A large multicentre, randomized, double-blind, cross-over study in healthy volunteers to compare pharmacokinetics, pharmacodynamics and safety of a pegfilgrastim biosimilar with its US- and EU-reference biologics.

AIMS: Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics. METHODS: Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults. RESULTS: Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar. CONCLUSIONS: Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified.

Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects.

AIMS: This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) matches reference pegfilgrastim (Neulasta® ) in healthy subjects. Safety and immunogenicity were also assessed. METHODS: The phase I, randomized, double-blind, two-period crossover study consisted of two treatment periods separated by an 8-week washout period. Healthy subjects aged 18-45 were randomized to either proposed biosimilar/reference pegfilgrastim or reference pegfilgrastim/proposed biosimilar. Proposed biosimilar and reference pegfilgrastim were administered on Day 1 of each treatment period (single 6 mg subcutaneous injection). Blood samples for PK/PD analysis were taken predose and ≤336 h postdose. PK/PD similarity was claimed if 90% (PK) and 95% (PD) confidence intervals (CI) for geometric mean ratios of the area under the serum concentration-time curve (AUC) from time of dosing and extrapolated to infinity (AUC0-inf ), or to the last measurable concentration (AUC0-last ), maximum observed serum concentration (Cmax ), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC0-last ) and ANC maximum effect attributable to the therapy under investigation (Emax ) were completely contained within the predefined margin (0.8 to 1.25). RESULTS: Overall, 169 subjects completed the study. PK/PD similarity was demonstrated; 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC0-inf (1.0559-1.2244), AUC0-last (1.0607-1.2328), Cmax (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC0-last (0.9948-1.0366), Emax (0.9737-1.0169) were completely contained within predefined margin of 0.8 to 1.25. Both biologics had similar safety profiles, were well tolerated and had low incidence of anti-drug antibodies. No neutralizing or clinically relevant antibodies were detected. CONCLUSIONS: PK/PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects.

Proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in Asian patients with breast cancer: an exploratory comparison from two Phase III trials.

AIM: This is a pooled subgroup analysis of Asian patients enrolled in two Phase III confirmatory studies comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer. PATIENTS & METHODS: Women were randomized to LA-EP2006 (n = 90) or reference (n = 84) pegfilgrastim (Neulasta®, Amgen, Inc., CA, USA) for ≤6 cycles of TAC chemotherapy. Primary end point was duration of severe neutropenia during Cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 109/l) with equivalence confirmed if 95% CIs were within a ±1-day margin. RESULTS: Mean duration of severe neutropenia (days) in Cycle 1 was 1.36 ± 0.98 (LA-EP2006) versus 1.35 ± 1.06 (reference) (difference 0.01 days; 95% CI: -0.30-0.32, indicating equivalence). CONCLUSION: LA-EP2006 showed similar clinical efficacy and safety compared with reference pegfilgrastim.

A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial.

BACKGROUND: Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. In highly regulated markets, there are currently no approved biosimilars of pegfilgrastim. Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare proposed biosimilar LA-EP2006 with reference pegfilgrastim (Neulasta, Amgen) in early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy. METHODS: A total of 308 patients were randomized to LA-EP2006 or reference pegfilgrastim. Each patient received TAC (intravenous docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2)) on day 1 of each cycle, for six or more cycles. Pegfilgrastim (LA-EP2006 or reference) was given subcutaneously (6 mg in 0.6 mL) on day 2 of each cycle. The primary endpoint was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with an absolute neutrophil count <0.5 × 10(9)/L), with equivalence confirmed if 90% and 95% confidence intervals (CIs) were within a 1-day margin. RESULTS: Baseline characteristics were well balanced. DSN was equivalent between groups at mean ± SD 1.36 ± 1.13 (LA-EP2006, n = 155) and 1.19 ± 0.98 (reference, n = 153) in cycle 1. With a treatment difference (reference minus LA-EP2006) of -0.16 days (90% CI -0.36 to 0.04; 95% CI -0.40 to 0.08), LA-EP2006 was equivalent to reference pegfilgrastim. Secondary efficacy parameters were similar between groups during cycle 1 and across cycles. Safety profiles were also similar between groups. No neutralizing antibodies against pegfilgrastim, filgrastim, or polyethylene glycol were detected. CONCLUSION: LA-EP2006 and reference pegfilgrastim were therapeutically equivalent and comparable regarding efficacy and safety in the prevention of neutropenia in patients with early-stage breast cancer receiving TAC. IMPLICATIONS FOR PRACTICE: The granulocyte colony-stimulating factor pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. Biosimilars are biologics with similar quality, safety, and efficacy to a reference product that may increase the affordability of treatment compared with their reference compounds. There are currently no approved biosimilars of pegfilgrastim in highly regulated markets. No previous phase III studies have been performed with LA-EP2006. PROTECT-2 was conducted to confirm the similarity of the proposed biosimilar LA-EP2006 to pegfilgrastim. Biosimilar pegfilgrastim (LA-EP2006) may benefit oncology patients by offering increased access to biological treatments that may improve clinical outcomes. This means that patients could potentially be treated prophylactically with biologics rather than only after complications have occurred.

Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer.

AIM: This randomized, double-blind trial compared proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer (PROTECT-1). PATIENTS & METHODS: Women (≥18 years) were randomized to receive LA-EP2006 (n = 159) or reference (n = 157) pegfilgrastim (Neulasta(®), Amgen) for ≤6 cycles of (neo)-adjuvant TAC chemotherapy. Primary end point was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 10(9)/l) with equivalence confirmed if 90% and 95% CIs were within a ±1 day margin. RESULTS: For DSN, LA-EP2006 was equivalent to reference (difference: 0.07 days; 90% CI: -0.09-0.23; 95% CI: -0.12-0.26). CONCLUSION: LA-EP2006 and reference pegfilgrastim showed no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving chemotherapy.

Meta-analysis of Pharmacokinetic/Pharmacodynamic Results of 3 Phase 1 Studies with Biosimilar Pegfilgrastim.

A meta-analysis using data from 3 phase 1 studies evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of Sandoz biosimilar versus US- and EU-reference pegfilgrastim. The studies included a single-dose, double-blind, 3-arm, parallel-group study (study 1); a single-dose, double-blind, 2-way crossover study (study 2); and a single-dose, double-blind, 3-way, 6-sequence crossover study (study 3). Healthy male and female subjects were randomized to receive the proposed biosimilar (all studies), US-reference biologic (studies 1 and 3), or EU-reference biologic (studies 1, 2, and 3). For PK parameters (area under the serum concentration-time curve from time of dosing and extrapolated to infinity, area under the serum concentration-time curve from the time of dosing to the last measurable concentration, and maximum observed serum concentration) and PD parameters (absolute neutrophil count area under the effect curve from the time of dosing to the last measurable concentration and maximum measured absolute neutrophil count) geometric mean ratios and 90% confidence intervals (CIs) for treatment comparisons were calculated using the meta-analysis approach with a fixed-effects model. PK/PD biosimilarity was concluded if the 90%CIs were within the equivalence margins of 0.80 to 1.25. The 90%CIs for the geometric mean ratios for the PK/PD parameters were all within the equivalence margins. Safety and tolerability were similar between the proposed biosimilar and the US- and EU-reference pegfilgrastim in healthy subjects. This meta-analysis of 3 phase 1 studies supports PK/PD similarity of Sandoz biosimilar pegfilgrastim to US- and EU-reference pegfilgrastim. No clinically meaningful differences in safety or tolerability were observed.

Use of the low-molecular-weight heparin reviparin to prevent deep-vein thrombosis after leg injury requiring immobilization.

BACKGROUND: Deep-vein thrombosis is a well-recognized complication after trauma to the legs and subsequent immobilization, but there are no generally accepted approaches to preventing this complication. METHODS: We performed a prospective, double-blind, placebo-controlled trial to evaluate the efficacy and safety of subcutaneous reviparin (1750 anti-Xa units given once daily) in 440 patients who required immobilization in a plaster cast or brace for at least five weeks after a leg fracture or rupture of the Achilles tendon. The study drug was given throughout the period of immobilization. Venography of the injured leg was performed within one week after removal of the plaster cast or brace, or earlier if there were symptoms suggesting deep-vein thrombosis. RESULTS: Data on efficacy and end points were available for 371 patients. Deep-vein thrombosis was diagnosed in 17 of the 183 patients randomly assigned to receive reviparin (9 percent) and in 35 of the 188 patients randomly assigned to receive placebo (19 percent) (odds ratio, 0.45; 95 percent confidence interval, 0.24 to 0.82). Most of the thromboses were distal (14 in the reviparin group and 25 in the placebo group). There were two cases of pulmonary embolism, both in patients in the placebo group who also had proximal deep-vein thrombosis. There were no differences between the two groups with respect to bleeding or other adverse events. CONCLUSIONS: Deep-vein thrombosis is common in persons with leg injury requiring prolonged immobilization. Reviparin given once daily appears to be effective and safe in reducing the risk of this complication.

Risk factors and coagulation parameters in relationship to phlebographic response and clinical outcome in the treatment of acute deep vein thrombosis.

Possible correlation of the effects of pharmacotherapy on the inhibition of the in-vivo generation of thrombin and on the prevention of thrombus extension in patients with deep vein thrombosis (DVT) could help to define patients at higher risk. Patients with symptomatic deep vein thrombosis confirmed by phlebography were randomised to intravenous unfractionated heparin (UFH), or a subcutaneous low-molecular-weight heparin (reviparin) twice daily for one week, or a subcutaneous reviparin once daily for four weeks. The patients were treated with oral anticoagulants for at least 3 months. Main endpoints were regression of thrombus on phlebography on Day 21 and recurrent symptomatic venous thromboembolism up to 3 months. Coagulation parameters, markers of in-vivo thrombin generation, and TFPI-release were determined at randomisation, weeks 1 and 3. Four hundred sixty six responders (reduction of at least 30 per cent in Marder score) and 419 non-responders (Marder score unchanged or changed less than +/-30%) showed no significantly different baseline characteristics. The non-responder group had a higher median Marder score at baseline and after one and three weeks of treatment, and had significantly higher fibrinogen levels, TAT complexes and F1+2 values than responders. There were no significant differences in coagulation parameters between non-responders and patients with asymptomatic + symptomatic VTE with the exception of higher TAT complexes at baseline. Significant differences in Marder score and coagulation parameters at baseline were found between responders and nonresponders. Non-responders have a higher risk tosuffer recurrent VTE and may need intensified treatment.

Darusentan: an effective endothelinA receptor antagonist for treatment of hypertension.

BACKGROUND: The antihypertensive efficacy and safety of darusentan, a new selective endothelin, antagonist was investigated. METHODS: In a multicenter randomized, double-blind, parallel-group, dose-response study, a 2-week placebo run-in period was followed by a 6-week treatment period and then a 2-week placebo withdrawal period. At baseline before darusentan therapy, the average blood pressure (BP) of the patient population studied was diastolic 103.49 (SD 3.55) and systolic 168.27 (SD 16.63) mm Hg. In total, 392 patients were randomized (darusentan 10 mg: 94 patients, 30 mg: 103 patients, 100 mg: 96 patients, placebo: 99 patients). RESULTS: Darusentan significantly reduced diastolic (mean difference to placebo: 10 mg: -3.7 mm Hg, 95% confidence interval (CI): -6.6, -0.9, P = .009; 30 mg: -4.9 mm Hg, 95% CI: -7.7, -2.2, P = .0005; 100 mg: -8.3 mm Hg, 95% CI: -11.1, -5.5, P = .0001) and systolic BP (mean difference to placebo: 10 mg: -6.0 mm Hg, 95% CI: -11.0, -0.9, P = .02; 30 mg: -7.3 mm Hg, 95% CI: - 12.3, -2.4, P = .004; 100 mg: - 11.3 mm Hg, 95% CI: -16.3, -6.2, P = .0001). Pulse rate remained unchanged in all groups. There was a trend toward more adverse events in the active treatment groups (placebo: 30.3%, 10 mg: 44.7%, 30 mg: 40.8%, 100 mg: 49.0%). Headache was the most commonly reported adverse event, with no relevant difference among treatments. Flushing and peripheral edema were seen in a dose-dependent fashion in the active treatment groups only. CONCLUSION: These data, the first, suggest the therapeutic benefit of selective endothelinA receptor antagonism in human hypertension.

Antihypertensive therapy with verapamil SR plus trandolapril versus atenolol plus chlorthalidone on glycemic control.

BACKGROUND: There is evidence that diuretics and beta blockers impair glucose tolerance, whereas calcium channel blockers and angiotensin converting enzyme blockers lack this metabolic effect. We compared the effect of a combination therapy with a nondihydropyridine calcium channel blocker plus an angiotensin converting enzyme inhibitor and a beta blocker plus a diuretic on hemoglobin A(1c) (Hb A(1c)) in patients with type 2 diabetes and mild-to- moderate hypertension. METHODS: A total of 463 hypertensive outpatients with non-insulin treated type 2 diabetes on stable antidiabetic therapy for at least 3 months and with HbA(1c) between 6.5% and 10% were recruited. In a randomized, double blind trial patients were treated for 20 weeks with fixed combinations of verapamil sustained release (SR) plus trandolapril and of atenolol plus chlorthalidone following a 2-week placebo run-in period. The main outcome measures were HbA(1c), fasting plasma glucose, and fructosamine levels as well as systolic and diastolic blood pressure. RESULTS: HbA(1c) remained stable at 7.9% after administration of verapamil SR plus trandolapril and increased from 7.8% to 8.6% with atenolol plus chlorthalidone; the differences between treatment groups were significant at 4, 12, and 20 weeks of treatment and at last visit (P <.0001). Mean blood pressure fell from 169/96 to 150/85 and from 168/95 to 145/83 mm Hg after administration of verapamil SR plus trandolapril and atenolol plus chlorthalidone, respectively. Both combinations were well tolerated. CONCLUSIONS: HbA(1c) and other parameters of short- and long-term glycemic control were in a more favorable range after antihypertensive treatment with verapamil SR plus trandolapril as compared with atenolol plus chlorthalidone.

The effects of the spleen tyrosine kinase inhibitor fostamatinib on ambulatory blood pressure in patients with active rheumatoid arthritis: results of the OSKIRA-ABPM (ambulatory blood pressure monitoring) randomized trial.

Clinical trials of fostamatinib in patients with rheumatoid arthritis showed blood pressure (BP) elevation using clinic measurements. The OSKIRA-ambulatory BP monitoring trial assessed the effect of fostamatinib on 24-hour ambulatory systolic BP (SBP) in patients with active rheumatoid arthritis. One hundred thirty-five patients were randomized to fostamatinib 100 mg twice daily (bid; n = 68) or placebo bid (n = 67) for 28 days. Ambulatory, clinic, and home BPs were measured at baseline and after 28 days of therapy. Primary end point was change from baseline in 24-hour mean SBP. Fostamatinib increased 24-hour mean SBP by 2.9 mm Hg (P = .023) and diastolic BP (DBP) by 3.5 mm Hg (P < .001) versus placebo. Clinic/home-measured BPs were similar to those observed with ambulatory BP monitoring. After treatment discontinuation (1 week), clinic BP values returned to baseline levels. Fostamatinib induced elevations in 24-hour mean ambulatory SBP and DBP. BP elevations resolved with fostamatinib discontinuation.

Cardio-renal effects of the A1 adenosine receptor antagonist SLV320 in patients with heart failure.

BACKGROUND: Blocking the tubuloglomerular feedback mechanism with adenosine A1 receptor antagonists seems to improve diuresis and sodium excretion without compromising the glomerular filtration rate in patients with heart failure. However, the direct cardiac effects of this compound class have not been investigated to date. METHODS AND RESULTS: In total, 111 patients (109 men and 2 women) received a 1-hour infusion of 5, 10, and 15 mg SLV320, an adenosine A1 receptor antagonist, placebo, or 40 mg furosemide. Mean age was 57.9 years, mean ejection fraction was 28.1%, 82 patients were of New York Heart Association class II, and 29 patients were of New York Heart Association class III. Hemodynamic parameters (heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, systemic vascular resistance, right atrial pressure, and cardiac output) were determined. Kidney function was assessed by cystatin C measurements and by analysis of urine output and urine electrolytes. In addition, pharmacokinetics of SLV320 and ex vivo inhibition of adenosine A1 receptor activity were performed. SLV320 was well tolerated, and no serious adverse events were observed. Heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, right atrial pressure, and cardiac output were not altered by any dose of SLV320. Pulmonary capillary wedge pressure was significantly (P=0.04) decreased by furosemide (-6.2+/-5.9 mm Hg). Systemic vascular resistance was significantly (P=0.04) increased in the furosemide group (+166.70+/-261.87 dynes . s(-1) . cm(-5)), whereas all SLV320 groups showed no significant alterations of systemic vascular resistance. Changes from baseline cystatin C plasma concentrations decreased after 10 mg SLV320 (-0.093+/-0.137 mg/L, P=0.046), whereas furosemide resulted in a significant (P=0.03) increase of cystatin C (+0.052+/-0.065 mg/L) versus baseline. All values represent mean changes+/-SD from baseline at 3 hours postdosing: SLV320 (10 and 15 mg) increased significantly sodium excretion and diuresis compared with placebo during the 0- to 6-hour collection period postdosing. CONCLUSIONS: SLV320 infusion shows no immediate effects on cardiac hemodynamics. SLV320 might improve glomerular filtration rate while simultaneously promoting natriuresis and diuresis. Clinical Trial Registration- clinicaltrials.gov Indentifier: NCT00160134.

Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin.

The frequency of heparin-induced thrombocytopenia (HIT) varies between different clinical treatment settings and remains unknown for patients treated with unfractionated (UFH) or low-molecular-weight heparin (LMWH) because of deep vein thrombosis. In this multicentre, open-label study, 1137 patients with deep vein thrombosis were randomly assigned to UFH for 5-7 d, reviparin, a LMWH, for 5-7 d (short-treated group) or reviparin for 28 d (long-treated group). Heparin-platelet factor 4 antibodies (HPF4-A) were determined on d 5-7 and d 21. Heparin-induced thrombocytopenia was defined by clinical evaluation. Two patients in the UFH group (incidence: 0.53%, 95% confidence interval (CI): 0.06-1.91) and two patients in the long-treated LMWH group (incidence: 0.53%, 95% CI: 0.06-1.92) had HIT, while no HIT was observed in the short-treated LMWH group. Pulmonary embolism developed in one of the HIT-patients, who had HPF4-A and was treated with UFH. On d 5-7 the incidence of HPF4-A was 9.1% in the UFH group, 2.8% in the short-treated LMWH group and 3.7% in the long-treated LMWH group, with a significant increase to 20.7% in the UFH group and to 7.5% in the long-treated LMWH group on d 21. Therefore the incidence of HPF4-A and heparin-induced thrombocytopenia was lower in patients treated with LMWH compared with UFH for the same duration of treatment.

Randomized trial of different regimens of heparins and in vivo thrombin generation in acute deep vein thrombosis.

Low-molecular-weight and unfractionated heparins are frequently used to treat venous thromboembolism, but it is not known whether they are equally effective in inhibiting in vivo generation of thrombin. In this multicenter trial, 1048 patients were randomized to intravenous unfractionated heparin (group A), twice daily low-molecular-weight heparin (reviparin) for 1 week (group B), or once daily reviparin for 4 weeks (group C). All patients received vitamin K antagonists. Blood samples withdrawn at the baseline and at weeks 1 and 3 were analyzed using markers of in vivo thrombin generation and other coagulation parameters. During the first 3 weeks symptomatic recurrent deep vein thrombosis-pulmonary embolism (DVT/PE) occurred in 17 (4.5%) of 375 patients in group A compared with 4 (1.0%) of 388 patients in group B, and 9 (2.4%) of 374 patients in group C. Forty percent of patients in group A, 53.4% in group B, and 53.5% in group C showed 30% or greater reduction in thrombus size assessed by venography. Patients in group B had significantly greater reduction in D-dimer, prothrombin fragments 1 and 2 (F1 + 2), endogenous thrombin potential (ETP), and thrombin-antithrombin (TAT) complexes compared to groups A and C. Greater release of tissue factor pathway inhibitor (TFPI) and reduction in levels of thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen were significantly more pronounced in group C patients. Reviparin administered twice daily plus vitamin K antagonist is more effective in inhibiting in vivo thrombin generation compared to intravenous unfractionated heparin plus vitamin K antagonist, and reviparin once daily produced significantly higher TFPI release and greater reduction in TAFI and fibrinogen levels.