October 27, 1999
`Volume 68 • Nu:maer 8
`
`graft PV
`
`recipient PV
`(a)
`
`(b)
`
`(c)
`
`OVERVIEW
`The human bone marrow as an immunoregulatory organ
`j. Miller,j. Mathew, R. Garcia-Morales, K.E. Zucker, M. Carreno,Y.jin, L. Fuller, G.w. Burke,
`G. Ciancio,AG. Tzakis, C. Ricordi, L. Olson, A Rosen, D. Roth, and V. Esquenazi
`ANALYSES AND COMMENTARIES
`The rejection of neural xenotransplants: a role for antibodies?
`R.A Barker, S.B. Dunnett, and A Richards
`Maximizing the benefits of HLA matching for renal transplantation:
`alleles, specificities, CREGs, epitopes, or residues?
`c.J. Taylor and P.A Dyer
`Hepatitis Clinks hepatologists, nephrologists and transplant
`surgeons
`O. Crosbie ana G.Alexander
`
`Persistence of donor antigen is necessary for maintenance of
`xenotolerance -
`a parallel to allogeneic systems?
`B.R. Rosengard and A Shaked
`
`Contents and other information available 1
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY Of
`MEDICINE
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`NOVARTIS EXHIBIT 2054
`Par v Novartis, IPR 2016-00084
`Page 1 of 8
`
`

`
`0041-1337/99/6808-1100/0
`'TRANSPLANTATION
`Copyright <D 1999 by Lippincott Williams & Wilkins, Inc.
`A PHASE I STUDY OF A 4-WEEK COURSE OF SDZ-RAD (RAD) IN
`QUIESCENT CYCLOSPORINE-PREDNISONE-TREATED RENAL
`TRANSPLANT RECIPIENTS 1,2
`BARRY D. KAHAN,3 ROBERT L. WONG,4 CATHERINE CARTER,3 STEPHEN H. RAn,3
`JANET VON FELLENBERG,4 CHARLES T. VAN BUREN,3 AND SILKE ApPEL-DINGEMANSE5
`
`Vol. 68, 1100-1106, No.8, October 27, 1999
`Printed in U.S.A.
`
`Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School,
`Houston, Texas 77030; Novartis Pharmaceuticals, East Hanover, New Jersey 07936; and Novartis Pharma AG,
`Basel 4002, Switzerland
`
`Background and Methods. This phase I, randomized,
`blinded, placebo-controlled study assessed the safety
`profile and pharmacokinetics of a 4-week course of
`once-daily, sequential ascending doses (0.75, 2.5, or 7.5
`mg/day) of SDZ-RAD (RAD) capsules in renal trans-
`plant recipients on a stable regimen of cyclosporine
`(CsA; Neoral®) and prednisone.
`Results. RAD displayed a similar spectrum of side
`effects as observed with rapamycin, namely, an in-
`creased incidence of infection associated with the aug-
`mented immunosuppression and a dose-related occur-
`rence of thrombocytopenia, hypercholesterolemia,
`and hypertriglyceridemia, particularly at the 7.5-mg
`dose. The pharmacoldnetic parameters of RAD
`showed dose proportionality, a good correlation be-
`tween trough and area under the curve (AUC) concen-
`trations, and a moderate accumulation of 2.5-fold. The
`drug was absorbed within 2 hr and displayed a 16-
`19-hr half-life, which is shorter than that of rap amy-
`cin. RAD reached steady state at 4 days. Preliminary
`kinetic-dynamic correlations indicate a correlation
`between thrombocytopenia (but not hyperlipidemia)
`and AUC, as well as maximum drug concentrations,
`and weight-adjusted dose. At the end of a 4-week
`course of simultaneous dosing, there was no evidence
`of a pharmacokinetic interaction between CsA and
`RAD.
`Conclusion. This study suggests that the shorter
`half-life of RAD compared to rapamycin may confer
`the benefits of rapid attainment of steady state and
`dissipation of effects upon drug cessation. Controlled,
`multicenter trials are being planned to assess the im-
`pact of these features on clinical outcomes.
`
`tion 40 on the rapamycin (RAPA) structure. RAD was devel-
`oped in an attempt to improve the pharmacokinetic charac-
`teristics of RAPA, particularly to increase the extent and
`reproducibility of its oral bioavailability, and to reduce the
`extensive tissue distribution by virtue of its greater polarity.
`RAD not only displays immunosuppressive properties, but
`also exerts a synergistic interaction with cyclosporine (CsA)
`to delay the acute rejection of heterotopic rat heart allografts
`(1, 2), as well as to alter the pace of rejection in a variety of
`other organ transplant models (3). Furthermore, RAD inter-
`rupts the proliferative responses of vascular and bronchial
`smooth muscle cells (4, 5). Shortly after completion of a
`German study of the tolerability and pharmacokinetics of
`ascending single doses of RAD (up to 25 mg) in stable renal
`transplant recipients (6), the present randomized, double-
`blind, placebo-controlled, ascending, multiple-dose study was
`initiated to evaluate the tolerability and pharmacokinetics of
`a 4-week course of RAD capsules in quiescent renal trans-
`plant recipients. This study sought particularly to assess the
`incidence and severity of the drug's adverse effects, including
`myelodepression and hyperlipidemia, as well as its pharma-
`cokinetic properties and its pharmacodynamidpharmacoki-
`netic interactions with CsA.
`
`PATIENTS AND METHODS
`Study design. The study, which was approved by our Institutional
`Committee for the Protection of Human Subjects (CPHS), was de-
`signed to include 24 evaluable subjects, namely, three cohorts of
`eight patients each (six RAD, two placebo). Entry criteria included a
`quiescent status of patients, aged 18-65 years, who were at least 6
`months past transplant, under treatment with the same CsA dose
`(Neoral®) for at least 3 months, and a daily dose of :0;15 mg of
`prednisone. Patients were excluded from participation if they dis-
`played baseline laboratory values indicating myelosuppression (he-
`moglobin <10 g/dl, white blood cell count <4000/mm3
`, or platelet
`count <150,000/mm 3); an episode of acute rejection within the pre-
`vious 3 months; evidence of chronic rejection; liver, pulmonary, or
`cardiac disease; abuse of recreational drugs; or co-administration of
`medications affecting the cytochrome P450 3A4 system. Each patient
`signed an informed consent form that was approved by the CPHS.
`After screening and selection for study entry, patients underwent
`a 4-week course of treatment with test medication. Patients were
`domiciled on the first day and last day (day 28) of the study for the
`purpose of performing RAD and CsA pharmacokinetic profiles. In
`
`SDZ-RAD (RAD*) is an immunosuppressive macrolide
`bearing a stable 2-hydroxyethyl chain substitution at posi-
`1 Presented at the 17th Annual Meeting of the American Society of
`Transplant Physicians, May 11, 1998, Chicago, IL.
`2 This work was supported by grant 38106-12 from the National
`Institute of Diabetes and Digestive Kidney Diseases and by a grant
`from Novartis Pharmaceuticals.
`3 Division of Immunology and Organ Transplantation, Depart-
`ment of Surgery, University of Texas Medical School.
`·1 Novartis Pharmaceuticals.
`5 Novartis Pharma AG.
`* Abbreviations: AUC, area under the concentration-time curve;
`AUC/s, AUC over a single-dose interval at steady state; Cuv, average
`atinine phosphokinase; CsA, cyclosporine; FSH, follicle-stimulating
`whole blood concentration; CuvS", average whole blood concentration
`hormone; LH, luteinizing hormone; In, logarithmic; r, accumulation
`at steady state; Cmux, maximum concentration; Cmu/s, maximum
`ratio; RAD, SDZ-RAD; RAPA, rapamycin; tmox , time to reach maxi-
`concentration at steady state; Cmin, trough concentration; Cmin"S,
`, time to reach maximum concentration at
`trough concentration at steady state; COl'" trough concentration; mum concentration, tma/
`CPHS, Committee for the Protection of Human Subjects; CPK, cre-
`steady state; Az ' terminal phase; t 112, terminal phase half-life.
`1100
`
`s
`
`This material was~".pied
`at the N LM a nd may tee
`5ubject US Copyright Laws
`
`NOVARTIS EXHIBIT 2054
`Par v Novartis, IPR 2016-00084
`Page 2 of 8
`
`

`
`October 27, 1999
`
`KAHAN ET AL.
`
`1101
`interval, AUC/" (0-24 hr for RAD, 0-12 hr for CsA), were calculated
`using the linear trapezoidal rule. The average whole-blood concen-
`tration (C,,/S) was derived from the relationship C,ws8 =AUC/"!T,
`with T denoting the dosing interval in hours. The accumulation ratio
`(r) was calculated using r=CminS8/C24hr, where C2.Jhr is the concen-
`tration at 24 hr after the first RAD dose (8).
`Statistical assessments. All safety analyses were performed on
`the safety population, which consisted of all randomized patients
`who received at least one dose of RAD and underwent at least one
`safety/tolerability assessment after baseline. Summary statistics
`were provided for the baseline demographics of age, weight, and
`height. Sex and race were summarized by means of frequency dis-
`tributions. Prior/concomitant (including immunosuppressive) medi-
`cation information was provided by treatment group and drug class.
`The daily dose of Neoral® (adjusted by body weight) at baseline, and
`the average daily dose over the period from baseline to each visit
`after initiation of study medication, were summarized by treatment
`group. Similarly, summary statistics by treatment group were pro-
`vided for corticosteroids expressed in doses equivalent to prednisone.
`Actual value, corresponding baseline, and absolute change from
`baseline were summarized by treatment group for the laboratory/
`electrocardiograms/vital signs data at each visit day during the
`treatment period, at all posttreatment visits, and at endpoint. End-
`point was defined as the last postbaseline observation within the
`treatment/posttreatment period (day 39). All safety summaries were
`based OIl the scheduled day rather than the actual day of visit; an
`unscheduled visit was allocated to the nearest scheduled visit. The
`incidence rates of all treatment emergence adverse events were
`summarized by body system and by treatment group.
`Adverse events and percentage of change from baseline laboratory
`determinations were stratified based on the RAD dose or concentra-
`tion as compared to placebo. Two approaches were used to assess the
`dose proportionality of RAD pharmacokinetics. Both the Cmux and
`the AUC, after either the first dose or at steady state (day 28), were
`subjected to conventional linear regression against the RAD dose
`(0.75-7.5 mg) to estimate the intercept and the slope (9). If the 95%
`confidence interval of the intercept of the regression line included
`zero, the pharmacokinetics of RAD were considered not to deviate
`from dose proportionality. In addition, a one-factor analysis of vari-
`ance (ANOVA) was performed on dose-normalized, logarithmically
`(In) transformed parameters, with RAD dose levels as the source of
`variation. The data for each subject and for each cohort were exam-
`ined for the presence of a clinical steady state of RAD using linear
`regression analysis of the consecutive HAD concentrations between
`days 4 and 29. When the slope was not significantly different from
`zero, the patient was believed to be in steady state.
`Linear regression analysis also was used to evaluate the associa-
`tion between demographic characteristics, such as body weight and
`age, and RAD pharmacokinetics. In the former instance, the vari-
`ability of pharmacokinetic parameters was compared between the
`observed and the body weight-adjusted data based on the Pitman-
`Morgan procedure for testing correlated variances (10). The pharma-
`cokinetic parameters of RAD were additionally assessed for both
`genders using t-tests. To explore the effects of multiple doses ofRAD
`on the steady state pharmacokinetics ofCsA, ANOVA was performed
`on In-transformed data from CsA pharmacokinetic profiles after
`administration of CsA alone, as compared with co-administration
`with RAD or placebo. These studies, which included time (Neoral®
`given alone and co-administered with RAD or placebo), the RAD dose
`(0, 0.75, 2.5, or 7.5 mg), and the time-dependent interaction with
`HAD dose as sources of variation, sought to examine whether any
`impact ofRAD was dose- or time-dependent. In addition, the changes
`in CsA Cmin"" during the protocol treatment were evaluated by linear
`regression (days 0-39).
`A kinetics-dynamics analysis was performed using a logistic re-
`gression model to predict the probability of a laboratory abnormality,
`given one of the pharmacokinetic parameters. Laboratory abnormal-
`ities analyzed included the incidence of platelet count <100,000/
`
`addition, patients were seen on seven interim outpatient visits (days
`2,4,8, 13, 19,24, and 26), and on two postadministration visits (days
`29 and 39). In no instance was the observation time more than 72 hr
`different from the study schedule. To estimate the terminal half-life
`ofRAD at steady state, blood samples were collected from patients on
`days 31, 34, 36, and 38 for drug concentration measurements.
`Drug formulations. Study medication was provided by Novartis
`Pharmaceuticals Corporation in the form of hard-gelatin, yellow,
`opaque capsules containing either placebo or RAD in doses of 0.75,
`2.5, or 7.5 mg. RAD was administered once daily in the morning. The
`CsA (Neoral®; 7) twice-daily dose was not changed during the entire
`study, having been individualized to produce a 350:!:50 ng/ml aver-
`age concentration (Cn), namely, the quotient of the area under the
`concentration-time curve (AUC) (ngXhr/m!) and the dosing interval
`(in hours). After an overnight fast of 12 hr, Neoral®, together with
`RAD or placebo, was administered concomitantly at 8 a.m. with 250
`ml of water. Patients undergoing pharmacokinetic profiling fasted
`for an additional 4 hr after dose, while those undergoing outpatient
`blood sampling took their breakfast 1 hr later. Except for mandatory
`administration of trimethoprim-sulfamethoxazole, the protocol did
`not stipulate any alterations to the maintenance drug regimen.
`Safety assessments. A physical examination was performed at
`screening and at the end of the study. Vital signs were measured at
`all steady visits through day 39, and ECG evaluations were obtained
`at all study visits through day 28. Laboratory determinations, in-
`cluding hematology and blood biochemistry measurements for urea,
`creatinine, electrolytes, liver enzymes, cholesterol, triglycerides, cre-
`atine phosphokinase (CPK), follicle-stimulating hormone (FSH), lu-
`teinizing hormone (LH), and testosterone, were also evaluated at
`each scheduled visit (except for days 2 and 26). An independent
`board composed of two physicians experienced in treating kidney
`transplantation patients evaluated safety summaries and adverse
`events. Serious adverse events were defined as those requiring hos-
`pital admission.
`Methods of measuring RAD and CsA. Whole blood samples for the
`determination of RAD (1.5 m!) and CsA (2 m!) were collected into
`tubes containing ethylenediaminetetraacetic acid via a catheter in-
`serted into a forearm vein. On days 1 and 28, pharmacokinetic
`profiles included samples taken before and at 0.25, 0.5, 0.75, 1, 1.5,
`2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hr after drug
`administration. On days 4, 8,13,19,24,26,29,31,34,36,38, and 39,
`additional predose blood samples were drawn in the morning. CsA
`pharmacokinetic profiles included whole blood samples collected just
`before and at 0.5, 1, 1.5,2,2.5,3,3.5,4,4.5,5,6,8, 10, and 12 hr after
`Neoral® administration alone at baseline between 3 days and 1 day
`before HAD administration, and at day 28 after co-administration of
`RAD or placebo. Samples were immediately frozen and stored below
`-20°C until analysis.
`RAD concentrations were quantified by means of a high-perfor-
`mance liquid chromatography/atmospheric pressure chemical ion-
`ization/mass spectrometry method (7). 'l'he limit of quantitation was
`0.333 ng/ml. CsA concentrations in whole blood were measured using
`a commercially available radioimmunoassay kit (Cyclo-Trac®, INC-
`STAR Corp., Stillwater, MN), the limit of quantification of which was
`23 ng/ml.
`Pharmacokinetic analysis. Standard noncompartmental methods
`were used to evaluate the whole-blood concentration-time profiles of
`RAD after single (day 1) or once-daily multiple doses (day 28), as well
`as the profiles of CsA before and 28 days after RAD treatment (8).
`Parameters assessed at steady state (for RAD at day 28) are desig-
`nated with the superscript "ss." The maximum plasma concentration
`(Cmu/"), the time to reach Cmux (t mux "H), and the trough concentration
`at steady state before the morning dose (Cmin"8), were obtained by
`direct measurement. The rate constant associated with the terminal
`phase (ll) and its corresponding half-life (t1l2) were calculated by
`least-squares linear regression analysis from the log-linear terminal
`slope of the washout kinetics of the last RAD dose on day 28. The
`areas within concentration-time curves measured over a single-dose
`
`.j.
`
`.~
`
`>
`
`This material was co-pied
`at the NLM and may bE
`~ubject US Copyright Laws
`
`NOVARTIS EXHIBIT 2054
`Par v Novartis, IPR 2016-00084
`Page 3 of 8
`
`

`
`Vol. 68, No.8
`
`1102
`TRANSPLANTATION
`mm3, incidence of platelet count decline from baseline >50,000/mm3,
`changes over the time of RAD treatment. Although daily
`administration of O. 75-mg doses produced no greater change
`incidence of leukocyte count <3,000/mm3, incidence of triglycerides
`> 10 mmoVL (>386 mg/dI), and incidence of total cholesterol >5
`than placebo, higher RAD doses produced significant in-
`mmoVL (>443 mg/dI). The pharmacokinetic parameters used to pre-
`creases in blood lipid levels. At the end of a treatment course
`dict laboratory abnormalities were AUe, Gmax, and weight-adjusted
`with 2.5 or 7.5 mg of RAD, the serum cholesterol values had
`dose.
`increased 89.5% and 54.9%, respectively (Fig. lA), and trig-
`lycerides, 459% and 159%, respectively (Fig. IB). There were
`no significant changes in other blood chemistries-including
`the serum creatinine, calculated creatinine clearance, blood
`urea nitrogen, or uric acid, CPK, FSH, LH, and testoster-
`one-among RAD-treated compared with placebo-treated pa-
`tients (data not shown). The incidence of patients who
`showed an increase in serum creatinine >30% above baseline
`at any time during the study was 33.3%, 33.3%, 57.1%,
`42.1%, and 50% for the 0.75-mg, 2.5-mg, 7.5-mg, all RAD, and
`placebo-treated patients, respectively. For these respective
`groups, the mean and standard deviation (SD) (% change)
`values at the end of treatment were 1.5±0.78 (13.2),
`1.45±0.51 (12.6), 1.89±0.75 (28.1), 1.63±0.69 (18.5), and
`1.57±0.61 (-3.1), and at 11 days after the end of treatment
`were 1.35±77 (5), 1.18±0.70 (-13.3), 1. 73±0.64 (23),
`1.44±0.70 (6), and 1.57±0.61 (-3).
`Whereas no significant changes in white blood cell and
`platelet counts occurred among patients treated with either
`0.75 or 2.5 mg of RAD compared with placebo, individuals
`treated with 7.5-mg doses of RAD showed significant mean
`changes from baseline values, namely, -2.6% and -51.4%,
`respectively, at the nadir day 19 (Fig. 2). The cell counts
`improved spontaneously; drug was not withheld from any
`patient. In contrast, changes in the erythroid series were not
`significant, save for one thrombocytopenic patient who be-
`came anemic (seemingly independent of obvious bleeding
`except for purpura).
`Pharmacokinetics of RAD. Figure 3A shows the entire set
`of mean and SD values of whole-blood concentrations ofRAD
`in patients treated with once-daily doses of 0.75, 2.5, or 7.5
`mg for 28 days. The mean trough concentrations (COhr) from
`days 2 to 28 are shown in Figure 3B, and the full concentra-
`tion-time curves after the first (day 1) and last dose (day 28)
`are shown in Figure 3 (C and D). The derived pharmacoki-
`netic characteristics of RAD are summarized in Table 3.
`RAD was absorbed rapidly with mean t max values ranging
`across dose levels from 1.3 to 1.8 hr for the first dose, and
`from 1.5 to 2 hr at steady state. Steady-state (day 28) Cmuxss,
`Cmins., Cuvss, and AUC/s showed dose proportionality; the
`
`RESULTS
`Demographics of the study populations. Table 1 summa-
`rizes the prestudy features of the 25 patients who entered
`this study; the additional patient was entered into the high-
`est dose group as a replacement for one subject, who, after 1
`week of therapy, had to discontinue the study owing to in-
`tercurrent pneumonia. There were no obvious differences
`between the demographic characteristics or the doses of base-
`line immunosuppressive drugs administered to patients
`treated with RAD or placebo. The overall population was
`slightly biased toward males and toward cadaver renal allo-
`graft recipients, and heavily biased toward non-black pa-
`tients. The range of immunosuppressive drug doses, namely,
`3-4 mg/kg Neoral® and 5-12.5 mg prednisone, was custom-
`ary for a maintenance population (11).
`Adverse clinical events. Table 2 summarizes the clinical
`adverse events by body system, including every event that
`occurred at least once in either the placebo or the active drug
`arm. Virtually every patient in the study displayed at least
`one adverse event. Forty-three percent of patients treated
`with the highest RAD dose (7.5 mg) experienced serious
`adverse events. One subject suffered leg pain, purpura, nau-
`sea, vomiting, and anemia; a second, multiple herpetic oral
`lesions; and a third (discontinued) patient, pneumonia.
`Among all RAD groups, there was an increased incidence of
`infectious episodes, including herpes simplex (n=3), upper
`respiratory infection (n=3), pharyngitis (n=3), and one case
`each of pneumonia and sinusitis, presumably reflecting, at
`least in part, the enhanced immunosuppression resulting
`from the addition of RAD to the CsA-based regimen. There
`was an increased incidence of adverse events involving the
`gastrointestinal system, namely, diarrhea (n=3), nausea
`(n=3), and vomiting (n=2), that were probably related to
`drug administration. There were no significant increase in
`the systolic, diastolic, or mean blood pressure values among
`patients treated with RAD versus placebo.
`Drug-induced abnormalities in laboratory values. Only
`the serum triglycerides and total cholesterol concentrations
`among all the blood chemistry values showed significant
`
`TAnLE 1. Pre study features of the stable renal transplant patients receiving multiple doses of RAD or placebo"
`RAD dose (mg/day)
`2.5 (n=6)
`7.5 (n=7)
`4/2
`4/3
`54 (31-68)
`43 (25-61)
`6/0
`6/1
`1.5 (0.5-2.1)
`5.7 (0.6-15.2)
`1/5
`2/5
`33.3
`42.9
`3.7:!:0.61
`3.7:!:0.42
`399:!:60
`402:!:89 b
`9.2:!:3.42
`8.6:!:3.70
`
`0.75 (n=6)
`Gender (male/female)
`3/3
`Age (mean [range])
`50 (40-58)
`Race (non-blacklblack)
`4/2
`3.5 (1.1-6.0)
`'l'ime after transplant (mean years [range])
`Donor source (living-related donor/cadaveric)
`2/4
`Diabetics (%)
`66.7
`Initial esA dose (mean mglkg:!:SD)
`3.3:!:0.42
`Initial esA Gav (mean [ng/ml] :!:SD)
`310:!:58
`Prednisone dose (mean [mg/day]:!:SD)
`8.1:!:2.20
`a None of the differences were statistically significant.
`b The esA values for the 7.5-mg dose and the overall group reflect the 6 patients that completed the study and, for the aggregate of all
`doses, the 18 patients that completed the study.
`
`Placebo (n=6)
`
`4/2
`43 (28-56)
`6/0
`2.5 (0.6-6.2)
`1/5
`33.3
`3.5:!:0.56
`326:!:88
`8.8:!:3.45
`
`Characteristic
`
`All doses (n= 19)
`11/8
`49 (25-68)
`16/3
`3.4 (0.5-15.2)
`5/14
`47.4
`3.6:!:O.49
`367:!:78"
`8.6:!:2.82
`
`Th is materia I was co'pied
`at th,e N LM a nd may b,e
`~ubje{t US Copyright Laws
`
`NOVARTIS EXHIBIT 2054
`Par v Novartis, IPR 2016-00084
`Page 4 of 8
`
`

`
`October 27, 1999
`
`KAHANET AL.
`
`1103
`
`Body system
`
`TABLE 2. Adverse events by body system among stable renal transplant patients treated with RAD or placeboa
`Incidence of adverse events (%)
`RAD dose (mg/day)
`2.5 (n=6)
`7.5 (n=7)
`0.75 (n=6)
`At least one event
`100
`100
`66.7
`Cardiovascular
`33.0
`43.0
`0
`14.3
`New onset hypertension
`0
`0
`57.1
`Central and peripheral nervous system
`66.7
`50.0
`57.1
`Gastrointestinal
`0
`50.0
`Metabolic/nutritional
`14.3
`50.0
`16.7
`28.6
`Musculoskeletal
`33.3
`33.3
`71.4
`Infection
`16.7
`66.7
`Respiratory
`57.7
`16.7
`50.0
`42.9
`Skin and appendages
`16.7
`33.3
`42.9
`Body as a whole
`16.7
`0
`a Only adverse events occurring in two or more RAD-treated patients in at least one group are shown.
`
`All doses (n=19)
`89.5
`26.3
`5.3
`57.9
`36.8
`26.3
`31.6
`52.6
`42.7
`31.6
`21.1
`
`Placebo
`(n=6)
`
`83.3
`0
`16.7
`83.3
`16.7
`16.7
`16.7
`16.7
`16.7
`0
`16.7
`
`___ 0.75
`---a-- 2.5
`-fr-- 7.5
`
`~r--r--r-~--~-.--~------~~~~ P
`4
`6
`13
`19
`24 26
`39 Endpoint
`Days
`
`___ 0.75
`
`--9--- 2.5
`-fr-- 7.5
`
`100.0
`
`80.0
`
`60.0
`
`40.0
`
`20.0
`
`0.0
`
`-20.0
`
`A
`
`OJ
`.~
`ID
`(J) ro
`aJ
`E ,g
`OJ rn
`c:
`ro
`.<::
`()
`rl-
`
`B
`
`4
`
`8
`
`13
`
`24 28
`19
`Days
`
`500.0
`OJ 400.0
`.!:
`ill
`(J) 300.0
`ro
`aJ
`E 200.0
`,g 100.0
`OJ
`0> c:
`0.0
`ro
`.<::
`() -100.0
`rl-
`
`A
`
`60.0
`
`20.0
`
`0.0
`
`OJ
`.~ 40.0
`ill
`UJ ro
`aJ
`E ,g
`OJ
`0> -20.0
`c: ro
`.<::
`() -40.0
`rl-
`
`-60.0
`
`B
`
`2.0
`
`0.0
`
`OJ
`.!: 1.0
`ID
`(J) ro
`aJ
`E
`,g
`0> c: ro
`
`-1.0
`
`OJ
`
`.<::
`()
`~ 0
`
`-2.0
`
`-3.0
`
`___ 0.75
`-e- 2.5
`-fr-- 7.5
`"""*- p
`39 Endpoint
`
`___ 0.75
`
`-e- 2.5
`-fr-- 7.5
`
`-200.0 ~r-~--~~--~~~-.------~~~~P
`4
`8
`13
`19
`24 26
`39 Endpoint
`Days
`FIGUHE 1. Relation of changes in serum lipids to RAD dose: mean
`percentage of change from the baseline in the values of serial deter-
`minations of cholesterol (A) or of triglycerides (B) among patients
`treated with placebo (x), 0.75 mg ofRAD (0),2.5 mg ofRAD (0), or
`7.5 mg ofRAD (6) throughout the 28-day treatment period and for 14
`days thereafter (endpoint).
`
`39 Endpoint
`
`4
`
`8
`
`13
`
`19
`
`24 28
`Days
`FIGURE 2. Relation of peripheral blood cell counts to RAD dose over
`time. Mean percentage of change from baseline in the number of
`platelets (A) or white blood cells (B) among patients treated with
`placebo (x), 0.75 mg of RAD (0), 2.5 mg of RAD (0), or 7.5 mg of
`RAD (6) throughout the 28-day treatment period and for 14 days
`thereafter.
`
`intercepts of the concentration-dose plots were not signifi-
`cantly different from zero (data not shown). Also, Table 3
`shows that the values of these parameters when dose-nor-
`malized did not differ significantly (P=0.50, P=0.25, P=0.30,
`and P=0.08, respectively). There was evidence of drug accu-
`mulation of up to 2.5-fold for the 0.75-mg daily dose only
`(Table 3).
`Steady state appeared to be reached at day 4, based upon
`linear regression analysis of the Cmin values of individual
`subjects from days 4 to 29, as well as graphic inspection of
`
`Figure 3. There was a strong correlation between the predose
`whole-blood RAD trough concentration and the steady-state
`AUCTsS (r2 =0.9045 for AUCTsS compared to COh/s, and
`/"2=0.9274 for AUCTsS compared to C24hr"s; Fig. 4). The phar-
`macokinetic profile of RAD after the last dose on day 28
`(washout kinetics) indicated linearity in the terminal phase
`(Fig. 3A), with the mean t1l2 ranging between 16 and 19 hr. In
`the present study, there did not appear to be a correlation
`between body weight or age with RAD Cmnx or AUC (data not
`
`This material was HJpied
`atthe NLM and may be
`~ubject US Copyright Laws
`
`NOVARTIS EXHIBIT 2054
`Par v Novartis, IPR 2016-00084
`Page 5 of 8
`
`

`
`1104
`
`A
`1000
`
`:;
`~ 100 .
`,s
`c o
`~
`~ 10
`
`1~
`
`N
`o (f)
`
`~ .~'fI
`
`TRANSPLANTATION
`
`Vol. 68, No.8
`
`B
`
`20
`
`18
`
`16
`14 -
`12
`
`10
`
`A
`
`600
`
`500
`
`:::J
`E
`0, 400
`
`.c e-o 300
`:J «
`0 200
`~
`~ 100
`
`Cf)
`
`B
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`a 2 4 6 8 10 12 14 16 18
`2 4 6 8 10 12 14 16 18
`SDZ-RAD COh (ng/mL)
`SDZ-RAD C24h (ng/mL)
`FIGURE 4. Linear correlation between the pharmacokinetic param-
`eters on day 28 of HAD after a 4-week treatment regimen of once-
`daily doses of 0.75 (D), 2.5 (0), or 7.5 mg (6) (n=6 per dose levell. (A)
`AUC/s vs. COhr"" (Po;O.OI, 1'2=0.9045). (E) AUC/" compared to
`C2.1hr"" (Po;O.OI, 1'2=0.9274).
`
`cohorts) of dose-normalized Cmux S3 and AUC/" of RAD were
`not significantly altered by body-weight normalization.
`Lack of impact of concomitant RAD therapy on steady-state
`CsA concentrations. Compared with placebo, co-administra-
`tion of once-daily doses of 0.75, 2.5, or 7.5 mg ofRAD for 28
`days did not affect the steady-state pharmacokinetics of CsA
`given as Neoral®. There was an observed increase in Cmax"s
`and AUC 7 83 ofCsA upon co-administration with RAD. Figure
`5 shows that, for placebo and for each of the RAD doses (0.75,
`2.5, and 7.5 mg), the ratios of CsA Cmax"s were 1.17±0.42,
`1.31±0.32, 1.41±0.32, and 1.28±0.29, and, for CsA AUCss,
`1.20±0.31, 1.19±0.14, 1.26±0.23, and 1.17±0.28, respective-
`ly-values that were similar to the baseline of 1.17±0.3.
`There was no apparent relationship between RAD dosage
`and the increase in the CsA pharmacokinetic parameters; the
`90% confidence intervals of the Cmllx"B and AUC/s ratios
`included 1.0 for both the placebo and 7.5-mg RAD dose levels.
`
`0.1-'--,,-, 'I " 'I " 'I " 'I " .1 " .1 ,..,....,
`o 4
`8 12 16 20 24 28 32
`Study Days
`
`o 4
`
`6
`
`I
`
`I
`
`i
`I · j
`J
`12 16 20 24 26 32
`Study Days
`
`C
`
`100
`
`0
`
`:;
`.§
`S c
`~ 60 -
`" u c
`0
`0
`0
`~
`N
`0
`(f)
`
`80 -
`
`40 -
`
`20
`
`o
`100
`
`80 -
`
`60
`
`40
`
`24
`
`20
`16
`12
`20
`16
`12
`Time Post-dose (hr)
`Time Post-dose (hr)
`FIGURE 3. Whole-blood concentration-time profiles ofRAD after oral
`once-daily multiple administrations of 0.75 ( D), 2.5 (0), or 7.5 mg
`(6). (A) All measured drug concentrations displayed on a semiloga-
`rithmic scale. (El Daily COhr values on a linear scale. (C and D)
`Linear presentations of the pharmacokinetic data on day 1 and day
`28, respectively (mean + SD, n=6 per dose levell.
`
`24
`
`'fABLE 3. Pharmacokinetic parameters of RAD
`Mean value:!: SD at RAD dose:
`0.75 mg/day 2.5 mg/day 7.5 mg/day
`
`Parameter
`
`Day 1
`tmux (hr)
`Cmux (ng/mll
`AUC0-2.1h (hrXng/mD
`Day 28
`tmux"s (hr)
`Cmux"" (ng/mll
`CminS" (ng/mll
`Cu/" (ng/mll
`AUC/" (hrXmg/mll
`t1l2 (hr)
`I'
`Cmu/B/mg (ng/mlxmg- 1)
`Cminss/mg (ng/mlxmg- 1)
`Cu/"/mg (ng/mIXmg-l)
`AUC/"/mg (hrXng/mIXmg- 1)
`
`1.8:t0.5
`7.6:t3.1
`44:t 15
`
`1.3:t0.5
`1.3:t0.3
`31.4:t8.5 82.8:t22.8
`161±38
`398±88
`
`2.0±0.3
`8.3 :t3.4
`1.4:t0.7
`2.8±1.1
`67±26
`19.2:t3.4
`2.5:t0.8
`11.1±4.5
`1.9:t0.9
`3.8±1.4
`90:t35
`
`1.5±0.3
`1.8±0.8
`77:tll
`33:t 12
`4.4:t2.0
`7.9:t3.2
`19:t6
`8.8±3.5
`465±138
`211:t83
`18.1±7.6 16.0±5.6
`1.4:t0.5
`1.1:t0.4
`13.3:t4.7 10.3±1.5
`1.8±0.8
`1.1±0.4
`2.6±0.8
`3.5± 1.4
`62:t18
`84:t33
`
`shown). RAD pharmacokinetic characteristics also did not
`differ between male and female patients (P=0.4912 for
`CmuxS3 and P=0.4313 for AUC/B). In addition, intersubject
`variabilities (the percent coefficient of variation across all
`
`0
`
`0
`
`0
`
`t:,.
`
`t:,.,
`
`A
`200
`
`~ 180
`
`~ 160
`'"
`ro
`iE:l 140
`>-
`'"
`'; 120
`~
`a:
`~ 100
`E
`0
`"ili
`0
`
`80
`
`Q) g: °1
`f! 1
`
`B
`200
`
`~ 180
`
`Q)
`
`120
`
`~ 160
`'"
`ro
`<0 140
`'"
`0
`~
`a:
`100
`0
`:::>
`«
`"ili 80
`0
`
`t:,.
`
`t:,.
`
`'" 1 >-
`
`o
`
`0
`0
`
`60
`
`60
`
`40
`20
`80 100
`60
`600
`400
`200
`SDZ-RAD Cmax (ng/mL)
`SDZ-RAD AUC (ng x hr/mL)
`FIGURE 5. Effect on CsA drug concentrations of a 4-week course of
`once-daily treatment with RAD (0.75 [0]' 2.5 [0], and 7.5 mg [6]) or
`placebo ( 0 ). (A) Cmux ratios at day 28 vs. baseline of CsA concentra-
`tions after co-administration ofRAD. (B) AUC ratios after co-admin-
`istration of RAD. X denotes the mean, and the error bars, the 90%
`confidence interval.
`
`Th is mate ria I was H}pied
`at the NLM and may bE
`~ubject US Copyright Laws
`
`NOVARTIS EXHIBIT 2054
`Par v Novartis, IPR 2016-00084
`Page 6 of 8
`
`

`
`October 27, 1999
`
`KAHAN ETAL.
`
`Furthermore, examination of the median CsA COhl" values in
`each placebolRAD cohort over 39 days failed to reveal a trend
`over time by linear regression analysis, save for a 12% in-
`crease in the median value among patients treated with 2.5
`mg. Although the majority of individual data (71% of the
`patients) failed to show a change over time in the slope of the
`regression line, the 29% of patients who did show differences
`were represented among all dosing cohorts, with no apparent
`differences by distribution based upon gender, body weight,
`race, age, or extremes of RAD Cmax ss or AUC/s.
`Pharmacokinetic 1 pharmacodynamic analyses. Table 4
`shows the results of a logistic regression analysis between
`pharmacodynamic covariates and pharmacokinetic parame-
`ters. The AUCS" appeared to be the most useful predictor of
`the probability that the platelet count drops below 100,0001
`mm3 (P=0.05). However, for reducti