Objectives. This study aimed to evaluate the efficacy and safety of once-per-cycle balugrastim versus pegfilgrastim for neutrophil support in breast cancer patients receiving myelosuppressive chemotherapy. Methods. Breast cancer patients (n 5 256) were randomized to 40 or 50 mg of subcutaneous balugrastim or 6 mg of pegfilgrastim 24 hours after chemotherapy (60 mg/m 2 doxorubicin and 75 mg/m 2 docetaxel, every 21 days for up to 4 cycles). The primary efficacy parameter was the duration of severe neutropenia (DSN) in cycle 1. Secondary parameters included DSN (cycles 2-4), absolute neutrophil count (ANC) nadir, febrile neutropenia rates, and time to ANC recovery (cycles 1-4). Safety, pharmacokinetics, and immunogenicity were assessed.Results. Mean cycle 1 DSN was 1.0 day with 40 mg of balugrastim, 1.3with50mgofbalugrastim,and1.2withpegfilgrastim(upperlimit of 95% confidence intervals for between-group DSN differences was ,1.0 day for both balugrastim doses versus pegfilgrastim). Between-group efficacy parameters were comparable except for time to ANC recovery in cycle 1 (40 mg of balugrastim, 2.0 days; 50 mg of balugrastim, 2.1; pegfilgrastim, 2.6). Median terminal elimination half-life was 37 hours for 40 mg of balugrastim, 36 for 50 mg of balugrastim, and 45 for pegfilgrastim. Antibody response to balugrastim was low and transient, with no neutralizing effect. Conclusion. Once-per-cycle balugrastim is not inferior to pegfilgrastim in reducing cycle 1 DSN in breast cancer patients receiving chemotherapy; both drugs have comparable safety profiles. The Oncologist 2016;21:7-15 Implications for Practice: This paper provides efficacy and safety data for a new, once-per-cycle granulocyte colony-stimulating factor, balugrastim, for the prevention of chemotherapy-induced neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. In this phase III trial, balugrastim was shown to be not inferior to pegfilgrastim in the duration of severe neutropenia in cycle 1 of doxorubicin/docetaxel chemotherapy, and the safety profiles of the two agents were similar. Once-per-cycle balugrastim is a safe and effective alternative to pegfilgrastim for hematopoietic support in patients with breast cancer receiving myelosuppressive chemotherapy associated with a greater than 20% risk of developing febrile neutropenia.

Rasagiline is a selective, monoamine oxidase (MAO)-B inhibitor indicated for treatment of Parkinson's disease. This double-blind, placebo-controlled study determined the tyramine sensitivity factor (TSF) and degree of MAO-A inhibition (ie, reduction in plasma dihydroxyphenylglycol) in healthy volunteers who received phenelzine (15 mg, 3 times daily; positive control), selegiline (5 mg, twice daily), or rasagiline (1-6 mg, once daily) for 14 days or rasagiline 2 mg/d for 30 days. The selegiline/rasagiline groups were randomized to placebo or active drug. TSF was highest with phenelzine (17.3) and lowest with placebo (1.5). TSF with selegiline was 2.5. TSFs for rasagiline were as follows: 2.0 for 1 mg/d; 3.3 and 2.4 for 2 mg/d administered for 14 and 30 days, respectively; 4.5 for 4 mg/d; and 5.1 for 6 mg/d. Plasma dihydroxyphenylglycol concentrations suggested that rasagiline 1 mg/d had no effect, whereas rasagiline 2 mg/d had only minimal effect. In contrast, rasagiline 4 and 6 mg/d reduced dihydroxyphenylglycol to a degree approaching that achieved by the positive control phenelzine. Results demonstrate that rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the indicated dose (1 mg/d). These data allowed removal of dietary tyramine restriction from rasagiline US labeling.

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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.

Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87% ) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p = 0.003). ON time with no/mild dyskinesia was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p <  0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[– 1.8, – 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (– 2.8[– 4.6, – 0.9] hours; p = 0.004) than in the 14-hour group (– 1.3[– 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. Conclusion: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.