Cougar Biotechnology, Inc.
`
`Abiraterone Acetate
`November 17, 2010
`Clinical Study Report: COU-AA-001 and COU-AA-001 EXT
`__________________________________________________________________________________________
`
`SYNOPSIS
`
`Sponsor:
`Cougar Biotechnology, Inc
`
`(For National Authority
`Use only)
`
`Individual Study
`Table
`Referring to Part
`of the Dossier
`Volume:
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`Page:
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`Name of Finished Product:
`TBD
`Name of Active Ingredient:
`Abiraterone Acetate
`Study Title:
`COU-AA-001
`An open label Phase I/II study to evaluate the safety and efficacy of an oral 17 α -
`hydroxylase and C17,20-lyase inhibitor, abiraterone acetate, administered daily to castrate
`males with chemotherapy-naïve castration refractory prostate cancer (HRPC) with a rising
`PSA (prostate specific antigen) despite hormonal therapy
`COU-AA-001 EXT
`An expanded access open-label study of CB7630 (abiraterone acetate) in patients with
`advanced prostate cancer who have completed CB7630 clinical study COU-AA-001
`Investigator(s) and Study Center(s):
`Investigator: Johann De Bono, PhD
`Co-Investigators: Dr. Gerhardt Attard
`
`Professor Ian Judson
`
`Professor David Dearnaley
`
`Dr. Chris Parker
`Study Center: Institute of Cancer Research, Royal Marsden Hospital, Sutton, UK
`Publication (reference): see Appendix 12.1.11
`Studied Period:
`COU-AA-001
`23 November, 2005 (first subject enrolled) to
`20 November, 2008 (last subject completed)
`COU-AA-001 EXT
`20 July, 2007 (first subject enrolled) to
`Ongoing
`Study Phase: Phase 1/2
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`Confidential
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`Page 1 of 6
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`MYLAN PHARMS. INC. EXHIBIT 1095 PAGE 1
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`

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`Cougar Biotechnology, Inc.
`
`Abiraterone Acetate
`November 17, 2010
`Clinical Study Report: COU-AA-001 and COU-AA-001 EXT
`__________________________________________________________________________________________
`
`Objectives for COU-AA-001:
`Primary Objective:
`• To evaluate the safety, tolerability, and recommended dose of abiraterone acetate
`administered orally by continuous once-daily administration in patients with HRPC.
`• To evaluate the activity of abiraterone acetate in HRPC at recommended dose. (PSA
`working group (PSAWG) criteria and, in patients with measurable disease, RECIST
`criteria was utilized.
`Secondary Objectives:
`• To evaluate the pharmacokinetic profile of abiraterone acetate
`• To determine the effect of abiraterone acetate on the pituitary-adrenal-gonad endocrine
`axis and on adrenal hormones by evaluating serum levels of testosterone and its
`precursors
`• To estimate duration of PSA and objective tumor response
`Objectives for COU-AA-001 EXT:
`Primary Objective:
`• To provide access to abiraterone acetate for patients who have completed 12 cycles of
`abiraterone acetate treatment and continue to receive clinical benefit from such a
`treatment.
`Secondary Objectives:
`• To evaluate the safety of abiraterone acetate.
`• To evaluate the efficacy of abiraterone acetate.
`Methodology:
`Both protocols, COU-AA-001 and COU-AA-001 EXT, were open-label, one-arm,
`single-center studies.
`COU-AA-001 consisted of the Dose Escalation Stage (Phase 1) and the Activity Evaluation
`Stage (Phase 2).
`Dose escalation Stage (Phase 1): Based on the conventional three to six evaluable patients
`per dose cohort used for dose escalation and PK studies, 18 patients participated in this study.
`The starting dose for the dose escalation phase was 250 mg. If no Common Criteria
`Terminology for Adverse events (CTCAE) grade 3 toxicity was documented in the first 28
`days of continuous daily dosing in a dose escalation cohort, the dose was then escalated to
`500, 750, 1000 and finally 2000 mg/day.
`Phase 1 also included exploratory Food Effect assessments.
`Efficacy (Activity) Evaluation Stage (Phase 2): A two-stage Attained design study was
`performed. A total of 36 patients with HRPC were recruited to assess the activity of daily
`continuous abiraterone acetate dosing. The PSA response rate following three cycles, 12
`weeks, of abiraterone acetate was determined.
`In addition, this study was designed prospectively to allow the addition of dexamethasone
`(0.5 mg daily) to abiraterone acetate in all patients at disease progression to test the
`hypothesis that drug resistance could be reversed by suppressing ACTH and the 21 carbon
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`Confidential
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`Cougar Biotechnology, Inc.
`
`Abiraterone Acetate
`November 17, 2010
`Clinical Study Report: COU-AA-001 and COU-AA-001 EXT
`__________________________________________________________________________________________
`
`steroids upstream of the CYP17 drug target in the steroid biosynthesis pathway.
`All patients without disease progression after completion of 12 months of therapy (the
`maximum treatment period in COU-AA-001), were offered the choice to participate in a
`protocol extension (COU-AA-001 EXT), which permitted continuation of the study
`medications abiraterone acetate with dexamethasone or prednisolone until disease
`progression
`COU-AA-001 EXT
`Patient continued with the same dose/regimen administered at the end of study COU-AA-001
`until disease progression or the time when abiraterone acetate (CB7630) became available
`through local healthcare provider(s) or development programs cease to exist.
`Number of Subjects (Planned and Analyzed):
`COU-AA 001
`Forty-seven patients were planned in the protocol. A total of 54 patients were enrolled.
`COU-AA-001 EXT
`Thirty patients that completed COU-AA-001 continued on to COU-AA-001 EXT.
`From both studies combined, data from 54 patients were analyzed.
`Diagnosis and Main Criteria for Inclusion:
`For COU-AA-001 the main criterion was patients with chemotherapy-naïve hormone
`refractory prostate cancer (HRPC) who have failed LHRH analogue and/or antiandrogen
`therapy.
`For COU-AA-001 EXT the main criterion was the patients should have participated in the
`COU-AA-001 study.
`Test Product, Dose and Mode of Administration, Lot Number:
`Abiraterone acetate administered orally as 250 mg capsules. The lot numbers of abiraterone
`acetate used for Study COU-AA-001 were 0244A, 0356A, 0063B, 0272B, 0244B, 0357B,
`9407001, 0043C, 0079C, 0118C, 0133C, 0180C, 0299C, 0224C, 0113C, and 0252C.
`The lot numbers of abiraterone acetate used for Study COU-AA-001EXT were 0133C,
`0166C, 0252C, 0299C, 0224C, 0329C, and 0355C.
`Duration of Treatment:
`Patients in COU-AA-001 were treated for 12 cycles and each cycle was 28 days.
`Patients in COU-AA-001 EXT will be treated until CB7630 (abiraterone acetate) becomes
`available through local healthcare provider(s) or development programs cease to exist.
`Reference Therapy, Dose and Mode of Administration, Lot Number:
`Not applicable
`Criteria for Evaluation (COU-AA-001 and COU-AA-001EXT):
`Primary for COU-AA-001:
`Confirmed, objective PSA (according to PSAWG criteria) response rate resulting from
`abiraterone acetate therapy. All patients achieving a fall in PSA of >50% from baseline,
`confirmed by a second measurement at least 4 weeks after, fulfilled the criteria for PSA
`response
`Primary for COU-AA-001EXT
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`Confidential
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`Cougar Biotechnology, Inc.
`
`Abiraterone Acetate
`November 17, 2010
`Clinical Study Report: COU-AA-001 and COU-AA-001 EXT
`__________________________________________________________________________________________
`
`Serum PSA decline evaluation according to PSAWG criteria
`Secondary for COU-AA-001:
`• Objective response by RECIST criteria (CR/PR) in patients with measurable disease
`• Duration of response, by PSA and RECIST criteria
`• Time to disease progression, as assessed by time from start of therapy to the onset of the
`earliest PSA progression and evidence of disease progression according to RECIST
`criteria
`1. PSA progression as defined by PSAWG
`2. Evidence of disease progression according to RECIST criteria
`3. One bone scan at least 6 months subsequent to baseline demonstrating 2 or more new
`skeletal lesions
`4. An event due to metastatic prostate cancer requiring intervention (evidence of disease
`at the site is required
`5. Survival
`
`Safety:
`Safety was assessed for adverse events and laboratory data. Safety analyses included all
`patients enrolled into the study who received at least one dose of abiraterone acetate.
`Adverse events were summarized by System Organ Class and Preferred Term using
`MedDRA version 11.0. In addition, adverse events leading to the discontinuation from study
`were summarized. The severity of AEs was graded on a scale of 1 to 5 according to the NCI
`Common Terminology Criteria for Adverse Events (CTCAE version 3.0). Shift table
`analyses for select hematology variables (hemoglobin, hematocrit, platelets, white blood
`cells, and neutrophils, PT, and PTT) were performed summarizing the number of patients
`with shifts outside the normal ranges.
`Statistical Methods:
`All statistical analyses were performed using SAS® version 9 or higher. All confidence
`interval for the estimation will be reported using 2-sided 95% confidence intervals.
`Descriptive statistics were reported for all safety data. Unless otherwise specified, all
`continuous endpoints were summarized using descriptive statistics, which included the
`number of patients with a valid measurement (n), mean, standard deviation (SD), median,
`minimum, and maximum.
`All categorical endpoints were summarized using frequencies and percentages. Percentages
`(e.g. PSA response rate) were calculated by dividing the number of subjects with the
`characteristic of interest by the number of subjects in the analysis population. The 95%
`confidence interval was also calculated using the exact (Clopper-Pearson) confidence limits.
`Time-to-event endpoints were analyzed using Kaplan-Meier estimates of survival
`distributions and the median time-to-event. Kaplan-Meier estimates of the median time
`taken to reach the event was estimated with confidence intervals being calculated using the
`Brookmeyer-Crowley method.
`Pharmacokinetic Variables:
`A total of evaluable 12 patients were studied. Patients enrolled in cohorts 1-3 were
`
`Confidential
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`Cougar Biotechnology, Inc.
`
`Abiraterone Acetate
`November 17, 2010
`Clinical Study Report: COU-AA-001 and COU-AA-001 EXT
`__________________________________________________________________________________________
`
`administered a single dose of abiraterone acetate on Day -7, with PK blood samples being
`taken 1, 2, 4, 6, 8, 24, 48 and 72 hours post-dose for analysis and pre-dose on Day 1, Day 8
`and Day 15 Cycle 1, Day 1 Cycle 2 and Day 1 Cycle 3.
`Patients enrolled in cohorts 4 to 5 were administered two single doses of abiraterone acetate
`separated by 6 days to evaluate the effects of food on bioavailability.
`Summary of Results
`Pharmacokinetic:
`Following an oral dose of abiraterone acetate at 250 mg (N=3), 500 mg (N=4), 750 mg
`(N=3), 1000 mg (N=9) or 2000 mg (N=3), no abiraterone acetate was detected in vivo.
`Abiraterone pharmacokinetic parameters showed variability between patients. Maximum
`drug concentration (Cmax) was reached between 1.03 – 6.00 hr post doses across all cohorts.
`The mean terminal half-life was relatively consistent between cohorts (9.5 – 12.0 hr). Mean
`clearance values ranged from 494.3 – 1347.2 L/hr. Mean drug exposure (AUC) and Cmaxdid
`not increase linearly with dose.
`A significant difference was observed between the administration of drug with or without
`food (p = 0.004, 1000 mg cohort; p = 0.049, 2000 mg cohort). In the 1000 mg cohort (food
`effect study) a 2.8 fold difference in mean Cmax drug levels was observed between the
`dosing regimes, while in the 2000 mg cohort a 3.4 fold difference was observed.
`Efficacy:
`The primary activity end-point of confirmed PSA response (decline of ≥ 50% from baseline)
`following three cycles of treatment showed that 60% of the patients had confirmed response.
`Total (confirmed and unconfirmed) PSA decline of ≥50% was observed in 69.0%.
`With regard to the secondary endpoint of maximal PSA response rates approximately 64% of
`the patients showed ≥ 50% decline in PSA levels.
`The median time to PSA Progression was 330 days (95% CI: 197, 530). The median time to
`PSA response duration was 141 days (95% CI: 85, 235). Post baseline best tumor response
`for patients with measurable and non-measurable disease was measured. Eight (19.0%)
`patients showed partial response and 28 (66.7%) patients had stable disease. Two (4.8%) had
`progressive disease.
`Baseline ECOG was 0 in 25 (59.5%) patients. Of the 17 patients with ECOG 1 at baseline,
`8/17 (47.1%) improved to ECOG PS 0. All together, 34 patients maintained their ECOG
`score.
`Safety:
`In summary, adverse events were reported in 54 (100 %) patients for all the safety population
`analyzed. The most common (≥ 5%) AEs reported by 53 (98.1%) patients were
`hypokalaemia experienced by 75.9% (41 patients), fatigue by 46.3 % (25 patients) and
`hypertension by 33.3% (18 patients). The majority of these adverse events were grade 1 or 2.
`In the Dose Escalation Stage, most of the AEs reported by the patients were grade 1 and 2.
`Twenty-one patients (38.9%) had grade 3 AEs and three (5.6%) patients had grade 4 AEs.
`Ten (18.5%) patients had of grade 3 treatment-related AEs and 1 (1.9%) patient had grade 4
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`Confidential
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`

`

`Cougar Biotechnology, Inc.
`
`Abiraterone Acetate
`November 17, 2010
`Clinical Study Report: COU-AA-001 and COU-AA-001 EXT
`__________________________________________________________________________________________
`
`treatment-related AEs. A total of five patients with six adverse events discontinued from
`study, and four of the six AEs were considered treatment related.
`Serious adverse events were reported in 24 (44.4%) patients. Of the 52 SAEs reported, 18
`(33.3%) were reported by the investigator as treatment-related and 34 (65.4%) were reported
`as unrelated to study drug. The majority of these events were grade 3. Twenty-five of the 53
`SAEs were reported as recovered.
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`Confidential
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`Disclaimer
`
`Information in this posting shall not be considered to be a claim for any marketed
`product. Some information in this posting may differ from, or not be included in,
`the approved labeling for the product. Please refer to the full prescribing
`information for indications and proper use of the product.
`
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