CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
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`
`Cross-Discipline Team Leader Review Memo
`
`
`
`Date of review
`January 5, 2011
`From
`Robert L. Levin, M.D.
`Subject
`Cross-Discipline Team Leader Review
`NDA
`22-567
`Sponsor
`PGx Health, LLC
`Submission Date March 22, 2010
`Related IND
`54-613
`Proprietary /
`VIIBRYD
`Established name
`Vilazodone Hydrochloride
`Dosage forms /
`10, 20, and 40 mg oral tablets
`strength
`Proposed
`Indication
`Recommended:
`
`
`Major Depressive Disorder in Adults
`
`Approval
`
`1. Introduction to the Review
`
`The sponsor has submitted NDA 22-567 for vilazodone hydrochloride oral tablets in the
`treatment of adults with major depressive disorder. Vilazodone is a new molecular entity
`that has selective serotonin reuptake inhibitor (SSRI) properties as well as 5-HT1A partial
`agonist properties. The sponsor has evaluated vilazodone in 24 phase 1 studies, five
`phase 2 studies, and three phase 3 studies. The five phase 2 controlled studies were either
`negative (2) or failed (3). In these studies, the sponsor explored a dose range of 5-100 mg
`per day. There was no clear trend toward a beneficial treatment effect. Gastrointestinal
`adverse reactions (nausea, vomiting, and diarrhea) were dose-limiting toxicities
`associated with a significant proportion of discontinuations, especially at doses above 40
`mg/day.
`
`In the two pivotal phase 3 trials, the sponsor studied a single dose (40 mg/day). There
`were no active comparators in either study. In one study, subjects who did not tolerate 40
`mg/day could continue treatment with 20 mg/day. This included a very small number of
`subjects. In the second study, subjects were discontinued if they could not tolerate 40
`mg/day. In all other respects, the studies had the identical design. The review team agrees
`that, in both studies, the sponsor demonstrated the efficacy of vilazodone 40 mg/day in
`the treatment of adult subjects with major depressive disorder. The review team also
`agrees that treatment was reasonably safe and well tolerated in the studies. In general, the
`safety and tolerability profiles of vilazodone were highly similar to those of other SSRI
`antidepressants. There were no new or unexpected safety findings with vilazodone,
`compared to those observed with SSRIs. Currently, it is unclear whether the 5-HT1A
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`partial agonist properties of vilazodone confer additional benefit or risk compared to
`SSRI antidepressants.
`
`The review team’s main concern about the vilazodone clinical program is whether the
`sponsor adequately explored a range of doses in the trials, given that the pivotal trials
`assessed only one dose (40 mg/day). Two of the phase 2 studies (246 and 248) used fixed
`doses of vilazodone (5, 10, and 20 mg/day). Study 246 included an active control, but
`Study 248 did not. While these studies were negative or failed on the primary efficacy
`endpoint (HAMD scores), there appeared to be a trend toward an effect on the secondary
`endpoint (MADRS scores). However, there are a number of problems in relying on the
`secondary efficacy analysis. Overall, it is uncertain whether the 20 mg dose might be
`effective. On the other hand, there are dose-related adverse reactions (nausea and
`vomiting) that were associated with discontinuation of treatment. Thus, the review team
`has concluded that the sponsor should be required to conduct a postmarketing placebo-
`controlled and active-controlled study using fixed doses of vilazodone (20 mg and 40
`mg), in order to further explore the effective dose range of vilazodone.
`
`2. Background/Regulatory History
`
`The initial IND (54-613) for vilazodone in the treatment of major depressive disorder was
`submitted on November 21, 1997 by Lipha Pharmaceuticals, an associate of Merck. A
`number of sponsors have held the vilazodone IND during the clinical development
`program. Lipha transferred ownership to Merck on August 26, 1998. On May 1, 2001
`Merck transferred ownership to GSK; and on February 11, 2003 GSK transferred
`ownership to Merck. On November 7, 2003 EMD Pharmaceuticals became the IND
`holder. On October 25, 2004 EMD transferred ownership to Genaissance
`Pharmaceuticals. Subsequently, the company name of Genaissance changed to Cogenics
`on January 8, 2007. The name then changed to PGxHealth on September 28, 2007.
`
`The clinical program was discussed with the sponsor at an end of Phase 2 (EOP2)
`meeting on December 20, 2005. The Division and the Sponsor reached agreement on the
`design of the Phase 3 studies (GNSC-04-DP-02 and GNSC-07-02). There was agreement
`that the Montgomery-Asberg Depression Rating Scale (MADRS) was an acceptable
`primary endpoint for a study in major depressive disorder. The Division and the Sponsor
`also agreed that ophthalmologic exams would not be required for these 8-week studies.
`However, for longer term exposures, the Sponsor would be required to conduct baseline
`and repeat (every 6 months) slit lamp exams and dilated fundoscopy to assess for
`lenticular and retinal changes.
`
`During the period, May 8, 2008 and June 10, 2009, the Division provided guidance and
`feedback to the sponsor during face-face meetings, teleconferences, letters, and email
`communications. The topics of discussion included pivotal clinical protocols, a thorough
`QT study protocol, proposed analyses regarding possible genetic markers of response to
`vilazodone. During a pre-NDA meeting (June 17, 2009), we discussed the content and
`format of the clinical section for the subsequent NDA submission. We agreed that the
`efficacy data from the two pivotal trials would be presented separately and would not be
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`pooled. In addition, we agreed that the 5 phase 2 studies would not be considered
`supportive of the indication. The sponsor would submit the individual study reports.
`
`3. Chemistry Manufacture and Controls (CMC) Review
`
`Pei-I Chu, Ph.D. from ONDQA DPA1 performed the CMC review for the Division of
`Psychiatry Products. Dr. Chu has concluded that the sponsor has provided adequate CMC
`data to support approval of the NDA. There are no outstanding CMC issues. I agree with
`her conclusions.
`
`3.1 Drug Substance
`
`Dr. Chu has concluded that the drug substance and stability data provided support
`approval of the NDA.
`
`Vilazodone hydrochloride is a new chemical entity belonging to the structural chemical
`group of the indolalkylamines. The full chemical designation is 2-benzofuran-
`carboxamide, 5-[4-[4-(5- cyano- 1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride
`(1:1) indolalkylamines. The full chemical designation is 2-benzofurancarboxamide, 5-[4-
`[4-(5- cyano- 1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1). Vilazodone HCl
`drug substance is a white to cream-colored solid. It is achiral and slightly hygroscopic.
`Solid state form analysis demonstrates that it exists in multiple polymorphs
`
`.
` form IV was chosen for development.
`The solubility in water is 0.32mg/mL. The partition coefficient between n-octanol and
`water is
` The pKa is 7.1. The melting point and decomposition starts at ~270ºC.
`
`3.2 Drug Product
`
`Dr. Chu has concluded that the drug product and stability data provided support approval
`of the NDA.
`
`In her review, Dr. Chu notes that Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are
`immediate-release, oval, film-coated, tablets, manufactured from a
` with
`total tablet weights of 103 mg, 206 mg and 412 mg, respectively. The 10 mg tablets are
`pink; the 20 mg, orange; and the 40 mg, blue. The tablets are debossed with the strength
`on one side and plain on the other. The tablets are packaged in appropriately-sized, 30-
`count, 90-count and 500-count high-density polyethylene (HDPE) bottles, and in
`film/aluminum foil blisters.
`
`The drug product will be manufactured by Patheon Puerto Rico, Inc. (Manati, Puerto
`Rico). Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are manufactured from a
` process using standard techniques, equipment and
`
` Excipients
`used in the formulation include lactose, microcrystalline cellulose, colloidal silicone
`dioxide, magnesium stearate and
` film coating. The film coat is comprised of:
`
`controls. Manufacturing consists of
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` The batch formula for a
` for the 10mg, 20mg and 40mg tablets, which would
`commercial scale batch is
`results in
` 10mg tablets,
` 20mg tablets or
` 40mg tablets.
`Vilazodone HCl tablets may be stored in bulk prior to packaging to accommodate for
`packaging schedule. The HDPE bottles are sized to accommodate 30, 90, or 500
`tablets/bottle. Each bottle also contains a 1-g desiccant canister. The applicant has
`submitted 18 month stability data for 6 batches using drug substance manufactured by
`Merck (three each of 10mg and 40mg tablets) and 12 month stability data of drug product
`manufactured with API from Scino Pharm. Based on real time and accelerated stability
`data at the ICH conditions, the 10mg and 40mg tablets are considered stable under
`proposed storage container closure systems. Tablets manufactured with API from SPT
`have the same stability as those manufactured with API from Merck based on comparison
`of 12-month stability data for SPT-API tablets and Merck-API tablets. The data support
`the proposed shelf life of 24 months when stored at room temperature.
`
`3.3
`
`Pre-approval Inspection of Facilities and Quality Issues Observed
`
`The facilities inspection has been completed. The Office of Compliance has determined
`that the drug substance, drug product, and packaging facilities are adequate. Pre-approval
`inspections for the drug substance, drug product, and packaging sites are not needed
`based on the drug profile.
`
`3.4 Unresolved CMC Issues
`
`There are no unresolved CMC approvable issues. The sponsor has committed to meeting
`the following requests: 1) they will provide a revised
` validation report to
`demonstrate the limit of quantitation for Form IV
`, and 2) they
`will include an updated dissolution method validation report using a stability indicating
`analytical method. Dr. Chu does not recommend any phase 4 commitments.
`
`4. Nonclinical Pharmacology/Toxicology
`
`Violetta Klimek, Ph.D. performed the pharmacology/toxicology review. Dr. Klimek and
`the team leader, Linda Fossom, Ph.D. have concluded that the sponsor has provided
`adequate pharmacology/toxicology data for approval of the NDA. Dr. Klimek and Dr.
`Fossom have concluded that there are no unresolved pharmacology/toxicology issues. I
`agree with their conclusions. The pharm/tox team has made a number of
`recommendations for labeling that we have incorporated.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Bei Yu, Ph.D. performed the Clinical Pharmacology/Biopharmaceutics review. Dr. Yu
`and the OCP team have concluded that the sponsor has provided adequate clinical
`pharmacology and biopharmaceutics information to support approval of the NDA. There
`are no outstanding issues. I agree with Dr. Yu’s conclusions.
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`Pharmacokinetics Findings
`
`
`5.1
`
`5.1.1 Absorption and Food Effect
`
`Dr. Yu notes that vilazodone exhibits dose-proportional pharmacokinetics over the dose
`range of 5-80 mg after single-dose and multiple-dose administration. The absolute
`bioavailability of vilazodone is approximately 72% when administered with food.
`Administration of vilazodone 20 mg/day with food (a high fat/high calorie or a light
`meal/low calorie) increased exposures. The Cmax increased by 150-160%; and the AUC
`increased by approximately 85%. The sponsor has proposed in labeling that vilazodone
`should be taken with food, based on the higher systemic exposure under fed conditions.
`The Division agrees with this recommendation.
`
`The median Tmax is 4-5 hours. The T1/2 is approximately 25 hours. The accumulation ratio
`for vilazodone is approximately 1.5 to 1.8
`
`5.1.2 Distribution
`
`Vilazodone is highly protein-bound (96-99%). Vilazodone is widely distributed, with a
`volume of distribution of 605 L after a 5 mg infusion.
`
`5.1.3 Metabolism
`
`Vilazodone is extensively metabolized. It appears that there are no active metabolites.
`CYP450 pathways account for approximately 60% of vilazodone metabolism.
`Approximately 40% of vilazodone is possibly metabolized by carboxyl esterase.
`CYP3A4/5 is the major isoenzyme involved in the metabolism of vilazodone.
`Coadministration with ketoconazole increases the vilazodone AUC and Cmax by 50%.
`Presumably, coadministration with potent inducers of CYP3A4 (e.g., carbamazepine)
`would decrease vilazodone exposures; however, the sponsor has not conducted a study
`with a CYP3A4 inducer. OCP requests that the sponsor conduct an in vivo study of
`vilazodone used concomitantly with an inducer of CYP3A4, such as carbamazepine. I
`agree with this recommendation.
`
`The CYP2C19 and CYP2D6 isoenzymes make minor contributions to the metabolism of
`vilazodone. CYP2C19 and 2D6 genotypes are not associated with different drug
`response. CYP1A2, CYP2A6, CYP2C9, and CYP2E1 have minimal contribution to the
`metabolism of vilazodone.
`
`5.1.4 Elimination
`
`Fecal excretion is the major route of elimination of vilazodone. A mass balance study
`demonstrated that 85% of radioactivity was recovered overall. Approximately 65% was
`recovered in feces, and 20% was recovered in urine. Approximately 3% of the dose was
`recovered as unchanged drug (2% in feces and 1% in urine).
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`5.1.5 Specific Populations
`
`Dr. Yu has concluded that the PK profiles were comparable among: 1) healthy subjects,
`2) patients with moderate and mild hepatic impairment, and 3) patients with mild and
`moderate renal impairment. Patients with severe hepatic or renal impairment were not
`studied. There were no significant differences in the pharmacokinetics of vilazodone
`between subjects > 65 years of age and subjects < 65. Generally, lower body weights
`correlated with higher exposures. Systemic exposures were higher in females than males;
`however, female subjects had lower body weights than males, overall.
`
`5.3 OCP Labeling Recommendations
`
`The Office of Clinical Pharmacology review team has recommended labeling language
`for a number of sections in labeling. I agree with all of the recommendations. The
`Division has incorporated the recommendations in a separate labeling document in the
`following sections: Highlights, Dosing and Administration, Drug Interactions, Use in
`Specific Populations, and Clinical Pharmacology.
`
`5.4
`
`Dr. Yu and the OCP review team recommend that the sponsor conduct the following
`studies as postmarketing commitments:
`
`
`Recommended Postmarketing Commitments
`
`1. A controlled, fixed-dose study assessing the efficacy and safety of vilazodone
`20 mg and 40 mg, compared to placebo in the treatment of subjects with major
`depressive disorder.
`2. An in vivo study of a CYP3A4 inducer. OCP recommends a randomized, two-
`way crossover study in healthy subjects treated with vilazodone 20 mg under
`basal conditions and after pre-treatment with carbamazepine 400 mg/day for 7-14
`days.
`3. A clinical study of vilazodone treatment in patients with severe hepatic
`impairment.
`4. An in vitro study of the effect of PgP on the pharmacokinetics of vilazodone and
`the effect of vilazodone on PgP.
`
` I
`
` agree with Dr. Yu’s recommendations for postmarketing commitments. The Division
`has conveyed these commitments to the sponsor.
`
`6. Thorough QT Study
`
`The Cardiorenal QT Interdisciplinary Review Team reviewed the data from the sponsor’s
`thorough QT study. The team has concluded that treatment with vilazodone did not
`prolong the QTc interval. I agree with this conclusion.
`
`The largest upper bounds of the 2-sided 90% CI for the mean difference between
`vilazodone (doses 10 mg – 80 mg) and placebo were below 10 ms. The largest lower
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`bound of the two-sided 90% CI for the ∆∆QtcI for moxifloxacin was greater than 5 ms at
`Day 6, and the moxifloxacin profile over time is adequately demonstrated in Figure 4
`(Day 6), indicating that assay sensitivity was established.
`
`Study PGX-08-P1-06 was phase 1, single-center, randomized, double-blind, placebo-
`controlled and active-controlled (moxifloxacin 400 mg), 3-arm, parallel-group, thorough
`QT study in 157 healthy male and female subjects. The administration of moxifloxacin
`was not administered in a double-blind manner. The primary objective was to determine
`the time-matched change from baseline QTc, based on an individual correction (QtcI)
`method. This method provides an optimization of QT correction for heart rate, in contrast
`to fixed exponent approaches such as Bazett (QTcB) or Fridericia (QTcF) methods. The
`secondary objective was to evaluate the safety and tolerability of vilazodone (up to 80
`mg/d) compared to placebo or moxifloxacin. The table below illustrates the summary of
`findings from the QT study.
`
`Table 1: The Point Estimates and the 90% CIs Corresponding to the Largest Upper
`Bound of QtcI for Vilazodone and the Largest Lower Bound for Moxifloxacin
`
`
`Multiple endpoint adjustment was not applied. The largest lower bounds after Bonferroni
`adjustment for 4 time points are 6.8 ms, 5.8 ms, 2.9 ms, and 3.4 ms, respectively, for Day
`6, 9, 12 and 15, respectively.
`
`The QTIRT notes that the supratherapeutic dose of vilazodone (80 mg) produces mean
`Cmax and AUC values 2.0-fold higher than the observed Cmax for the dose studied (40
`mg) in the clinical trials. This increase in exposures is expected to be greater than the
`increase in exposure due to drug-drug interaction with ketoconazole (1.5-fold increase).
`
`There were no sudden deaths or significant ventricular arrhythmias in this study. One
`subject experienced convulsive syncope while having her blood drawn. This was reported
`as convulsive syncope of vasovagal etiology. ECG taken soon after the episode was
`reportedly normal. However this event also had temporal association to study drug and
`may be due to non-arrhythmogenic mechanisms. There were 3 other episodes of syncope
`in the vilazodone group reported as vasovagal. No narratives are available for these
`events. There were no sudden deaths, and there were no significant ventricular
`arrhythmias in the study.
`
`The QTIRT has recommended deletion of the sponsor’s proposed language regarding
` in section 6. They recommend including the description of the QT study
`results in Section 12.2 as follows:
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`Generally, I agree with the proposed labeling. We have incorporated a slightly modified
`version in the Clinical Pharmacology section of labeling.
`
`
`7. Ophthalmology Consult
`
`We have requested an ophthalmology consult due to the finding of cataract development
`during controlled trials of vilazodone. Currently, the ophthalmology consult is not
`available.
`
`Under the vilazodone IND (54-613), Merck conducted clinical ophthalmological testing
`in two phase 2, eight-week, placebo- and active-controlled studies (studies 009 and 010),
`due to the findings in dogs of reduced tear production and streak-like corneal opacities.
`
`7.1
`
`In previous consults (2001 and 2005) regarding cataract development in the phase 2,
`8-week, controlled studies, Wiley Chambers, M.D. expressed concern about the
`development of cataracts. In the May, 2001 consult, Dr. Chambers discussed the
`following observations and conclusions regarding studies 009 and 010:
`
`1. It is not clear how the data has been reported in this table. Corneal abnormalities
`should include all events in the stroma, endothelium and epithelium. Anterior
`chamber should include cell and flare. Lens should include all types of cataracts.
`The data should be verified before final conclusions are drawn.
`
`Previous FDA Ophthalmology Consult Findings
`
`
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`
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`2. The rate of reporting for cataract formation is very high for an eight week study.
`Cataract formation appears to be occurring at an unacceptable rate. This needs to
`be explained.
`
`3. The retina abnormalities should be explained.
`
`4. The reduction in tear production as measured by Schirmer demonstrated a dose
`dependent response.
`
`5. Ocular testing has detected abnormalities in tear production, cataract formation,
`and retinal abnormalities. Conclusions on the cornea cannot be made because of
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`inconsistent data. In the absence of negative ocular findings, ocular testing should
`be continued. Ocular testing should continue during the development of this drug
`product.
`
`
`On December 20, 2005 the Division met with Genaissance Pharmaceuticals to discuss the
`design of the pivotal phase 3 studies. The sponsor requested that the Division not require
`ophthalmological examinations in these studies. In his December 19, 2005 consult, Dr.
`Chambers stated the following in response to the sponsor’s questions:
`
`
`1. The determinations of Vilazodone’s potential to cause cataract and retinal lesions
`will need to be evaluated in longer term studies.
`
`
`
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`2. Ocular testing has detected abnormalities in tear production, cataract formation
`and retinal abnormalities, but there have been methodological problems in the
`monitoring. The ocular dryness and corneal opacities appear to be a related
`problem, i.e., ocular dryness, if left untreated can lead to corneal opacities
`particularly in dogs. Vilazodone appears to cause ocular dryness within the first
`two weeks of treatment. This is similar to many other drug products and could be
`labeled and treated with Over-the-Counter demulcents. It is unlikely that
`significant additional information will be learned from ocular monitoring for dry
`eye in the proposed eight week study.
`
`3. Lens opacities and the development of retinal lesions can only be evaluated in
`studies extending for 18-24 months in the case of lens opacities and 12-24 months
`in the case of retinal lesions. The likelihood of detecting significant changes in the
`lens or retina in 8 week studies is very low.
`
`4. Recommended Regulatory Action: Ocular testing is not necessary in the
`currently proposed study. Ocular testing should be conducted in longer term
`(18-24 month) studies during the development of this drug product. Monitoring
`should occur at 6 month intervals in the longer term studies.
`
`Discussion with Dr. Chambers
`
`
`7.2
`
`During a discussion on December 9, 2010, Dr. Chambers stated that the rate of cataract
`formation in the phase 2 controlled studies was higher than expected. In addition, Dr.
`Chambers stated that the rate of cataract formation and progression in the phase 3, long-
`term, open-label vilazodone study was higher than expected. However, Dr. Chambers
`stated that he could not conclude from these studies whether treatment with vilazodone
`was causally related to the development of cataracts. For a definitive assessment of
`cataract formation, he would recommend that the sponsor conduct an 18-24 month
`controlled study. When asked about whether to consider a warning for cataracts in
`labeling, Dr. Chambers stated that part of the reason for not pushing for a warning for
`cataracts is that cataracts are not life-threatening and can be corrected with surgery. He
`also said that one could consider including a warning for cataracts and encourage the
`sponsor to conduct a definitive, controlled, long-term study assessing for cataracts. With
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`Sponsor’s Analysis of the Ophthalmologic Findings
`
`the available data, Dr. Chambers emphasized that he could not conclude that vilazodone
`treatment did or did not lead to cataract development.
`
`7.3
`
`The sponsor consulted an independent ophthalmologist to review the data from the
`ophthalmology and adverse events assessments performed in the phase 2 studies (009 and
`010). In March, 2005,
` noted that the ophthalmological examinations
`and the data collection methods were not optimal. There was no requirement for serial
`evaluations to be performed by the same examiner, which complicated the interpretation
`of the results.
` concluded that vilazodone was associated with ocular drying
`in humans but was not associated with cataracts or retinal abnormalities.
`
`The sponsor stated that in the phase 3, uncontrolled, long-term study, visual acuity scores
`remained stable for 98% of the subjects, and few subjects had abnormal findings on slit-
`lamp biomicroscopy, corneal evaluations, or dilated fundoscopy. In summary, the
`sponsor concluded that the results of detailed ophthalmologic exams did not demonstrate
`clinically significant eye changes, except for a mild drying effect. The sponsor stated that
`there is no indication of any clinically important ophthalmologic effects of vilazodone.
`
`7.4
`
`Conclusions and Recommendations Regarding the Risk of Cataract
`Development
`
`
`Currently, the ophthalmology consult is pending. At this point, it is difficult for the
`Division to interpret the data. However, in previous consults and in recent discussions,
`Dr. Chambers has stated that the rate of cataract formation was higher than expected in
`two controlled phase 2 studies and in the phase 3, open-label, long-term study. The
`sponsor did not conduct ophthalmological assessments in the phase 3 studies. My
`impression is that there is a signal for cataract formation associated with vilazodone
`treatment that the sponsor should explore in the type of definitive study that Dr.
`Chambers has described. None of the sponsors of the vilazodone IND have conducted
`such a study.
`
`I recommend that the Division consider requiring the sponsor to conduct a long-term (18-
`24 month), active-controlled (antidepressant) study to prospectively assess for
`ophthalmologic toxicity. I also recommend that the Division consider specific labeling
`regarding cataracts, including the possibility of a warning for cataracts. While the
`relationship between cataract development and treatment with vilazodone is unclear,
`cataracts can be a serious medical condition. It could be useful to inform clinicians and
`patients about this potential risk.
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`8. Clinical
`
`8.1 Efficacy
`
`Cheri Lindberg, M.D. performed the clinical review. Dr. Lindberg has concluded that, in
`two adequate and well controlled studies, the sponsor demonstrated the efficacy of
`vilazodone in the treatment of adult subjects with a diagnosis of major depressive
`disorder. I agree with Dr. Lindberg’s conclusions.
`
`8.1.1 Study GNSC-04-DP-02
`
`Study GNSC-04-DP-02 was an 8-week, phase 3, multicenter (18 U.S. sites), randomized,
`placebo-controlled, fixed-dose study of vilazodone 40 mg in the treatment of adults (18-
`70 years-old) with a diagnosis of major depressive disorder. The study included 407
`subjects. There were 198 subjects treated with vilazodone and 199 treated with placebo.
`The study was conducted from February 22, 2006 to May 23, 2007.
`
`Subjects initiated treatment with vilazodone 10 mg/day for 7 days, followed by 20
`mg/day for 7 days. Subjects were then treated with the target dose of 40 mg/day for up to
`6 weeks. Vilazodone was administered with food, because bioavailability is increased
`considerably (by approximately 85%) in the presence of food. If subjects could not
`tolerate the 40 mg dose, they could continue in the study while treated with 20 mg/day.
`
`
`The primary objective was to assess the efficacy of vilazodone, compared to placebo, in
`the treatment of MDD as measured by the mean change from baseline in the
`Montgomery-Asberg Depression Rating Scale (MADRS) score after 8 weeks of
`treatment. A secondary endpoint was the change from baseline to week 8 in the Clinical
`Global Impression-Severity (CGI-S) Scale score. The sponsor did not prospectively
`designate the CGI-S as a key secondary endpoint.
`
`As illustrated in the sponsor’s table below from the Clinical Summary of Efficacy, the
`least square mean (SE) changes in MADRS score were -12.9 (0.77) and -9.6 (0.76) for
`the vilazodone and placebo groups, respectively. The LS Mean treatment difference
`(-3.2) was statistically significant (p= 0.0010), in favor of vilazodone treatment.
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`Reference ID: 2886834
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`The results are supported by the secondary efficacy results of the CGI-S analysis as
`illustrated below. The least square mean (SE) changes in CGI-S score were -1.4 (0.010)
`and -1 (0.09) for the vilazodone and placebo groups, respectively. The LS Mean
`treatment difference (-0.4) was statistically significant (p= 0.0010), in favor of vilazodone
`treatment.
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`8.1.2 Study 2 (CLDA-07-DP-02)
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`Essentially, Study CLDA-07-DP-02 had an identical design to that of Study GNSC-04-
`DP-02, except that subjects who could not tolerate 40 mg/day could not continue in the
`study on 20 mg/day. This was an 8-week, phase 3, multicenter (15 U.S. sites),
`randomized, placebo-controlled, fixed-dose (40 mg/day) study of vilazodone in adult
`subjects with a diagnosis of major depressive disorder. The study was conducted from
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`Reference ID: 2886834
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`March 31, 2008 to February 10, 2009. The study included 470 subjects. In the ITT
`population, there were 231 subjects treated with vilazodone and 232 treated with placebo.
`Subjects initiated treatment with vilazodone 10 mg/day for 7 days, followed by 20
`mg/day for 7 days. Subjects were then treated with the target dose of 40 mg/day for up to
`6 weeks. Vilazodone was administered with food. Subjects who did not tolerate
`vilazodone 40 mg/day were discontinued from the study.
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`As in Study GNSC-04-DP-02, the primary efficacy endpoint was the change from
`baseline in MADRS total score at Week 8. As illustrated in the sponsor’s table 4 below
`from the Clinical Summary of Efficacy, the least square mean (SE) changes in MADRS
`score were -13.3 (0.090) and -10.8 (0.090) for the vilazodone and placebo groups,
`respectively. The LS Mean treatment difference (-2.5) was statistically significant
`(p= 0.0093), in favor of vilazodone treatment.
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`The results were supported by the secondary efficacy results of the CGI-S analysis
`illustrated below. The least square mean (SE) changes in CGI-S score were -1.4 (0.012)
`and -1.1 (0.12) for the vilazodone and placebo groups, respectively. The LS Mean
`treatment difference (-0.4) was statistically significant (p= 0.0035), in favor of vilazodone
`treatment.
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`8.2 Pediatric Use/PREA Waivers and Deferrals
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`The use of vilazodone has not been studied in pediatric patients. In accordance with the
`Pediatric Research Equity Act, the sponsor submitted a request for
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`Reference ID: 2886834
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`(b) (4)
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`A PeRC meeting was held on December 1, 2010. The PeRC agreed with the Division’s
`request for a waiver for children younger than 7 years-old and a deferral for studies in
`children and adolescents between the ages of 7 and 17. PeRC requested (as PMR) that the
`sponsor conduct one PK, safety and tolerability study and two placebo and active-
`controlled (fluoxetine) efficacy and safety studies. And, they requested that the sponsor
`conduct a juvenile animal study as a postmarketing requirement.
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`8.3 Safety Review
`
`Cheri Lindberg, M.D conducted the safety review. Dr. Lindberg has concluded that
`treatment with vilazodone was reasonably safe and well tolerated in the pivotal studies.
`Dr. Lindberg has also concluded that the safety profile of vilazodone is very similar to
`those of SSRI antidepressants. There were no new or unexpected adverse reactions,
`compared to what one would expect with an SSRI. I agree with Dr. Lindberg’s
`conclusions regarding the safety analysis.
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`8.3.1 General Safety Considerations
`
`Dr. Lindberg has concluded that the sponsor conducted adequate safety assessments and
`submitted adequate safety data for assessing the safety profile of treatment with
`vilazodone. I agree with her conclusion. The types and frequency of safety assessments
`were adequate for a short-term trial in subjects with major depressive disorder. The safety
`assessments included the following: adverse events monitoring, vital signs monitoring,
`ECG, pregnancy testing, systematic monitoring of extrapyramidal symptoms, clinical
`laboratory testing, urine drug screen, and alcohol screening.
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`8.3.2 Exposure
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`The vilazodone exposure was adequate to support the application. Ov