and would it to be sufficient for the approval of
505(b)(2) NDA?
Corporate [ZRA Pharma DBA 4301 W Markhan Strect t831 Little Rock, AR, 72205
Courier 401South Cedar Street Little Rock, AR, 72205
 8.4 Chemistry, Manufacturing and Controls (CMC)
size under cGMP for Phase
EZRAproposes to manufacture a 10,000 tablets batch be same as the
1clinical study. The formulation and process would essentiallytrials.
3 clinical
future larger scale batch that will be used for Phase
accelerated stability data for
EZRA proposes to submit minimum of two months'
non-GMP laboratory scale batch as per ICH Guidance with the IND while continuing
Phase 1 clinical study. Before the
to generate stability data on the cGMP batch for of 1 month accelerated stability
start of Phase 1study EZRA will have minimum for the acceptable batch
data on this cGMP batch. EZRA will provide assurance
1 study.
stability during the entire time interval of the Phase
supply for Phase 1 study of a
a. Does Agency agree with the use of the clinical
10.000-tablet batch size?
submission strategy provided?
b. Does Agency agree with the stability data

9.0 Meeting Attendees

9.1 EZRAAttendees
Chief Executive Officer
Michel Geranen

Shirish A. Shah, PhD, RAC Chief SCientific Officer- Development and

Regulatory
Joseph A. Fix, MBA, Ph Chief Operating Officer

9.2 Consultant Attendee

Joel M. Neutel, MD Clinical Professor of Medicine

University of California at lrvine
Director of Research
Orange County Research Center

9.3 Requested Agency Attendees

Director. Div. of Cardiovascular and Renal
Norman Stockbridge, MD. PhD Products (DCRP)
Supervisory Project Manager
Edward Fromm

Quynh Nguyen, MD Director of Regulatory

72205 6
Markham Street 831 Little Rock, AR,
Corporate EZRA Pharma DBA 43O1 W 722C5
Rock, AR,
401 South Ceda S:reet Little
Courier
 be
Note Project Manager, Medical Reviewer, CMC Reviewer are to
designated by the DCRP

10.0 Suggested Meeting Dates and Times

EZRA proposes the following dates and times:

April 16- 18, 2013 in the afternoon

April 23- 25. 2013 in the afternoon

11.0 Approximate Date of Submission of Briefing Document

The briefing document will be submitted to the Agency four weeks prior to the date
of the PRE-IND meeting.

480-659-8963.
If you have any questions or need further information, please contact me at

Sincerely.

Shirish A. Shah, PhD; RAC

Chief Scientific Officer
Development and Regulatory
EZRA Pharma dba
Div. of EZRA Innovations LLC
Phone: +1 480 659 8963
Fax: +1 855 424 9113
Mobile: +1 480 245 8311
sshah@ezrapharma.com

Mailing Address:
2814 W Wildwood Drive
Phoenix, AZ 85045

Corporate [2RA Pharma DBA 4301 W Markhan Street HB31 Little Rock, AR, 72205 7
Couner 401 Suuth Cedar Street Lttle Rock, AR, 72205