Orphan Therapeutics, LLCLucassin (terlipressin) injection, 1 mg

NDA 022231 COMPLETE RESPONSE

Orphan Therapeutics, LLC Attention: Candice Teuber, PharmD. 3 Werner Drive Suite 210

Lebanon, NJ 08833

Dear Dr. Teuber:

Please refer to your new drug application (NDA) dated May 4, 2009, received May 4, 2009, submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for Lucassin (terlipressin) injection, 1 mg.

We also refer to your submissions dated May 27, June 30, July 1 and 25, August 1, 8, 13, 20, September 5 and 8, October 3, 9, 29, 2008 and January 29, April 30, May 1 and 21, June 8, 9, 10, 11, 29, July 8, 28, 30, September 2, 8, 22, 30, October 12, 13,15 and 16, 2009.

We have completed our review of your application, and have determined that we cannot approve this application in its present form. We have described below our reasons for this action and, where possible, our recommendations to address the issues.

CLINICAL/STATISTICAL

To support a claim for the treatment of patients with hepatorenal syndrome (HRS) type I, you submitted two studies, OT-0401 (a double-blind, placebo-controlled study in HRS type I patients) and TAHRS (a smaller, open-label, cross-over study in HRS type I and II patients). In OT-0401, terlipressin, compared to placebo, appeared to show a modest reduction in serum creatinine, but the study failed to show durability of effect. Using the prespecified primary endpoint and the original analytic plan, the results of OT-401 were not statistically significant. Your most favorable analysis, using an endpoint developed post-hoc with a generally unacceptable redefinition of treatment success, reaches statistical significance, but comes nowhere close to the p-value necessary to support approval based upon a single study. The smaller, open-label TAHRS also failed on its pre-specified primary endpoint and failed to show a sustained effect on serum creatinine. In terms of support for the safety of the 14-day terlipressin regimen proposed in labeling, your application includes experience in only 11 subjects in study OT-0401 and 9 subjects in TAHRS with exposure for 14 days. The extent of exposure is clearly insufficient to support the safety of terlipressin for its intended use. Moreover, although the numbers of adverse events were small, many important serious adverse events tended to occur more frequently, or earlier (i.e., death), in terlipressin-treated subjects, compared to subjects in the respective control groups.

You will need to conduct at least one additional adequate and well-controlled study to demonstrate the efficacy and safety of intravenous terlipressin for the treatment of HRS type I. This study will need to be successful, using pre-specified endpoint(s) and analytic plan, at p<0.05. The Division is willing to meet with you to discuss possible trial designs and endpoints that you might wish to consider as alternatives to the endpoint pre-specified in OT-0401, as well as the extent of safety data that should be collected.

NDA 022231 Page 2 Orphan Therapeutics, LLC

Vital Signs: We note that the OT-0401 protocol directed assessment of vital signs at baseline and then two hours after each dose: in the TAHRS study, vital signs were obtained once each day. and the time of assessment relative to administration of study drug was not recorded. Given the brief half-life of terlipressin, it appears that there was no assessment of vitals signs during the peak drug effect. In future trial(s), we suggest you obtain vital sign data at peak drug effect, to better characterize the pharmacodynamic effects of terlipressin.

Laboratory Data: We note that the OT-0401 protocol did not include collection of complete blood counts in the monitoring scheme: TAHRS required a complete blood count at baseline, Day 7 and Day 15. For completeness, we suggest you obtain complete blood counts with leukocyte differential counts and platelet counts should you decide to undertake an additional trial.

PRODUCT QUALITY

1 Tn response to our recommendation for the confirmation of © von have stated that ww

oa) and include an acceptance limit in drug

Provide data in supvort of this statement ow

substance specification, if necessary.

2. The specification for drug substance should include testing for heavy metals to ensure that every batch meets the USP <231> requirement. Please provide a revised drug substance specification.

3. The analytical method intended for quantitation of residual solvents in the drug substance is considered inferior to USP method based on limit of detection (LOD) and limit of quantification (LOQ) values in the validation report. Additionally, data provided in Attachment 2 in response (dated 09-SEP-09) to the information request letter are inconsistent with the LOD and LOQ values per the validated method. For example, the LOD for the residual solvent, MO is yom per the validation data, whereas the results reported in Attachment 2 were ©@ ppm. Please provide an explanation and justification for the use of the validated method instead of the USP method.

4. Based on the results provided for three drug substance lots (S.3.2.2.3 Table 14), we recommend that

you incorporate testing for © in the specification for drug substance. 5. Characterize the oy] ma)

LABELING

We have provided draft recommendations to several sections of the labeling, but reserve comment on the remaining sections until the application is otherwise adequate. Please submit draft labeling that incorporates revisions to the attached labeling.

Your response must include updated content of labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

NDA 022231 Page 3 Orphan Therapeutics, LLC

Please submit draft carton and container labeling revised as follows:

e Vial Label: Include drug product composition (excipients and quantities) as required for parenteral dosage forms. * Carton Label: Revise the statement from: wo

To:

"Once reconstituted, store refrigerated (2-8°C) and use within a hours. Do not freeze." FACILITY INSPECTIONS During a recent inspection of the and manufacturing

facilities for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

(b) (4) (b) (4)

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at

21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

1. Describe in detail any significant changes or findings in the safety profile.

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as the original NDA submission.

e Present tabulations of the new safety data combined with the original NDA data.

e Include tables that compare frequencies of adverse events in the original NDA with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

5. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original NDA data.

6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

7. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

NDA 022231 Page 4 Orphan Therapeutics, LLC

8. Provide English translations of current approved foreign labeling not previously submitted.

Within one year after the date of this letter, you are required to resubmit or take one of the other actions available under 21 CFR 314.110. If you do not take one of these actions, we will consider your lack of response a request to withdraw the application under 21 CFR 314.65. A resubmission must fully address all the deficiencies listed. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the FDA’s Guidance for Industry - Formal Meetings Between the FDA and Sponsors or Applicants, May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1532 22.pdf.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, please call Anna Park, Regulatory Project Manager, at (301) 796-1129. Sincerely, {See appended electronic signature page} Ellis F. Unger, M.D. Deputy Director

Office of Drug Evaluation I Center for Drug Evaluation and Research

Enclosure: Draft labeling text

11 Pages of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page

Application Submission

Type/Number Type/Number Submitter Name Product Name

NDA-22231 ORIG-1 ORPHAN LUCASSIN (TERLIPRESSIN) THERAPEUTICS LLC

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

ELLIS F UNGER 11/04/2009