The Path Towards a Tailored Clinical Biosimilar Development.

Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity. In the remaining 5% (2 out of 38), despite meeting efficacy outcomes, the biosimilar candidates exhibited clinical differences in immunogenicity that required changes to the manufacturing process and additional clinical studies to enable biosimilar approval. Both instances of clinical differences in immunogenicity occurred prior to 2010, and the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities. Biosimilar candidates that were neither approved in the EU nor in the US were not approved due to reasons other than clinical confirmation of efficacy. This review of the development history of biosimilars allows the proposal of a more efficient and expedited biosimilar development without the routine need for comparative clinical efficacy and/or pharmacodynamic studies and without any compromise in quality, safety, or efficacy. This proposal is scientifically valid, consistent with regulation of all biologics, and maintains robust regulatory standards in the assessment of biosimilar candidates. Note: The findings and conclusion of this paper are limited to biosimilar products developed against the regulatory standards in the EU and the US.

A Phase 2, International, Multicenter, Open-label Clinical Trial of Subcutaneous Tbo-Filgrastim in Pediatric Patients With Solid Tumors Undergoing Myelosuppressive Chemotherapy.

This phase 2, multicenter, open-label trial investigated the safety and tolerability of tbo-filgrastim in pediatric patients receiving myelosuppressive chemotherapy. In total, 50 patients 1 month to below 16 years of age with solid tumors without bone marrow involvement were stratified into 3 age groups (2 infants, 30 children, 18 adolescents) and prophylactically administered tbo-filgrastim 5 µg/kg body weight once daily subcutaneously. The administration started after the last chemotherapy treatment in week 1 of the first cycle and continued until the expected neutrophil nadir had passed, and the neutrophil count had recovered to 2.0×10/L. The primary endpoint was safety and tolerability of tbo-filgrastim; secondary endpoints included efficacy. The mean (SD) number of doses administered was 9.2 (2.83) in children and 7.3 (1.88) in adolescents. Serious treatment-emergent adverse events were reported in 24% of patients; the most common were febrile neutropenia (FN) (12%), anemia (8%), and thrombocytopenia (8%). Nine patients (18%) experienced mild treatment-related treatment-emergent adverse events; the most common were musculoskeletal and connective tissue disorders (8%). No deaths or withdrawals occurred. The incidence of severe neutropenia (SN) was 52% and the mean (SD) duration of SN was 1.8 (2.21) days; FN incidence was 26%. A daily dose of tbo-filgrastim 5 µg/kg body weight administered to pediatric patients demonstrated a safety profile consistent with the safety profile in adult patients. The incidence of FN was on the lower end of the range reported in the literature and the SN results provide supportive data on the efficacy of tbo-filgrastim in pediatric patients.

A pharmacokinetic study of lipegfilgrastim in children with Ewing family of tumors or rhabdomyosarcoma.

PURPOSE: Neutropenia is a common complication from chemotherapy, limiting optimal dosing and treatment. Lipegfilgrastim is a long-acting granulocyte colony-stimulating factor developed for the management of chemotherapy-induced neutropenia. The objectives of this phase 1, multinational, open-label, single-arm study were to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a single body weight-adjusted dose of lipegfilgrastim and to evaluate the efficacy, safety, and tolerability of the drug in children with Ewing family of tumors or rhabdomyosarcoma treated with myelosuppressive chemotherapy. METHODS: Enrolled patients received lipegfilgrastim (100 µg/kg) 24 h after the last chemotherapy treatment in week 1. Patients were stratified into three age groups: 2 to <6, 6 to <12, and 12 to <18 years. Blood samples for PK analyses were obtained at baseline and at 3, 8, 24, 30, 48, 72, 96, 144, and 240 h postdose for the two oldest groups and up to 144 h in the youngest group. RESULTS: Twenty-one patients were enrolled and received lipegfilgrastim, seven in each age group. Lipegfilgrastim exposure levels were comparable across age groups, with concentrations maintained over a prolonged period after a single injection. Differences in PD were mainly associated with chemotherapy type. Most investigator-reported adverse events were attributed to chemotherapy and not to lipegfilgrastim. Severe adverse events were noted in 57% of patients; febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia were more frequent among the oldest patients. CONCLUSIONS: Results support the use of a body weight-adjusted dose to achieve equivalent initial peak exposure levels of lipegfilgrastim in children of various ages.

Efficacy and safety of lipegfilgrastim compared with placebo in patients with non-small cell lung cancer receiving chemotherapy: post hoc analysis of elderly versus younger patients.

PURPOSE: Lipegfilgrastim, a glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF), reduces neutropenia duration and febrile neutropenia (FN) incidence in patients with cancer receiving myelosuppressive chemotherapy. A phase 3 trial of lipegfilgrastim was conducted in patients with advanced non-small cell lung cancer (NSCLC) receiving cisplatin/etoposide (which produces mild-to-moderate myelosuppression). Because patients aged >65 years are at higher risk for FN versus younger patients, this post hoc analysis compared outcomes in elderly (>65 years) versus younger participants in this trial. METHODS: Patients were randomized 2:1 to receive a once-per-cycle single subcutaneous injection of lipegfilgrastim 6 mg or placebo, with up to 4 cycles of every-3-week cisplatin (day 1) and etoposide (days 1-3). The primary end point was FN incidence during cycle 1. Outcomes were compared across treatment groups and by age groups (≤65 and >65 years). RESULTS: For patients aged ≤65 years, FN incidence during cycle 1 was similar in the lipegfilgrastim and placebo groups (3.0 vs 3.2 %, respectively), whereas for elderly patients, there was a reduction in FN incidence with lipegfilgrastim (0 vs 13.3 %, respectively). In both age subgroups, lipegfilgrastim showed a propensity to reduce the incidence and duration of severe neutropenia, time to absolute neutrophil count (ANC) recovery, and depth of ANC nadir. Adverse events were generally similar between groups. CONCLUSIONS: This analysis suggests that in patients with a higher FN risk, such as the elderly patients of this study, lipegfilgrastim reduces not only the duration of severe neutropenia but also the incidence of FN.

Safety and efficacy of Ovaleap® (recombinant human follicle-stimulating hormone) for up to 3 cycles in infertile women using assisted reproductive technology: a phase 3 open-label follow-up to Main Study.

BACKGROUND: Ovaleap® (follitropin alfa), a recombinant human follicle-stimulating hormone intended for use in controlled ovarian stimulation in women undergoing assisted reproductive technologies (ART), showed therapeutic equivalence to Gonal-f® in a multinational, multicenter, randomized, controlled, assessor-blind phase 3 Main Study. The current study examined safety, including immunogenicity, and efficacy of Ovaleap® in an open-label, uncontrolled, follow-up treatment period of up to 2 additional treatment cycles in patients who did not become pregnant in the phase 3 Main Study. METHODS: Patients with negative biochemical or clinical pregnancy in the phase 3 Main Study, regardless of treatment group (ie, Ovaleap® or Gonal-f®), were eligible to participate. Patients received Ovaleap® (Merckle Biotec GmbH, Ulm, Germany) for up to 2 additional cycles, administered using a reusable semi-automated pen device. The primary objective was the assessment of safety, including adverse events (AEs), ovarian hyperstimulation syndrome (OHSS), and anti-drug antibodies. Tolerability, patient satisfaction with the Ovaleap® pen device, and efficacy outcomes (as evaluated in the Main Study) were also assessed. RESULTS: One hundred forty-seven patients were included in cycle 2, and 61 patients were included in cycle 3. In cycles 2 and 3, 10.9 % (16/147) and 6.6 % (4/61) of patients experienced treatment-emergent AEs (TEAEs), respectively. Three serious TEAEs (ie, appendicitis, OHSS, and borderline ovarian tumor) were reported and successfully resolved. The OHSS TEAE was the only OHSS reported in the study (0.7 % [1/147]). Positive findings on anti-drug antibody assays in 6 serum samples did not show neutralizing activity or clinical relevance in biochemical pregnancy rate. No hypersensitivity reaction occurred. Most patients reported "very good"/"good" local tolerability. All patients were "very confident"/"confident" about dose accuracy and correctness of the injection. They all found use of the pen "very convenient"/"convenient" and were all "very satisfied"/"satisfied" with the pen device. Efficacy outcomes were consistent with the phase 3 Main Study. CONCLUSIONS: These findings further support the safety, including immunogenicity, and efficacy of Ovaleap® for stimulation of follicular development in infertile women undergoing ART. The findings support continued use of Ovaleap® for multiple cycles or a switch to Ovaleap® if pregnancy is initially not achieved with Gonal-f®. TRIAL REGISTRATION: EudraCT number: 2009-017674-20. Current controlled trials register number: ISRCTN74772901 .

Randomized, active-controlled, comparative phase 3 efficacy and safety equivalence trial of Ovaleap® (recombinant human follicle-stimulating hormone) in infertile women using assisted reproduction technology (ART).

BACKGROUND: Pharmacokinetic studies with XM17 (Ovaleap®), a recombinant human follicle-stimulating hormone (r-hFSH, follitropin alfa), have demonstrated good safety and tolerability in healthy women whose endogenous FSH levels were down-regulated with a long agonist protocol. In these studies, Ovaleap® pharmacokinetics were dose-proportional and bioequivalent to the reference follitropin alfa product (Gonal-f®). The objective of the present study is to determine whether Ovaleap® is equivalent to Gonal-f® with respect to the number of oocytes retrieved in infertile but ovulatory women undergoing assisted reproductive technology (ART) therapy. METHODS: This multinational, multicenter, randomized (1:1), active-controlled, assessor-blind, comparative study included infertile normally gonadotrophic women 18 to 37 years old with a body mass index of 18 to 29 kg/m(2) and regular menstrual cycles of 21 to 35 days undergoing ART therapy. During a 5-day fixed-dose phase, women received 150 IU/day of Ovaleap® (n = 153) or Gonal-f® (n = 146), followed by an up to 15-day dose-adaptation phase during which doses could be adjusted every 3 to 5 days, up to a maximum of 450 IU/day. Ovaleap® was to be deemed equivalent to Gonal-f® if the two-sided 0.95 confidence interval (CI) for the difference in the number of oocytes retrieved fell within the equivalence range of ±3 oocytes. RESULTS: Similar numbers of oocytes were retrieved in the 2 treatment groups. The mean ± SD number of oocytes retrieved was 12.2 ± 6.7 in the Ovaleap® group and 12.1 ± 6.7 in the Gonal-f® group (intent-to-treat [ITT] population). Regression analysis estimated a mean difference of 0.03 oocytes between the treatment groups (95 % CI: -0.76-0.82), which was well within the prespecified equivalence range of ±3 oocytes. Ovaleap® and Gonal-f® showed favorable and comparable safety profiles, with no unexpected safety findings. CONCLUSIONS: Ovaleap® has shown the same efficacy and safety as Gonal-f® for stimulation of follicular development in infertile women (up to 37 years of age) who are undergoing ART therapy. TRIAL REGISTRATION: EudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901 . Date of trial registration: 19 March 2010.

Clinical safety of tbo-filgrastim, a short-acting human granulocyte colony-stimulating factor.

The recombinant human granulocyte colony-stimulating factor (G-CSF) known as filgrastim (Tevagrastim(®), Ratiograstim(®), Biograstim(®)) in Europe (approved in 2008) and tbo-filgrastim (Granix(®)) in the USA (approved in 2012; Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel) is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. This article presents pooled clinical data for tbo-filgrastim compared with Neupogen(®) (Amgen, Thousand Oaks, CA, USA) as well as tbo-filgrastim post-marketing safety data. The safety and efficacy of tbo-filgrastim were evaluated in three phase III studies in 677 patients receiving myelosuppressive chemotherapy and study drug (348 patients with breast cancer, 237 with lung cancer, 92 with non-Hodgkin lymphoma). In each study, the efficacy of tbo-filgrastim was similar to that of Neupogen. Overall, 633 (93.5 %) patients receiving the study drug experienced 6093 treatment-emergent adverse events (AEs), most of which were related to chemotherapy. Adverse events related to the study drug (tbo-filgrastim or Neupogen) were experienced by 185 (27.3 %) patients; 19 (2.8 %) had severe drug-related AEs, 5 (0.7 %) had drug-related serious AEs, and 6 (0.9 %) discontinued the study due to drug-related AEs. Overall, the most common drug-related AEs were bone pain (7.1 %), myalgia (4.0 %), and asthenia (4.4 %). The post-marketing safety profile of tbo-filgrastim was consistent with that observed during the clinical studies. The availability of tbo-filgrastim, a G-CSF with safety and efficacy comparable to those of Neupogen, provides physicians with an alternative treatment option for supportive care of patients with non-myeloid malignancies receiving myelosuppressive chemotherapy.

Cardiovascular Morbidity and Pure Red Cell Aplasia Associated With Epoetin Theta Therapy in Patients With Chronic Kidney Disease: A Prospective, Noninterventional, Multicenter Cohort Study.

PURPOSE: The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia. METHODS: In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7-11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62-125, and >125 IU/kg/wk for low, intermediate, and high). FINDINGS: Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person-year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person-year. No cases of pure red cell aplasia were reported. IMPLICATIONS: The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10-12 g/dL according to the current summary of product characteristics for epoetin theta; 10-11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.

Chemotherapy-associated treatment burden in breast cancer patients receiving lipegfilgrastim or pegfilgrastim: secondary efficacy data from a phase III study.

PURPOSE: Lipegfilgrastim is a once-per-cycle glycoPEGylated granulocyte colony-stimulating factor (G-CSF). Noninferiority of lipegfilgrastim versus pegfilgrastim was demonstrated in a phase III trial in chemotherapy (CTx)-naïve breast cancer patients. Secondary outcomes relating to treatment burden are reported here. METHODS: Patients with high-risk stage II, III, or IV breast cancer were randomized to receive lipegfilgrastim 6 mg (n = 101) or pegfilgrastim 6 mg (n = 101) subcutaneously on day 2 of each CTx cycle. Doxorubicin 60 mg/m(2) plus docetaxel 75 mg/m(2) commenced on day 1, for up to four cycles. Secondary end points included days in the hospital or intensive care unit (ICU), use of intravenous antibiotics for febrile neutropenia (FN) or related infections, and measures of CTx delivery (dose delays, reductions, and omissions). RESULTS: One lipegfilgrastim recipient and two pegfilgrastim recipients were hospitalized in cycle 1 because of FN or associated infection. The lipegfilgrastim-treated patient spent 1 day in the ICU for FN, and the two pegfilgrastim-treated patients were hospitalized for FN for 5 and 6 days, respectively. All hospitalized patients received antibiotics. An additional pegfilgrastim-treated patient received antibiotics but was not hospitalized. Most patients received CTx as scheduled; over 98% received their planned doxorubicin and docetaxel doses in all cycles. In the lipegfilgrastim group, no patients had a CTx dose reduced or omitted; eight patients in the pegfilgrastim group had a CTx dose reduced or omitted during cycles 2-4. CONCLUSIONS: The burden of treatment associated with myelosuppressive CTx was similar in breast cancer patients treated with lipegfilgrastim or pegfilgrastim.

Phase I, two-way, crossover study to demonstrate bioequivalence and to compare safety and tolerability of single-dose XM17 vs Gonal-f® in healthy women after follicle-stimulating hormone downregulation.

BACKGROUND: XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in controlled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to establish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the reference follitropin alfa (Gonal-f(®)) in healthy young women. METHODS: This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from February to May 2009. Thirty-six women aged 18-39 years were included, with a study duration of ~27 days per participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and Gonal-f(®) were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for standard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability were assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability. RESULTS: Ratios of XM17 to Gonal-f(®) for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080) and 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25). Ratios for AUC0-168h, AUC0-∞ and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and Gonal-f(®) were well tolerated, with no detectable anti-FSH antibodies, serious AEs or AEs leading to discontinuation or dose reduction. CONCLUSIONS: PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-f® was statistically demonstrated. XM17 was well tolerated both systemically and locally. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02592031 ; date of registration: 28 October, 2015.

Phase 1 safety, tolerability, and pharmacokinetic study of single ascending doses of XM17 (recombinant human follicle-stimulating hormone) in downregulated healthy women.

BACKGROUND: XM17 is a recombinant human follicle-stimulating hormone (follitropin alfa) for stimulation of multifollicular development in women undergoing controlled ovarian hyper-stimulation during assisted reproductive therapy and for treatment of anovulation. Manufactured using Chinese hamster ovary cells transfected with the human follicle-stimulating hormone gene, XM17 has an identical amino acid sequence to that of the human protein as well as to those of the other approved recombinant human follicle-stimulating hormone products. Glycosylation patterns may differ slightly between products. The objectives of this first-in-human study were to assess the safety, tolerability, pharmacokinetics, and dose-proportionality of single ascending subcutaneous doses of XM17 in healthy young female volunteers. METHODS: Endogenous follicle-stimulating hormone was downregulated by implanting a 1-month depot of goserelin acetate 3.6 mg on day 0 in eligible subjects. On day 14 of the experimental period, subjects received one of four ascending doses of XM17. Blood sampling to obtain the pharmacokinetic profile of XM17 was done at frequent intervals until 168 hours post-dose. RESULTS: Following downregulation of endogenous follicle-stimulating hormone to <4 IU/L, 40 subjects (of mean age 29±5.4 years) received single subcutaneous doses of 37.5 (n=4, pilot group), 75, 150, or 300 IU (n=12 each) of XM17. The mean serum concentration-time profiles of XM17 revealed dose-related increases in maximum concentration (Cmax) within 24 hours followed by monoexponential decay for the three higher dose levels. Slopes estimated by linear regression for Cmax and AUC0-168h were ~1.0 (0.9052 IU/L and 1.0964 IU·h/L, respectively). For each IU of XM17 administered, Cmax and AUC0-168h rose by 0.032 IU/L and 2.60 IU·h/L, respectively. Geometric mean elimination half-life ranged from 54 to 90 hours. No antibodies to XM17 were detected. The most common treatment-emergent adverse events were headache (12 events in eleven [27.5%] subjects) and dizziness (four events in four [10%] subjects); two subjects (5%) reported mild pain on touch at the injection site. CONCLUSION: Single subcutaneous doses of XM17 up to 300 IU in healthy young women exhibited dose-proportional pharmacokinetics with good safety and tolerability.

Phase III, randomized, double-blind, placebo-controlled, multicenter study of lipegfilgrastim in patients with non-small cell lung cancer receiving myelosuppressive therapy.

PURPOSE: The aim of this study was to demonstrate lipegfilgrastim superiority versus placebo in adults with non-small cell lung cancer receiving myelosuppressive chemotherapy. METHODS: This phase III, double-blind study randomized chemotherapy-naive patients to receive cisplatin and etoposide with either lipegfilgrastim 6 mg or placebo. Because of the placebo control, patients at individual high risk for febrile neutropenia (FN; ≥20%) were excluded. Study drug was administered on day 4 (24 h after chemotherapy) of a 21-day cycle for ≤4 cycles. Primary efficacy measure was FN incidence in cycle 1. Secondary assessments included duration of severe neutropenia (DSN), absolute neutrophil count (ANC) profile, and adverse events (AEs). RESULTS: The study included 375 patients (lipegfilgrastim, n = 250; placebo, n = 125). Lipegfilgrastim superiority for FN incidence in cycle 1 was not achieved but incidence was lower (2.4%) versus placebo (5.6%). Cycle 1 mean DSN was significantly shorter for lipegfilgrastim (0.6 ± 1.1 days) versus placebo (2.3 ± 0.5 days; p < 0.0001). Incidence of severe neutropenia was significantly lower for lipegfilgrastim versus placebo overall and in each cycle (all, p < 0.0001). Mean ANC nadir was lowest in cycle 1 but significantly higher for lipegfilgrastim (1.60 ± 1.64) than placebo (0.67 ± 0.85; p < 0.0001). Mean time to ANC recovery was shorter with lipegfilgrastim in each cycle. Treatment-emergent AEs were similar between treatment groups. CONCLUSIONS: Lipegfilgrastim was not statistically superior to placebo for incidence of FN in cycle 1, but was more effective in reducing incidence of severe neutropenia, DSN, and time to ANC recovery, with an acceptable safety profile. Controlled-trials.com identifier: ISRCTN55761467.

Phase II dose-finding study of balugrastim in breast cancer patients receiving myelosuppressive chemotherapy.

Balugrastim is a once-per-cycle, fixed-dose recombinant protein comprising human serum albumin and granulocyte colony-stimulating factor under development for prevention of severe neutropenia in cancer patients receiving myelosuppressive chemotherapy. This phase II, multicenter, active-controlled, dose-finding pilot study evaluated balugrastim safety and efficacy versus pegfilgrastim in breast cancer patients scheduled to receive myelosuppressive chemotherapy and investigated two doses with similar efficacy to pegfilgrastim for a subsequent phase III study. Patients received four cycles of doxorubicin/docetaxel chemotherapy and with each successive cycle were randomized sequentially to escalating doses of balugrastim [30 (n = 11), 40 (n = 21), or 50 mg (n = 20)] or a fixed dose of pegfilgrastim [6 mg (n = 26)] post-chemotherapy. Balugrastim doses were escalated as planned. The incidence of adverse events was similar among the balugrastim groups and between all balugrastim doses and pegfilgrastim. The most frequently reported adverse events were neutropenia, alopecia, and nausea. During cycle 1, severe neutropenia (absolute neutrophil count of <0.5 × 10(9)/L) occurred in 40, 67, and 50 % and febrile neutropenia occurred in 20.0, 9.5, and 10.0 % of patients receiving balugrastim 30, 40, and 50 mg, respectively; in patients receiving pegfilgrastim, 48 % experienced severe neutropenia and 8 % experienced febrile neutropenia. Duration of severe neutropenia (DSN) for each treatment group was 0.9, 1.6, 1.1, and 0.9 days, respectively. In the remaining three chemotherapy cycles, DSN was ≤1 day across all treatment groups. Balugrastim 50 mg was comparable to pegfilgrastim in terms of safety and overall efficacy in breast cancer patients receiving myelosuppressive chemotherapy.

Lipegfilgrastim: pharmacodynamics and pharmacokinetics for body-weight-adjusted and 6 mg fixed doses in two randomized studies in healthy volunteers.

OBJECTIVE: Two phase I, single-blind (subject blinded to treatment), randomized studies were conducted to assess the pharmacodynamics, pharmacokinetics, safety, and tolerability of lipegfilgrastim compared with pegfilgrastim in healthy adult volunteers. METHODS: Study 1 consisted of a pilot safety phase (N = 8) during which subjects received a single body-weight-adjusted subcutaneous dose of lipegfilgrastim 25 µg/kg and a dose escalation phase (N = 45) wherein subjects received lipegfilgrastim 50 or 100 µg/kg or pegfilgrastim 100 µg/kg. Study 2 was a single-blind, fixed-dose study (N = 36) comparing subcutaneous lipegfilgrastim 6 mg and pegfilgrastim 6 mg. RESULTS: Cumulative exposure (AUC0-t last and AUC 0-∞) and peak exposure (Cmax) were higher for lipegfilgrastim than pegfilgrastim after both weight-adjusted and fixed dosing. In both studies, the terminal elimination half-life of lipegfilgrastim was 5-10 hours longer than the terminal elimination half-life for pegfilgrastim at the maximum dose, and the time to maximum serum concentration (tmax) was observed later for lipegfilgrastim than for pegfilgrastim. The area over the baseline effect curve (AOBEC) for absolute neutrophil count (ANC) was approximately 30% greater after lipegfilgrastim dosing compared with the same dose of pegfilgrastim at the maximum dose. Both drugs were well tolerated, with a similar occurrence of adverse events between treatment groups. Key limitations of these studies include the small numbers of subjects and differences in dosage regimens between the two studies. CONCLUSIONS: In these studies, lipegfilgrastim provided a longer-lasting increase in ANC compared with pegfilgrastim at an equivalent dose, without increasing the peak ANC values. This may reflect the higher cumulative exposure and slower clearance (therefore longer body residence) of lipegfilgrastim. These data support the use of single-dose lipegfilgrastim 6 mg in subsequent phase III trials as prophylactic treatment for patients receiving myelosuppressive chemotherapy.

A randomized, double-blind, active control, multicenter, dose-finding study of lipegfilgrastim (XM22) in breast cancer patients receiving myelosuppressive therapy.

This dose-ranging study was conducted to identify the optimal fixed dose of lipegfilgrastim compared with pegfilgrastim 6.0 mg for the provision of neutrophil support during myelosuppressive chemotherapy in patients with breast cancer. A phase 2 study was conducted in which 208 chemotherapy-naive patients were randomized to receive lipegfilgrastim 3.0, 4.5, or 6.0 mg or pegfilgrastim 6.0 mg. Study drugs were administered as a single subcutaneous injection on day 2 of each chemotherapy cycle (doxorubicin/docetaxel on day 1 for four 3-week cycles). The primary outcome measure was duration of severe neutropenia (DSN) in cycle 1. Patients treated with lipegfilgrastim experienced shorter DSN in cycle 1 with higher doses. The mean DSN was 0.76 days in the lipegfilgrastim 6.0-mg group and 0.87 days in the pegfilgrastim 6.0-mg group, with no significant differences between treatment groups. Treatment with lipegfilgrastim 6.0 mg was consistently associated with a higher absolute neutrophil count (ANC) at nadir, shorter ANC recovery time, and a similar safety and tolerability profile compared with pegfilgrastim. This phase 2 study demonstrated that lipegfilgrastim 6.0 mg is the optimal dose for patients with breast cancer and provides neutrophil support that is at least equivalent to the standard 6.0-mg fixed dose of pegfilgrastim.

Efficacy and safety of balugrastim compared with pegfilgrastim in patients with breast cancer receiving chemotherapy.

BACKGROUND: Recombinant granulocyte colony-stimulating factors (G-CSFs) reduce the incidence and duration of chemotherapy-induced neutropenia and febrile neutropenia when given as adjunct therapy to patients receiving myelosuppressive chemotherapy. Balugrastim is a long-acting G-CSF composed of a genetic fusion between recombinant human serum albumin and G-CSF. We compared the efficacy and safety of balugrastim and pegfilgrastim, a long-acting pegylated recombinant G-CSF, in patients with breast cancer who were scheduled to receive chemotherapy. PATIENTS AND METHODS: In this double-blind randomized phase III trial, patients with ≥ 1.5 × 10(9) neutrophils/L were randomly assigned to subcutaneous injections of balugrastim 40 mg (n = 153) or pegfilgrastim 6 mg (n = 151). The primary efficacy end point was the duration of severe neutropenia (DSN) (days with an absolute neutrophil count [ANC] < 0.5 × 10(9) cells/L) during cycle 1. Efficacy analyses were performed in the per-protocol (PP) population. In a separate open-label single-arm study, newly recruited patients (n = 77) received balugrastim 40 mg and were included in the safety analysis. RESULTS: The mean DSN in cycle 1 was 1.1 days in the balugrastim group and 1.0 days in the pegfilgrastim group (95% confidence interval [CI], -0.13-0.37). Two and 4 patients, respectively, had febrile neutropenia during cycle 1. Twenty percent of patients in the balugrastim group and 19% in the pegfilgrastim group had adverse events (AEs) considered to be related to study medication; 3.9% and 4.7% of patients, respectively, experienced serious AEs. CONCLUSIONS: This study demonstrates the comparable safety and efficacy profile of balugrastim and pegfilgrastim and the noninferiority of balugrastim for reduction in DSN. There were no unexpected safety events.

Efficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized, multicenter, active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy.

BACKGROUND: Lipegfilgrastim is a novel glyco-pegylated granulocyte-colony stimulating factor in development for neutropenia prophylaxis in cancer patients receiving chemotherapy. This phase III, double-blind, randomized, active-controlled, noninferiority trial compared the efficacy and safety of lipegfilgrastim versus pegfilgrastim in chemotherapy-naïve breast cancer patients receiving doxorubicin/docetaxel chemotherapy. METHODS: Patients with high-risk stage II, III, or IV breast cancer and an absolute neutrophil count ≥1.5 × 109 cells/L were randomized to a single 6-mg subcutaneous injection of lipegfilgrastim (n = 101) or pegfilgrastim (n = 101) on day 2 of each 21-day chemotherapy cycle (4 cycles maximum). The primary efficacy endpoint was the duration of severe neutropenia during cycle 1. RESULTS: Cycle 1: The mean duration of severe neutropenia for the lipegfilgrastim and pegfilgrastim groups was 0.7 and 0.8 days, respectively (λ = -0.218 [95% confidence interval: -0.498%, 0.062%], p = 0.126), and no severe neutropenia was observed in 56% and 49% of patients in the lipegfilgrastim and pegfilgrastim groups, respectively. All cycles: In the efficacy population, febrile neutropenia occurred in three pegfilgrastim-treated patients (all in cycle 1) and zero lipegfilgrastim-treated patients. Drug-related adverse events in the safety population were reported in 28% and 26% of patients in the lipegfilgrastim and pegfilgrastim groups, respectively. CONCLUSION: This study demonstrates that lipegfilgrastim 6 mg is as effective as pegfilgrastim in reducing neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. TRIAL REGISTRATION: Eudra EEACTA200901599910.

Epoetin Theta with a New Dosing Schedule in Anaemic Cancer Patients Receiving Nonplatinum-Based Chemotherapy: A Randomised Controlled Trial.

INTRODUCTION: Recombinant human erythropoietin (r-HuEPO) is used to treat symptomatic anaemia due to chemotherapy. A new r-HuEPO, Epoetin theta (Eporatio®), was investigated and compared to placebo in a randomised, double-blind clinical trial in adult cancer patients receiving nonplatinum-based chemotherapy. The primary efficacy endpoint was the responder rate (complete haemoglobin (Hb) response, i.e., Hb increase ≥2 g/dl) without the benefit of a transfusion within the previous 4 weeks. RESEARCH DESIGN AND METHODS: 186 patients were randomised to s.c. treatment for 12 weeks with either Epoetin theta (N = 95) or placebo (N = 91). The starting dose was 20,000 IU once weekly Epoetin theta or placebo. RESULTS: The incidence of complete Hb responders was significantly higher in the Epoetin theta group than in the placebo group (72.6 vs. 25.3%, P < 0.0001). More patients in the placebo group than in the Epoetin theta group received blood transfusions after randomisation (23 patients, 25.3% vs. 13 patients, 13.7%, P = 0.0277). The majority of patients with a complete Hb response had 20,000 IU/week as their maximum dose prior to response, indicating that a dose of 20,000 IU is an appropriate starting dose. The overall frequencies of adverse events (AEs) were similar in both treatment groups. Hypertension was the only AE that was more frequent in the Epoetin theta group compared to the placebo group (8.4 vs. 1.1%). CONCLUSIONS: Epoetin theta showed a superior efficacy to placebo in terms of complete Hb response without blood transfusion within the previous 4 weeks. Treatment with Epoetin theta resulted in a statistically significant increase in mean haemoglobin levels compared to placebo. The overall frequencies of adverse events were similar in both treatment groups.

Epoetin Theta in Anaemic Cancer Patients Receiving Platinum-Based Chemotherapy: A Randomised Controlled Trial.

INTRODUCTION: Recombinant human erythropoietin (r-HuEPO) is used to treat symptomatic anaemia due to chemotherapy. A new r-HuEPO, Epoetin theta (Eporatio®), was investigated and compared to placebo and Epoetin beta in a randomised, double-blind clinical trial in adult cancer patients receiving platinum-based chemotherapy, using a fixed weekly starting dose of 20,000 IU Epoetin theta. The primary efficacy endpoint was the responder rate (complete Hb response, Hb increase ≥ 2 g/dL). RESEARCH DESIGN AND METHODS: 223 patients were randomised to s.c. treatment for 12 weeks with either Epoetin theta (n = 76) once per week, Epoetin beta (n = 73) three times per week or placebo (n = 74). The starting dose was 20,000 IU once weekly Epoetin theta or 450 IU/kg(BW) per week Epoetin beta administered in 3 equal weekly doses. RESULTS: In the Epoetin theta group were significantly more responders than in the placebo group (65.8 vs. 20.3%, P < 0.0001). Epoetin beta was also more effective than placebo (71.2 vs. 20.3%, P < 0.0001). The mean weekly dose at the time of complete Hb response was lower in the Epoetin theta group (30,000 IU) than in the Epoetin beta group (42,230 IU). Epoetin theta was clearly more effective than placebo. CONCLUSION: This small study showed, that Epoetin theta is a safe and effective treatment of symptomatic anaemia due to platinum-based chemotherapy in cancer patients.