CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205395Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (damnavir/cobicistat)
`
`Clinical Review
`
`December 19, 2014
`Date
`
`From
`Sarita Boyd, PharmD.
`Sub'ect
`Clinical Review
`
`NDA 205395
`NDA/BLA #
`
`Supplement#
`A n nlicant
`
`Janssen
`
`Date of Submission
`
`PDUFA Goal Date
`
`March 28, 2014
`
`Jan
`
`31, 2015
`
`Recommended:
`
`Proprietary Name /
`Established
`S .
`
`names
`
`Prezcobix mammavir/cobicistat)
`
`Dosa_e forms / Stren_ h
`
`Tablet / 800 m of damnavir and 150 m of cobicistat
`
`Proposed Indication(s)
`
`Fixed dose combination indicated in combination with
`other antiretroviral agents for the treatment of HIV-1
`infection in adults
`
`1. Introduction
`
`This review summarizes the main issues for NDA 205395, which includes Week 24 safety and
`efficacy data from Protocol GS-US-216-0130: A Phase 3b, Open-Label, Single Arm Study to
`Evaluate the Safety and Eflicacy ofCobicistat-boosted Darunavir Plus Two Fully Active
`Nucleoside Reverse Transcriptase Inhibitors in HIV-1 Infected, Antiretroviral Treatment-
`Nai've and -Expetiettced Adults with No Darunavir Resistance-associated Alutations.
`Additionally, the review considers data from the bioavailability (BA) and pivotal
`bioequivalence (BE) studies, TMC 1 14IFD1001and TMC 1 14IFD1003, respectively.
`
`2. Background
`
`Darunavir (DRV) is an HIV protease inhibitor (PI) approved in combination with low-dose
`ritonavir (RTV), a cytochrome P450 3A (CYP3A) inhibitor that increases DRV exposure.
`Darunavir coadministered with ritonavir (DRV/r) and other antiretroviral agents is indicated
`for treatment of HIV-1 infection with two different dosage recommendations based on past
`treatment experience. Once daily DRV 800 mg with RTV 100 mg is recommended for
`treatment—naive and -experienced adults with no DRV resistance-associated substitutions.
`DRV/r is not available as a fixed-dose combination (FDC) tablet.
`
`Cobicistat (COBI) received approval on September 24, 2014 as a CYP3A inhibitor indicated
`to increase systemic exposure of DRV (once daily dosing regimen) or atazanavir (ATV) in
`combination with other antiretroviral agents for treatment of HIV-1 infection. The Applicant
`
`Page 1 of 21
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`Reference ID: 3676833
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`1
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`

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`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (danmavir/cobicistat)
`
`is proposing approval of a FDC product containing DRV and COBI, two currently approved
`drugs.
`
`The Applicant has developed darunavir/cobicistat GDRV/co) as a FDC product in collaboration
`with Gilead Sciences, Inc. The bioequivalence (BE) study results are considered pivotal for
`approval of this application of DRV/co 800/ 150 mg as a FDC tablet indicated in combination
`with other antiretroviral agents for treatment of HIV-1 infection in adults. A clinical trial with
`DRV/co was not required because DRV and COBI are approved as individual drugs, and
`pharmacokinetic studies demonstrating bioequivalence 0f the FDC tablet to the approved,
`individual components are adequate. Efficacy and safety of DRV/co is extrapolated from
`DRV/r clinical trials; the link between DRV and COBI as single drugs and DRV/r was
`established during the COBI NDA review. This NDA includes safety and efficacy results for
`Protocol GS-US-216-0130 as a supportive clinical trial.
`
`3. CMCIDevice
`
`DRV/co FDC tablets contain 800 mg of DRV
`
`m” and 150 mg of COBI
`
`“M"
`
`”(n-shaped and film-coated
`The tablets are
`with the color pink. The core tablet contains the following inactive ingredients: hypromellose,
`colloidal silicon dioxide, silicified microcrystalline cellulose, crospovidone, and magnesium
`stearatec. The fihn coating is composed of
`mm) Pink, which contains
`polyvinyl alcohol-partially hydrolyzed, titanium dioxide,
`mm, mm iron oxide
`red, and iron oxide black. The proposed shelf life is 24 months in all climatic zones. Please
`refer to the CMC Reviews by Drs. Fuqiang Liu and Krishnakali Gosh for complete details.
`
`4. Nonclinical Pharmacology/Toxicology
`Nonclinical studies were not conducted with DRV in combination with COBI. The combined
`
`use of DRV and COBI is not expected to produce clinically relevant additive or synergistic
`effects. Additionally, DRV and COBI are approved as single agents to use in combination for
`the same indication proposed in this NDA. Comprehensive nonclinical programs for single
`agents DRV and COBI have been conducted by the Applicant and Gilead Sciences,
`respectively. The nonclinical program for COBI included safety pharmacology, nonclinical
`pharmacokinetics, and toxicology of COBI as a single agent and in combination with ATV or
`elvitegravir (EVG). Please refer to the original NDA reviews for DRV and COBI as single
`agents for complete details.
`
`5. Clinical PharmacologyIBiopharmaceutics
`
`The development program for DRV/c0 FDC is based on comprehensive development and
`approval of DRV and COBI as single agents and phannacokinetic (PK) bridging of DRV/co
`FDC to the single agents. Study TMC114IFD1001 evaluated relative BA of DRV with two
`
`Page 2 of 21
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`Reference ID: 3676833
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`

`

`Clinical Review
`Sarita Boyd
`NDA 205395
`Prezcobix (darunavir/cobicistat)
`
`different DRV/co 800/150 mg FDC formulations compared to DRV/r 800/100 mg in 36
`healthy subjects following repeated once daily dosing under fed conditions. Results from this
`study led to selection of one of these formulations, with use of a different color coating, to
`move forward in development. Study TMC114IFD1003 evaluated BE of DRV with the
`selected DRV/co 800/150 mg FDC formulation compared to DRV 800 mg and COBI 150 mg
`administered as single agents in 133 subjects following single doses under fasted and fed
`(standard meal) conditions. Additionally, Study TMC114IFD1003 assessed the effect of a
`high-fat breakfast on the BA of the selected DRV/COBI FDC formulation (food effect).
`
`Overall, Study TMC114IFD1003 showed acceptable BE of DRV/co FDC compared to the
`single agents under fasted and fed (standard meal) conditions. Although the study formulation
`(white) differs from the commercial formulation (pink) in its color coating, the change does
`not impact the BE study results per the Biopharmaceutics Reviewer, Dr. Minerva Hughes,
`because the film coating is nonfunctional.
`
`A high-fat meal (vs. fasting) increased the area under the concentration time curve (AUC) and
`maximum plasma concentration (Cmax) for DRV by 70% and 127%, respectively, with the
`FDC. However, absolute DRV Cmax values overlap for DRV/co FDC administered with either
`a standard meal (i.e., recommended administration) or a high fat meal. DRV AUCs observed
`or estimated in the original DRV NDA (with RTV) were comparable or higher than those
`observed in the DRV/co FDC food effect study. In the original NDA for DRV/r once daily
`dosing, there were no apparent relationships between DRV exposures and maximum changes
`in laboratory parameters or occurrence of adverse events (AEs). Therefore, the increased
`DRV exposures occurring when DRV/co is coadministered with a high fat meal are not
`expected to be clinically relevant.
`
`Please refer to the Biopharmaceutics Review by Dr. Minerva Hughes and the Clinical
`Pharmacology Review by Dr. Stanley Au for complete details.
`
`6. Clinical Microbiology
`Study GS-US-216-0130 provides supportive virology data for the use of DRV and COBI as
`single agents in treatment-naïve and -experienced subjects with no DRV resistance-associated
`substitutions, which are bridged to the FDC via the pivotal, BE study. In the Week 24 analysis
`of Study GS-US-216-0130, 10 of 313 subjects who received at least 1 dose of study drug
`(DRV/co) met the criteria for resistance test analysis. One treatment-experienced subject
`developed a DRV resistance-associated substitution, I84I/V, and one treatment-naïve subject
`developed a secondary PI substitution, I93I/L. Phenotypic resistance to DRV or other PIs was
`not seen in either of these subjects or in any other subjects. One treatment-experienced subject
`developed 2 reverse transcriptase (RT) substitutions, L74I/L and P225H/P, which are
`associated with resistance to abacavir and didanosine and to efavirenz, respectively. M184I/V
`was present at baseline and on treatment in this subject. Of note, the subject’s background
`regimen in the study included emtricitabine, tenofovir, and zidovudine. Although
`interpretation of results is relatively limited in an open-label, single arm trial with Week 24
`
`Page 3 of 21
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`Reference ID: 3676833
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`3
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`

`

`Clinical Review
`Sarita Boyd
`NDA 205395
`Prezcobix (darunavir/cobicistat)
`
`results, the low rate of resistance development with DRV/co is consistent with that observed
`for DRV/r in the same population. Please refer to the Clinical Virology review by Dr. Takashi
`Komatsu for complete details.
`
`7. Clinical Efficacy
`
`Efficacy Summary
`
`Study GS-US-216-0130 is an ongoing Phase 3b, open-label, single arm, multicenter study
`evaluating the safety and efficacy of DRV/co (as single agents) coadministered with 2 fully
`active NRTIs in HIV-1 infected, antiretroviral treatment-naïve (n=295) and treatment-
`experienced (n=18) adults with no DRV resistance-associated mutations. At baseline, the
`median age of subjects was 35 years, 11% were female, 40% were non-white, 42% had HIV-1
`RNA >100,000 copies/mL, and 19% had CD4+ cell count <200 cells/mm3. At 24 weeks, 82%
`of subjects treated with darunavir and cobicistat plus two nucleoside reverse transcriptase
`inhibitors achieved HIV RNA <50 copies/mL. Although interpretation of clinical efficacy in a
`single-arm trial is somewhat limited, the results provide support that DRV and COBI have
`adequate antiviral activity.
`
`7.1 Indication
`
`The proposed indication for DRV/co 800/150 mg FDC is for use in combination with other
`antiretroviral agents for the treatment of HIV-1 infection in adults. The recommended patient
`population includes treatment-naïve and -experienced patients with no DRV resistance-
`associated substitutions, which is the same for DRV/co administered as single agents (see
`approved prescribing information for TYBOST [cobicistat]) and DRV/r 800/100 mg once
`daily regimen (see approved prescribing information for PREZISTA [darunavir]).
`
`7.1.1 Methods
`
`The indication is based on clinical pharmacology data from Studies TMC114IFD1001 and
`TMC114IFD1003, which compared BA and BE of DRV/co FDC to DRV/r and DRV/co as
`single agents, respectively. See Section 5 for discussion of these studies.
`
`There are no clinical efficacy data with the DRV/co administered as the FDC formulation.
`Study GS-US-216-0130 provides supportive clinical data for DRV/co administered as single
`agents,
`The efficacy review includes Week 24 data analysis of GS-US-216-0130 using JReview.
`
`.
`
`7.1.2 Demographics
`
`The full analysis set includes 313 HIV-infected subjects who received at least 1 dose of
`DRV/co. The majority of subjects were treatment-naïve (n=295) vs. treatment-experienced
`
`Page 4 of 21
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`Reference ID: 3676833
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`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (damnavir/cobicistat)
`
`(n=18). All subjects were enrolled at 56 US. sites. The majority of subjects were male (90%)
`and white (60%) or black (35%). Five subjects (1.6%) were hepatitis B surface antigen
`positive, and 8 subjects (2.6%) were HCV seropositive. Select demographic and baseline
`characteristics are displayed in Table 1 and match the Applicant’s analysis.
`
`Table 1. GS—US—216-0130: Demographic and Baseline Characteristics
`Treatment-naive
`Treatment-
`
`Total
`
`Characteristic
`
`(n=295)
`
`experienced (n=18)
`
`(n=313)
`
`Age
`
`Median (Min, Max)
`
`34 (18, 72)
`
`48 (22, 69)
`
`35 (18, 72)
`
`279 (89%)
`34 (11%)
`
`187 (60%)
`108 (35%)
`4
`(1%)
`
`4
`
`(1%)
`
`1o (3%)
`
`68 (22%)
`
`245 (78%)
`
`
`
`13 (72%)
`5 (28%)
`
`11 (61%)
`7 (39%)
`
`o o o
`
`4 (22%)
`
`14 (78%)
`
`Race
`
`White
`
`Black or African
`American Indian
`
`Asian
`
`Other
`
`Ethnicity
`
`Hispanic or Latino
`
`Not Hispanic or Latino
`Baseline HIV-1 RNA
`
`266 (90%)
`29 (10%)
`
`176 (60%)
`101 (34%)
`4
`(1%)
`
`4
`
`(1%)
`
`10 (3%)
`
`64 (22%)
`
`231 (78%)
`
`Median (Min, Max)
`
`4.8 (2.6, 7.0)
`
`5 100,000 copies/mL
`
`173 (59%)
`
`5.0 (2.7, 6.8)
`
`9 (50%)
`
`4.8 (2.6, 7.0)
`
`182 (58%)
`
`> 100,000 copies/mL
`Baseline CD4 Cell Count
`
`122 (41%)
`
`9 (50%)
`
`131 (42%)
`
`361 (5, 1473)
`107 (5, 643)
`370 (6, 1473)
`Median (Min, Max)
`59 (19%)
`12 (67%)
`47 (16%)
`g 200 cells/mm3
`
`> 200 cells/mm3
`248 (84%)
`6 (33%)
`254 (81%)
`Source: ADSL and ADLB datasets
`
`7.1.3 Subject Disposition
`
`Of 313 subjects in the full analysis set, 39 subjects (12.5%) discontinued study drug before the
`Week 24 data cutoff date. The most common reason for premature discontinuation was
`adverse events (15 subjects, 4.8%) followed by lost to follow-up (11 subjects, 3.5%). Table 2
`displays subject disposition, which matches the Applicant’s analysis.
`
`Table 2. GS—US—216—0130: Subject Disposition
`
` Treatment-
`
`Subject Disposition
`
`na'ive
`
`Full Analysis Set (Received 2 1 Dose)
`
`Treatment-
`
`experienced
`
`Discontinued Study Drug Before W24
`Adverse event
`
`36
`15
`
`3
`0
`
`39
`15
`
`Page 5 of 21
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`Reference ID: 3676833
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`5
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`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (danmaVir/cobicistat)
`
`Table 2. GS—US—216—0130: Subject Disposition
`
`Treatment-
`
`Treatment-
`
`Subject Disposition
`
`na'ive
`
`experienced
`
`
`
`lnvestigator’s discretion
`
`Lack of efficacy
`
`Lost to follow-up
`Pregnancy
`Protocol violation
`
`Subject non-compliance
`Withdrew consent
`
`Taking Study Drug at W24 Data Cut-off
`Source: ADSL dataset
`
`7.1.4 Analysis of Primary Efficacy Endpoint
`
`Study GS-US-216-0130 had no pre-specified primary efficacy endpoint.
`
`7.1.5 Analysis of Secondary Efficacy Endpoints
`
`Secondary efficacy endpoints include the proportion of subjects achieving HIV RNA <50
`copies/mL as determined by the FDA—defmed snapshot analysis at Weeks 24 and 48. This
`reviewer’s analysis of Week 24 efficacy results are displayed in Table 3 and match the
`Applicant’s analysis. As previously mentioned, the study is supportive but not pivotal, and
`efficacy in this single arm trial was a secondary endpoint.
`
`Table 3. GS—US—216-0130: Week 24 Efficacy Analysis (Snapshot Analysis, Full Analysis Set)
`Treatment-naive Treatment-
`Total
`
`HIV RNA Category
`
`(n=295)
`
`experienced (n=18)
`
`(n=313)
`
`
`
`Virologic Success at W24
`
`HIV RNA < so cImL
`95% Confidence Interval
`
`Virologic Failure at W24
`
`HIV RNA 3 50 c/mL
`Discontinued Study Drug and
`
`Last HIV RNA 2 50 c/mL
`
`No Virologic Data at W24 Window
`Discontinued Due to AE
`
`Discontinued Due to Other Reasons
`and Last HIV RNA < 50 c/mL
`
`247 (84%)
`79-88%
`
`29 (10%)
`
`17 (6%)
`12 (4%)
`
`19 (6%)
`14 (5%)
`
`3 (1%)
`
`Missing Data on Study Drug
`
`2 (<1%)
`
`11 (61%)
`36—83%
`
`7 (39%)
`
`5 (28%)
`2 (11%)
`
`258 (82%)
`78-87%
`
`36 (12%)
`
`22 (7%)
`14 (5%)
`
`19 (6%)
`14 (5%)
`
`3 (1%)
`
`2 (<1%)
`
`Source: ADEFFOUT dataset (Reviewer’s analysis)
`
`Overall, the results demonstrate reasonable ability of DRV/co plus 2 NRTIs to suppress HIV
`RNA at Week 24. Although full interpretation of efficacy is challenging without a comparator
`
`Page 6 of 21
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`Reference ID: 3676833
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`6
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`

`

`Clinical Review
`Sarita Boyd
`NDA 205395
`Prezcobix (darunavir/cobicistat)
`
`group, the results raise no general concerns about 24-week efficacy of DRV/co in treatment-
`naïve subjects. The treatment-experienced group is too small to interpret separately.
`
`Historically, the proportion of subjects with HIV RNA <50 copies/mL at Week 48 in
`treatment-naïve subjects randomized to DRV/r 800/100 mg once daily vs. lopinavir/ritonavir
`was 84% vs. 78%, respectively (Trial TMC114-C211). In Trial TMC114-C229 which
`enrolled treatment-experienced subjects with no DRV resistance-associated substitutions and
`randomized subjects to DRV/r 800/100 mg once daily or DRV/r 600/100 mg twice daily, 69%
`of subjects in both groups achieved HIV RNA <50 copies/mL at Week 48. Study GS-US-216-
`0130 results cannot be directly compared to historical controls given different time points of
`measure of virologic suppression (Week 24 vs. 48) and different trial designs (open-label,
`single arm vs. randomized, double-blind). Nonetheless, Study GS-US-216-0130 provides
`supportive data for DRV/co efficacy.
`
`7.1.6 Other Endpoints
`
`Subjects experienced considerable increases in CD4 cell count from baseline through Week 24
`with DRV/co plus 2 NRTIs. The mean (SD) increases from baseline CD4 cell count in
`treatment-naïve and -experienced subjects were 145 (132) cells/(cid:80)L and 99 (162) cells/(cid:80)L,
`respectively, at Week 24, based on observed data. The mean (SD) increases from baseline
`CD4% in treatment-naïve and -experienced subjects were 7.2% (4.5%) and 4.1% (3.3%),
`respectively.
`
`8. Safety
`
`Safety Summary
`
`Overall, there are no new safety concerns for DRV/co that were not previously assessed during
`the NDA reviews for DRV and COBI as single agents and included in the DRV or COBI
`labels. Safety information for DRV/co is available for 313 subjects (295 treatment-naïve and
`18 treatment-experienced) who received at least 1 dose of study drug in Study GS-US-216-
`0130. The most common AEs with DRV/co are generally consistent with either DRV/r once
`daily dosing or cobicistat-containing regimens, but the incidence of individual AEs cannot be
`directly compared across clinical trials because of the different trial designs. Interpretation of
`the incidence of AEs with DRV/co itself is also limited in an open-label, single-arm study.
`However, this trial supports safety of DRV/co.
`
`8.1 Methods
`
`The main source of data for the safety review is Study GS-US-216-0130, the ongoing Phase
`3b, open-label, single arm study. The treatment-naïve and -experienced groups were
`combined for the safety review because the treatment-experienced group was too small to
`
`Page 7 of 21
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`Reference ID: 3676833
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`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (danmavir/cobicistat)
`
`evaluate separately and the safety results are expected to be similar across both groups. The
`study results were reviewed as follows:
`
`0 Week 24 data analysis using JReview (data cut date August 16, 2012)
`0 Week 48 narrative review of available reports for deaths, nonfatal SAEs, and AEs
`leading to treatment discontinuation (data cut date July 1, 2013)
`
`0
`
`Safety update for new deaths and nonfatal SAEs (data cut date April 30, 2014)
`
`The Applicant also submitted results from Study GS-US-236-0118, a Phase 3 single-arm,
`open-label safety study in patients with mild to moderate renal impairment. In this trial
`subjects with eGFR calculated by the Cockcroft-Gault equation (eGFRCG) 50 to <90 mL/min
`enrolled in one of two cohorts to receive 96 weeks of treatment with Stribild (Cohort 1) or
`with DRV/co or ATV/co (Cohort 2). Subjects in Cohort 2 were virologically suppressed on
`DRV/r or ATV/r plus 2 NRTIs and had RTV replaced with COBI at baseline. In the Safety
`Update Report, the Applicant provided Week 48 interim analysis for subjects in Cohort 2;
`subjects who received DRV/co (n=21) are discussed in Section 8.4. For more details
`pertaining to the DRV/co group, please see the clinical review for NDA 203094 resubmission.
`
`8.2 Major Safety Results
`
`8.2.1 Deaths
`
`No deaths occurred in Study GS-US-216-0130.
`
`8.2.2 Nonfatal Serious Adverse Events (SAEs)
`
`A total of 15 (4.8%) subjects experienced a treatment-emergent SAE through Week 24. The
`most common SAE by System Organ Class (SOC) was “Infection and Infestation” occurring
`in 3 (1.0%) subjects. SAEs by preferred term (PT) reported in more than one subject were
`pyrexia and rash, which occurred in two subjects each. Investigators considered 3 (1.0%)
`SAEs related or possibly related to study drug: immune reconstitution syndrome, rash, and
`maculopapular rash. Table 4 lists all SAEs by PT.
`
`Table 4. All Treatment-Emergent SAEs Occurring in Study GS-US~216—Ol30
`Number of
`
`Preferred Term
`
`subjects (96)
`DRV/co (n=313)
`
`Number of subjects experiencing any treatment-emergent SAE
`
`15 (4.8%)
`
`
`
`PYREXIA
`
`ANAEMIA
`
`IDIOPATHIC THROMBOCYTOPENIC PU RPURA
`
`REI'INAL DETACHMENT
`
`GASTRITIS
`
`BILE DUCT STONE
`
`BILIARY DYSKINESIA
`
`CHOLECYSTITIS ACUTE
`
`2 (0.6%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`Page 8 of2l
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`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (danmavir/cobicistat)
`
`Table 4. All Treatment-Emergent SAEs Occurring in Study GS-US~216—0130
`Number of
`
`Preferred Term
`
`HYPERSENSITIVI‘IY
`
`IMMUNE RECONSTITUTION SYNDROME
`
`FURUNCLE
`
`PELVIC INFLAMMATORY DISEASE
`
`
`
`subjects (96)
`
`DRV/co (n=313)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`PILONIDAL CYST
`
`LACERATION
`
`CASTLEMAN'S DISEASE
`
`KAPOSI'S SARCOMA
`
`ALCOHOL ABUSE
`
`DRUG DEPENDENCE
`
`RASH
`
`RASH MACULO-PAPULAR
`
`Source: ADAE dataset using JReview (Reviewer’s Analysis)
`
`Subject 1541-4147 experienced immune reconstitution inflammatory syndrome (IRIS) that
`manifested as left eye zoster ophthalmicus and led to hospitalization approximately two
`months after initiating DRV/co and TDF/FTC. The event resolved with acyclovir treatment
`and continuation of study drug. Association of IRIS with initiation of ART is well known and
`labeled as a Warning and Precaution in the current DRV label.
`
`The serious, drug-related rash events are reviewed with the rash events that led to treatment
`discontinuation in Section 8.2.3 due to the similar nature of the reports.
`
`From Week 24 through the Safety Update Report, 25 additional subjects experienced any
`treatment-emergent SAE for a total of 40 (12.8%) subjects. No additional serious pyrexia or
`rash events occurred after Week 24. SAEs reported in more than one subject since the Week
`24 safety report were pneumonia, suicide attempt, and abdominal pain, all of which occurred
`in two subjects each and none of which were related to study drug according to the
`investigator. Overall, SAEs in 35 of 40 subjects were considered not related to study drug by
`the investigator; based on a review of all narratives, these assessments are reasonable.
`
`Since the safety report at Week 24, one subject (Subject 1780-4245) experienced ectopic
`pregnancy, which the investigator reported as having an unknown relationship to study drug
`exposure. The Applicant assessed the patient’s ectopic pregnancy as likely a background
`event, which is a reasonable assessment at this time. One subject (Subject 0729-4313)
`experienced myocardial infarction, which the investigator assessed as having an unknown
`relationship to study drug. The event occm'red ahnost two years after initiation of DRV/co and
`TDF/FTC in a 52-year-old male of African descent with hyperlipidemia and hypertension.
`Causality assessment is difficult, particularly with underlying cardiac risk factors.
`
`Page 9 of 21
`
`Reference ID: 3676833
`
`9
`
`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (darunavir/cobicistat)
`
`Two SAEs of suicide attempt prompted a review of all SAEs reported for the SOC Psychiatric
`Disorders. Table 5 describes the psychiatric-related SAEs, all of which had plausible alternate
`causes.
`
`Table 5: SAEs of Interest — Psychiatric Disorders Occurring in Study GS—US—216-0130
`Treat—
`Related
`
`ment
`d/c
`
`(lnvestigator/
`Reviewer)
`
`Possible Alternate
`Cause/Confounders
`
`Proposed
`labeling
`
`0754-4070
`
`Suicide attempt
`
`No / Unlikely
`
`1534-4305
`
`Suicide attempt
`
`No / Unlikely
`
`Recent discontinuation of
`bipolar medications
`
`Unspecified traumatic life
`events; under the influence
`
`of marijuana and ethanol at
`time of event
`
`1236-4291
`
`Suicidal ideation
`
`No / Unlikely
`
`Recent discontinuation of
`
`
`
`Depression .- multiplepsychiatric
`
`medications
`
`0754-4216
`
`Anxiety
`
`No / Unlikely
`
`Pre-existing anxiety and
`
`Stribild
`
`di=scontinuation
`
`Source. Narrative revien ofSAES through Week 48 (Rexzener’3 Analysis)
`
`8.2.3 Dropouts and/or Discontinuations
`
`A total of 15 (4.8%) subjects experienced an AB leading to discontinuation of study drug
`through Week 24. The most common AE leading to discontinuation of study drug by System
`Organ Class (SOC) was “Skin and Subcutaneous Disorders” occurring in 7 (2.2%) subjects.
`Additional AEs resulting in treatment discontinuation and occurring in more than one subject
`were hypersensitivity and nausea. Table 4 lists all AEs leading to study drug discontinuation
`by SOC and PT.
`
`Table 6. AB Leading to Study Drug Discontinuation in Study GS—US—216-0130
`
`ORV/co
`
`(N=313)
`
`_—
`
`Page 10 of 21
`
`Reference ID: 3676833
`
`10
`
`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (darunafir/cobicistat)
`
`Table 6. AB Leading to Study Drug Discontinuation in Study GS—US—216-0130
`
`
`NAUSEA
`2 (0.6%)
`
`(N=313I
`
`1 (0.3%)
`
`
`
`VOMITING
`
`—m)—
`
`—IIEEE—
`
`Source: ADAE dataset using JReview (Reviewer’s Analysis)
`
`Narratives for treatment discontinuations due to rash and hypersensitivity were very similar in
`nature and are discussed together (Subjects 2154-4111, 2843-4190, 0121-4113, 0407-4100,
`0589-4316, 0991-4067, 1950-4269, 1978-4069, 2157-4130). All subjects were also taking
`TDF/FTC. The investigator assessed these AEs as serious (medically significant) in two
`subjects, severe (Grade 3) in three subjects, and mild or moderate (Grade 1-2) in four subjects.
`Rash and hypersensitivity events assessed as serious or Grade 3 are described below.
`
`Subject 2843-4190
`A 33-year—old male developed a maculopapular rash on his thorax, arms, and legs on
`Day 11 afier initiating DRV/co and TDF/FTC. He was not taking any other
`medications. He stopped the study drugs and received diphenhydramine for 10 days
`until the rash resolved. The investigator assessed the rash as serious (medically
`significant), most likely related to DRV, and possibly related to FTC.
`
`Subject 0121-4113
`A 36-year—old male developed a diffilse rash that spread to the face on Day 7 afler
`initiating DRV/co and TDF/FTC. He was not taking any other medications. He
`received diphenhydramine, but the rash worsened from Grade 2 to Grade 3. He
`discontinued study drugs, and the rash resolved on Day 11. The investigator assessed
`the rash as related to DRV/co.
`
`Subject 0589—4316
`A 49-year—old female developed pmritus on her hands and feet on Day 24 after
`initiating DRV/co and TDF/FTC . On Day 25 the reaction progressed to a diffuse
`erythematous rash, some angioedema, and pruritus at which time study drugs were
`discontinued. Liver enzymes, white blood cell count, and eosinophil count were
`normal. The next day, the subject had no oral lesions, blistering, or noticeable
`angioedema. The subject received antihistamines and prednisone, and the event
`
`Page 11 of21
`
`Reference ID: 3676833
`
`11
`
`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (danmavir/cobicistat)
`
`resolved over a few days. The investigator assessed the event as Grade 3 and related to
`study medications.
`
`Subject 2157—4130
`A 24-year-old male developed a Grade 2 non-pruritic rash without oropharynx
`involvement on Day 10 after initiating DRV/co and TDF/FTC. Liver enzymes, white
`blood cell count, and eosinophil count were normal. He received antihistamines and
`continued study drugs. On Day 80 the subject experienced Grade 3 allergic dermatitis
`with unchanged laboratory results. He received methylprednisolone and discontinued
`study drugs, and the rash resolved on Day 86.
`
`There were no cases of Stevens—Johnson syndrome or toxic epidermal necrolysis. All nine
`events were related to study drug, most likely DRV and possibly COBI, and all resolved with
`discontinuation of DRV/co and treatment with antihistamines and/or corticosteroids. The
`
`events are consistent with the current labels for DRV and COBI as single agents.
`
`Since Week 24, two additional subjects discontinued study drug due to an AB, one of which
`was the aforementioned anxiety event listed in Table 5 in Section 8.2.2. The second AE
`resulting in treatment discontinuation was proximal renal tubulopathy in a subject (Subject
`1236-4051) also taking TDF/FTC. The event is consistent with the proximal renal tubulopathy
`events seen with COBI and TDF (in combination with either EVG or ATW and labeled for
`COBI.
`
`8.3 Supportive Safety Results
`
`8.3.1 Common Adverse Events
`
`All tables in this section were produced in JReview using the ADAE dataset and represent this
`reviewer’s analyses.
`
`Table 7 provides an overview of treatment—emergent clinical ABS by severity and relatedness.
`Four of the five subjects with Grade 3—4 study drug-related AEs experienced rash (2) or
`hypersensitivity (2).
`
`Table 7. Overview of Treatment-Emergent AEs Occurring in Study GS—US-216-0130
`Number of
`
`5 (1.6%)
`
`subjects (96)
`
`DRV/co (n=313)
`
`275 (87.9%)
`
`139 (44.4%)
`
`18 (5.8%)
`
`123 (39.3%)
`
`42 (13.4%)
`
`Treatment-Emergent AE
`
`Any AE
`
`Any AE Grade 2-4
`
`Any AE Grade 3-4
`
`Any Study Drug-Related AE
`
`Any Study Drug-Related AE Grade 2-4
`
`Any Study Drug-Related AE Grade 3-4
`
`Page 12 of 21
`
`Reference ID: 3676833
`
`12
`
`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezeobix (danmavir/cobicistat)
`
`The most common AEs by SOC irrespective of grade or causality were Gastrointestinal
`Disorders (52%), Infections and Infestations (49%), and Skin and Subcutaneous Tissue
`Disorders (28%). The most common ABS by PT irrespective of grade or causality reported in
`25% of DRV/co-treated subjects included diarrhea, nausea, upper respiratory tract infection,
`headache, rash, vomiting, fatigue, flatulence, nasopharyngitis, and sinusitis.
`
`Table 8 lists Grade 2-4 ABS by PT regardless of causality and occurring in at least 2% of
`subjects. The Applicant’s grouped terms for rash did not include dermatitis, dermatitis
`allergic, drug eruption, rash vesicular, or urticaria. Addition of these rash terms resulted in a
`slightly higher percentage of rash events.
`
`Table 8. Treatment-Emergent AEs by Preferred Term Regardless of Causality
`
`Occurring in At Least 2% of Subjects in Study GS-US-216-0130
`
`Number of
`
`Preferred Term
`RASH (Reviewer’s Grouped Termsl)
`RASH (Applicant’s Grouped Termsz)
`DIARRHEA (Applicant's Grouped Termsa)
`UPPER RESPIRATORY TRACT INFECTION
`
`NAUSEA
`
`
`
`subjects (96)
`
`DRV/co (n=313)
`21 ( 6.7%)
`18 ( 5.8%)
`16 ( 5.1%)
`11 ( 3.5%)
`
`10 ( 3.2%)
`
`l Dermatitis. Dermatitis allergic, Drug eruption, Generalized erythema. Rash, Rash erythematous,
`Rash generalized. Rash macular, Rash maculo-papular. Rash morbilliform, Rash papular. Rash
`pruritic, Rash vesicular. Urticaria
`2 Generalized erythema, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-
`papular, Rash morbilliform, Rash papular. Rash prun'tic
`3 Diarrhea. Frequent bowel movements
`4 Hypersensitivity. Drug hypersensitivity
`
`Table 9 lists Grade 2-4 ABS by PT at least possibly attributed to study drug by the investigator
`and occurring in at least 2% of subjects. Both versions of grouped terms for rash resulted in an
`equal number of events. The terms are consistent with drug-related AEs in the DRV and
`COBI labels.
`
`Page 13 of 21
`
`Reference ID: 3676833
`
`13
`
`

`

`Clinical Review
`
`Sarita Boyd
`NDA 205395
`
`Prezcobix (danmavir/cobicistat)
`
`Table 9. Treatment-Emergent Drug-Related AEs by Preferred Term Occurring in At
`Least 2% of Subjects in Study GS—US-216-0130
`
`Preferred Term
`
`Number of
`
`subjects (96)
`
`ORV/co (n=313)
`
`
`
`27( 45%)
`
`27( 4.5%)
`
`7(2-2%)
`
`5(1-6%)
`
`1 Dermatitis. Dermatitis allergic, Drug eruption, Generalized erythema, Rash. Rash erythematous.
`Rash generalized, Rash macular. Rash maculo-papular, Rash morbilliform, Rash papular. Rash
`pruritic, Rash vesicular. Urticaria
`2 Generalized erythema. Rash, Rash erythematous. Rash generalized. Rash macular, Rash maculo-
`papular, Rash morbilliform, Rash papular. Rash pruritic
`3 Diarrhea. Frequent bowel movements
`
`8.3.2 Laboratory Findings
`
`The laboratory analysis in Table 10 reflects treatment-emergent laboratory abnormalities that
`increased at least one toxicity grade from baseline. Individual subjects are counted once for
`each laboratory abnormality, with the maximum toxicity grade reported. Missing baseline
`values are assumed to be Grade 0.
`
`Interpretation of the incidence of laboratory abnormalities with DRV/co is limited in an open-
`label, single-arm study, but no new safety concerns emerged through Week 24 in this study.
`Grade 3-4 liver or pancreatic enzyme abnormalities were not associated with clinical AEs,
`including pancreatitis, in any subject. No subject had concurrent ALT and bilirubin elevations
`consistent with Hy’s law criteria; and Grade 3 triglyceride elevations were not associated with
`pancreatitis.
`
`The percentage of subjects who experienced Grade 1 serum creatinine elevations is consistent
`with the known safety profile of cobicistat. A similar percentage of Grade 1 serum creatinine
`elevations occurred in clinical trials with cobicistat and atazanavir (see Dr. Peter Miele’s
`Clinical Review for the original cobicistat NDA).
`
`Grade 3-4 neutropenia was not associated with any clinically significant or related AEs,
`including infections. One subject experienced Grade 4 thrombocytopenia, which was
`associated with the SAE idiopathic thrombocytopenic purpura noted in Section 8.2.2 and was
`considered