CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`207946Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`Janssen Ex. 2011
`Mylan v. Janssen
`IPR2020-00440
`
`

`

` M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`FROM:
`
`18 May 2015
`
`Mitchell V. Mathis, M.D.
`Director
`Division of Psychiatry Products, HFD-130
`
`TO:
`
`SUBJECT:
`
`File NDA 207946
`
`Summary memo and approval decision for paliperidone palmitate extended-release
`injectable suspension (3-month injection interval formulation, PP3M) for the
`treatment of schizophrenia
`
`Background and Summary
`Paliperidone palmitate extended-release injectable formulation (3-month injection interval), or
`PP3M, is a 3-month formulation of paliperidone palmitate, a selective D2 and 5-HT2A antagonist
`(atypical antipsychotic) already approved in a 1-month formulation for injection. The PP3M
`formulation allows for every three month dosing which has potential clinical utility for patients who
`are, by the nature of their disease, often noncompliant with treatment.
`
`Paliperidone is the metabolite of risperidone, an atypical antipsychotic approved since 1993. Oral
`paliperidone was approved in 2006 and the one month injectable formulation (PP1M) was approved
`in 2009. PP3M was designed to be given only to patients who have tolerated the PP1M
`formulation. Titration of PP1M can take up to 4 months and so PP3M is to be labeled for use in
`patients who have already had efficacy from and demonstrated tolerability to PP1M.
`
`Clinical Summary and Statistics
`
`Efficacy
`Dr. Christina Burkhart conducted the clinical review and Dr. Wang conducted the statistical review.
`Efficacy was based on a randomized, double-blind, placebo-controlled relapse-prevention study
`wherein patients were stabilized for 12 weeks on PP3M after a transition from PP1M. The primary
`efficacy endpoint was Time to Relapse after randomization to continue PP3M or switch to placebo
`(see below).
`
`Reference ID: 3757609
`
`1
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`Janssen Ex. 2011
`Mylan v. Janssen
`IPR2020-00440
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`

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`Study Design
`
`Results—Time to Relapse During DB Phase, Interim Analysis
`
`The study was halted in accordance with the protocol when statistical significance in favor of PP3M
`was demonstrated at the pre-planned interim analysis of Time to Relapse. The results were highly
`statistically significant at the interim analysis p=0.0002. Approximately three times as many
`patients in the placebo group (29%) as in the PP3M group (9%) experienced a relapse event with
`the most common relapse events being worsening of psychotic symptoms or psychiatric
`hospitalization. These results were the same in subgroup analyses based upon age, sex, race BMI,
`and region. Secondary efficacy variable analysis provided further support of efficacy.
`
`Reference ID: 3757609
`
`2
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`Janssen Ex. 2011
`Mylan v. Janssen
`IPR2020-00440
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`

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`Safety
`There is a large safety database for evaluating this drug given the multiple oral formulations and
`injections of risperidone/paliperidone products. No unique safety findings were noted for this
`formulation other than a small increase in subjectively rated pain on injection, presumably related to
`the increased injection volume.
`
`Conclusion
`
`Sufficient evidence has been presented to support the safety and efficacy of PP3M for the treatment
`of schizophrenia.
`
`Chemistry Manufacturing and Controls (CMC)
`Dr. David Claffey and the CMC team have recommended approval. Manufacturing and sterility
`were adequately addressed by the Sponsor.
`
`Nonclinical Pharmacology/Toxicology
`Dr. Chalecka-Franaszek completed the review and recommended approval. There were limited data
`required of this submission secondary to similarities between PPM3 and the approved PPlM
`formulation, but the Sponsor did conduct two local tolerability studies in the mini pig. The team
`identified similar granulomatous lesions at the injection site for both PPlM and PP3M, but noted
`that the injection sites of the PP3M had more advanced histologic appearance than in the PPlM
`injection sites. While not an approval issue, the team recommended that this difference be included
`in labeling and we have incorporated that language.
`
`ted to limit the dose of each of
`Dr. Chalecka—Franaszek also recommended that the DMF be u
`) to
`two Ames mutation assay positive impurities (- and
`oxo per
`injection. Dr. Atrakchi, the nonclinical team supervisor, cites ICH M7 (June 2014) in disagreeing
`with Dr. Chalecka-Franaszek’s recommendation. Dr. Atrakchi argues that Section 7.3 of M7
`(Acceptable intakes in relation to LTL [Less than Lifetime] Exposure), discusses the approach to
`LTL exposure to mutagenic impurities in pharmaceuticals in which the cumulative lifetime dose is
`uniformly distributed over the total number of exposure days during LTL. This would allow for a
`higher “daily” intake of impurity with drug than would be the case for lifetime exposure, and still
`maintain a comparable carcinogenic risk for daily and non-daily dosing (1 in 100,000). When
`calculated in this way, PP3M administered every 90 days will have 280 dosing days over 70 years
`(a “lifetime”), which for these impurities, would result in less than the 20 micrograms/day limit as
`presented in ICH M7. Therefore, the nonclinical supervi
`ecommends the limits for the 2
`genotoxic impurities in the drug substance be set at NM
`pm for each impurity based on the
`LTL approach outlined in the 2014 ICH M7 Guideline. I interpret ICH M7 '
`he same way as Dr.
`
`AtrakchiandthereforeIagreewithher. TheDMFholderhadsetalimitofgmforthese
`
`impurities as was done for PPlM, and they have recently reduced this limit t
`
`PM.
`
`Office of Clinical Pharmacology (OCP)
`Dr. Kumi reviewed Study PSY—1005, a single-dose Phase 1 PK study, as well as data from the
`Phase 3 study, and he has recommended approval. He concluded that PP3M dissolves slowly after
`injection and becomes hydrolyzed to paliperidone and absorbed. Drug release begins at Day 1 and
`minimal concentrations are still measurable at 18 months after the last dose. Time to maximum
`
`concentration is 30-33 days and total exposure is proportional over the dosing range of 273 mg to
`819 mg. Dr. Kumi determined that PP3M administered at doses 3.5—times higher than PPlM result
`in paliperidone exposures similar to those obtained with three monthly dose of PPlM. Differences
`
`Reference ID: 3757609
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`Janssen Ex.32011
`Mylan V. Janssen
`IPR2020-00440
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`Janssen Ex. 2011
`Mylan v. Janssen
`IPR2020-00440
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`

`in gluteal versus deltoid injection sites were minimal, and dosing is therefore the same for both sites
`of administration. Multiple models were constructed to provide information on switching between
`formulations of paliperidone, as well as calculated best corrections for missed dose scenarios and
`this information has been included in labeling to assist the prescriber.
`
`Labeling
`The team constructed labeling based upon PP1M labeling, and updated it to include information
`specific to the PP3M formulation. Comments/suggestions/edits from the team were considered and
`sent to the Sponsor multiple times for concurrence. The Office of Prescription Drug Promotion also
`reviewed the label and their changes were incorporated. The sponsor has accepted the labeling
`changes and a final version will be attached to the letter.
`
`Postmarketing Requirements/Commitments
`No post-marketing requirements or commitments have been identified.
`
`Conclusions
`Sufficient information has been submitted to conclude that PP3M is safe and effective in treating
`schizophrenia
`
`The labeling has been negotiated to current Division standards.
`
`The sponsor has agreed to the negotiated label; this application should be approved by the PDUFA
`date.
`
`Reference ID: 3757609
`
`4
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`Janssen Ex. 2011
`Mylan v. Janssen
`IPR2020-00440
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`

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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/
`----------------------------------------------------
`MITCHELL V Mathis
`05/18/2015
`
`Reference ID: 3757609
`
`Janssen Ex. 2011
`Mylan v. Janssen
`IPR2020-00440
`
`