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Neu-Ulm, Germany

Merckle GmbH

Neu-Ulm, Germany
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Bondarenko I.M.,Dnipropetrovsk State Medical Academy | Bias P.,Teva Ratiopharm | Buchner A.,Merckle GmbH
Supportive Care in Cancer | Year: 2016

Purpose: Lipegfilgrastim is a once-per-cycle, fixed-dose, glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF) recently approved in Europe to reduce the duration of chemotherapy-induced neutropenia and incidence of febrile neutropenia in patients with cancer receiving chemotherapy. Bone pain-related (BPR) adverse events are commonly associated with G-CSF therapy. This post hoc analysis examined BPR treatment-emergent adverse events (TEAEs) in two comparative studies of lipegfilgrastim or pegfilgrastim in patients receiving chemotherapy. Methods: A post hoc analysis was conducted using integrated data from two double-blind randomized studies in patients with breast cancer receiving docetaxel and doxorubicin and treated prophylactically with subcutaneous lipegfilgrastim 6 mg or pegfilgrastim 6 mg once per cycle. BPR TEAEs were defined as arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, noncardiac chest pain, and pain in extremity. Relationship of BPR TEAEs to study treatment or chemotherapy was also reported by the investigators. Results: The analysis included 306 patients (lipegfilgrastim: n = 151; pegfilgrastim: n = 155). The proportion of patients experiencing BPR TEAEs was similar with lipegfilgrastim and pegfilgrastim (25.2 vs 21.9 %, respectively), as was the proportion of patients experiencing BPR treatment-emergent adverse drug reactions (TEADRs) (18.5 vs 16.8 %, respectively). No BPR TEADRs were serious, and none led to discontinuation. Conclusions: Nonsevere BPR TEAEs and TEADRs were observed in patients with breast cancer receiving chemotherapy and G-CSF; rates of BPR events were similar between lipegfilgrastim and pegfilgrastim. The similar BPR safety profile of lipegfilgrastim and pegfilgrastim provides support for use in patients with breast cancer receiving chemotherapy. © 2015, Springer-Verlag Berlin Heidelberg.

PubMed | Centrul de Oncologie Medicala, Merckle GmbH, Dnipropetrovsk State Medical Academy and Chelyabinsk Regional Clinical Oncology Dispensary
Type: Journal Article | Journal: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer | Year: 2016

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 >65years are at higher risk for FN versus younger patients, this post hoc analysis compared outcomes in elderly (>65years) versus younger participants in this trial.Patients were randomized 2:1 to receive a once-per-cycle single subcutaneous injection of lipegfilgrastim 6mg 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 >65years).For patients aged 65years, 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.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.

Buchner A.,Merckle GmbH | Lammerich A.,Merckle GmbH | Abdolzade-Bavil A.,BioGeneriX GmbH | Muller U.,Teva Pharmaceuticals Inc | Bias P.,Merckle GmbH
Current Medical Research and Opinion | Year: 2014

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-weightadjusted subcutaneous dose of lipegfilgrastim 25 mg/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 6mg and pegfilgrastim 6 mg.Results: Cumulative exposure (AUC0-tlast and AUC0-∞) 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 6mg in subsequent phase III trials as prophylactic treatment for patients receiving myelosuppressive chemotherapy. © 2014 All rights reserved: reproduction in whole or part not permitted.

PubMed | INC Research, Merckle GmbH and Teva Pharmaceuticals Inc.
Type: | Journal: Journal of immunology research | Year: 2016

Lipegfilgrastim is a long-acting, once-per-cycle, glycopegylated recombinant granulocyte colony-stimulating factor (G-CSF) used to prevent neutropenia in patients receiving myelosuppressive chemotherapy. This integrated analysis examined the immunogenicity of lipegfilgrastim and its potential clinical impact in two double-blind randomized studies (phases II and III) of patients with breast cancer receiving chemotherapy. Serum samples were analyzed using sequential assays for screening, confirmation, antibody titer, and characterization of antidrug antibodies (ADA). Neutropenia-related efficacy measures were reviewed for each ADA-positive patient. Among 255 patients receiving lipegfilgrastim (154 in phase II, 101 in phase III) and 155 patients receiving pegfilgrastim (54 in phase II, 101 in phase III), the incidence of treatment-emergent ADA was low and similar between the lipegfilgrastim (phase II: 1.3%; phase III: 1.0%) and pegfilgrastim (phase II: 1.9%; phase III: 1.0%) arms. None of the treatment-emergent ADA-positive samples exhibited neutralizing activity against lipegfilgrastim, pegfilgrastim, or glycosylated G-CSF in a cell-based neutralizing antibody assay. No changes were observed in neutropenia-related efficacy measures among ADA-positive patients, and no treatment-related hypersensitivity or anaphylaxis occurred. These results indicate that there is no apparent impact of ADA on lipegfilgrastim efficacy and safety.

PubMed | Merckle GmbH, Center for Reproductive Medicine and University of Heidelberg
Type: Journal Article | Journal: Reproductive biology and endocrinology : RB&E | Year: 2016

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.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.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.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.EudraCT number: 2009-017674-20. Current controlled trials register number: ISRCTN74772901 .

PubMed | Merckle GmbH, Center for Reproductive Medicine and University of Heidelberg
Type: | Journal: Reproductive biology and endocrinology : RB&E | Year: 2016

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.This multinational, multicenter, randomized (1:1), active-controlled, assessor-blind, comparative study included infertile normally gonadotrophic women 18 to 37years old with a body mass index of 18 to 29kg/m(2) and regular menstrual cycles of 21 to 35days undergoing ART therapy. During a 5-day fixed-dose phase, women received 150IU/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 5days, up to a maximum of 450IU/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.Similar numbers of oocytes were retrieved in the 2 treatment groups. The meanSD number of oocytes retrieved was 12.26.7 in the Ovaleap group and 12.16.7 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.Ovaleap has shown the same efficacy and safety as Gonal-f for stimulation of follicular development in infertile women (up to 37years of age) who are undergoing ART therapy.EudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901 . Date of trial registration: 19 March 2010.

PubMed | Nuventra Inc, City Clinical Hospital and 31, Merckle GmbH, Semmelweis University and West Ukrainian Specialized Childrens Medical Center
Type: Journal Article | Journal: Cancer chemotherapy and pharmacology | Year: 2016

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.Enrolled patients received lipegfilgrastim (100g/kg) 24h after the last chemotherapy treatment in week 1. Patients were stratified into three age groups: 2 to <6, 6 to <12, and 12 to <18years. Blood samples for PK analyses were obtained at baseline and at 3, 8, 24, 30, 48, 72, 96, 144, and 240h postdose for the two oldest groups and up to 144h in the youngest group.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.Results support the use of a body weight-adjusted dose to achieve equivalent initial peak exposure levels of lipegfilgrastim in children of various ages.

PubMed | University Hospital St Poelten And Karl Landsteiner Institute Of Nephrology And Hematology and Merckle GmbH
Type: Journal Article | Journal: Clinical therapeutics | Year: 2016

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.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).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.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.

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: NCT02592031; date of registration: 28 October, 2015. © 2015 Lammerich et al.

Lammerich A.,Merckle GmbH | Bias P.,Merckle GmbH | Gertz B.,Merckle GmbH
International Journal of Women's Health | Year: 2015

Background: XM17 is a recombinant human follicle-stimulating hormone (follitropin alfa) for stimulation of multifollicular development in women undergoing controlled ovarian hyperstimulation 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 AUC0–168hwere ~1.0 (0.9052 IU/L and 1.0964 IU•h/L, respectively). For each IU of XM17 administered, Cmaxand 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. © 2015 Lammerich et al.

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