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Purpose: Sandoz biosimilar denosumab (GP2411 [SDZ-deno]; Jubbonti/Wyost) is approved by the US FDA, EMA and Health Canada for all indications of reference denosumab (REF-deno; Prolia/Xgeva), a fully human IgG2κ monoclonal antibody that binds with high affinity and specificity to receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab blocks RANKL, preventing bone resorption and loss of bone density/architecture in conditions characterized by excessive bone loss such as osteoporosis in postmenopausal women and metastatic bone disease, among others., Methods: This narrative review summarizes the totality of evidence (ToE) for SDZ-deno that supported its approval as Jubbonti/Wyost in the EU and US., Findings: Analytical evaluation indicated that SDZ-deno has high purity and structural homology with REF-deno. SDZ-deno also demonstrated similar binding affinities, size and charge variants, and disulfide isoforms to REF-deno, and did not trigger clinically meaningful antibody-dependent cellular cytotoxicity. In clinical evaluation, SDZ-deno was similar to REF-deno in pharmacokinetics (PK) and pharmacodynamics (PD) in a 39-week Phase I study in 502 healthy male participants, and to REF-deno in a 72-week Phase III study in 527 postmenopausal women with osteoporosis. In both studies, the 90% and 95% confidence intervals (for PK and PD endpoints, respectively) of the geometric mean ratios for AUC inf , C max (and AUC last in the Phase I study; PK endpoints), and area under the effect versus time curve of percent change from baseline in serum carboxy-terminal crosslinked telopeptide of type I collagen (PD endpoint), were fully contained within the prespecified equivalence margins (0.80, 1.25). The Phase III study also demonstrated SDZ-deno is similar in efficacy to REF-deno in postmenopausal women with osteoporosis, as the difference in percent change from baseline in lumbar spine bone mineral density at week 52 between REF-deno and SDZ-deno was fully contained within the prespecified equivalence margins (-1.45, 1.45). SDZ-deno was well tolerated in both studies. As the ToE has established biosimilarity of SDZ-deno and REF-deno, extrapolation to all indications is justified based on the common mechanism of action and the comparable PK, safety, and immunogenicity across all indications., Implications: The ToE for SDZ-deno suggests it will be an effective biosimilar to REF-deno, and its lower unit price is anticipated to increase the number of appropriate patients who will benefit., Competing Interests: Declaration of competing interest BV, JP, AS, SS, NK, and OR, are employees of Hexal AG (a Sandoz company). AS owns shares in Sandoz Group. AK has received consulting fees from AbbVie, Coval, Ecor1, Fresenius Kabi, Genzyme, Gilead, Grunenthal, GSK, Halia, Horizon, Janssen, Prime, Prometheus, Selecta, Synact, Takeda, UCB, and XBiotech; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, GSK, Eli Lilly, Pfizer, Sanofi-Regeneron, AbbVie, and UCB; been part of a board or advisory board for Fresenius Kabi, Horizon, Janssen, Novartis, Princeton Biopartners, and UCB; and has stock or stock options in Pfizer, GSK, Gilead, Novartis, and Amgen. JJB has received consultancy funding or lecture fees from Amgen, Cole Pharma, and UCB; and grant funding from UCB. RE has received consultancy funding from Biocon, CL Bio, CureTeQ, Immunodiagnostic Systems, Samsung, Sandoz, Takeda, UCB; has given meeting presentations for Pharmacosmos, Alexion, Amgen and UCB; received support for attending meetings from CL Bio and Samsung; received grant funding from Alexion and Osteolabs; and has chaired a Data Safety Monitoring Board or Advisory Board for Biocon, CuRaTEQ, and STOPFOP., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal antibody for specific pro-resorptive conditions)., Research Design and Methods: Healthy males (28-65 years, 50-90 kg) were randomized to a single sub-therapeutic subcutaneous injection of 35 mg GP2411, EU-Xgeva® or US-Xgeva®, and followed for 39 weeks. The primary endpoints were AUC inf , AUC last , and C max ., Results: Four hundred ninety-two participants completed treatment. The 90% confidence intervals (CIs) (AUC inf , AUC last , and C max ) and 95% CI of the geometric mean ratios of AUEC of % change from baseline in serum CTX were fully contained within the prespecified equivalence margins (0.80, 1.25), demonstrating similarity. The occurrence of treatment-emergent adverse events (TEAEs) with GP2411, EU-Xgeva® and US-Xgeva® was similar (72.9%, 76.0%, and 71.0% of participants, respectively). Most were Grade 1 or 2, <30% were treatment-related, and there was only one TEAE-related study discontinuation. Rates of positive anti-drug antibodies (ADAs) were similar (57.8%, 64.9%, and 69.1% of participants respectively), but immunogenicity was only borderline detectable and of very low magnitude. Ninety-nine percent of positive ADAs were transient., Conclusion: GP2411 demonstrated similarity with EU-Xgeva® and US-Xgeva® in PK, PD, safety, and immunogenicity in this population., Clinical Trial Registration: EudraCT 2019-001651-39.

Objectives: To demonstrate the equivalent efficacy and compare the safety and immunogenicity of an etanercept biosimilar, GP2015, with reference etanercept (ETN) in patients with moderate-to-severe, active rheumatoid arthritis (RA), characterised by an inadequate response to synthetic or biologic disease-modifying antirheumatic drugs (DMARDs)., Methods: In the EQUIRA study, eligible patients (n=376) were randomised 1: 1 to 50  mg GP2015 or ETN subcutaneously, once weekly, for 24 weeks (treatment period 1). Patients from both groups, with at least moderate European League Against Rheumatism response at week 24, received GP2015 up to week 48 (treatment period 2). All patients continued to receive concomitant methotrexate at a stable dose (10-25  mg/week) until end of the study. The 24-week results are presented here., Results: Equivalent efficacy between GP2015 and ETN was demonstrated if the 95% CI for the difference in disease activity score 28-joint count C reactive protein (DAS28-CRP) change from baseline to week 24 between treatment arms was contained within the prespecified equivalence margin range of -0.6 to 0.6. The least squares mean difference (GP2015-ETN) in change from baseline in DAS28-CRP up to week 24 was -0.07 (95% CI -0.26 to 0.12 [primary endpoint)]. The incidence of treatment-emergent adverse events was comparable between GP2015 (43.5%) and ETN (49.5%). None of the GP2015-treated patients developed neutralising anti-drug antibodies (NAbs) whereas 1.6% and 0.6% of patients in ETN group were NAb positive at weeks 4 and 12, respectively., Conclusion: In patients with RA who had an inadequate response to DMARDs, GP2015 demonstrated a similar efficacy and a comparable safety and immunogenicity profile with ETN., Trial Registration: NCT02638259., Competing Interests: Competing interests: MM-C reports no conflicts of interest. YA reports personal fees from Sandoz, grants and personal fees from Pfizer, grants and personal fees from Roche, during the conduct of the study. AK reports personal fees from Sandoz, outside the submitted work. MHB reports personal fees from Sandoz during the conduct of the study. HS-K reports personal fees from Sandoz/Hexal during the conduct of the study, personal fees from Sandoz/Hexal, grants and personal fees from Novartis, outside the submitted work. EJK reports no conflict of interest. HW, GB, JP and AS are employees of Hexal AG. AD is an employee of Sandoz Inc.

Background: Biosimilar granulocyte-colony-stimulating factors (G-CSFs) have been available in the European Union since 2008, and Sandoz' biosimilar filgrastim was approved in the United States in March 2015 for all of the reference product's indications except acute radiation syndrome. Biosimilar G-CSFs have been largely embraced by the medical community, except for some reservations about healthy-donor stem cell mobilization, for which use outside of clinical studies was cautioned against by some members of the scientific community., Study Design and Methods: In a two-center safety surveillance study (National Clinical Trial NCT01766934), 245 healthy volunteer stem cell donors were enrolled. Of 244 donors who began mobilization with twice-daily Sandoz biosimilar filgrastim, 242 received a full (n = 241) or partial (n = 1) course of G-CSF and underwent apheresis. Efficacy and safety were assessed and are reported here., Results: Biosimilar filgrastim was accompanied by the typical G-CSF class-related adverse effects of expected frequency and severity. Median mobilization for CD34-positive stem cells was 97/µL (range, 20-347/µL); after one apheresis (91%) or two aphereses (9%) from all but three donors (1.2%), cell doses in excess of the typical 4 × 10 6 CD34-positive cells/kg of the recipient had been collected (range, 3-52 × 10 6 /kg). Biochemical and hematologic alterations were consistent with previous reports; all had normalized by the first follow-up 1 month after mobilization. Stem cell products engrafted with typical probability and kinetics for G-CSF-mobilized stem cell products., Conclusion: These data support the use of biosimilar filgrastim for healthy-donor stem cell mobilization as safe and effective., (© 2016 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.)

Background: Biosimilars of filgrastim are in widespread clinical use in Europe. This phase III study compares biosimilar filgrastim (EP2006), with the US-licensed reference product, Neupogen(®), in breast cancer patients receiving (neo)adjuvant myelosuppressive chemotherapy (TAC)., Patients and Methods: A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomized 1:1:1:1 into four arms. Two arms received only one product (nonalternating), biosimilar or reference, and two arms (alternating) received alternating treatments during each cycle (biosimilar then reference or vice versa). The primary end point was duration of severe neutropenia (DSN) during cycle 1., Results: The baseline characteristics were balanced between the four treatment arms. Noninferiority of biosimilar versus the reference was demonstrated: DSN (days) in cycle 1 was 1.17 ± 1.11 (biosimilar, N = 101) and 1.20 ± 1.02 (reference, N = 103), 97.5% confidence interval lower boundary for the difference was -0.26 days (above the predefined limit of -1 day). No clinically meaningful differences were observed regarding any other efficacy parameter: incidence of febrile neutropenia (FN); hospitalization due to FN; incidence of infections; depth and time of absolute neutrophil count (ANC) nadir and time to ANC recovery during cycle 1 and across all cycles. The pattern and frequency of adverse events were similar across all treatments., Conclusion: This study demonstrates that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment., Study Number: NCT01519700., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Biosimilars provide safety, purity, and potency similar to those of a reference biologic product., Methods: An array of protein analytical techniques was used to compare the physicochemical properties of proposed biosimilar filgrastim (EP2006), US-approved originator filgrastim, and EU-approved originator filgrastim. Biological characterization involved surface plasmon resonance spectroscopy analyses and in vitro proliferation assays. A randomized, double-blind, two-way crossover, phase I study in healthy volunteers assessed the pharmacodynamics, pharmacokinetics, and safety profiles of EP2006 and US-approved originator filgrastim (administered as a single subcutaneous 10 µg/kg injection)., Results: EP2006 and originator filgrastim (US and EU approved) were highly similar with respect to primary, secondary, and tertiary protein structures; mass, size, purity, charge, and hydrophobicity. No differences in receptor binding affinity were observed, and all samples demonstrated similar in vitro bioactivity. In the phase I study, no statistically significant differences between EP2006 and US-approved originator filgrastim were noted in pharmacodynamic or pharmacokinetic parameters, and all confidence intervals were within the equivalence boundaries. The two products had similar safety profiles., Conclusion: These studies provide robust evidence of the structural and functional similarity between the proposed biosimilar filgrastim (EP2006) and the US-approved originator filgrastim.

Biosimilars are approved biologics with comparable quality, safety, and efficacy to a reference product. Unlike generics, which are chemically manufactured copies of small-molecule drugs with relatively simple chemical structures, the biosimilar designation is applied to drugs that are produced by living organisms, implying much more difficult to control manufacturing and purification procedures. To account for these complexities, the European Medicines Agency (EMA), the US Food and Drug Administration, the Australian Therapeutic Goods Administration, and other regulatory authorities have devised and implemented specific, markedly more demanding pathways for the evaluation and approval of biosimilars. To date, several biosimilars have been approved, including versions of somatropin, erythropoietin, and granulocyte-colony-stimulating factor (G-CSF), and several biosimilar monoclonal antibodies are currently in development. The reference G-CSF product (Neupogen, Amgen) has been used for many years for prevention and treatment of neutropenia and also for mobilization of peripheral blood stem cells (PBSCs). However, concerns have been raised about the safety and efficacy of biosimilar G-CSF during PBSC mobilization procedures, especially in healthy donors. This article reviews the available evidence on the use of biosimilar G-CSF in this setting. Aggregate clinical evidence supports the assessment by the EMA of biosimilar and originator G-CSF as highly biologically similar, with respect to desired and undesired effects., (© 2014 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.)

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.

Objectives: Treatment of ankylosing spondylitis (AS) with the tumour necrosis factor alpha (TNF-alpha) receptor fusion protein etanercept has shown efficacy in patients with active disease in randomized controlled trials (RCTs) for limited periods. The objective of the study was to assess the long-term efficacy and safety of etanercept over 1 yr, including discontinuation and readministration., Methods: In this 54-week open observational study, 26 AS patients received 25 mg etanercept subcutaneously twice weekly after several months of discontinuation following a 6-month RCT with the same agent. All patients who developed high disease activity after cessation of etanercept, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > or = 4 and pain > or = 4 on a numerical rating scale, entered the study. Standard assessment tools, such as the Bath Ankylosing Spondylitis functional index (BASFI), were used. An intention-to-treat (ITT) and a completer analysis were performed. The results were compared with the baseline values of the open study., Results: Out of the initial 30 patients, 26 (87%) were eligible for the open extension study after a mean of about 27 weeks. At week 54, 23/26 patients (88%) were still on treatment with etanercept. The ITT analysis showed that 58% (95% confidence interval 39-74%) of the patients achieved a 50% improvement of BASDAI at week 54. According to the Assessments in Ankylosing Spondylitis working group criteria, 8/26 patients (31%) were in partial remission at week 54. Function, metrology and quality of life improved significantly. Only one patient had a serious adverse event that resulted in discontinuation., Conclusions: This study shows that treatment with etanercept is efficacious and safe after readministration over 1 yr in patients with active AS not taking DMARDs or steroids.

Background: A work force based case-control study of lung cancer was performed in non-silicotic subjects exposed to crystalline silica to investigate the association between silica dust and lung cancer excluding the influence of silicosis., Methods: Two hundred and forty seven patients with lung cancer and 795 control subjects were enrolled, all of whom had been employed in the German stone, quarrying, or ceramics industries. Smoking was used as a matching criterion. Exposure to silica was quantified by measurements, if available, or otherwise by industrial hygienists. Several indices (peak, average and cumulative exposure) were used to analyse the relationship between the level of exposure and risk of lung cancer as odds ratios (OR)., Results: The risk of lung cancer is associated with the year of and age at first exposure to silica, duration of exposure, and latency. All odds ratios were adjusted for these factors. Considering the peak exposure, the OR for workers exposed to high levels (>/=0.15 mg/m3 respirable silica dust which is the current occupational threshold value for Germany) compared with those exposed to low levels (<0.15 mg/m3) was 0.85 (95% CI 0.58 to 1. 25). For the time weighted average exposure the OR was 0.91 (95% CI 0.57 to 1.46). The OR for the cumulative exposure was 1.02 (95% CI 0. 67 to 1.55). No increase in risk was evident with increasing exposure., Conclusions: This study shows no association between exposure to crystalline silica and lung cancer. The exclusion of subjects with silicosis may have led to dilution with respect to the level of exposure and therefore reduced the power to detect a small risk. Alternatively, the risk of getting lung cancer may be restricted to subjects with silicosis and is not directly linked to silica dust.

Medicine combinations for AIDS and cancer treatment are becoming common practice in most clinical stages. These combinations are based on clinical developments which do not follow established guidelines such as those for fixed combinations. There are no current recommendations which can guide these developments and we have tried to identify the critical steps. The main difficulty is to balance the fast development required by the poor prognosis of these diseases and the protection of patients who can only be subjected to combinations for which reasonable expectation of a favourable therapeutic index is foreseen. For each pathology, the pre-clinical evidence-needed before pilot clinical studies and the surrogate clinical end-points are considered (viral load for AIDS and response rate for cancer). These are prerequisities for randomized clinical trials, which are the only means of definitive assessment of new combinations versus existing therapies.

A multicentre controlled trial was carried out to determine the optimal dosage of a 2/1 combination of captopril plus hydrochlorothiazide (HCTZ) in mild hypertension at three doses against placebo in a 6 week double-blind trial. The number of patients was 111:27 received placebo; 26 were treated with captopril 25 mg plus HCTZ 12.5 mg (25/12.5); 25 with captopril 50 mg plus HCTZ 25 mg (50/25); and 33 with captopril 100 mg plus HCTZ 50 mg (100/50). A significant fall in blood pressure was seen in all four groups, but was greater with the active treatments. The percentage of patients who were normalized [diastolic blood pressure (DBP) less than or equal to 90 mm Hg] or good responders (10% fall in DBP) increased as a function of the dose. At Day 21, the antihypertensive effect of 50/25 was similar to that of 100/50, but greater than that of captopril 25-HCTZ 12.5. At Day 42, the antihypertensive effects of the three doses were similar. Tolerance data showed a higher incidence of side-effects with 100/50 than with the other dosages. Thus, 50/25 appeared to be the optimal dosage for the control of mild hypertension.

With an informatized sample of 123 patients taking Captopril and treated for a total duration of 1,321 month/patients, the frequency of the dermatological symptoms induced by the drug is related. Pruritus is found in 10,5 p. 100 and rashes in 2,4 p. 100 of cases. The results are compared with those of preceeding reports, although some authors have found a higher percentage because of highin doses of the drug. The clinical features of the rashes and the proposed mechanisms are also reported.

A comparative study was made of the effects of a new therapeutic agent consisting of 50 mg captopril and 25 mg hydrochlorothiazide (Capozide) with an already existing agent Moduretic (50 mg hydrochlorothiazide and 5 mg amiloride). In the Capozide group (32 patients), 20 achieved normal blood pressure, 8 responded but were not brought under control, and 3 were non-responders. In the Moduretic group (31 patients), 17 achieved normal blood pressure, 10 were partially controlled and 4 were non-responders. Moduretic appeared to be most effective in patients previously untreated or who had been taking only one drug, while Capozide controlled patients who had been taking 1 or 2 antihypertensive drugs which had been either ineffective or poorly tolerated. The long-acting effect of a single dose of Capozide was demonstrated by blood pressure measurements taken at least 10 hours later. Both drugs were generally well tolerated and no significant changes were observed in the laboratory measurements. The combination of an angiotensin converting enzyme inhibitor with a diuretic proved more effective than single agents in lowering raised blood pressure. We therefore conclude that Capozide is an effective alternative to traditional medication in the treatment of moderate hypertension.