Shandong Luye Pharmaceutical Co., Ltd.Rykindo (risperidone) for extended-release injectable suspension

NDA 212849 COMPLETE RESPONSE

Shandong Luye Pharmaceutical Co., Ltd. Attention: Qi Cheng, PhD

Associate Director of Global Regulatory Affairs 502 Carnegie Center, Suite 100

Princeton, NJ 08540

Dear Dr. Cheng:

Please refer to your new drug application (NDA) dated March 28, 2019, received March 28, 2019, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Rykindo (risperidone) for extended-release injectable suspension.

We acknowledge receipt of your amendment dated August 19, 2021, which constituted a complete response to our January 28, 2020, action letter.

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

CLINICAL AND CLINICAL PHARMACOLOGY

The January 28, 2020 complete response (CR) letter advised you to conduct a root- cause analysis that would adequately explain the origin of the concentration spikes observed in LY03004/CT-USA-102. We acknowledge that you have re- analyzed the pharmacokinetic (PK) samples of two patients (Subjects 9) and identified the presence of cocaine. We acknowledge your conclusion that high concentrations of LY03004 were not caused by unanticipated drug release related to the drug product quality but were most likely caused by the extrinsic factor cocaine (which you believe acted as a CYP2D6 inhibitor).

However, we disagree that concomitant use of cocaine adequately explains the high concentrations of LY03004. Labels for risperidone products, which are supported by clinical data, clearly indicate that risperidone concentrations increase less than ~80% in the presence of strong CYP2D6 inhibitors. The published literature consistently suggests that a ~40 to 75% increase in concentration occurs with the most potent CYP2D6 inhibitors, which aligns with language in approved labeling. Additionally, the concentrations are generally unchanged in extensive metabolizers (EMs) of CYP2D6 versus poor metabolizers (PMs) of CYP2D6, who are intrinsically devoid of CYP2D6

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activity and thus reflect a drug interaction scenario via strong CYP2D6 inhibition. The extensive clinical data demonstrate that CYP2D6 inhibition cannot explain the significant extent of concentration spikes (i.e., unexplained intra-subject variability with 300 to 500% increase in concentration observed within a subject) for LY03004.

Most importantly, there is no available information indicating that cocaine may serve as a strong CYP2D6 inhibitor. Based on the available data, cocaine is either a non-inhibitor or at most a weak CYP2D6 inhibitor.

In addition, your other justifications and analyses did not provide any new information to explain the origin of the concentration spikes.

The safety issues with LY03004 remain and the potential for dose dumping cannot be ruled out based on your root-cause analysis.

To address this safety issue, you must provide us the following data in an NDA re- submission:

e Detailed study reports including all PK data (mean and individual subject data) for all the clinical trials that have been conducted outside of the United States with LY03004. This should include, but is not limited to, reports from studies conducted in China as well as in the European Union. Please ensure that the comprehensive data package includes a presentation of detailed PK data from all subjects (in relevant plots/figures/tables) to unequivocally rule out any incidence of dose dumping with LY03004. Additionally, include any/all other appropriate information (e.g., real world drug use data from China, ongoing studies, etc.) that you deem relevant to demonstrate the PK and safety of your product.

e In addition to the required safety update information described below, you must report adverse events of special interest (e.g., those related to warnings and precautions of the Listed Drug) that occurred in any Clinical trials of LY03004 that you include in the resubmission. For any subject with concentration spikes or (suspected) dose-dumping events in clinical trials of LY03004, provide a summary of adverse events along with vital sign and electrocardiogram data.

PRODUCT QUALITY Biopharmaceutics deficiency:

e The biowaiver request for the additional strengths (12.5 mg, 37.5 mg, and 50 mg strengths) cannot be granted at this time because of the continued clinical concerns related to results of the pivotal BE study. Therefore, satisfactory resolution of the clinical and clinical pharmacology concerns is required to establish the adequate BE between the proposed and Listed Drug products.

U.S. Food and Drug Administration

Silver Spring, MD 20993 www.fda.gov

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PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources! and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(I)(1)(i)].°

CARTON AND CONTAINER LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate.

PROPRIETARY NAME

Please refer to correspondence dated, December 9, 2021, which addresses the proposed proprietary name, Rykindo. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

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:

https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

2 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs- final-rule

3 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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

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

e Include tables that compare frequencies of adverse events in the original application 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 application 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.

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

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference 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 draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

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, contact Tiffanie Taylor, Regulatory Project Manager, at Tiffanie. Taylor@fda.hhs.gov.

Sincerely,

{See appended electronic signature page}

Tiffany R. Farchione, MD

Director

Division of Psychiatry

Office of Neuroscience

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

TIFFANY R FARCHIONE 02/18/2022 11:33:40 AM

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