Phase 3 Trial of BI 695502 Plus Chemotherapy Versus Bevacizumab Reference Product Plus Chemotherapy in Patients With Advanced Nonsquamous NSCLC.

INTRODUCTION: Biological therapies such as bevacizumab have improved survival in patients with NSCLC. This study was conducted to confirm the equivalent efficacy of the biosimilar candidate BI 695502 to the bevacizumab reference product (RP). METHODS: In this phase 3, multicenter, randomized, double-blind trial of 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 end point was the 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 at one-to-one ratio 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 end point, 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 to 0.951) was within the prespecified range for equivalence (0.736-1.359). Adverse events were class-related and similar between the two treatment arms. CONCLUSIONS: This study revealed equivalent ORR after 18 weeks of treatment with BI 695502 or bevacizumab RP, with similar adverse event profiles.

Safety and efficacy of BI 695501 versus adalimumab reference product in patients with advanced Crohn's disease (VOLTAIRE-CD): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: BI 695501 is a biosimilar that has demonstrated similar efficacy, safety, and immunogenicity to adalimumab reference product in patients with rheumatoid arthritis and chronic plaque psoriasis. The VOLTAIRE-CD study aimed to compare the efficacy and safety of BI 695501 with adalimumab reference product in patients with Crohn's disease. METHODS: This phase 3, randomised, double-blind study was done at 92 centres in 12 countries across Europe and the USA in patients aged 18-80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score 220-450). Patients were randomly assigned 1:1 using an interactive response technology system to the BI 695501 group or adalimumab reference product group, stratified by previous exposure to infliximab (yes vs no) and simple endoscopic score for Crohn's disease at screening (<16 vs ≥16). All investigators involved in trial assessments or procedures and all patients were masked to treatment allocation until week 24. Patients received BI 695501 (40 mg/0·8 mL formulation) or adalimumab reference product (either 40 mg/0·4 mL citrate-free or 40 mg/0·8 mL) 160 mg on day 1 and 80 mg on day 15, followed by 40 mg every 2 weeks, via subcutaneous injection. The primary endpoint was the proportion of patients with clinical response (CDAI decrease ≥70 points) at week 4, with an exploratory non-inferiority margin of 0·76 for the lower limit of the two-sided 90% CI of the risk ratio (RR). The primary analysis was done in a modified full analysis set of all patients who received at least one dose of study medication and had a baseline and at least one post-baseline CDAI assessment. Safety was assessed in all patients who received at least one dose of study medication. After week 4, responders were treated until week 46; those randomly assigned to adalimumab reference product switched to BI 695501 at week 24. This study is registered at ClinicalTrials.gov (NCT02871635) and EudraCT (2016-000612-14). FINDINGS: Between Jan 4, 2017, and April 5, 2018, 147 patients were enrolled and randomly assigned to BI 695501 (n=72) or adalimumab reference product (n=75). At week 4, 61 (90%) of 68 patients in the BI 695501 group and 68 (94%) of 72 in the adalimumab reference product group had a clinical response (adjusted RR 0·945 [90% CI 0·870-1·028]). In the safety analysis set, 45 (63%) of 72 patients in the BI 695501 group and 42 (56%) of 75 in the adalimumab reference product group had an adverse event during weeks 0-24; 31 (43%) and 34 (45%) had adverse events during weeks 24-56. The most common drug-related treatment-emergent adverse events during weeks 0-24 were weight increase (three [4%] patients in the BI 695501 group) and injection-site erythema and upper respiratory tract infection (three [4%] patients for each event) in the adalimumab reference product group. The only drug-related TEAEs reported in two or more patients during weeks 24-56 were weight increase and increased γ-glutamyltransferase, which occured in two (3%) patients each in the BI 695501 group. No drug-related TEAEs were reported in two or more patients during weeks 24-56 in the adalimumab reference product followed by BI 699501 group. Serious adverse events occurred in six (8%) patients in the BI 695501 group and eight (11%) in the adalimumab reference group between weeks 0-24, and two (3%) and nine (12%) patients between weeks 24-56. Adverse events of special interest occurred in two (3%) patients in each treatment group during weeks 0-24 (acute sinusitis and pulmonary tuberculosis in the BI 695501 group and anal abscess and postoperative wound infection in the adalimumab reference product group) and two (3%) patients in each group during weeks 24-56 (psoas abscess and hypersensitivity in the BI 695501 group and pulmonary tuberculosis and erythematous rash in the adalimumab reference product followed by BI 699501 group). INTERPRETATION: Safety and efficacy were similar in patients with Crohn's disease treated with BI 695501 or adalimumab reference product. Treatment benefits were maintained in patients receiving adalimumab reference product who switched to BI 695501. These results further support the existing licensure of BI 695501 as an alternative to adalimumab reference product for patients with Crohn's disease, as well as the other indications for which BI 695501 is approved. FUNDING: Boehringer Ingelheim.

Similar efficacy, safety, and immunogenicity of the biosimilar BI 695501 and adalimumab reference product in patients with moderate-to-severe chronic plaque psoriasis: results from the randomized Phase III VOLTAIRE-PSO study.

Background: BI 695501 is an approved biosimilar to Humira® reference product (RP). Research design and methods: In this randomized Phase III trial (VOLTAIRE-PSO), patients with moderate-to-severe chronic plaque psoriasis received BI 695501 or adalimumab RP (24-week treatment). Primary efficacy endpoint: the proportion of patients with ≥75% reduction in Psoriasis Area and Severity Index (PASI 75) response at week 16 (±18% equivalence limits for two-sided 95% confidence interval between treatment groups). Safety, pharmacokinetics, and immunogenicity were also assessed. Results: Baseline characteristics were balanced between treated groups (BI 695501, n = 159; adalimumab RP, n = 158). PASI 75 response rates (full analysis set, n = 158; n = 157) were 68.2% (BI 695501) and 70.4% (adalimumab RP) at week 16 (95% CI: -14.4%, 8.7%), and 75.3% and 72.4%, at week 24, respectively. At week 24, 41.5% (BI 695501) and 44.9% (adalimumab RP) of treated patients had treatment-emergent adverse events (AEs), 3.1% and 4.4% had serious AEs, and 0.0% and 1.9% had AEs of special interest. Of treated patients, 75.3% (BI 695501) and 77.9% (adalimumab RP) were anti-drug antibody-positive. Conclusion: These data demonstrate equivalent efficacy and highly similar safety and immunogenicity between BI 695501 and adalimumab RP in patients with chronic plaque psoriasis. Study identifier: NCT02850965.

Population pharmacokinetic and pharmacodynamic model-based comparability assessment of a recombinant human Epoetin Alfa and the Biosimilar HX575.

The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic (PK/PD) model and assess the comparability between epoetin alfa HEXAL/Binocrit (HX575) and a comparator epoetin alfa by a model-based approach. PK/PD data-including serum drug concentrations, reticulocyte counts, red blood cells, and hemoglobin levels-were obtained from 2 clinical studies. In sum, 149 healthy men received multiple intravenous or subcutaneous doses of HX575 (100 IU/kg) and the comparator 3 times a week for 4 weeks. A population model based on pharmacodynamics-mediated drug disposition and cell maturation processes was used to characterize the PK/PD data for the 2 drugs. Simulations showed that due to target amount changes, total clearance may increase up to 2.4-fold as compared with the baseline. Further simulations suggested that once-weekly and thrice-weekly subcutaneous dosing regimens would result in similar efficacy. The findings from the model-based analysis were consistent with previous results using the standard noncompartmental approach demonstrating PK/PD comparability between HX575 and comparator. However, due to complexity of the PK/PD model, control of random effects was not straightforward. Whereas population PK/PD model-based analyses are suited for studying complex biological systems, such models have their limitations (statistical), and their comparability results should be interpreted carefully.

Effect of switching recombinant human growth hormone: Comparative analysis of phase 3 clinical data.

INTRODUCTION: Recombinant human growth hormone (rhGH) is effective and safe when used to treat growth hormone deficiency (GHD) in children. However, it has been suggested that switching between different types of rhGH can have a detrimental effect on patients. METHODS: The current analysis assessed the efficacy and safety of rhGH in children who received continuous Omnitrope® (Sandoz GmbH, Kundl, Austria) therapy either with lyophilized powder for solution or ready-to-use solution, with children who received 9 months of treatment with Genotropin® (Pfizer Limited, Sandwich, UK) followed by Omnitrope solution thereafter. Changes to height, height SD score (SDS), height velocity SDS, insulin-like growth factor (IGF-1) levels, and IGF binding protein (IGFBP-3) levels were assessed using data from three trials. RESULTS: Baseline demographics of the three study groups were similar. Over an 18-month period there were no observable differences between the three groups with respect to height, height SDS, height velocity SDS, IGF-1 levels, and IGFBP-3 levels. This result was corroborated by the model data, whereby most data points for Omnitrope-treated children fell within the defined limits of the prediction model based on Genotropin data. Few adverse drug reactions (ADRs) occurred. CONCLUSIONS: Switching from Genotropin to Omnitrope solution has no impact on efficacy or safety in children with GHD, and the various rhGH preparations are well tolerated.

Population modeling of filgrastim PK-PD in healthy adults following intravenous and subcutaneous administrations.

Filgrastim is a recombinant human granulocyte colony stimulating factor (G-CSF) that stimulates production of neutrophils. The objective of this analysis was to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model to account for an increase in G-CSF clearance on multiple dosing because of an increase of the G-CSF receptor-mediated endocytosis. Data from 4 randomized studies involving healthy volunteers were used for analysis. Subjects received filgrastim (Neupogen) via subcutaneous (SC) and intravenous (IV) routes. Filgrastim was administered SC daily for 1 week at 2.5, 5, and 10 µg/kg doses and as single IV infusions (5 µg/kg over 0.5 hours) and SC (1 µg/kg) doses. PK data comprised serum concentration-time measurements and the blood absolute neutrophil count (ANC) was used for PD evaluations. Population nonlinear mixed-effect modeling was done using NONMEM VI (Version 6.1.0, Icon Development Solutions, Ellicott City, Maryland). The model depicted the decaying trend in C(max) values with repeated doses and an increase in ANC(max) values consistently with an increase in the G-CSF receptor pool. Simulated time courses of the total clearance exhibited an increasing pattern. The increase in filgrastim clearance on multiple dosing was attributed to the increased neutrophil count in the bone marrow and blood paralleled by an increase in the total G-CSF receptor density.

Bioequivalence between novel ready-to-use liquid formulations of the recombinant human GH Omnitrope and the original lyophilized formulations for reconstitution of Omnitrope and Genotropin.

OBJECTIVE: Two strengths of a novel ready-to-use liquid preparation of the recombinant human GH (rhGH) Omnitrope were developed to increase the convenience for the patients. DESIGN: Omnitrope 3.3 mg/ml solution or Omnitrope 6.7 mg/ml solution was compared to Omnitrope 5 mg/ml powder and Genotropin 5 mg/ml powder in terms of pharmacokinetics, pharmacodynamics, safety, and local tolerance after a single s.c. dose of 5 mg. METHODS: Two randomized, double-blind, single-dose, three-way crossover studies were carried out in 36 young healthy volunteers each. Endogenous GH secretion was suppressed with a 25-h continuous i.v. infusion of octreotide (40 microg/h) starting 1 h before rhGH administration. RESULTS: Pharmacokinetic parameters were similar for the three treatments in both studies respectively. Bioequivalence criteria were met for area under the concentration-time curve (AUC) and C(max). Likewise, the pharmacodynamic parameters for IGF1, IGF-binding protein 3, and non-esterified fatty acid were similar for all preparations. No differences in adverse events were observed between groups. CONCLUSIONS: Omnitrope 3.3 mg/ml solution, 6.7 mg/ml solution, and 5 mg/ml powder, and Genotropin 5 mg/ml powder are bioequivalent, have similar pharmacokinetic and pharmacodynamic profiles, and are equally safe. Overall, the products can be considered to be therapeutically interchangeable.

Population pharmacokinetic modelling of filgrastim in healthy adults following intravenous and subcutaneous administrations.

BACKGROUND AND OBJECTIVE: Filgrastim is a human granulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim. METHODS: A mechanism-based population pharmacokinetic model was developed to account for receptor-mediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 microg/kg and intravenous infusion of 5 microg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed target-mediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance. RESULTS: Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (K(d)) was estimated as 16.38 pM. CONCLUSION: The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the K(d), target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.

Establishment and validation of an ex vivo human cervical tissue model for local delivery studies.

The objective of this study was to establish and validate an ex vivo human cervical tissue model appropriate for transport studies of molecular and especially nucleic acid based drugs. For that purpose conditions had to be established for a standardized tissue handling and preparation following hysterectomy to allow an immediate experimental use of fresh tissue samples. Samples of the ectocervical, endocervical and the transition zone representing the entire cervix organ were characterized in Franz diffusion cells by the determination of the in vitro permeation of low and high molecular weight markers (propanolol, mannitol, dextran 4000, 10,000, 20,000 and 40,000Da). Additionally, the permeability of mannitol and dextran 4000 across fresh and frozen cervical tissue was compared. The apparent permeability coefficients (P(app)) of the various markers demonstrated (i) that with increasing molecular weight the marker permeability decreases, (ii) an upper permeability limit between 10,000 and 20,000Da, (iii) no significant difference of the permeability across the three cervical tissue zones, (iv) a statistically significant but effectively small variation of the permeability among different patient samples. A continuous difference of approximately two log values between the P(app) values of mannitol and dextran 4000 makes them suitable as an internal marker control pair for each biopsy. Moreover, the P(app) values of both markers across fresh and frozen tissue are comparable. According to the presented data we conclude that the human cervical tissue model has been well characterized and is therefore suitable for local delivery and permeation studies.