A randomized, double-blind, single-dose, three-arm, parallel group study to determine pharmacokinetic similarity of ABP 959 and eculizumab (Soliris® ) in healthy male subjects.

OBJECTIVES: ABP 959 is a proposed biosimilar to eculizumab, a monoclonal antibody targeting the human C5 complement protein. The objective of this randomized, double-blind, three-arm, study was to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity of ABP 959 relative to the eculizumab reference product (RP) in healthy adult male subjects. METHODS: Eligible subjects aged 18-45 years were randomized to receive a 300-mg IV infusion of ABP 959, or FDA-licensed eculizumab (eculizumab US), or EU-authorized eculizumab (eculizumab EU). Primary PK endpoint was area under the total serum concentration-time curve from 0 to infinity (AUC0-∞ ); primary PD endpoint was area between the effect curve (ABEC) of CH50-time data. RESULTS: The geometric mean of PK and PD parameters were similar between ABP 959 versus eculizumab US and eculizumab EU; PK and PD similarity was established based on 90% confidence intervals of the geometric mean ratio being within prespecified equivalence margin of 0.8 and 1.25. The incidence of treatment-emergent adverse events was similar across groups. The incidence of binding anti-drug antibodies was similar across treatments; no subjects developed neutralizing antibodies. CONCLUSIONS: This study demonstrated PK and PD similarity of ABP 959 to eculizumab RP; safety and immunogenicity profiles were also similar.

Biosimilars: what the oncologist should know.

As originator biologic medicines lose patent protection, some biopharmaceutical companies are focusing on developing similar versions of these costly and complex therapies with a goal of providing more affordable treatment options. Many of these molecules, known as biosimilars, are now approved worldwide and several more are expected to be introduced in the near future. As more biosimilars become available, it is important for clinicians to become familiar with this new category of products and understand how biosimilars are developed, how their development differs from that of originator biologics and how they differ from generics. This review aims to provide the practicing clinician with the knowledge needed to understand biosimilars, along with some guidance on their use in treating oncologic diseases.

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.

BACKGROUND: ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. METHODS: We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29. FINDINGS: Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43-53) of 358 patients in the ABP 980 group and 137 (41%, 35-46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2-13·4; RR 1·188, 90% CI 1·033-1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI -0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab. INTERPRETATION: Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study. FUNDING: Amgen.

Evaluation of the Sexual Desire Relationship Distress Scale (SDRDS) in women with hypoactive sexual desire disorder.

INTRODUCTION: The Sexual Desire Relationship Distress Scale (SDRDS) was developed to address the need for a patient-reported outcome (PRO) measure of sexual distress associated with hypoactive sexual desire disorder (HSDD). The SDRDS is a 17-item PRO that includes items related to personal distress and distress related to relationship with partner. AIM: The aim of this article was to evaluate the psychometric properties of the SDRDS among women with HSDD. METHODS: Pre- and post-menopausal women with HSDD or with no sexual dysfunction completed the SDRDS, Sexual Activity Questions, Female Sexual Distress Scale-Revised (FSDS-R), and desire domain of the Female Sexual Function Index (FSFI) at baseline and 2 and 4 weeks later. MAIN OUTCOME MEASURES: The main outcome measures of this article were item performance, internal consistency, test-retest reliability, construct validity, known groups validity, and responsiveness of the SDRDS. RESULTS: Data from 260 women were analyzed: 101 in each of the pre- and post-menopausal HSDD groups and 29 in each of the pre- and post-menopausal control groups. No differences emerged between pre- and post-menopausal women. Least-squares mean (±standard errors [SE]) SDRDS score was higher in women with HSDD than in women with no sexual dysfunction (43.1 ± 0.9 vs. 6.1 ± 1.7; P < 0.0001), supporting known groups validity. Individual item scores correlated with total scores (r = 0.7-0.9; P < 0.0001). Internal consistency was high, with a Cronbach's alpha of 0.973 at baseline. Test-retest reliability was good, with an intraclass correlation coefficient of 0.89. SDRDS scores correlated strongly with other measures of sexual distress and sexual function including the FSDS-R and FSFI desire domain items. Preliminary analyses suggested that the SDRDS was sensitive to changes in clinical status. CONCLUSIONS: The SDRDS provides a comprehensive and reliable assessment of distress due to decreased sexual desire in women with HSDD and may be a useful measure of treatment effects in clinical trials in women with this condition.

A review of the totality of evidence in the development of ABP 798, a rituximab biosimilar.

ABP 798 (RIABNI™) is a biosimilar to rituximab reference product (RP), a monoclonal antibody that targets CD20. Approval of ABP 798 was based on the totality of evidence generated using a stepwise approach which began by showing that it is structurally and functionally similar to rituximab RP. This analytical assessment was followed by a demonstration of pharmacokinetic/pharmacodynamic similarity in patients with rheumatoid arthritis. Comparative clinical efficacy and safety of ABP 798 with rituximab RP was demonstrated as a final step in patients with non-Hodgkin lymphoma and in those with rheumatoid arthritis. Overall, the totality of evidence supported the conclusion that ABP 798 is highly similar to rituximab RP and provided scientific justification for extrapolation to other approved indications of rituximab RP.

Content validity of the Female Sexual Function Index (FSFI) in pre- and postmenopausal women with hypoactive sexual desire disorder.

INTRODUCTION: The Female Sexual Function Index (FSFI) has consistently been shown to have discriminant validity, test-retest reliability, and internal consistency as a measure of female sexual function. However, the content validity (relevance, clarity, comprehensiveness) of the instrument in women with hypoactive sexual desire disorder (HSDD) must also be established. AIM: The aim of this study were to assess the content validity of the FSFI, specifically the FSFI desire domain, in pre- and postmenopausal women with HSDD. METHODS: Two single-visit content validation studies were conducted in the United States. Eligible premenopausal (both studies) and postmenopausal (second study only) women with HSDD completed the FSFI followed by one-on-one, face-to-face cognitive debriefing interviews including open-ended questions to capture information on their perceptions of the instrument. Information on women's experiences of decreased sexual desire was also captured. MAIN OUTCOME MEASURES: The main outcome measures of this study were the women's ratings of the clarity, ease of understanding, comprehensiveness, and relevance of the 19 items of the FSFI. RESULTS: Interviews with 15 premenopausal women (first study), and 30 pre- and 31 postmenopausal women (second study), were analyzed. Across the whole sample, most women (80-100%) found every item of the FSFI clear and easy to understand. The majority (53-70%) felt that the FSFI captured all their feelings about decreased sexual desire and other sexual problems, and most (84-90%) indicated that additional questions were unnecessary. Most women in both studies (93-100%) reported that the two items comprising the FSFI desire domain were clear, easy to understand, and were relevant to them. The majority of women thought that a recall period of ≥7 days is most relevant for recall of their sexual desire. CONCLUSIONS: These studies establish the content validity of the FSFI in pre- and postmenopausal women with HSDD, supporting the use of this instrument as a measure of sexual function in women with this condition.

The Totality of Evidence and Use of ABP 215, a Biosimilar to Bevacizumab.

ABP 215 (MVASI™, Amgen, Thousand Oaks, CA; MVASI™, Amgen Europe B.V., Netherlands) is a biosimilar to bevacizumab (Avastin®, Genentech, South San Francisco, CA) reference product (RP), a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A). Here we provide a brief overview of the totality of evidence that supported the approval of ABP 215, along with practical considerations to ensure safe and effective administration.ABP 215 has been shown to be highly similar to the RP, with similar mechanism of action, analytical (structural and functional) characteristics, binding, and potency. The similarity of PK parameters of ABP 215 and bevacizumab RP has been confirmed in healthy volunteers.In a comparative clinical trial, patients with stage IV or recurrent non-squamous non-small cell lung cancer receiving carboplatin and paclitaxel were randomized to ABP 215 or bevacizumab RP. No clinically meaningful differences were found between ABP 215 and RP. The objective response rate (ORR) was 39% for ABP 215 and 41.7% for bevacizumab RP. The risk ratio for the ORR was 0.93 [90% confidence interval (CI), 0.80-1.09], which fell within the prespecified margin for equivalence of 0.67-1.5, indicating similar clinical efficacy.Similar to bevacizumab RP, ABP 215 is supplied as a clear to slightly opalescent, colorless to pale yellow, sterile solution in a glass vial. It should be diluted in 0.9% sodium chloride in polyvinylchloride or polyolefin bags before administering as an intravenous infusion. The ABP 215 solution should be stored at 2-8 °C (36-46°F) prior to use. Physicochemical stability studies showed that there were no meaningful changes in purity or potency and no loss of protein after storage at 2-8 °C for 35 days followed by storage at 30 °C for 48 h.

Totality of Evidence Supporting the Use of ABP 980, a Trastuzumab Biosimilar: Practical Considerations.

ABP 980 (KANJINTI™, Amgen, Thousand Oaks, CA, USA; Amgen Europe B.V., The Netherlands) is a biosimilar to trastuzumab (Herceptin®), a monoclonal antibody that selectively binds human epidermal growth factor receptor-2 (HER2). Here we provide a brief overview of the totality of evidence (including analytical [structural and functional] characterization, nonclinical evaluation, and human pharmacokinetic [PK], pharmacodynamic, and clinical assessment comparing ABP 980 with trastuzumab reference product [RP]) that supported the approval of ABP 980, along with practical considerations on the reconstitution and use of the lyophilized product to ensure safe and effective administration. ABP 980 has been shown to be highly similar to the RP, with similar mechanism of action, binding, and potency. Key PK parameters, geometric means ratio (GMR [90% CI]) of Cmax and AUCinf, are comparable and within the equivalence margin of 0.80 to 1.25 (ABP 980: 1.04 [0.99-1.08] versus trastuzumab US: 1.06 [1.00-1.12]; ABP 980: 0.99 [0.95-1.03] versus trastuzumab EU: 1.00 [0.95-1.06]). No clinically meaningful differences were found between ABP 980 and RP in a comparative clinical trial in patients with HER2-positive early breast cancer. Pathological complete response-ABP 980: 48% versus RP: 41% (risk difference [RD], 90% CI: 7.3%, 1.2-13.4; relative risk [RR], 90% CI: 1.188, 1.033-1.366). Sensitivity analyses per central pathology review-ABP 980: 48%; RP: 42% (RD: 5.8%, -0.5 to 12.0; RR: 1.142, 0.993-1.312), with RD and RR falling within predefined equivalence margins. Similar to trastuzumab RP, KANJINTI™ is supplied as a sterile, lyophilized cake to be reconstituted with bacteriostatic water for injection (BWFI) for multiple-dose injection or sterile WFI for single use. Stability data support storage of reconstituted solution at 2-8°C (36-46°F), up to 28 days. Reconstituted solution can be diluted in infusion bags containing 0.9% saline and stored for up to 24 h prior to intravenous administration.

A randomized, double-blind, single-dose study (LAVENDER) to assess the safety, tolerability, pharmacokinetics, and immunogenicity of a combined infusion of ABP 980 and pertuzumab in healthy subjects.

PURPOSE: ABP 980 (KANJINTI™) is a biosimilar to reference product HERCEPTIN® (trastuzumab RP). The goal of this study was to characterize the safety, tolerability, and immunogenicity of ABP 980 plus pertuzumab (PERJETA®) when co-administered in a single infusion bag in healthy subjects. METHODS: This randomized, double-blind, single-dose, 2-arm, parallel-group study (LAVENDER Study) evaluated an intravenous (IV) infusion of ABP 980 (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag relative to an IV infusion of trastuzumab RP (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag given over 60 min. The subjects were followed for 92 days post dosing. RESULTS: A total of 42 subjects were enrolled in the study and treated with investigational product. Due to an operational issue during dosing, the first 6 subjects enrolled in the study were replaced. A total of 36 randomized subjects, n = 18 for ABP 980 plus pertuzumab and n = 18 for trastuzumab RP plus pertuzumab, were treated. Resulting serum concentrations of ABP 980 and trastuzumab RP were similar. There were no serious adverse events, no deaths, and no cardiac disorders during the study. No subject developed anti-drug antibodies throughout the study. CONCLUSIONS: This study demonstrated the safety and tolerability of ABP 980 and pertuzumab admixture in a single infusion bag. The safety profiles and pharmacokinetic parameters of ABP 980 and pertuzumab were consistent with what is known for trastuzumab RP and pertuzumab. CLINICAL TRIAL LISTING: EudraCT 2018-002903-33.

Is weight-based IV dosing of trastuzumab preferable to SC fixed-dose in some patients? A systematic scoping review.

Trastuzumab, a key treatment for HER2-positive breast cancer, is available in weight-based IV and fixed-dose (600 mg) SC formulations. While the Phase 3 HannaH trial indicated non-inferiority of the SC formulation, there is some concern that the target plasma concentration may not be reached in overweight/obese patients whereas low-body-weight patients may be at risk of toxicity. This scoping review evaluated whether overweight/obese patients are at risk of below-target exposure with fixed-dose SC trastuzumab, whether low-body-weight patients are at risk of increased toxicity, especially cardiotoxicity, and whether IV and SC trastuzumab are equivalent in terms of treatment-emergent adverse events (TEAEs) (e.g. infections). Thirty-seven publications that met the eligibility criteria were included. Body weight is not an important determinant of exposure to trastuzumab at steady state (i.e. pre-dose cycle 8); however, real-world evidence suggests that the target concentration (20 µg/mL) may not be reached with the first SC dose in overweight/obese patients. There is no evidence that low-body-weight patients are at increased risk of cardiotoxicity with SC trastuzumab, although this may be confounded by the higher rate of cardiovascular comorbidities in overweight patients. In Phase 3 trials, SC trastuzumab was associated with higher rates of ISRs, ADAs and SAEs, the latter often requiring hospitalization and occurring during adjuvant treatment when patients are not burdened by chemotherapy. The route of administration of trastuzumab (IV vs SC) in different treatment settings should be discussed with the patient, taking into account the risks and benefits associated with each route.

Correction to: Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product.

Page 608, 4 Discussion, right column, second paragraph.

Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product.

INTRODUCTION: ABP 798 is being developed as a biosimilar to rituximab reference product (RP), a CD20-directed cytolytic antibody that is approved in the US and EU for the treatment of non-Hodgkin lymphoma (NHL). METHODS: This randomized, double-blind, comparative clinical study (JASMINE) evaluated the efficacy and safety of ABP 798 compared with rituximab RP. Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab RP once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28. Primary endpoint was the risk difference (RD) of overall response rate (ORR) of complete response, unconfirmed complete response, or partial response by week 28 based on data from central, independent, and blinded assessments of disease. RESULTS: Of the 256 randomized patients, 254 were treated with ABP 798 (n = 128; 100%) or rituximab RP (n = 126; 98.4%); 96 (78.0%) patients in the ABP 798 group and 87 (70.2%) in the rituximab RP group had a best ORR by week 28. The point estimate of RD in ORR between ABP 798 and rituximab RP from the adjusted generalized linear model for stratification factors was 7.7%. Clinical equivalence was based on sequential testing of the one-sided 95% lower confidence limits and one-sided 95% upper confidence limits of RD in ORR (- 1.4% and 16.8%, respectively) which was within the prespecified non-inferiority margin (- 15%) and non-superiority margin (35.5%), respectively. Results of sensitivity analyses were consistent with the primary efficacy analysis. ABP 798 was also comparable to rituximab RP across additional secondary endpoints, further supporting the conclusion of similarity, and including: RD of ORR at week 12; trough serum concentrations; percent of patients with complete depletion of CD19+ cell count at day 8; safety; and immunogenicity. CONCLUSIONS: These results support a conclusion of similar clinical efficacy between ABP 798 and rituximab RP in patients with follicular lymphoma. NCT NUMBER: NCT02747043; first posted April 21, 2016. EUDRACT NUMBER: 2013-005,542-11; submitted 14 October, 2014.

Cardiac Safety of the Trastuzumab Biosimilar ABP 980 in Women with HER2-Positive Early Breast Cancer in the Randomized, Double-Blind, Active-Controlled LILAC Study.

INTRODUCTION: Although the human epidermal growth factor receptor 2 (HER2) blocker trastuzumab is generally well tolerated, cardiotoxicity can be an important therapeutic limitation. OBJECTIVE: In this prespecified analysis, we compared the cardiac safety of the trastuzumab biosimilar ABP 980 (KANJINTI™) and the trastuzumab reference product (RP; Herceptin®) in the phase III LILAC study (ClinicalTrials.gov identifier NCT01901146). METHODS: In the neoadjuvant phase of LILAC, after run-in chemotherapy, 725 patients were randomized 1:1 to ABP 980 (n = 364) or trastuzumab RP (n = 361) plus paclitaxel (every 3 weeks [Q3W] or every week [QW]) for four cycles. After surgery, patients continued treatment Q3W for up to 1 year; ABP 980-treated patients continued ABP 980 (ABP 980/ABP 980; n = 364), and trastuzumab RP-treated patients either continued on the RP (trastuzumab RP/trastuzumab RP; n = 190) or switched to ABP 980 (trastuzumab RP/ABP 980; n = 171). Cardiac safety was monitored by computerized 12-lead electrocardiogram, and left ventricular ejection fraction (LVEF) was assessed by two-dimensional (2D) echocardiogram. LVEF decline was defined as LVEF value decrease from study baseline by ≥ 10 percentage points and to < 50%. RESULTS: Over the entire study, 22 (3.1%) patients had protocol-defined LVEF decline; no meaningful between-group differences were observed (ABP 980/ABP 980: 2.8%; trastuzumab RP/trastuzumab RP: 3.3%; trastuzumab RP/ABP 980: 3.5%). The incidence of cardiac adverse events was low and comparable in the treatment groups. One grade 3 cardiac failure event reported in the trastuzumab RP/ABP 980 arm, and another in the trastuzumab RP/trastuzumab RP arm, were coincident with LVEF decline. One patient discontinued the investigational product during the adjuvant phase because of cardiac failure. CONCLUSION: These prespecified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and trastuzumab RP with respect to cardiac safety. No new cardiac safety signals were observed whether patients were receiving ABP 980 or switched from the RP to ABP 980.

Totality of evidence in the development of ABP 215, an approved bevacizumab biosimilar.

ABP 215 (MVASI™) is the first approved biosimilar to Avastin® (bevacizumab). It is approved in the USA and the European Union (EU) for all bevacizumab indications in these jurisdictions except for ovarian cancer in the USA due to orphan drug exclusivity. ABP 215 was shown to be structurally, functionally and clinically (pharmacokinetic, efficacy and safety) similar to the bevacizumab reference product; the pharmacokinetic study was conducted in healthy adult men (n = 202); safety and efficacy were evaluated in patients with advanced nonsquamous non-small-cell lung cancer (n = 642). Together, these results comprise the totality of evidence that provides scientific justification for extrapolation to all approved indications of the reference product and supports the clinical value of ABP 215 as an additional treatment option.

Totality of Scientific Evidence in the Development of ABP 980, a Biosimilar to Trastuzumab.

ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the treatment of HER2-positive metastatic breast cancer, early breast cancer (EBC), and metastatic gastric cancer. ABP 980 is approved in the United States, European Union, and Japan for all the indications of trastuzumab, based on the totality of evidence (TOE) gathered by the systematic step-wise accumulation of comparative analytical, preclinical, and clinical (pharmacokinetics [PK], efficacy, safety and immunogenicity) data for ABP 980 and trastuzumab reference product (RP). As a key first step of the ABP 980 biosimilar program, comprehensive analytical characterization of critical quality attributes established that ABP 980 is structurally and functionally similar to trastuzumab RP. Complementing these data, results of non-clinical pharmacology, toxicology, and toxicokinetic studies supported similarity between ABP 980 and trastuzumab RP. A randomized study in healthy subjects demonstrated clinical PK equivalence of ABP 980 relative to trastuzumab RP in these subjects. In the final clinical evaluation step, a randomized comparative study (LILAC) confirmed the lack of clinically meaningful differences between ABP 980 and trastuzumab RP in efficacy, safety, and immunogenicity in women with HER2-positive EBC in the neoadjuvant-adjuvant setting. Neoadjuvant EBC represented a sensitive homogenous population for biosimilar demonstrations, and the primary endpoint of pathologic complete response served as a sensitive surrogate endpoint. An important aspect of the LILAC study design is that it is the only study that evaluated the effect of switching from the trastuzumab RP to a trastuzumab biosimilar during the adjuvant phase. No new or unexpected safety signals emerged in the clinical evaluations, with the safety profile of ABP 980 consistent with that previously described for trastuzumab. Overall, the TOE data generated for ABP 980 support the conclusion that it is highly similar to trastuzumab RP, thus providing the scientific justification for extrapolation to all the approved indications of trastuzumab.

Efficacy and Safety of the Biosimilar ABP 215 Compared with Bevacizumab in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (MAPLE): A Randomized, Double-blind, Phase III Study.

PURPOSE: This phase III study compared clinical efficacy and safety of the biosimilar ABP 215 with bevacizumab reference product (RP) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized 1:1 to ABP 215 or bevacizumab 15 mg/kg every three weeks for 6 cycles. All patients received carboplatin and paclitaxel every three weeks for ≥4 and ≤6 cycles. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% confidence interval (CI) of the risk ratio was within the margin of 0.67 to 1.5. Secondary endpoints included risk difference of ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS); pharmacokinetics, adverse events (AEs), and incidence of antidrug antibodies (ADAs) were monitored. RESULTS: A total of 820 patients were screened; 642 were randomized to ABP 215 (n = 328) and bevacizumab (n = 314). Overall, 128 (39.0%) and 131 (41.7%) patients in the ABP 215 and bevacizumab groups, respectively, had objective responses [ORR risk ratio: 0.93 (90% CI, 0.80-1.09)]. In the ABP 215 and bevacizumab group, 308 (95.1%) and 289 (93.5%) patients, respectively, had at least 1 AE; 13 (4.0%) and 11 (3.6%) experienced a fatal AE. Anti-VEGF toxicity was low and comparable between treatment groups. At week 19, median trough serum drug concentration was 132 µg/mL (ABP 215 group) and 129 µg/mL (bevacizumab group). No patient tested positive for neutralizing antibodies. CONCLUSIONS: ABP 215 is similar to bevacizumab RP with respect to clinical efficacy, safety, immunogenicity, and pharmacokinetics. The totality of evidence supports clinical equivalence of ABP 215 and bevacizumab.

The effect of ultralow-dose transdermal estradiol on sexual function in postmenopausal women.

OBJECTIVE: This study was undertaken to examine the effect of ultralow-dose transdermal estradiol on sexual function in postmenopausal women. STUDY DESIGN: Analysis of data from a multicenter, randomized, double-blind, placebo-controlled trial of a 0.014 mg/day transdermal estradiol patch in 417 women aged 60 to 80 years. Sexual function was assessed by self-administered questionnaires at baseline and 4, 12, and 24 months. A linear effects model was used to assess treatment effects using data from all on-study assessments. RESULTS: Women randomly assigned to estradiol had a 4.3 point greater improvement in the vaginal pain/dryness domain relative to placebo (95% CI = 0.3-8.4, P = .04). No significant differences in frequency of sexual activity or other sexual function domains (desire, satisfaction, problems, or orgasm) were observed between treatment groups (P > or = .10 for all). CONCLUSIONS: Ultralow-dose estradiol resulted in modest improvement in sexual function related to vaginal pain and dryness, but not in other domains of sexual function.

A randomized, single-blind, single-dose study to assess the pharmacokinetic equivalence of the biosimilar ABP 215 and bevacizumab in healthy Japanese male subjects.

PURPOSE: Analytic, pharmacokinetic (PK), and clinical similarity between the biosimilar ABP 215 and bevacizumab has previously been demonstrated in global studies. Here we present a phase 1 study in healthy adult Japanese men. METHODS: This study was a randomized, single-blind, single-dose, parallel-group study comparing PK parameters of ABP 215 versus EU-authorized bevacizumab in healthy Japanese men. Primary endpoints were maximum observed serum concentration (Cmax) and area under the serum concentration-time curve from time 0 to infinity (AUCinf). Secondary endpoints included AUC from time 0 to time of last quantifiable concentration (AUClast), safety, tolerability, and immunogenicity. RESULTS: Baseline characteristics were similar among study subjects (n = 24/group). After a 3-mg/kg intravenous infusion, the geometric means (GMs) of Cmax, AUCinf, and AUClast were 71.2 µg/mL, 25,259 µg h/mL, and 22,499.3 µg h/mL, respectively, for ABP 215 and 70.16 µg/mL, 25,801 µg h/mL, and 22,604.6 µg h/mL, respectively, for bevacizumab. The GM ratios (90% confidence interval; CI) for Cmax, AUCinf, and AUClast were 1.015 (0.946-1.088), 0.979 (0.914-1.049), and 0.995 (0.941-1.053) for ABP 215 versus bevacizumab. All CIs fell within the prespecified bioequivalence margin (0.80-1.25). Adverse events (AEs) occurred in 2/24 subjects receiving ABP 215 and 1/24 receiving bevacizumab. There were no deaths or AEs leading to study discontinuation; no subject was positive for binding anti-drug antibodies (ADAs). CONCLUSIONS: ABP 215 and bevacizumab showed PK similarity in Japanese men. Safety profiles were comparable between the two groups. The pharmacokinetics in Japanese subjects were consistent with those in a previous global PK equivalence study.

Correction to: A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men.

The article [A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men].

Randomized, placebo-controlled trial of the effects of drospirenone-estradiol on blood pressure and potassium balance in hypertensive postmenopausal women receiving hydrochlorothiazide.

OBJECTIVE: Drospirenone (DRSP), a spironolactone analog with aldosterone antagonist activity, is a novel progestogen developed for use as hormone therapy in postmenopausal women in combination with 17beta-estradiol (E2). DRSP/E2 lowers blood pressure when used alone in hypertensive postmenopausal women or when administered concomitantly with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. DRSP/E2 has not been studied in combination with the widely prescribed hydrochlorothiazide (HCTZ). We investigated the effects of 3 mg DRSP/1 mg E2 versus placebo on blood pressure and potassium balance when added to existing therapy with 25 mg HCTZ in postmenopausal women with established stage I hypertension. DESIGN: This was a single-center, double-blind, randomized, placebo-controlled, two-treatment, two 4-week treatment period crossover study in 36 postmenopausal women with stage I hypertension maintained on 25 mg HCTZ. The endpoint was a change from baseline in systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring. Safety monitoring included serum potassium (mEq/L) and adverse events. RESULTS: Mean systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring were reduced significantly, by -7.2 and -4.5 mm Hg, respectively, with DRSP/E2 as compared with placebo. The decrease in potassium with HCTZ was 0.2 mEq/L less with DRSP/E2 than placebo, suggesting a potassium-sparing effect. The most frequently observed adverse events with DRSP/E2 were vaginal bleeding and breast tenderness, which were attributable to the hormone therapy. CONCLUSIONS: DRSP/E2 substantially lowers systolic and diastolic blood pressure when added to existing antihypertensive therapy with HCTZ in hypertensive postmenopausal women. In addition, DRSP/E2 has a potassium-sparing effect that counteracts HCTZ-induced potassium loss.