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`BRISTOL-MYERS SQUIBB COMPANY
`
`BMS-201038
`
`INVESTIGATOR BROCHURE
`GENERAL ADDENDUM
`
`BRISTOL-MYERS SQUIBB PHARMACEUTICAL
`RESEARCH INSTITUTE
`P.O. Box 4000
`Princeton, NJ 08543-4000 USA
`
`This Investigator Brochure contains information that is confidential and
`proprietary to Bristol-Myers Squibb (BMS).
`
`Addendum Date: October 11 1997
`
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`October 1, 1997
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`Bristol-Myers Squibb: Proprietary Information
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`Page47
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`matched placebo. One subject who received 1 OD mg of BMS-201038 had six
`AE's, one of which was severe; these were all in association with a vasovagal
`reaction and felt by the investigator to be unrelated to study drug. Another
`subject had eight AE1s; all appeared to be in association with an upper
`
`respiratory infection. The remaining 11 adverse events were minor complaints
`
`such as lightheadedness, weakness, salty taste, or nausea and considered by
`
`the investigator in each case to be unassessable as to causal relationship to
`study drug administration. There were two laboratory AE1s of an increased CK
`in one subject and asymptomatic pyuria in two others. 27
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`3.1.2 CV145-002, Multiple Dose PO
`
`In this protocol, 36 hypercholesterolemic (fasting total cholesterol of ~200
`
`mg/dL) healthy volunteers were recruited in four groups of nine subjects each to
`receive in an ascending fashion doses of BMS-201038 of 101 251 50 or 1 OD mg
`or matched placebo capsules QD for 14 days. Due to AE's (predominantly
`gastrointestinal AE1s) 1 subjects in the 100 mg group were discontinued at Day 8 .
`All subjects entered for a seven day dietary lead-in with an AHA Step I diet
`
`which was maintained throughout the study. Within each group six subjects
`
`received active drug and three subjects received placebo.
`
`In the course of the
`
`study plasma samples for analysis of BMS-201038 1 BMS-203304 and BMS-
`Plasma
`203215 were obtained at specified
`time points post-dosing.
`
`concentrations of BMS-203304 were predominant. The mean T % for both BMS-
`
`203334 and BMS-203215 was approximately 21 hours. The accumulation index
`(Al) for the parent compound was calculated from AUC1au Day 14/AUC13u Day 1.
`At doses of 25 mg QD there was no significant accumulation of BMS-201038.
`
`BMS-201038 had a marked dose and time related effect an cholesterol and
`
`triglycerides. By Day 14 the mean fasting LDL cholesterol at 25 mg QD
`
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`October 1 , 1997
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`Bristol-Myers Squibb: Proprietary Information
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`Page48
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`compared to baseline was -56% 1 at 50 mg QD - 73% (mean placebo -1%) and
`on Day 8of100 mg QD - 82% (mean placebo - 8%). The mean triglycerides at
`
`25 mg QD on Day 14 were - 12% from baseline, at 50 mg QD - 54% (mean
`
`placebo -2%) and on Day 8 of 100 mg QD - 62% (mean placebo +54% }.
`
`Additional pharmacodynamic measures were also performed. These included
`
`Magnetic Resonance
`
`Imaging
`
`(MRI) and Nuclear Magnetic Resonance
`
`Spectroscopy (NMRS) of the liver, techniques which use no ionizing radiation, to
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`assess for potential accumulation of hepatic fat content which may occur as an
`
`extension of the pharmacologic effect. These procedures were performed at
`
`baseline before dosing and at end of the study. The spectroscopic results
`
`indicate that in comparison with baseline and with placebo, there appeared to be
`
`some increase in hepatic fat content at all doses. Preliminary results from the
`
`NMRS data indicate for the dose groups 1 O mg, 25 mg and 50 mg QD x 14 days,
`
`the mean hepatic fat content at baseline was in the range of 1.9% and at the end
`
`of the study was in the range of 8.8%. Following the discontinuation of dosing at
`
`100 mg QD 1 an additional MRl/NMRS was obtained on Day 8. There was a
`clear indication that fat accumulation had occurred after eight days of dosing;
`
`when measured again at Day 14 there was virtually no change from Day 8.
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`There were no SAE's. A total of 111 AE's were reported, 95 in the treated groups
`
`and 16 in the placebo group. Most of these events occurred pre-dosing, were
`
`judged by the investigator as unrelated to administration of BMS-201038 or
`
`matched placebo, or the same AE was reported on multiple occasions for a
`
`subject. The frequency of AE's was dose-related: three in the 25 mg QD group,
`
`26 at 50 mg QD group, and 57 at 100 mg QD group.
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`October 1, 1997
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`Bristol-Myers Squibb: Proprietary Information
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`Page49
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`Of the 95 AE's in the drug treated groups, 72 were gastrointestinal in origin
`including nausea, flatulence, abdominal cramping and loose stools or diarrhea.
`
`In association with these symptoms, subjects complained of gaseousness or
`flatulence type symptoms with some associated abdominal cramping. After a
`
`week of dosing at 100 mg QD the subjects were discontinued from dosing due to
`
`intolerable adverse -gastrointestinal effects. One subject was discontinued for a
`
`five-fold increase in ALT. The investigator reported that all symptoms and signs
`resolved within a week following discharge.28
`
`0
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`3.1.3 CV145-003, Single Dose IV
`
`In this protocol, 32 hypercholesterolemic healthy volunteers were recruited in
`
`four groups of eight subjects each to receive in an ascending fashion single IV
`
`doses of BMS-201038 of 7.5, 15, 30 or 60 mg or matched placebo administered
`
`as a constant rate 30 minute IV infusion. All subjects entered for a two day lead(cid:173)
`
`in with an AHA Step I diet which was maintained throughout the study. Within
`
`each group six subjects received active drug and two subjects received placebo .
`
`Plasma samples for analysis of BMS-201038, BMS-203304 and BMS-203215
`
`were obtained at specified time points for 72 hours post-dosing. Concentrations
`
`of BMS-203304 were predominant. The mean T ~ for BMS-201038 was
`
`approximately 25 hours.
`
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`Several pharmacodynamic measures of BMS-201038 on lipid lowering were
`
`obtained by frequent post dose monitoring of lipid profiles; including frequent
`
`post dose triglycerides, cholesterol, LDL-C, HDL-C, VLDL-C and Apo B. BMS-
`
`201038 had a marked dose- and time-related effect on cholesterol and
`
`triglyceride lowering. The mean post dose LDL-C at 60 mg was reduced by
`
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`4 of 4
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`PENN EX. 2058
`CFAD V. UPENN
`IPR2015-01836