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`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER:
`22-192
`22-192
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`APPLICA TION NUMBER:
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`UOFFICE DIRECTOR MEMO
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`OFFICE DIRECTOR MEMO
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`Ofioe Director’s Memo to File ..
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`Date:
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`May 6, 2009
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`From:
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`Robert Temple, MD
`Director, ODE-l
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`To:
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`Memo to File, NDA 22—192
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`Subject: Approval of iloperidone (FANAPT, NDA 22-192) for acute treatment of
`schizophrenia. Sponsor Vanda
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`I. Background
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`lloperidone is an atypical antipsychotic submitted for use in acute and maintenance
`treatment of schizophrenia. A not approvable letter was issued on 7/25/08 based on
`the applicant’s failure to have submitted two adequate and well-controlled studies
`showing effectiveness and a strong tendency toward substantial inferiority to the
`comparator drugs used in the trials. Dr. Laughren’s July 11, 2008 review and my July
`21, 2008 review detailed the reasons. Both of us agreed that study 3101, a 4 week
`3—arm comparison of iloperidone 24 mg (12 mg bid), ziprasidone 160 mg and placebo,
`the only study sponsored by the applicant, Vanda, clearly showed an effect on the
`PANSS (the PANSS and the BPRS are standard measures of severity of
`schizophrenia, regularly used in clinical trials) that was significantly greater than
`placebo and approximately equal to the effect of ziprasidone. That mostly domestic
`study had 50% African-American participants.
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`For various reasons we were not able to conclude that there was a second supportive
`study, although several of them were “close” and their flaws were at least debatable.
`Drs. Khin (team leader) and Dinh (biostats) considered study 3005, a 6 week
`comparison of iloperidone 12—16 mg, and iloperidone 20-24 mg, risperidone 6-8 mg,
`and placebo also positive, but Dr. Laughren and i had reservations about it related to
`the sequence of analyses (their planned primary endpoint analysis of the whole
`population (both schizo—affective and schizophrenic patients) given 12—16 mg failed (p
`= 0.09), so that the positive finding for the whole group at 20-24 mg (p= 0.01) could
`not be reached. Actually our own analysis of the population of interest (just the
`schizophrenic patients), attained nominal significance at 0.03 (12-16 mg) and 0.005
`(20-24 mg). Two problems kept us from accepting it. First, the effect size was almost
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`significantly less than risperidone (p = 0.09 for 20—24; p = 0.005 for 12-16 mg).
`Substantially smaller effectiveness of an anti-schizophrenic drug was considered a
`safety problem. Second, all of the favorable effect was in the outside-US sites, a
`troubling finding.
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`Two other placebo—controlled studies showed either no effect in the schizophrenic
`population (study 3004, with a high dose of iloperidone 10-16 mg) or a borderline
`effect (study 3000, with doses up to 12 mg/day). Actually the 12 mg dose in study
`3000 was nominally significant and reasonably large, but the effect of the combined 8
`+ 12 mg groups, which was the primary endpoint, was NS, so the analysis of the 12
`mg dose could, technically, not be reached. Certainly, however, study 3000 provides
`some support for effectiveness of even a low dose (12 mg), particularly given our
`“priors” based on studies 3101 and 3005. it was also noted that haloperidol was nearly
`significantly superior to even the high dose. Also noted as supportive were 3 positive
`control (vs haloperidol maintenance) studies. Without a placebo these cannot be
`considered definitive but they suggest activity as maintenance (randomized
`withdrawal) studies of drug vs placebo almost never fail, suggesting that any
`substantial inferiority would have been detected.
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`Our NA letter also identified insufficient evidence of safety, specifically concern about
`the size of the safety database, as only the 24 mg dose seemed likely to be effective
`and exposure to that dose was only about 500 patients. Chemistry issues were
`resolved at the time of the letter and the letter asked for a repeat hepatic impairment
`study and a P—GP intervention study. There were no other outstanding issues. For
`discussion of other issues and further details on trials, see Dr. Ni Khin’s team leader
`review of June 26, 2008 and Dr. Laughren’s July 11, 2008 review.
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`2 Effectiveness revisited
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`In his memo of March 27, 2009 Dr. Laughren describes his reconsideration of the 4
`placebo—controlled studies. As noted, study 3101 is clearly positive. Following
`discussions with Vanda we considered _a_l_l patients (schizophrenic and schizo—
`affective) in study 3000, a study comparing iloperidone 4, 8, and 12 mg, haloperidol
`15 mg and placebo. The study plan required that the 8+12 mg combined groups
`analysis must be done first and succeed, in order to go in to any other analyses. The
`analyses of either the schizophrenic or total population are in fact NS for the combined
`iloperidone groups. As noted, however, the 12 mg dose is nominally significant for
`both the total and schizophrenic population, although still quite inferior to haloperidol.
`Dr. Laughren still considers this a negative study providing m support, because of the
`failed primary endpoint (pooled 8 and 12 mg doses), but although this is statistically
`correct, and I certainly would not consider the study one that meets criteria for a
`supportive adequate well—controlled study, i would describe the study as providing
`some support for effectiveness. iloperidone continues to look much less effective than
`haloperidol.
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`Study 3004, with a high dose of 10—16 mg, using the planned analysis of all patients,
`schizophrenic and schizo-affective, was positive but the result was driven by a huge
`effect in the roughly 20 (out of 150) patients per group who were schizo-affective, with
`almost no effect in the larger schizophrenic group. That is not the population of
`interest and the result is strange. Study 3004 remains a negative study in our view.
`The sponsor argues that the distinction between schizophrenic and schizo-affective is
`difficult and that treatment is the same anyway, but it seems unreasonable to ignore a
`diagnostic distinction built into the study, clearly made in DSM-IV, and that was so
`influential on the results. I note also that for study 3005, the sponsor is comfortable
`with excluding the schizo-affective subgroup, focusing on the schizophrenics (i.e., the
`opposite of what is argued for 3004).
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`Dr. Laughren now considers 3005 a second supportive study. He was persuaded that
`the lack of effect in the US subgroup was “one of those outcomes that happen in
`subsets” and noted that the risperidone group also did poorly in the US. He notes that
`there were other data supporting effectiveness in the US, notably study 3101.
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`Dr. Laughren also considers, in his memo, the apparent consistent disadvantage of
`iloperidone compared to haloperidol and risperidone (but not ziprasidone). Like
`iloperidone, ziprasidone is an alpha blocker that must be slowly titrated, giving, as Dr.
`Laughren describes in his March 27, 2009 memo, a one week or greater delay in
`reaching an effective dose. Haloperidol and risperidone, in contrast, reach full doses
`more rapidly.
`'
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`The sponsor argued that slower titration led to greater dropout rates for lack of
`effectiveness (vs haloperidol or risperidone). in study 3005 rates were 23% for
`iloperidone in both groups vs 8% for risperidone LOCF analysis, because there is
`considerable improvement over time in the placebo groups, disadvantages the
`treatment with greater dropout rates. Examination of patients treated > 2 weeks in
`study 3005 showed little iloperidone-risperidone difference, but that, of course, is a
`comparison enriched for early responders, a possible biased analysis. Of perhaps
`greater interest, our own MMRM analysis, which better handles dropouts than LOCF,
`showed a highly significant effect in both dose groups in study 3005, still somewhat
`inferior to risperidone, however. Dr. Laughren concludes, and I agree, that it is not
`clear that iloperidone is inferior to available therapy, although the need for titration is
`plainly a disadvantage, one shared by ziprasidone and quetiapine.
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`3. Safety
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`No new safety data have emerged, but iloperidone has 2 major problems: First, it
`prolongs the QT substantially, > 15 msec and somewhat more if its metabolism by
`CYP 450 2D6 or 3A4 is interfered with. it also works less rapidly because of the need
`to titrate slowly. Labeling'will reflect this; Indications and Usage will point out the need
`to consider, in choosing iloperidone, its QT prolonging properties (worse than many
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`alternatives) and delayed response compared to alternatives, i.e., a “sort of” second
`line claim, much like ziprasidone.
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`Iloperidone has side effects expected of an alpha blocker (tachycardia, dizziness, and
`hypotension), all dose-related, as well as dose-related weight gain, a class effect. It
`had a low rate of extrapyramidal symptoms (akathisia, bradykinesia, dyskinesia,
`distonia and Parkinsonism) all at rates indistinguishable from placebo. Tremor may
`have been slightly increased at the high dose (3.1% vs 1.9% on placebo). At the high
`dose, it had the usual increases, compared to placebo, in total cholesterol and
`triglycerides. Labeling will bear the class warning language on
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`1. Risk of death and stroke in elderly patients with dementia
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`2. Neuroleptic malignant syndrome
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`3. Max 1 DM
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`13(4)
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`4. Weight gain (a 7% gain was seen in 4%, 12%, and 18% in patients given
`placebo, iloperidone 10-16 mg/day and iloperidone 20-24 mg/day. Mean
`weight increase vs placebo was about 2 kg.
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`5. Leukopenia, neutropenia, agranulocytosis
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`6. Hyperprolactinemia
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`7. Disruption of body temperature regulation
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`8. Dysphagia and possible aspiration
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`9. Suicide
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`10. Possible cognitive and motor impairment (somnolence 12% vs 5% on
`placebo)
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`iloperidone labeling also will bear warning language about
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`1. Orthostatic hypotension and syncope (0.4% vs 0.2% on placebo)
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`2. Priapism (4 cases)
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`4. Conclusion
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`Iloperidone should be approved with appropriate labeling, as partly described above.
`The sponsor has committed to the conduct of a long-term effectiveness (maintenance)
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`study (placebo—controlled randomized withdrawal study), as well as a PK study in
`patients with moderately impaired hepatic function and a study of in vitro interactions
`of iloperidone with P-Glycoprotein, and has agreed to complete the P95
`carcinogenicity study. The application, once reanalyzed as above, did not raise issues
`needing advisory committee input. iloperidone has effectiveness and safety limitations
`similar to those of several marketed drugs.
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`APPEARS THIS WAY
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`0N ORiGINAL
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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.
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`Robert Temple
`5/6/2009 07:31:28 PM
`MEDICAL OFFICER
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