NEUPOGEN~ (Filgrastim)
`
`DESCRIPTION
`
`Filgrastim is a human granulocyte colony stimulating factor (G-CSF), produced by
`recombinant DNA technology. NEUPOGEN~ is the Amgen Inc. trademark for
`Filgrastim, which has been selected as the name for recombinant methionyl human
`granulocyte colony stimulating factor (r-metHuG-CSF).
`
`NEUPOGEN is a 175 amino acid protein manufactured by recombinant DNA
`technology.1 NEUPOGEN is produced by Escherichia coli (E coli) bacteria int~ which
`has been inserted the human granulocyte colony stimulating factor gene. NEUPOGEN
`has a molecular weight of 18,800 daltons. The protein has an amino acid sequence that is
`identical to the natural sequence predicted from human DNA sequence analysis, except for
`the addition of an N-terminal methionine necessary for expression in E coli. Because
`NEUPOGEN is produced in E coli, the product is nonglycosylated and thus differs from
`G-CSF isolated from a human cell.
`
`NEUPOGEN is a sterile, clear, colorless, preservative-free liquid for parenteral
`administration. Each single-use vial of NEUPOGEN contains 300 mcg/mL of Filgrastim
`at a specific activity of 1.0 -v 0.6 x 108 U/mg, (as measured by a cell mitogenesis assay).
`The product is formulated in a 10 mM sodium acetate buffer at pH 4.0, containing 5%
`sorbitol, and 0.004% Tween® 80. The quantitative composition (per mL) of
`NEUPOGEN is:
`
`Filgrastim
`
`Acetate
`
`Sorbitol
`
`Tween® 80
`
`Sodium
`
`Water for Injection
`USP q.s. ad
`
`300 mcg
`
`0.59 mg
`
`50.0 mg
`
`0.004%
`
`0.035 mg
`
`1.0 mL
`
`1072
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0001
`
`

`
`CLINICAL PHARMACOLOGY
`Colony Stimulating Factors
`
`Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding
`to specific cell surface receptors and stimulating proliferation, differentiation commitment,
`and some end-cell functional activation.
`
`Endogenous G-CSF is a lineage specific colony stimulating factor which is produced by
`monocytes, fibroblasts, and endothelial cells. G-CSF regulates the production of
`neutrophils within the bone marrow and affects neutrophil progenitor proliferation,2’3
`differentiation,2’4 and selected end-cell functional activation (including enhanced
`phagocytic ability,5 priming of the cellular metabolism associated with respiratory burst,6
`antibody dependent killing/and the increased expression of some functions associated
`with cell surface antigens8). G-CSF is not species specific and has been shown to have
`minimal direct in vivo or in vitro effects on the production ofhematopoietic cell types
`other than the neutrophil lineage.
`
`Preclinical Experience
`
`Filgrastim was administered to monkeys, dogs, hamsters, rats, and mice ’as part of a
`preclinical toxicology program which included single-dose acute, repeated-dose subacute,
`subchronic, and chronic studies. Single-dose administration of Filgrastim by the oral,
`intravenous (IV), subcutaneous (SC), or intraperitoneal (IP) routes resulted in no
`significant toxicity in mice, rats, hamsters, or monkeys. Although no deaths were
`observed in mice, rats, or monkeys at dose levels up to 3450 mcg/kg or in hamsters using
`single doses up to approximately 860 mcg/kg, deaths were observed in a subchronic (13-
`week) study in monkeys. In this study, evidence of neurological symptoms was seen in
`monkeys treated with doses of Filgrastim greater than 1150 mcg/kg/day for up to 18 days.
`Deaths were seen in five of the eight treated animals and were associated with 15- to 28-
`fold increases in peripheral leukocyte counts, and neutrophil-infiltrated hemorrhagic foci
`were seen in both the cerebrum and cerebellum. In contrast, no monkeys died following
`13 weeks of daily IV administration of Filgrastim at a dose level of 115 mcg/kg. In an
`ensuing 52-week study, one 115 mcg/kg dose female monkey died atter 18 weeks of daily
`IV administration of Filgrastim. Death was attributed to cardiopulmonary insufficiency.
`
`In subacute, repeated-dose studies, changes observed were attributable to the expected
`pharmacological actions of Filgrastim (ie, dose-dependent increases in white cell counts,
`increased circulating segmented neutrophils, and increased myeloid:erythroid ratio in bone
`marrow). In all species, histopathologic examination of the liver and spleen revealed
`evidence of ongoing extramedullary granulopoiesis; increased spleen weights were seen in
`all species and appeared to be dose-related. A dose-dependent increase in serum alkaline
`
`2
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0002
`
`

`
`phosphatase was observed in rats, and may reflect increased activity of osteoblasts and
`osteoclasts. Changes in serum chemistry values were reversible following discontinuation
`of treatment.
`
`In rats treated at doses of 1150 mcg/kg/day for 4 weeks (5 of 32 animals) and for 13
`weeks at doses of 100 mcg/kg/day (4 of 32 animals) and 500 mcg/kg/day (6 of 32
`animals), articular swelling of the hind legs was observed. Some degree of hind leg
`dysfunction was also observed; however, symptoms reversed following cessation of
`dosing. In rats, osteoclasis and osteoanagenesis were found in the femur, humerus,
`coccyx, and hind legs (where they were accompanied by synovitis) after IV treatment for
`4 weeks (115 to 1150 mcg/kg/day), and in the sternum after IV treatment for 13 weeks
`(115 to 575 mcg/kg/day). These effects reversed to normal within 4 to 5 weeks following
`cessation of treatment.
`
`In the 52-week chronic, repeated-dose studies performed in rats (IP injection up to 57.5
`mcg/kg/day), and cynomolgus monkeys (IV injection of up to 115 mcg/kg/day), changes
`observed were similar to those noted in the subacute studies. Expected pharmacological
`actions of Filgrastim included dose-dependent increases in white cell counts, increased
`circulating segmented neutrophils and alkaline phosphatase levels, and increased
`myeloid:erythroid ratios in the bone marrow. Decreases in platelet counts were also noted
`in primates. In no animals tested were hemorrhagic complications observed. Rats
`displayed dose-related swelling of the hind limb, accompanied by some degree of hind
`limb dysfunction; osteopathy was noted microscopically. Enlarged spleens (both species)
`and livers (monkeys), reflective of ongoing extramedullary granulopoiesis, as well as
`myeloid hyperplasia of the bone marrow, were observed in a dose-dependent manner.
`
`Pharmacologic Effects of NEUPOGEN
`
`In phase 1 studies involving 96 patients with various nonmyeloid malignancies,
`NEUPOGEN administration resulted in a dose-dependent increase in circulating
`neutrophil counts over the dose range of 1 to 70 mcg/kg/day.911 This increase in
`neutrophil counts was observed whether NEUPOGEN was administered IV (1 to 70
`mcg/kg twice daily),9 SC (1 to 3 mcgikg once daily),1~ or by continuous SC infusion (3 to
`11 mcgikg/day).1° With discontinuation of NEUPOGEN therapy, neutrophil counts
`returned to baseline, in most cases within 4 days. Isolated neutrophils displayed normal
`phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic
`[measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine
`(fMLP) as the chemotaxin] activity in vitro.
`
`The absolute monocyte count was reported to increase in a dose-dependent manner in
`most patients receiving NEUPOGEN, however, the percentage ofmonocytes in the
`differential count remained within the normal range. In all studies to date, absolute counts
`of both eosinophils and basophils did not change and were within the normal range
`following administration of NEUPOGEN. Increases in lymphocyte counts following
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0003
`
`

`
`NEUPOGEN administration have been reported in some normal subjects and cancer
`patients.
`
`White blood cell (WBC) differentials obtained during clinical trials have demonstrated a
`shift towards earlier granulocyte progenitor cells (left shift), including the appearance of
`promyelocytes and myeloblasts, usually during neutrophil recovery following the
`chemotherapy-induced nadir. In addition, Dohle bodies, increased granulocyte
`granulation, as well as hypersegmented neutrophils have been observed. Such changes
`were transient, and were not associated with clinical sequelae nor were they necessarily
`associated with infection.
`
`Pharmacokinetics
`
`Absorption and clearance of NEUPOGEN follows first-order pharmacokinetic modeling
`without apparent concentration dependence. A positive linear correlation occurred
`between the parenteral dose and both the serum concentration and area under the
`concentration-time curves. Continuous IV infusion of 20 mcg/kg of NEUPOGEN over 24
`hours resulted in mean and median serum concentrations of approximately 48 and 56
`ng/mL, respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg
`resulted in maximum serum concentrations of 4 and 49 ng/mL, respectively, within 2 to 8
`hours. The volume of distribution averaged 150 mL/kg in both normal subjects and
`cancer patients. The elimination half-life, in both normal subjects and cancer patients, was
`approximately 3.5 hours. Clearance rates of NEUPOGEN were approximately 0.5 to 0.7
`mL/minute/kg. Single parenteral doses or daily IV doses, over a 14-day period, resulted
`in comparable half-lives. The half-lives were similar for IV administration (231 minutes,
`following doses of 34.5 mcgikg) and for SC administration (210 minutes, following
`NEUPOGEN doses of 3.45 mcg/kg). Continuous 24-hour IV infusions of 20 mcg/kg
`over an 11- to 20-day period produced steady-state serum concentrations of NEUPOGEN
`with no evidence of drug accumulation over the time period investigated.
`
`CLINICAL EXPERIENCE
`
`Cancer Patients Receiving Myelosuppressive Chemotherapy
`
`NEUPOGEN has been shown to be safe and effective in accelerating the recovery of
`neutrophil counts following a variety of chemotherapy regimens. In a phase 3 clinical trial
`in small cell lung cancer, patients received SC administration of NEUPOGEN (4 to 8
`mcg/kg/day, days 4 to 17) or placebo. In this study, the benefits of NEUPOGEN therapy
`were shown to be prevention of infection as manifested by febrile neutropenia, decreased
`hospitalization, and decreased IV antibiotic usage. No difference in survival or disease
`progression was demonstrated.
`
`In the phase 3, randomized, double-blind, placebo-controlled trial conducted in patients
`
`4
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0004
`
`

`
`with small cell lung cancer, patients were randomized to receive NEUPOGEN (n = 99) or
`placebo (n = 111) starting on day 4, after receiving standard dose chemotherapy with
`cyclophosphamide, doxorubicin, and etoposide. A total of 210 patients were evaluated
`for efficacy and 207 evaluated for safety. Treatment with NEUPOGEN resulted in a
`clinically and statistically significant reduction in the incidence of infection, as manifested
`by febrile neutropenia; the incidence of at least one infection over all cycles of
`chemotherapy was 76% (84/111) for placebo-treated patients, versus 40% (40/99) for
`NEUPOGEN-treated patients (p < 0.001). The following secondary analyses were also
`performed. The requirements for in-patient hospitalization and antibiotic use were also
`significantly decreased during the first cycle of chemotherapy; incidence of hospitalization
`was 69% (77/11 l) for placebo-treated patients in cycle 1, versus 52% (51/99) for
`NEUPOGEN-treated patients (p = 0.032). The incidence of IV antibiotic usage was 60%
`(67/111) for placebo-treated patients in cycle 1, versus 38% (38/99) for NEUPOGEN-
`treated patients (p = 0.003). The incidence, severity, and duration of severe neutropenia
`[absolute neutrophil count (ANC) < 500/mm3] following chemotherapy were all
`significantly reduced. The incidence of severe neutropenia in cycle 1 was 84% (83/99) for
`patients receiving NEUPOGEN versus 96% (106/110) for patients receiving placebo (p =
`0.004). Over all cycles, patients randomized to NEUPOGEN had a 57% (286/500 cycles)
`rate of severe neutropenia versus 77% (416/543 cycles) for patients randomized to
`placebo. The median duration of severe neutropenia in cycle 1 was reduced from 6 days
`(range 0 to 10 days) for patients receiving placebo to 2 days (range 0 to 9 days) for
`patients receiving NEUPOGEN (p < 0.001). The mean duration of neutropenia in cycle 1
`was 5.64 ± 2.27 days for patients receiving placebo versus 2.44 ± 1.90 days for patients
`receiving NEUPOGEN. Over all cycles, the median duration ofneutropenia was 3 days
`for patients randomized to placebo versus 1 day for patients randomized to NEUPOGEN.
`The median severity of neutropenia (as measured by ANC nadir) was 72/mm3 (range
`0/mm3 to 7912/mm3) in cycle 1 for patients receiving NEUPOGEN versus 38/mm3 (range
`0/mm3 to 9520/mm3) for patients receiving placebo (p = 0.012). The mean severity of
`neutropenia in cycle 1 was 496/mm3 ± 1382/mm3 for patients receiving NEUPOGEN
`versus 204/mm3 + 953/mm3 for patients receiving placebo. Over all cycles, the ANC nadir
`for patients randomized to NEUPOGEN was 403/mm3, versus 161/mm3 for patients
`randomized to placebo. Administration of NEUPOGEN resulted in an earlier ANC nadir
`following chemotherapy than was experienced by patients receiving placebo (day 10 vs
`day 12). NEUPOGEN was well tolerated when given SC daily at doses of 4 to 8 mcg/kg
`for up to 14 consecutive days following each cycle of chemotherapy (see ADVERSE
`REACTIONS).
`
`Several other phase 1/2 studies, which did not directly measure the incidence of infection,
`but which did measure increases in neutrophils, support the efficacy of NEUPOGEN. The
`regimens are presented to provide some background on the clinical experience with
`NEUPOGEN. No claim regarding the safety or efficacy of the chemotherapy regimens is
`made. The effects of NEUPOGEN on tumor growth or on the anti-tumor activity of the
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0005
`
`

`
`chemotherapy were not assessed. The doses of NEUPOGEN used in these studies are
`considerably greater than those found to be effective in the phase 3 study described above.
`Such phase 1/2 studies are summarized in the following table.
`
`Type of
`Malignancy
`
`Small Cell
`Lung Cancer
`
`Small Cell
`Lung Cancer11
`
`Urothelial
`Cancer12
`
`Various
`Nonmyeloid
`Malignancies13
`
`Regimen
`
`Chemotherapy
`Dose
`
`No. Trial
`Pts. Phase
`
`NEUPOGEN Daily
`Dosagea
`
`Cyclophosphamide
`Doxorubicin
`Etoposide
`
`Ifosfamide
`Doxorubicin
`Etoposide
`Mesna
`
`Methotrexate
`Vinblastine
`Doxorubicin
`Cisplatin
`
`I g/m2/day
`50 mg/m2/day
`120 mg/m2/day x 3
`q 21 days
`
`5 g/m2/day
`50 mg/m2/day
`120 mg/m2/day x 3
`8 g/m2/day
`q 21 days
`
`30 mg/m2/day x 2
`3 mg/m2/day x 2
`30 mg/m2/day
`70 mg/m2/day
`q 28 days
`
`210
`
`3
`
`4-8 mcg/kg SC
`days 4-17
`
`12
`
`1/2
`
`5.75-46 mcg/kg IV
`days 4-17
`
`40
`
`1/2
`
`3.45-69 mcg/kg IV
`days 4-11
`
`Cyclophosphamide
`Etoposide
`Cisplatin
`
`2.5 g/m2/day x 2
`500 mg/m2/day x 3
`50 mg/m2/day x 3
`q 28 days
`
`18
`
`1/2
`
`23-69 mcg/kgb IV
`days 8-28
`
`Breast/Ovarian
`Cancer14
`
`Doxorubicin~
`
`Neuroblastoma
`
`Cyclophosphamide
`Doxorubicin
`Cisplatin
`
`21
`
`11.5 mcg/kg IV
`days 2-9
`5.75 mcg/kg IV
`days 10-12
`
`12
`
`2
`
`5.45-17.25 mcg/kg SC
`days 6-19
`
`75 mg/m2
`100 mg/m2
`125 mg/m2
`150 mg/m~
`
`q 14 days
`
`150 mg/m2 x 7
`35 mg/m2
`90 mg/m2
`q 28 days
`(cycles 1,3,5) ~t
`
`NEUPOGEN doses were those that accelerated neutrophil production. Doses which provided no additional
`acceleration beyond that achieved at the next lower dose are not reported.
`Lowest dose(s) tested in the study.
`Patients received doxorubicin at either 75, 100, 125, or 150 mg/mz.
`2
`2
`Cycles 2,6 = cyclophosphamide 150 mg/m x 7 and etoposide 280 mg/m x 3.
`Cycle 4 = eisplatin 90 m$/m2 x 1 and etoposide 280 mg/m2 x 3.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0006
`
`

`
`Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation
`Chemotherapy
`
`In a randomized, double-blind, placebo-controlled, multi-center, phase 3 clinical trial, 521
`patients (median age 54, range 16 to 89 years) were treated for de novo acute myeloid
`leukemia (AML). Following a standard induction chemotherapy regimen comprising
`daunorubicin, cytosine arabinoside, and etoposide17 (DAV 3÷7+5), patients received
`either NEUPOGEN at 5 mcg/kg/day or placebo, SC, from 24 hours after the last dose of
`chemotherapy until neutrophil recovery (ANC 1000/mm3 for 3 consecutive days or
`10,000/mm3 for 1 day) or for a maximum of 35 days.
`
`Treatment with NEUPOGEN significantly reduced the median time to ANC recovery and
`the median duration of fever, antibiotic use, and hospitalization following induction
`chemotherapy. In the NEUPOGEN-treated group, the median time from initiation of
`chemotherapy to ANC recovery (ANC > 500/mm3) was 20 days (vs 25 days in the control
`group, p = 0.0001), the median duration of fever was reduced by 1.5 days (p = 0.009),
`and there were statistically significant reductions in the durations of IV antibiotic use and
`hospitalization. During consolidation therapy (DAV 2+5+5), patients treated with
`NEUPOGEN also experienced significant reductions in the incidence of severe
`neutropenia, time to neutrophil recovery, the incidence and duration of fever, and in the
`durations of IV antibiotic use and hospitalization. Patients treated with a further course of
`standard (DAV 2+5+5) or high-dose cytosine arabinoside consolidation also experienced
`significant reductions in the duration of neutropenia.
`
`There were no statistically significant differences between NEUPOGEN and placebo
`groups in complete remission rate (69% NEUPOGEN vs 68% placebo, p = 0.77), disease-
`free survival [median 342 days NEUPOGEN (n = 178), 322 days placebo (n = 177), p =
`0.99], time to progression of all randomized patients (median 165 days NEUPOGEN, 186
`days placebo, p = 0.87), or overall survival (median 380 days NEUPOGEN, 425 days
`placebo, p = 0.83).
`
`Cancer Patients Receiving Bone Marrow Transplant
`
`In two separate randomized, controlled trials, patients with Hodgkin’s disease (HD) and
`non-Hodgkin’s lymphoma (NHL) were treated with myeloablative chemotherapy and
`autologous bone marrow transplantation (ABMT). In one study (n = 54), NEUPOGEN
`was administered at doses of 10 or 30 mcg/kg/day; a third treatment group in this study
`received no NEUPOGEN. A statistically significant reduction in the median number of
`days of severe neutropenia (ANC < 500/mm~) occurred in the NEUPOGEN-treated group
`versus the control group [23 days in the control group, 11 days in the 10 mcg/kg/day
`group, and 14 days in the 30 mcg/kg/day group, (11 days in the combined treatment
`groups, p = 0.004)]. In the second study (n = 44, 43 patients evaluable), NEUPOGEN
`was administered at doses of 10 or 20 mcg/kg/day; a third treatment group in this study
`received no NEUPOGEN. A statistically significant reduction in the median number of
`
`7
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0007
`
`

`
`days of severe neutropenia occurred in the NEUPOGEN-treated group versus the control
`group (21.5 days in the control group and 10 days in both treatment groups, p < 0.001).
`The number of days of febrile neutropenia was also reduced significantly in this study
`[13.5 days in the control group, 5 days in the 10 mcg/kg/day group, and 5.5 days in the 20
`mcgikg/day group, (5 days in the combined treatment groups, p < 0.0001)]. Reductions
`in the number of days of hospitalization and antibiotic use were also seen, although these
`reductions were not statistically significant. There were no effects on red blood cell or
`platelet levels.
`
`In a randomized, placebo-controlled trial, 70 patients with myeloid and nonmyeloid
`malignancies were treated with myeloablative therapy and allogeneic bone marrow
`transplant followed by 300 mcg/m2/day ofa Filgrastim product. A statistically significant
`reduction in the median number of days of severe neutropenia occurred in the treated
`group versus the control group (19 days in the control group and 15 days in the treatment
`group, p < 0.001) and time to recovery of ANC to > 500/mm3 (21 days in the control
`group and 16 days in the treatment group, p < 0.001).
`
`In three nonrandomized studies (n = 119), patients received ABMT and treatment with
`NEUPOGEN. One study (n = 45) involved patients with breast cancer and malignant
`melanoma. A second study (n = 39) involved patients with HD. The third study (n = 35)
`involved patients with NHL, acute lymphoblastic leukemia (ALL), and germ cell tumor.
`In these studies, the recovery of the ANC to > 500/mm3 ranged from a median of 11.5 to
`13 days.
`
`None of the conditioning regimens used in the ABMT studies included radiation therapy.
`
`While these studies were not designed to compare survival, this information was collected
`and evaluated. The overall survival and disease progression of patients receiving
`NEUPOGEN in these studies were similar to those observed in the respective control
`groups and to historical data.
`
`Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients
`
`All patients in the Amgen-sponsored trials received a similar mobilization/collection
`regimen: NEUPOGEN was administered for 6 to 7 days, with an apheresis procedure on
`days 5, 6, and 7 (except for a limited number of patients receiving apheresis on days 4, 6,
`and 8). In a non-Amgen-sponsored study, patients underwent mobilization to a target
`number of mononuclear cells (MNC), with apheresis starting on day 5. There are no data
`on the mobilization of peripheral blood progenitor cells (PBPC) after days 4 to 5 that are
`not confounded by leukapheresis.
`
`Mobilization: Mobilization of PBPC was studied in 50 heavily pretreated patients
`(median number of prior cycles = 9.5) with NHL, HD, or ALL (Amgen study 1). CFU-
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0008
`
`

`
`GM was used as the marker for engrafiable PBPC. The median CFU-GM level on each
`day of mobilization was determined from the data available (CFU-GM assays were not
`obtained on all patients on each day of mobilization). These data are presented below.
`
`The data from Amgen study 1 were supported by data from Amgen study 2 in which 22
`pretreated breast cancer patients (median number of prior cycles = 3) were studied. Both
`the CFU-GM and CD34÷ cells reached a maximum on day 5 at > 10-fold over baseline and
`then remained elevated with leukapheresis.
`
`Progenitor Cell Levels in Peripheral Blood by Mobilization Day
`
`Overall Study 1
`CFU-GM/mL
`
`Study 2
`CFU-GM/mL
`
`Study 2
`CD34+ (x 104/mL)
`
`No.
`Samples
`
`Median
`(25%-75%)
`
`No.
`Samples
`
`Median
`(25%-75%)
`
`No.
`Samples
`
`Median
`(25%-75%)
`
`Day 1
`
`Day 2
`
`Day 3
`
`Day 4
`
`Day 5
`
`Day 6
`
`Day 7
`
`Day 8
`
`11
`
`7
`
`10
`
`18
`
`36
`
`46
`
`37
`
`15
`
`n/a = not available
`
`18
`(13-62)
`
`22
`(3-61)
`
`138
`(39-364)
`
`365
`(158-864)
`
`781
`(391-1608)
`
`505
`( 199-1397)
`
`333
`(111-938)
`
`383
`(94-815)
`
`20
`
`n/a
`
`n/a
`
`18
`
`21
`
`22
`
`22
`
`12
`
`42
`(15-151)
`
`n/a
`
`n/a
`
`576
`(108-1819)
`
`960
`(72-1677)
`
`756
`(70-3486)
`
`597
`(118-2009)
`
`51
`(10-746)
`
`20
`
`n/a
`
`n/a
`
`17
`
`22
`
`22
`
`21
`
`12
`
`0.13
`(0.02-0.66)
`
`n/a
`
`n/a
`
`2.11
`(0.58-3.93)
`
`3.16
`(1.08-6.11)
`
`2.67
`(1.09-4.40)
`
`2.64
`(0.78-4.22)
`
`1.61
`(0.38-4.31)
`
`In three studies of patients with prior exposure to chemotherapy, the median CFU-GM
`yield in the leukapheresis product ranged from 20.9 to 32.7 x 104/kg body weight (n =
`105). In two of these studies where CD34+ yields in the leukapheresis product were also
`determined, the median CD34+ yields were 3.11 and 2.80 x 106/kg, respectively (n = 56).
`In an additional study of 18 chemotherapy-naive patients, the median CFU-GM yield was
`123.4 x 104/kg.
`
`Engraftment: Engraftment following NEUPOGEN-mobilized PBPC is summarized for
`101 patients in the table below. In all studies a Cox regression model showed that the
`total number of CFU-GM and/or CD34÷ cells collected was a significant predictor of time
`to platelet recovery.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0009
`
`

`
`In a randomized unblinded study of patients with HD or NHL undergoing myeloablative
`chemotherapy (Amgen study 3), 27 patients received NEUPOGEN-mobilized PBPC
`followed by NEUPOGEN and 31 patients received ABMT followed by NEUPOGEN.
`Patients randomized to the NEUPOGEN-mobilized PBPC group compared to the ABMT
`group had significantly fewer days ofplatelet transfusions (median 6 vs 10 days), a
`significantly shorter time to a sustained platelet count > 20,000/mm3 (median 16 vs 23
`days), a significantly shorter time to recovery of a sustained ANC _> 500/mms (median I 1
`vs 14 days), significantly fewer days of red blood cell transfusions (median 2 vs 3 days)
`and a significantly shorter duration ofposttransplant hospitalization.
`
`Amgen-
`sponsored
`Study !
`N = 13
`
`Amgen-
`sponsored
`Study 2
`N =22
`
`Amgen-
`sponsored
`Study3
`N =27
`
`Non-Amgen-
`sponsored
`Study
`N=39
`
`Median PBPCikg Collected
`
`MNC
`
`9.5 x 108
`
`9.5 x 10s
`
`8.l x 108
`
`CD34"
`
`n/a
`
`3,1 x 106
`
`, 2.8 x 106
`
`CFU-GM 63.9 x 104
`
`25.3 x 104
`
`32.6 x 104
`
`Days to ANC > 500/mm3
`
`Median
`Range
`
`Days to Pit. > 20,000/rnm3 Median
`
`Range
`
`9
`8-10
`
`10
`
`7-16
`
`10
`8-15
`
`12.5
`
`10-30
`
`11
`9-38
`
`16
`
`8-52
`
`10.3 x 108
`
`6,2 x 106
`
`n/a
`
`10
`7-40
`
`15.5
`
`7-63
`
`n/a -- not available
`
`Three of the 101 patients (3%) did not achieve the criteria for engraftment as defined by a
`platelet count > 20,000/ram3 by day 28. In clinical trials of NEUPOGEN for the
`mobilization of PBPC, NEUPOGEN was administered to patients at 5 to 24 mcg/kg/day
`after reinfusion of the collected cells until a sustainable ANC (> 500/mm3) was reached.
`The rate of engraftment of these cells in the absence ofNEUPOGEN posttransplantation
`has not been studied.
`
`Patients With Severe Chronic Neutropenia
`
`Severe chronic neutropenia (SCN) (idiopathic, cyclic, and congenital) is characterized by
`a selective decrease in the number of circulating neutrophils and an enhanced susceptibility
`to bacterial infections.
`
`The daily administration of NEUPOGEN has been shown to be safe and effective in
`causing a sustained increase in the neutrophil count and a decrease in infectious morbidity
`
`10
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0010
`
`

`
`in children and adults with the clinical syndrome of SCN.15 In the phase 3 trial,
`summarized in the following table, daily treatment with NEUPOGEN resulted in
`significant beneficial changes in the incidence and duration of infection, fever, antibiotic
`use, and oropharyngeal ulcers. In this trial, 120 patients with a median age of 12 years
`(range 1 to 76 years) were treated.
`
`Overall Significant Changes in Clinical Endpoints Median Incidencea
`(Events) or Duration (Days) per 28-day Period
`
`Control
`Patientsb
`
`NEUPOGEN-treated
`Patients
`
`p-value
`
`Incidence of Infection
`
`Incidence of Fever
`
`Duration of Fever
`
`Incidence of
`Oropharyngeal Ulcers
`
`Incidence of Antibiotic Use
`
`0.50
`
`0.25
`
`0.63
`
`0.26
`
`0.49
`
`0.20
`
`0.20
`
`0.20
`
`0.00
`
`0.20
`
`< 0.001
`
`< 0.001
`
`0.005
`
`< 0.001
`
`< 0.001
`
`Incidence values were calculated for each patient, and are defined as the total number of events
`experienced divided by the number of 28-day periods of exposure (on-study). Median incidence
`values were then reported for each patient group.
`
`Control patients were observed for a 4-month period.
`
`The incidence for each of these five clinical parameters was lower in the NEUPOGEN arm
`compared to the control arm for cohorts in each of the three major diagnostic categories.
`All three diagnostic groups showed favorable trends in favor of treatment. An analysis of
`variance showed no significant interaction between treatment and diagnosis, suggesting
`that efficacy did not differ substantially in the different diseases. Although NEUPOGEN
`substantially reduced neutropenia in all patient groups, in patients with cyclic neutropenia,
`cycling persisted but the period of neutropenia was shortened to 1 day.
`
`As a result of the lower incidence and duration of infections, there was also a lower
`number of episodes of hospitalization [28 hospitalizations in 62 patients in the treated
`group vs 44 hospitalizations in 60 patients in the control group over a 4-month period (p =
`0.0034)]. Patients treated with NEUPOGEN also reported a lower number of episodes of
`diarrhea, nausea, fatigue, and sore throat.
`
`In the phase 3 trial, untreated patients had a median ANC of210/mm3 (range 0 to
`
`11
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0011
`
`

`
`1550/mm3). NEUPOGEN therapy was adjusted to maintain the median ANC between
`1500 and 10,000/mm3. Overall, the response to NEUPOGEN was observed in 1 to 2
`weeks. The median ANC after 5 months of NEUPOGEN therapy for all patients was
`7460/mm3 (range 30 to 30,880/mm3). NEUPOGEN dosing requirements were generally
`higher for patients with congenital neutropenia (2.3 to 40 mcg/kg/day) than for patients
`with idiopathic (0.6 to 11.5 mcg/kg/day) or cyclic (0.5 to 6 mcg/kg/day) neutropenia.
`
`INDICATIONS AND USAGE
`
`Cancer Patients Receiving Myelosuppressive Chemotherapy
`
`NEUPOGEN is indicated to decrease the incidence of infection, as manifested by febrile
`neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-
`cancer drugs associated with a significant incidence of severe neutropenia with fever (see
`CLINICAL EXPERIENCE). A complete blood count (CBC) and platelet count should
`be obtained prior to chemotherapy, and twice per week (see LABORATORY
`MONITORING) during NEUPOGEN therapy to avoid leukocytosis and to monitor the
`neutrophil count. In phase 3 clinical studies, NEUPOGEN therapy was discontinued
`when the ANC was > 10,000/mm3 after the expected chemotherapy-induced nadir.
`
`Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation
`Chemotherapy
`
`NEUPOGEN is indicated for reducing the time to neutrophil recovery and the duration of
`fever, following induction or consolidation chemotherapy treatment of adults with AML.
`
`Cancer Patients Receiving Bone Marrow Transplant
`
`NEUPOGEN is indicated to reduce the duration of neutropenia and neutropenia-related
`clinical sequelae, eg, febrile neutropenia, in patients with nonmyeloid malignancies
`undergoing myeloablative chemotherapy followed by marrow transplantation (see
`CLINICAL EXPERIENCE). It is recommended that CBCs and platelet counts be
`obtained at a minimum of three times per week (see LABORATORY MONITORING)
`following marrow infusion to monitor the recovery of marrow reconstitution.
`
`Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy
`
`NEUPOGEN is indicated for the mobilization of hematopoietic progenitor cells into the
`peripheral blood for collection by leukapheresis. Mobilization allows for the collection of
`increased numbers of progenitor cells capable of engraftment compared with collection by
`leukapheresis without mobilization or bone marrow harvest. After myeloablative
`chemotherapy, the transplantation of an increased number of progenitor cells can lead to
`more rapid engraftment, which may result in a decreased need for supportive care (see
`
`12
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1072-0012
`
`

`
`CLINICAL EXPERIENCE).
`
`Patients With Severe Chronic Neutropenia
`
`NEUPOGEN is indicated for chronic administration to reduce the incidence and duration
`of sequelae of neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic
`patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia (see
`CLINICAL EXPERIENCE). It is essential that serial CBCs with differential and platelet
`counts, and an evaluation of bone marrow morphology and karyotype be performed prior
`to initiation of NEUPOGEN therapy. The use of NEUPOGEN prior to confirmation of
`SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment
`of an underlying condition, other than SCN, causing the neutropenia.
`
`C ONTRAINDICATIONS
`
`NEUPOGEN is contraindicated in patients with known hypersensitivity to E coli-derived
`proteins, Filgrastim, or any component of the product.
`
`WARNINGS
`
`Allergic-type reactions occurring on initial or subsequent treatment have been reported in
`< 1 in 4000 patients treated with NEUPOGEN. These have generally been characterized
`by systemic symptoms involving at least two body systems, most often skin (rash,
`urticaria, facial edema), respiratory (wheezing, dyspnea), and cardiovascular
`(hypotension, tachycardia). Some reactions occurred o