A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo

Background: Cycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points. Methods/Design: 3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids. Discussion: This study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens. Trial registration: clinical trials.gov NCT0037767

A Phase III, Randomized, Multi-Center, Open-Label, Fixed Dose, Neulasta Active-Controlled Clinical Trial of F-627, a Novel G-CSF, in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

Abstract Background - Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients receiving myelotoxic chemotherapy which is associated with increased morbidity and early mortality. Ryzneuta TM (F-627), a recombinant fusion protein containing human granulocyte-colony stimulating factor (G-CSF) and IgG2-Fc fragment, is intended to reduce CIN by utilizing the neutrophilic proliferating and activating properties of G-CSF. F-627 was designed as a novel, non-pegylated molecule with dimeric G-CSF, which may possess stronger G-CSF receptor activating properties and improved efficacy compared to filgrastim and pegfilgrastim. The primary objective of this study was to evaluate the safety and efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe (PFS) as compared to Neulasta® (6 mg) in the first chemotherapy cycle. Methods - This was a phase III, multi-center, randomized, open-label, two-arm, active-controlled study that randomized female patients with Stage I to III invasive breast cancer who received 4 cycles of myelotoxic taxane + cyclophosphamide chemotherapy treatment. Forty-one (41) sites across 5 countries participated in the trial, including Bulgaria, Hungary, Russia, Ukraine, and US. Patients were randomized to F-627 or Neulasta® in a 1:1 ratio on the day of chemotherapy and administered study drug 24 hours after chemotherapy administration in each cycle. A total of 393 patients were randomized and analyzed for efficacy and safety. Clinical assessments were cycle-specific and included physical examination, serum samples for immunogenicity before each chemotherapy cycle, laboratory assessments, hematology and CBC with differentials, urinalysis, body weight, vital signs, adverse event (AE) collection, and concomitant medications. The pharmacokinetics (PK) and the pharmacodynamics (PD) of F-627 were also assessed. The primary efficacy endpoint was the duration in days of Grade 4 (severe) neutropenia (ANC &amp;lt;0.5 × 10 9/L) during cycle 1 of chemotherapy. Results - The mean duration of Grade 4 neutropenia in chemotherapy cycle 1 was 0.2 days for both F-627 and Neulasta®. F-627 was non-inferior compared to Neulasta® for the duration of Grade 4 neutropenia in chemotherapy cycle 1 with a mean difference of 0.0 days (95% CI: -0.1, 0.1), utilizing a non-inferiority margin of 0.6 days. The incidence of Grade 4 neutropenia in chemotherapy cycle 1 was comparable between F-627 and Neulasta®, 11.7% for both treatment groups. For chemotherapy cycles 2, 3, and 4, the incidence and duration of Grade 4 neutropenia was generally lower than in chemotherapy cycle 1. The mean durations of Grade 4 neutropenia were 0.1, 0.0, and 0.0 days for F-627 and 0.1, 0.1, and 0.1 days for Neulasta® in chemotherapy cycles 2,3,4, respectively. The incidence of Grade 4 neutropenia was 4.6%, 2.6%, and 1.6% for F-627 and 5.1%, 6.3%, and 5.3% for Neulasta® in chemotherapy cycles 2, 3, and 4, respectively. Across all chemotherapy cycles and for each chemotherapy cycle, the mean duration and the incidence of IV antibiotic use and hospitalization due to febrile neutropenia or any infection were low and comparable between F-627 and Neulasta®. The depth of ANC nadir was comparable in each chemotherapy cycle between F-627 and Neulasta®. For each chemotherapy cycle, time to ANC nadir was slightly longer for patients treated with F-627 than those with Neulasta®; the mean time to ANC nadir was 6.4, 6.1, 6.2, and 6.2 days for F-627, compared to 6.1,5.3, 5.7, and 5.5 days for Neulasta® in cycles 1, 2, 3, and 4, respectively. F-627 was well tolerated, with a low incidence of serious AEs and AEs leading to discontinuation, comparable to the profile for Neulasta®. There were 3 deaths during the study (1 for F-627 and 2 for Neulasta®). None of the deaths were related to study drug treatment. Clinical laboratory abnormalities were observed to be similar between the two treatment groups. Conclusion - Once-per-cycle F-627, given as a fixed 20 mg dose, was non-inferior to Neulasta® in reducing the duration of severe neutropenia following TC chemotherapy. F-627 was well tolerated during the study with an overall safety profile comparable to that for Neulasta®. F-627 is a safe, effective, and easy to use alternative to current CIN therapy. Disclosures Daley: Evive: Current Employment, Current holder of stock options in a privately-held company. Chen: Evive: Current Employment. </jats:sec

A Phase II, Randomized, Multi-Centre, Open-Label, Active-Controlled, Dose-Finding Trial of F-627 (benefilgrastim) in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

Abstract Neutropenia is common in patients receiving myelotoxic chemotherapy. Benefilgrastim, an rhG-CSF dimer (rhG-CSF-FC fusion protein), is a once-per-cycle therapy for prophylactic neutrophil support. In this Phase II trial, 230 women with stage I-IV breast cancer are to be treated for 4 chemotherapy cycles with either docetaxel/cyclophosphamide (TC) or doxorubicin/docetaxel/cyclophosphamide (TAC) chemotherapy, with each cycle lasting approximately 21 days. Patients will be randomized to receive either benefilgrastim or pegfilgrastim (Neulasta; 6 mg fixed dose) one day after chemotherapy during each cycle, as a subcutaneous injection. Dose levels of benefilgrastim examined are 80 µg/kg (TC patients only), and 240 and 320 µg/kg (TC and TAC patients). The primary endpoint is the duration of grade 3/4 neutropenia in chemotherapy cycle 1. As of August 1, 2014, 232 patients have completed chemotherapy cycle 1; safety and efficacy were analyzed for these enrolled patients. For the TC chemotherapy regimen, a total of 141 patients were randomized (ratio = 1:1:1:1) into 4 arms (80, 240, and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). In the TAC chemotherapy regimen, a total of 91 patients were randomized (ratio = 1:1:1) into 3 arms (240 and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). The incidence of grade 3/4 and grade 4 neutropenia and their mean durations in cycle 1 are provided in Table 1. There were higher incidences of grade 3/4 and grade 4 neutropenia in the TAC regimen compared to the TC regimen. The safety profiles of benefilgrastim and pegfilgrastim were similar. A total of 10 SAEs were reported in 6 patients with the majority (7 SAEs in 4 patients) occurring in those receiving pegfilgrastim. The most commonly observed treatment emergent adverse events (&gt;10% of total TC + TAC patients) were: alopecia, nausea, asthenia, neutropenia, bone pain, and fatigue. The rates were similar amongst treatment regimens and treatment groups. In summary, a single subcutaneous injection of benefilgrastim 240 or 320 µg/kg provided neutrophil support to patients treated with both the TC and TAC chemotherapy regimens. The safety profile of benefilgrastim was comparable to that of pegfilgrastim during multiple chemotherapy cycles. The results suggest a potential use of benefilgrastim for the management of severe neutropenia in cancer patients undergoing high dose chemotherapy. Abstract 1584. Table 1: Preliminary Results TC Regimen TAC Regimen Benefilgrastim Pegfilgrastim 6 mg (N=35) Benefilgrastim Pegfilgrastim 6 mg (N=29) 80 µg/kg (N=35) 240 µg/kg (N=37) 320 µg/kg (N=34) 240 µg/kg (N=29) 320 µg/kg (N=30) Grade 3/4 neutropenia n/N (%) 10/35 (28.6) 10/37 (27.0) 7/34 (20.6) 7/35 (20.0) 17/25 (68.0) 19/26 (73.1) 17/24 (70.8) Duration (days) Mean (SD) 95% CI 2.4 (2.07) 1.2, 3.6 2.2 (0.79) 1.7, 2.7 1.9 (0.38) 1.6, 2.1 1.4 (0.79) 0.9, 2.0 2.8 (1.67) 2.1, 3.5 2.6 (1.07) 2.2, 3.1 2.2 (0.73) 1.9, 2.5 Grade 4 neutropenia n/N (%) 4/35 (11.4) 7/37 (18.9) 6/34 (17.6) 3/35 (8.6) 14/25 (56.0) 17/26 (65.4) 15/24 (62.5) Duration (days) Mean (SD) 95% CI 2.0 (1.15) 0.6, 3.4 2.1 (0.90) 1.5, 2.8 1.2 (0.41) 0.8, 1.5 1.0 (0.00) 1.0, 1.0 1.9 (1.33) 1.3, 2.6 2.0 (0.87) 1.6, 2.4 1.5 (0.64) 1.2, 1.8 SAEs n (%) # SAEs 0 0 1 (2.7) 1 0 0 2 (5.7) 3 0 0 1 (3.3) 2 2 (6.9) 4 CI=confidence interval; SAE=serious adverse event; SD=standard deviation Disclosures Glaspy: Generon (Shanghai) Corporation Ltd.: Research Funding. Tang:Generon (Shanghai) Corporation Ltd.: Employment. Rutty:Everest Clinical Research Services Inc.: Employment; Generon (Shanghai) Corporation Ltd.: Consultancy; Schering Corporation: Consultancy; Roche: Consultancy; Methylgene: Consultancy; Steba Biotech SA: Consultancy; Aderans Research Institute Inc: Consultancy; Stem Cell Theraputics: Consultancy; Genentech: Consultancy; Pearly Therapeutics: Consultancy; Sundise Chinese Medicine Technology Development Corp: Consultancy; Endocyte, Inc: Consultancy; Hutchison Medipharma: Consultancy; Nutrition Science Partners Limited: Consultancy. Yan:Generon (Shanghai) Corporation Ltd.: Employment. </jats:sec

Timed Bromocriptine-QR Therapy Reduces Progression of Cardiovascular Disease and Dysglycemia in Subjects with Well-Controlled Type 2 Diabetes Mellitus

Background. Type 2 diabetes (T2DM) patients, including those in good glycemic control, have an increased risk of cardiovascular disease (CVD). Maintaining good glycemic control may reduce long-term CVD risk. However, other risk factors such as elevated vascular sympathetic tone and/or endothelial dysfunction may be stronger potentiators of CVD. This study evaluated the impact of bromocriptine-QR, a sympatholytic dopamine D2 receptor agonist, on progression of metabolic disease and CVD in T2DM subjects in good glycemic control (HbA1c ≤7.0%). Methods. 1834 subjects (1219 bromocriptine-QR; 615 placebo) with baseline HbA1c ≤7.0% derived from the Cycloset Safety Trial (this trial is registered with ClinicalTrials.gov Identifier: NCT00377676), a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were evaluated. Treatment impact upon a prespecified composite CVD endpoint (first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina/congestive heart failure) and the odds of losing glycemic control (HbA1c >7.0% after 52 weeks of therapy) were determined. Results. Bromocriptine-QR reduced the CVD endpoint by 48% (intention-to-treat; HR: 0.52 [0.28−0.98]) and 52% (on-treatment analysis; HR: 0.48 [0.24−0.95]). Bromocriptine-QR also reduced the odds of both losing glycemic control (OR: 0.63 (0.47−0.85), p=0.002) and requiring treatment intensification to maintain HbA1c ≤7.0% (OR: 0.46 (0.31−0.69), p=0.0002). Conclusions. Bromocriptine-QR therapy slowed the progression of CVD and metabolic disease in T2DM subjects in good glycemic control

Efbemalenograstim alfa, an Fc fusion protein, long-acting granulocyte-colony stimulating factor for reducing the risk of febrile neutropenia following chemotherapy: results of a phase III trial.

PURPOSE: Evaluate the safety and efficacy of efbemalenograstim alfa for reducing the risk of febrile neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy. METHODS: A phase III, randomized, double-blind, placebo-controlled study was conducted. A total of 122 subjects received up to 4 cycles of TA chemotherapy (75&nbsp;mg/m2 docetaxel + 60&nbsp;mg/m2 doxorubicin). Patients were randomized in a 2:1 ratio to subcutaneously inject a single 20&nbsp;mg of efbemalenograstim alfa or placebo on day 2 of cycle 1, and all subjects received efbemalenograstim alfa on day 2 of cycles 2, 3, and 4. Duration of severe (grade 4) neutropenia (DSN), depth of neutrophil nadir, incidence of febrile neutropenia (FN), time to neutrophil recovery, and safety information were recorded. RESULTS: For the primary endpoint, the mean DSN in cycle 1 was 1.3&nbsp;days and 3.9&nbsp;days for efbemalenograstim alfa and placebo respectively (95% CI, 2.3, 3.4). As the lower bound of the 95% CI was &gt; 0, superiority of efbemalenograstim alfa over placebo can be declared. In addition, the incidence of FN in Cycle 1 was lower in efbemalenograstim alfa group than in placebo group (4.8% vs. 25.6%; p = 0.0016). Patients in the efbemalenograstim alfa group required less intravenous antibiotics (3.6% vs. 17.9%; p = 0.0119). Most adverse events were consistent with those expected for breast cancer patient receiving TA chemotherapy. CONCLUSION: Efbemalenograstim alfa is effective and safe for significantly decreasing the duration of severe neutropenia and the incidence of febrile neutropenia in breast cancer patients who are receiving TA chemotherapy. TRIAL REGISTRATION: NCT02872103, August 19, 2016

Efbemalenograstim alfa not inferior to pegfilgrastim in providing neutrophil support in women with breast cancer undergoing myelotoxic chemotherapy: results of a phase 2 randomized, multicenter, open-label trial.

PURPOSE: Evaluate the safety and efficacy of efbemalenograstim alfa for neutrophil support in breast cancer patients undergoing myelosuppressive chemotherapy in a phase 2, dose-finding, open-label study (NCT01648322, ClinicalTrials.gov, 2012-07-19). METHODS: 232 patients received up to 4 cycles of chemotherapy, 141 patients with docetaxel + cyclophosphamide (TC) and 91 patients with docetaxel + doxorubicin + cyclophosphamide (TAC). Patients were randomized to efbemalenograstim alfa (80, 240, or 320&nbsp;µg/kg [TC]; 240&nbsp;or 320&nbsp;µg/kg [TAC]) or pegfilgrastim (6&nbsp;mg) on Day 2 of each cycle. RESULTS: Efbemalenograstim alfa was non-inferior to pegfilgrastim in duration of moderate and severe neutropenia (absolute neutrophil count [ANC] &lt; 1.0 × 109/L) in TAC Cycle 1 (mean [SD] of 2.1 [1.58] and 2.1 [1.46] days for 240&nbsp;µg/kg and 320&nbsp;µg/kg efbemalenograstim alfa, respectively, and 1.8 [1.28] days for pegfilgrastim), with a difference (95% CI) of 0.3 (-0.4, 1.1) days. ANC nadir occurred between Days 7-8 of TAC Cycle 1, with mean [SD] of 0.68 [1.064], 0.86 [1.407] and 0.78[1.283] × 109/L for 240&nbsp;µg/kg, 320&nbsp;µg/kg efbemalenograstim alfa and pegfilgrastim, respectively. Time to ANC recovery post nadir (defined as an ANC &gt; 2.0 × 109/L after the expected ANC nadir) was 2.0-2.4 and 1.9&nbsp;days for TAC patients treated with efbemalenograstim alfa and pegfilgrastim, respectively. No significant difference was found between any dose of efbemalenograstim alfa and pegfilgrastim in TAC Cycle 1 for incidence of moderate to severe neutropenia (76%-77% of patients) or incidence of severe neutropenia (ANC &lt; 0.5 × 109/L; 63%-72%). Efbemalenograstim alfa exhibited similar safety profile to pegfilgrastim. Febrile neutropenia occurred in 4 (1.8%) patients, 2 patients each for 320&nbsp;µg/kg efbemalenograstim alfa and pegfilgrastim, with no event considered related to study drug. CONCLUSION: Efbemalenograstim alfa was comparable to pegfilgrastim in efficacy and safety. GOV IDENTIFIER: NCT01648322