Purpose: This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer. Patients and methods: Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks). Results: A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was −1.6 (CI −9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%). Conclusions: MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints. Trial Registry Information EU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32 Plain language summary Previous studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O ( n = 337) demonstrated comparable efficacy to bevacizumab ( n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was −1.6 (95% CI −9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months ( p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

Aims To report phase 1 bioequivalence results comparing MYL‐1501D, US reference insulin glargine (US IG), and European reference insulin glargine (EU IG). Materials and methods The double‐blind, randomized, three‐way crossover study compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MYL‐1501D, US IG and EU IG. In total, 114 patients with type 1 diabetes (T1DM) received 0.4 U/kg of each study treatment under automated euglycaemic clamp conditions. Insulin metabolite M1 concentrations, insulin glargine (IG) and glucose infusion rates (GIRs) were assessed over 30 hours. Primary PK endpoints were area under the serum IG concentration–time curve from 0 to 30 hours (AUCins.0–30h) and maximum serum IG concentration (Cins.max). Primary PD endpoints were area under the GIR–time curve from 0 to 30 hours (AUCGIR0–30h) and maximum GIR (GIRmax). Results Bioequivalence among MYL‐1501D, US IG and EU IG was demonstrated for the primary PK and PD endpoints. Least squares mean ratios were close to 1, and 90% confidence intervals were within 0.80 to 1.25. The PD GIR–time profiles were nearly superimposable. There were no noticeable differences in the safety profiles of the three treatments, and no serious adverse events were reported. Conclusions Equivalence with regard to PK and PD characteristics was shown among MYL‐1501D, US IG and EU IG in patients with T1DM, and each treatment was well tolerated and safe.

MYL-1401O was well tolerated and demonstrated PK and safety profiles similar to EU-trastuzumab and US-trastuzumab in healthy volunteers (ClinicalTrials.gov, NCT02594761).

BACKGROUND: Nebivolol (N) is believed to be a unique cardiovascular agent studied worldwide for the treatment of HTN, CHF and other cardiovascular conditions owing to its vascular endothelial nitric oxide modulating capabilities and its highly selective ␤ 1antagonism. It is extensively metabolized with Ͻ0.1% of unchanged nebivolol excreted in urine. The present study examined what effect, if any, renal impairment has on oral N or its separate enantiomers.METHODS: Twenty-one subjects were divided into 3 renal impairment categories (mild, moderate, severe) based upon either measured (24-hour urine collection) or calculated (by Cockroft-Gault equation) creatinine clearance. Four healthy subjects, matched for age, gender, weight, and smoking habit, were selected as a control group.RESULTS: N (5 mg) was well tolerated with C max and T max being comparable across renal function classifications. Similar results were seen for the enantiomers and the active nebivolol glucuronide metabolites.

Background MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. Methods INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti–host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). Results Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999). Conclusions In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. Trial registration ClinicalTrials.gov, INSTRIDE 1 (NCT02227862; date of registration, August 28, 2014); INSTRIDE 2 (NCT02227875; date of registration, August 28, 2014).

Background Nebivolol (N) has been shown through a number of studies to be a cardioselective β1‐antagonist with vascular endothelial nitric oxide releasing capabilities that exhibits CYP2D6‐mediated polymorphic metabolism. Losartan (L), an ARB, is extensively metabolized by CYP2C9 (a known polymorphic enzyme) and is likely to be used concomitantly. This study examined if co‐administration of N and L alters the pharmacokinetic (PK) characteristics of either agent, or the active metabolite of L, EXP‐3174. Methods This open‐label study was conducted in 24 subjects, genotyped for CYP2D6 status (EM n=20; PM n=4). Using a two‐sequence, two‐treatment design, single doses of 10 mg N (Day 1 or 29), 50 mg L (Day 1 or 29), or their combination (Day 15) were given. Blood samples for PK assessment were taken on Days 1, 15 and 29. Results (see Table) Conclusion There were no clinically meaningful changes observed in the PK of either L or N, confirming that the two agents should be capable of being safely co‐administered. Clinical Pharmacology & Therapeutics (2005) 77, P82–P82; doi: Cmax AUC0‐∞ Parameter Ratio 90% CI Ratio 90% CI EM‐N0.800.68–0.930.890.82–0.97PM‐N0.930.76–1.140.940.68–1.29L0.890.77–1.020.860.81–0.92EXP‐31740.940.86–1.030.980.94–1.02

Background Nebivolol (N) is considered a unique racemic cardio‐selective β1‐antagonist with vascular endothelial nitric oxide modulating capabilities that undergoes extensive metabolism to active moieties via the CYP2D6 enzymatic pathway. Fluoxetine (F), one of the most studied potent inhibitors and substrates of CYP2D6 enzyme used clinically, was selected to assess the potential interactions with N. Methods Ten CYP2D6 extensive metabolizers (EM) received an oral 10 mg dose of N on Day 1, an oral 20 mg dose of F QD on Days 8 through 27, and 10 mg N plus 20 mg F on Day 28. PK estimates for N were assessed. Results (see Table) Co‐administration of N with F was well tolerated. Conclusions The results confirm N's reliance on the CYP2D6 enzymatic pathway for elimination. The elevated N plasma concentrations seen with the co‐administration of F were considerably lower than the clinically safe and well‐tolerated levels of N alone previously observed in poor metabolizer subjects (AUC∞: 614 ng·hr/mL; Cmax: 9.21 ng/mL). Clinical Pharmacology & Therapeutics (2005) 77, P38–P38; doi: Parameter Day 1 Day 28 Ratio 90% CI AUC∞ (ng hr/mL)13.8792.336.024.57–7.91Cmax (ng/mL)2.335.452.271.83–2.80Tmax (hr)1.302.602.001.58–2.42t1/2 (hr)12.5117.451.401.07–1.72Cl/F (L/hr)787.0142.90.180.014–0.35

Aim: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence (BE) of MYL-1601D biosimilar with originator, NovoLog (Ref-InsAsp-US), and NovoRapid (Ref-InsAsp-EU).Materials and Methods: This was a double-blind, randomized, crossover study that enrolled 71 healthy subjects to receive a single subcutaneous dose (0.2 U/kg) of each formulation under automated euglycaemic clamp conditions (ClampArt, level 81 mg/dL, duration 12 hours postdose). Primary PK endpoints were area under the plasma insulin aspart concentration-time curve from 0 to 12 hours (AUC 0-12h ) and maximum plasma insulin aspart concentration (C max ). Primary PD endpoints were area under the glucose infusion rate (GIR) time curve from 0 to 12 hours (AUC GIR0-12h ) and maximum GIR (GIR max ). Insulin aspart in plasma was quantified using immunoaffinity purification followed by ultraperformance liquid chromatography and tandem mass spectrometric detection. The pairwise comparisons of geometric least square mean (LS-mean) ratio for a 90% confidence interval (CI) of primary PK, and 90% CIs (MYL-1601D vs. Ref-InsAsp-US) and 95% CIs (MYL-1601D vs. Ref-InsAsp-EU) of primary PD variables, were to be within 80% to 125% to show BE.Results: MYL-1601D showed PK BE to both Ref-InsAsp-US (AUC 0-12h geometric LS-mean ratio 102.17, 90% CI [100.26; 104.11]; C max 106.13 [100.71; 111.85]) and Ref-InsAsp-EU