Request Letter for PRE-IND Meeting

Valsartan ER Tablets

Corporate: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 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 B PRE-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 form the primary basis of an effectiveness claim. Pursuant to the implementation of section 119(a), 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 FDAs 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 I and Stage II hypertension (HTN).

1.0 Product Name Valsartan Extended Release Tablets 160 mg and 80 mg Interchangeably referenced as Valsartan ER and Valsartan XL Tablets.

Corporate: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 Courier: 401 South Cedar Street Little Rock, AR, 72205

2.0 Chemical Names and Structure

Valsartan USP

Molecular Formula: C24H29N5O3

Molecular Weight: 435.51876

(S)-N-valeryl-N-{2-(1H-Tetrazol5yl) biphenyl-4-yl] methyl}valine

OR

N-[p-(o-1H-Tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine (Valsartan USP) IUPAC Name: (2S)-3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl] methyl]amino]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: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 Courier: 401 South Cedar Street Little Rock, AR, 72205

5.0 Statement Purpose of Meeting 1. Confirm that 505(b)(2) NDA is the appropriate filing mechanism. 2. Discuss the sponsors plans to demonstrate safety and efficacy via existing pharmacokinetics (PK) studies and literature. 3. Confirm that the existing scientific literature is sufficient such that no additional clinical safety or clinical safety/efficacy 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 presented in this meeting package and to address any unresolved issues related in 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 1 clinical study as supporting information to facilitate the meeting request. Supporting information on CMC and Phase 1 clinical design is provided in the attachment 1 of this request letter.

6.0 List of Specific Outcomes Expected from the Meeting Agreement that 505(b)(2) NDA is the appropriate filing mechanism for Valsartan ER Tablets. Agreement that the sponsors 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 protocol synopsis questions presented in this Meeting Package and to address any unresolved issues related in the proposed IND.

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

Corporate: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 Courier: 401 South Cedar Street Little Rock, AR, 72205

8.0 Draft List of Questions 8.1 General/Regulatory a. Does the Agency agree that a 505(b)(2) is the appropriate filing mechanism for Valsartan ER Tablets? b. Does the Agency agree that Diovan Tablets 160 mg of Novartis Pharmaceuticals Corporation (Novartis) is an appropriate reference listed drug (RLD) strength to use for Phase I clinical and subsequent Phase 3 clinical studies. c. Does the Agency agree that no additional pre-clinical safety studies will be required? 8.2 Non-clinical The sponsor proposes to support the safety of EZRAs Valsartan ER Tablets in the following manner: a. The approval of an NDA for Diovan brand of Valsartan Tablets 160 mg (NDA 021283) approved on July 18, 2001 owned by Novartis Pharmaceuticals Corporation. b. Available literature on safety and efficacy of Valsartan Tablets. 8.3 Clinical EZRA proposes to evaluate the superior therapeutic efficacy and safety of Valsartan ER Tablets for the treatment of HTN. Phase I: A prospective, randomized, open label, blinded endpoint, crossover study to 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 I and Stage II 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 Synopsys that prove the product effective? b. Does FDA agree with the use of the initial Ambulatory 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: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 Courier: 401 South Cedar Street Little Rock, AR, 72205

8.4 Chemistry, Manufacturing and Controls (CMC) EZRA proposes to manufacture a 10,000 tablets batch size under cGMP for Phase 1 clinical study. The formulation and process would essentially be same as the future larger scale batch that will be used for Phase 3 clinical trials. EZRA proposes to submit minimum of two months accelerated stability data for non-GMP laboratory scale batch as per ICH Guidance with the IND while continuing to generate stability data on the cGMP batch for Phase 1 clinical study. Before the start of Phase 1 study EZRA will have minimum of 1 month accelerated stability data on this cGMP batch. EZRA will provide assurance for the acceptable batch stability during the entire time interval of the Phase 1 study. a. Does Agency agree with the use of the clinical supply for Phase 1 study of a 10,000-tablet batch size? b. Does Agency agree with the stability data submission strategy provided?

9.0 Meeting Attendees 9.1 EZRA Attendees Michel Geranen Shirish A. Shah, PhD, RAC Chief Executive Officer Chief Scientific Officer Development and Regulatory Chief Operating Officer

Joseph A. Fix, MBA, PhD

9.2 Consultant Attendee Joel M. Neutel, MD Clinical Professor of Medicine University of California at Irvine Director of Research Orange County Research Center

9.3 Requested Agency Attendees Norman Stockbridge, MD, PhD Director, Div. of Cardiovascular and Renal Products (DCRP) Supervisory Project Manager Director of Regulatory

Edward Fromm Quynh Nguyen, MD

Corporate: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 Courier: 401 South Cedar Street Little Rock, AR, 72205

Note: Project Manager, Medical Reviewer, CMC Reviewer are to be 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.

If you have any questions or need further information, please contact me at 480-659-8963. 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: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 Courier: 401 South Cedar Street Little Rock, AR, 72205

Corporate: EZRA Pharma DBA 4301 W. Markham Street #831 Little Rock, AR, 72205 Courier: 401 South Cedar Street Little Rock, AR, 72205