The Treatment Gap in Osteoporosis.

Worldwide, there are millions of people who have been diagnosed with osteoporosis, a bone disease that increases the risk of fracture due to low bone mineral density and deterioration of bone architecture. In the US alone, there are approximately ten million men and women diagnosed with osteoporosis and this number is still growing. Diagnosis is made by measuring bone mineral density. Medications used for the treatment of osteoporosis are bisphosphonates, denosumab, raloxifene, and teriparatide. Recently, romosozumab has been added as well. In recent years, a number of advances have been made in the field of diagnostic methods and the diverse treatment options for osteoporosis. Despite these advances and a growing incidence of osteoporosis, there is a large group being left undertreated or even untreated. This group of the under/untreated has been called the treatment gap. Concerns regarding rare side effects of the medications, such as osteonecrosis of the jaw, have been reported to be one of the many causes for the treatment gap. Also, this group seems not to be sufficiently informed of the major benefits of the treatment and the diversity in treatment options. Knowledge of these could be very helpful in improving compliance and hopefully reducing the gap. In this paper, we summarize recent evidence regarding the efficacy of the various treatment options, potential side effects, and the overall benefit of treatment.

Adverse immunostimulation caused by impurities: The dark side of biopharmaceuticals.

Drug safety is an important issue, especially in the experimental phases of development. Adverse immunostimulation (AI) is sometimes encountered following treatment with biopharmaceuticals, which can be life-threatening if it results in a severe systemic inflammatory reaction. Biopharmaceuticals that unexpectedly induce an inflammatory response still enter the clinic, even while meeting all regulatory requirements. Impurities (of microbial origin) in biopharmaceuticals are an often-overlooked cause of AI. This demonstrates that the current guidelines for quality control and safety pharmacology testing are not flawless. Here, based on two case examples, several shortcomings of the guidelines are discussed. The most important of these are the lack of sensitivity for impurities, lack of testing for pyrogens other than endotoxin, and the use of insensitive animal species and biomarkers in preclinical investigations. Moreover, testing for the immunotoxicity of biopharmaceuticals is explicitly not recommended by the international guidelines. Publication of cases of AI is pivotal, both to increase awareness and to facilitate scientific discussions on how to prevent AI in the future.

Fluctuations in Pharmacokinetics Profiles of Monoclonal Antibodies.

Monoclonal antibodies (mAbs) are a group of drugs with predicted slow linear and target-mediated distribution and elimination. Visual inspection of published pharmacokinetic profiles of mAbs frequently reveals plateaus in the distribution phase or an increasing concentration many days after a single intravenous dose. A question which has been left unanswered until now is whether mAbs undergo recirculation mechanisms. If so, then which mechanisms are crucial for the fluctuation in their pharmacokinetics profiles? What is the impact of such mechanisms on mAb absorption, distribution and elimination? Current commentary accounts for the fluctuation of mAbs concentrations based on different mechanisms, as well in different phases of their in vivo disposition. Current knowledge shows significant impact of mAbs lymphatic recirculation on characteristics of their pharmacokinetics profiles. Fluctuating or plateau phases in pharmacokinetic profiles of mAbs are a consequence of multiple simultaneously occurring recirculatory as well as adsorption/desorption processes rather than only slow, continuous elimination. Lymphatic recirculation as well as other mechanisms appears to be an obvious element of the mAbs disposition. Periodic changes in the key factors affecting mAbs disposition can be responsible for the unpredictable concentration peaks in absorption, distribution and the elimination phase.

Potential Influence of Endothelial Adsorption on the Delayed Time to Maximum Concentration of Biopharmaceuticals.

BACKGROUND AND OBJECTIVES: Maximum plasma concentration of biopharmaceuticals sometimes occurs long after completion of intravenous infusion. The objective of this research was to study the hypothetical adsorption of biopharmaceuticals to endothelium and infusion material, which may theoretically explain this phenomenon. METHODS: Infusion procedures were mimicked in an artificial vessel covered with a confluent monolayer of endothelial cells. Three monoclonal antibodies (MAbs) and C1 inhibitor were studied. RESULTS: Adsorption of MAbs to endothelium was observed followed by release when the vessel was subsequently perfused with buffer. Adsorption to infusion material also occurred to various degrees and in a seemingly random fashion, with a loss of up to 15% during a single flush of the line, but release from the line was not seen. CONCLUSIONS: Our results indicate that adsorption of biopharmaceuticals to endothelium can occur. This observation can explain the increase in plasma concentration after completion of intravenous administration.

MDCO-216 Does Not Induce Adverse Immunostimulation, in Contrast to Its Predecessor ETC-216.

PURPOSE: Aim of this study was to demonstrate that MDCO-216 (human recombinant Apolipoprotein A-I Milano) does not induce adverse immunostimulation, in contrast to its predecessor, ETC-216, which was thought to contain host cell proteins (HCPs) that elicited an inflammatory reaction. METHODS: Data were taken from a clinical trial in which 24 healthy volunteers (HV) and 24 patients with proven stable coronary artery disease (sCAD) received a single intravenous dose of MDCO-216, ranging 5-40 mg/kg. Additionally, whole blood from 35 HV, 35 sCAD patients and 35 patients requiring acute coronary intervention (aCAD group) was stimulated ex vivo with MDCO-216 and ETC-216. RESULTS: No inflammatory reaction was observed in HV and sCAD patients following MDCO-216 treatment, judging by body temperature, white cell counts, neutrophil counts, C-reactive protein, circulating cytokines (IL-6, TNF-α), and adverse events. In the ex vivo experiment, the geometric means (SD) of the ratio of MDCO-216 stimulated IL-6 over background levels were 0.8 (1.9), 0.7 (1.5), 1.0 (2.0) for respectively HV, sCAD, aCAD. The corresponding ETC-216 stimulated values were 15.8 (2.9), 9.5 (3.6), 3.8 (4.0). TNF-α results were comparable. Because many ETC-216 stimulated samples had cytokine concentrations >ULOQ, ratios were categorised and marginal homogeneity of the contingency table (MDCO-216 versus ETC-216) was assessed with the Stuart-Maxwell test. P-values were ≤0.0005 for all populations. CONCLUSIONS: MDCO-216 did not induce adverse immunostimulation in HV and sCAD patients, in contrast to ETC-216. Results from the ex vivo stimulation suggests the same holds true for aCAD patients.

Remarkable Pharmacokinetics of Monoclonal Antibodies: A Quest for an Explanation.

Monoclonal antibodies (MAbs) usually display slow and limited distribution with combined linear and non-linear elimination mechanisms. While studying individual pharmacokinetic profiles, it was noticed that MAb plasma concentration can vary abruptly over time, with one or more increases after the time to maximum plasma concentration when theoretically the concentration should only decline. This article summarizes the frequency of these additional peaks and assesses whether normal intra-subject and assay variability can explain the observations. For this analysis, we used a benchmark consisting of three registered (adalimumab, bevacizumab, and trastuzumab) and three unregistered immunoglobulin G1 MAbs. At a selected 'normal' intra-subject variability of 12%, at least 70% of the study participants (approximately 90% for certain MAbs) still had at least one additional peak, which decreased when the 'normal' variability was increased. There was no difference in occurrence between the high- and low-concentration ranges. Only a high sample density was associated with an increased likelihood of detecting additional peaks. Based on the analytical variability for the applied ligand-binding assays (5-10%, up to 15% at the lower limit of quantitation), the number of observed increases was extremely improbable (p < 0.01) for most MAbs, especially for the large excursions. Therefore, the fluctuations are likely genuine. We discuss the possible explanations and the relevance for clinical practice.

Clinical Evaluation of Humira® Biosimilar ONS-3010 in Healthy Volunteers: Focus on Pharmacokinetics and Pharmacodynamics.

ONS-3010 is being developed by Oncobiologics Inc. (Cranbury, NJ, USA) as a biosimilar of Humira®. This randomized, double blind, single-center phase I study (EudraCT registration # 2013-003551-38) was performed to demonstrate pharmacokinetic (PK) biosimilarity between two reference products (Humira® EU and US) and ONS-3010 in healthy volunteers, and to compare the safety and immunogenicity profiles. In addition, the intended pharmacological activity was assessed and compared by application of a whole blood challenge. Hundred ninety-eight healthy volunteers received a single 40 mg subcutaneous dose of ONS-3010, Humira® EU, or US. The pharmacodynamic effects were assessed by lipopolysaccharide (LPS)/aluminum hydroxide whole blood challenges (n = 36; n = 12 per treatment arm; male:female, 1:1). Equivalence was demonstrated on the PK endpoints (AUC0-inf, Cmax, and AUC0-last) based on bounds of 80-125% for the ratio of the geometric means (ONS-3010/Humira®). The immunogenicity profiles were comparable between treatment groups, and there were no indications for differences in routine safety parameters. Administration of adalimumab resulted in the observation of dramatically reduced tumor necrosis factor-α (TNFα) levels upon stimulation with LPS/aluminum hydroxide (>99%), with no differences between the three treatment groups in terms of magnitude or duration. Adalimumab also resulted in a reduction of LPS/aluminum hydroxide-induced interleukin (IL)-8 release (maximally 30%), suggested to have a causal relationship with the anti-TNFα treatment. LPS/aluminum hydroxide-induced release of IL-1ß and IL-6 was not inhibited by anti-TNFα treatment. Taken together, these data are promising for the further clinical development of ONS-3010, demonstrate the relevance of the LPS/aluminum challenge to monitor Humira® effects, and emphasize the value of whole blood challenges for monitoring of proximal drug effects in healthy volunteers, and potentially in the target population.

Use of population approach non-linear mixed effects models in the evaluation of biosimilarity of monoclonal antibodies.

PURPOSE: Population pharmacokinetic analyses (PPK) have been used to establish bioequivalence for small molecules and some biologicals. We investigated whether PPK could also be useful in biosimilarity testing for monoclonal antibodies (MAbs). METHODS: Data from a biosimilarity trial with two trastuzumab products were used to build population pharmacokinetic models. First, a combined model was developed and similarity between test and reference product was evaluated by performing a covariate analysis with trastuzumab drug product (test or reference) on all model parameters. Next, two separate models were developed, one for each drug product. The model structure and parameters were compared and evaluated for differences. RESULTS: Drug product could not be identified as statistically significant covariate on any parameter in the combined model, and the addition of drug product as covariate did not improve the model fit. A similar structural model described both the test and reference data best. Only minor differences were found between the estimated parameters from these separate models. CONCLUSIONS: PPK can also be used to support a biosimilarity claim for a MAb. However, in contrast to the standard non-compartmental analysis, there is less experience with a PPK approach. Here, we describe two methods of how PPK can be incorporated in biosimilarity testing for complex therapeutics.

Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial.

BACKGROUND: The exact extent of and the mechanism by which trastuzumab causes cardiac side effects are not completely unravelled. We investigated the (cardiotoxic) side effects of trastuzumab in a relatively large homogeneous population. METHODS: Healthy male volunteers (n = 54) with a left ventricle ejection fraction (LVEF) > 55% were administered 6 mg/kg trastuzumab (n = 46) IV in 90 min in a placebo-controlled, parallel study. Placebo consisted of 0 · 9% NaCl (n = 8). Assessments included body weight, routine and cardiac laboratory markers and serial echocardiographic examinations (8 placebo and 9 trastuzumab treated participants) up to 63 days after dosing. Statistical analysis was done using repeated measurements of variance. FINDINGS: Following trastuzumab infusion, fluid retention was observed: mean body weight increased over the first 4 days post-administration with 0 · 4 kg (95%-confidence interval: - 0 · 2, 0 · 9, p = 0 · 2261) compared to placebo, mean haemoglobin concentration decreased with 0 · 3 mM (- 0 · 6, - 0 · 1; p = 0 · 0043), as did haematocrit (- 0 · 013 L/L [- 0 · 024, - 0 · 002], p = 0 · 0216), and protein (- 2 g/L [- 4, - 0], p = 0 · 0443) and albumin (- 2 g/L [- 3, - 1], p < 0 · 0001) concentrations. Elevations in NT-proBNP levels, parallel to the weight increase, were observed in individual cases, but not on a group level. Troponin-T concentrations did not increase. The only echocardiographic parameter that changed significantly at all studied dose levels was E/A-ratio, a load-dependent parameter: from 1 · 81 (SD 0 · 42) to 1 · 98 (0 · 31) 3-5 days after administration, contrast to placebo of 0 · 57 (90%-CI: 0 · 21-0 · 93, p = 0 · 0034). Ejection fraction and pulsed-wave Doppler recorded parameters remained unchanged. INTERPRETATION: Single dose administration of trastuzumab in humans is associated with an immediate, transient extracellular volume increase, either as a primary or secondary (compensatory) response, which can be detected easily using routine clinical assessments. Echocardiographic changes, both short and long term, could not be found after single dose administration to drug-naive patients.

A phase I dose-escalation and bioequivalence study of a trastuzumab biosimilar in healthy male volunteers.

BACKGROUND: Trastuzumab (Herceptin(®)) is a humanized monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2) and is used in the treatment of HER2-overexpressing breast and gastric cancer. FTMB is being developed as a biosimilar of trastuzumab. OBJECTIVE: In this combined dose-escalation and bioequivalence study of parallel design, the pharmacokinetic profile of FTMB was compared with Herceptin(®). METHODS: Healthy male volunteers received single doses of 0.5, 1.5, 3.0 or 6.0 mg/kg FTMB, or placebo, in consecutive dose-escalation cohorts to assess the safety profile. Thereafter, the 6 mg/kg cohort was expanded to establish bioequivalence between FTMB (Test) and Herceptin(®) (Reference) based on an acceptance interval of 80.0-125.0 %. In total, 118 subjects were enrolled in the study. RESULT: The mean area under the concentration-time curve from time zero to infinity (AUC∞) was 1,609 µg·day/mL (Test) and 1,330 µg·day/mL (Reference). The log-transformed geometric mean Test/Reference (T/R) ratio for AUC∞ was 89.6 % (90 % confidence interval [CI] 85.1-94.4), demonstrating bioequivalence. For the secondary endpoint, the maximum concentration observed (Cmax), the geometric mean T/R ratio was 89.4 % (90 % CI 83.4-95.9). Non-linear, target-mediated pharmacokinetics were also observed. Adverse events other than the documented side effects of Herceptin(®) (fever, influenza-like illness, and fatigue) did not occur. No signs of cardiotoxicity were observed. CONCLUSIONS: This bioequivalence study with a trastuzumab biosimilar in healthy male volunteers demonstrated bioequivalence of FTMB with Herceptin(®). FTMB was well tolerated in doses up to 6 mg/kg. Non-linear target elimination was also observed in the pharmacokinetic profile of trastuzumab.