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INTRODUCTION Biological therapies such as bevacizumab have improved survival in patients with non-small-cell lung cancer (NSCLC). This study was conducted to confirm equivalent efficacy of the biosimilar candidate BI 695502 to bevacizumab reference product (RP). METHODS In this phase III, multicenter, randomized, double-blind trial, adult patients with recurrent or metastatic NSCLC received up to 18 weeks of induction treatment with BI 695502 or bevacizumab RP 15 mg/kg plus paclitaxel and carboplatin. Subsequent maintenance therapy comprised BI 695502 or bevacizumab RP monotherapy until disease progression or unacceptable toxicity. The primary endpoint was best overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 assessed by central imaging review, until 18 weeks after the start of treatment. RESULTS In total, 671 patients were randomized 1:1 to BI 695502 or bevacizumab RP, of whom 335 and 328, respectively, received treatment. Of these, 228 (68.1%) and 256 (78.0%), respectively, proceeded to maintenance monotherapy. A manufacturing issue led to a small number of patients treated with BI 695502 switching to bevacizumab RP late in the study. The primary endpoint, best ORR, was 54.0% in the BI 695502 group and 63.1% in the bevacizumab RP group. The 90% confidence interval for the between-group ratio of best ORR (0.770–0.951) was within the pre-specified range for equivalence (0.736–1.359). Adverse events were class-related and similar between the two treatment arms. CONCLUSIONS This study demonstrated equivalent ORR after 18 weeks of treatment with BI 695502 or bevacizumab RP, with similar adverse event profiles.

This Phase I trial (INVICTAN®-1) evaluated three-way bioequivalence and safety of BI 695502 a bevacizumab biosimilar candidate, and reference product bevacizumab from two sources (US-approved Avastin®, Genentech; EU-approved Avastin, Roche).Healthy male subjects (N = 91) were randomized 1:1:1 to receive a single intravenous infusion of 1 mg/kg of BI 695502 or US- or EU-approved Avastin. An interim analysis was planned when ~50% of subjects were evaluable for the primary end point to determine if the prespecified criteria for bioequivalence were achieved; if demonstrated, the study could be stopped early. The primary end point was area under the concentration-time curve (AUC) of the analyte in plasma from time zero extrapolated to infinity (AUCThe interim analysis demonstrated three-way bioequivalence for all comparisons. The confidence intervals around the geometric mean ratios of the primary and secondary PK parameters were within the predefined acceptance ranges. Study drugs were well tolerated with no clinically relevant differences in safety.BI 695502 and US- and EU-approved Avastin showed three-way bioequivalence with similar safety profile.NCT01608087.

Bird embryos are exposed to maternal androgens deposited in the egg, but the role of these hormones in embryonic development and hatchling survival is unclear. To identify possible target organs, we used in situ hybridization to study the distribution of androgen receptor (AR) RNA in the developing zebra finch brain. The first brain expression domain of AR mRNA is in the hindbrain. From embryonic day 7 (E7) onward, when the hypoglossal motor nucleus (nXII) has just formed, there was AR mRNA expression in both its lingual (nXIII) and its tracheosyringeal (nXIIts) parts, and this was the major site of hindbrain expression at all embryonic stages and in both sexes. From E8 onward, we also found AR mRNA in the supraspinal motor nucleus (nSSp), which innervates neck muscles. Furthermore, the syrinx, the target of the nXIIts, contained AR mRNA by E10, localized principally in the perichondria. Muscle was first evident in the syringeal region at E9, but no AR was detected in syringeal muscles until after hatching. The expression pattern of AR in the zebra finch embryo suggests that maternal androgens act via AR in the brainstem and syrinx to influence hatching as well as acoustic and visual components of food-begging behavior. Maternal androgens seem unlikely to function in the development of sexual dimorphisms in the zebra finch nXIIts and syrinx, insofar as these are not evident until between 10 and 20 days posthatching. © 2002 Wiley-Liss, Inc.

The performance of C57BL/6J (6J), C57BL/6N (6N), DBA/2J (2J) and DBA/2N (2N) mice in context- and tone-dependent fear conditioning was determined 24 h after fear conditioning to evaluate and compare different behavioral measures as indices of emotional learning. Freezing, the change in activity and the size of the explored area were evaluated as behavioral parameters indicating fear. Additionally, the heart rate (HR) increase elicited by tone presentation was evaluated as an autonomic indicator of fear. During the context-dependent memory test, freezing was high only in 6J and 6N mice, whereas a drop of activity and a reduced exploratory area was measured in all strains. During the tone-dependent memory test, high freezing, low activity, reduced exploratory area and a strong HR increase were demonstrated only in 6N and 6J mice, whereas behavioral and HR changes of 2J and 2N mice were always low. In extinction tests, context- and tone-dependent freezing of 6J mice decayed significantly faster than the freezing of 6N mice, whereas in both substrains the conditioned tachycardia to tone extinguished similarly in the home cage. The data demonstrate that monitoring of additional behavioral measures besides freezing and autonomic measures is necessary to interpret differences in associative learning performance of mouse strains that could be related to a differential expression of fear.