Efficacy, safety and immunogenicity of GP2015, an etanercept biosimilar, compared with the reference etanercept in patients with moderate-to-severe rheumatoid arthritis: 24-week results from the comparative phase III, randomised, double-blind EQUIRA study.

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.

Longitudinal assessment of the impact of multiple switches between a biosimilar and its reference product on efficacy parameters.

Patients, physicians, and health care providers in Europe have more than 10 years of experience with biosimilars. However, there are still debates if switching between a biosimilar and its reference product influences the efficacy of the treatment. In this paper, we address this uncertainty by developing a formal statistical test that can be used for showing that switching has no negative impact on the efficacy of biosimilars. For that, we first introduce a linear mixed-effects model that is used for defining the null hypothesis (switching influences the efficacy) and the alternative hypothesis (switching has no influence on the efficacy). Using this as the foundation of our work, we propose several approaches for testing for changes in the efficacy of the treatment due to switching and discuss the properties of these tests in an extensive simulation study. It is shown that all these methods have advantages and disadvantages and the decision regarding which method is preferred depends on the expectation of a switching assessment. To demonstrate the applicability of the methods in practice, the approaches were applied to the data of the EGALITY study, which compares the reference product Enbrel® (Amgen) with the approved biosimilar Erelzi® (Sandoz).

GP2015, a proposed etanercept biosimilar: Pharmacokinetic similarity to its reference product and comparison of its autoinjector device with prefilled syringes.

AIMS: To assess pharmacokinetics (PK) and safety of GP2015, a proposed etanercept biosimilar, in two studies: comparison with etanercept originator (ETN, bioequivalence study) and comparison of GP2015 administered via an autoinjector (AI) or prefilled syringes (PFS, delivery study). METHODS: Both studies were randomized, two-sequence, two-period, crossover studies conducted in healthy male subjects. In the bioequivalence study, subjects were randomized to receive a single 50 mg subcutaneous (s.c.) injection of GP2015 or ETN. In the delivery study, subjects were randomized to receive a single 50 mg s.c. injection of GP2015 via AI or PFS. Following a wash-out period of 35 days, subjects in the bioequivalence study received single 50 mg s.c. injection of GP2015 or ETN, and subjects in the delivery study received single 50 mg s.c. injection of GP2015 via AI or PFS. RESULTS: The geometric mean ratios (90% confidence interval) of GP2015/ETN for Cmax (1.11 [1.05-1.17]), AUC0-tlast (0.98 [0.94-1.02]) and AUC0-inf (0.96 [0.93-1.00]) were within the predefined bioequivalence range of 0.80-1.25. The geometric mean ratios (90% confidence interval) of AI/PFS for Cmax (1.01 [0.94-1.08]), AUC0-tlast (1.01 [0.95-1.07]) and AUC0-inf (1.01 [0.96-1.07]) were also within the range 0.80-1.25. No new safety issues were reported. Three subjects had low titres of non-neutralising anti-drug antibodies during a follow-up visit in the bioequivalence study. CONCLUSIONS: The PK of GP2015 was similar to ETN, demonstrating bioequivalence. The safety profile of GP2015 was consistent with previous reports for ETN. The GP2015 AI provided equivalent dosing and tolerability to the GP2015 PFS.

Two-Year Data from a Long-Term Phase IV Study of Recombinant Human Growth Hormone in Short Children Born Small for Gestational Age.

INTRODUCTION: This ongoing, prospective, open-label, non-comparative, multicenter phase IV study is evaluating the safety and efficacy of recombinant human growth hormone (rhGH; Omnitrope(®), Sandoz GmbH) in short children born small for gestational age (SGA). Here we report data from patients who have completed 2 years' treatment. METHODS: Eligibility criteria included prepubertal children born SGA with growth disturbances defined as current height standard deviation score (HSDS) <-2.5 and parental adjusted SDS <-1; birth weight and/or length <-2 SDS; and failure of catch-up growth [height velocity (HV) SDS <0 during the last year] by 4 years of age or later. The primary study objective is to assess the long-term effect of Omnitrope treatment on the development of diabetes in short children born SGA. Secondary objectives include evaluation of efficacy, incidence and severity of adverse events (AEs), occurrence of malignancies during treatment, and detection of anti-rhGH antibodies during treatment. RESULTS: In total, 278 children have been enrolled and received study medication; 249 have completed 2 years of treatment. No child has developed diabetes mellitus during the first 2 years; no fasting glucose or 2-h oral glucose tolerance test value exceeded the pre-defined limits of >126 or >200 mg/dL, respectively. No adverse alterations in body mass were noted. Treatment-emergent AEs were experienced by 211 (76.2%) children; most of these were of mild-to-moderate intensity (99.3%) and considered unrelated to study medication (97.6%). Treatment with Omnitrope was effective; mean HSDS was -3.39 at baseline, -2.57 at 1 year and -2.15 at 2 years of treatment. Mean HVSDS (peak-centered) also improved, from -2.13 at baseline to +4.16 at 1 year and +2.23 at 2 years. CONCLUSION: In this second interim analysis, short children born SGA were safely and effectively treated with rhGH (Omnitrope), and 2 years' treatment had no major adverse impact on carbohydrate metabolism or body mass. FUNDING: Sandoz.

Assessing switchability for biosimilar products: modelling approaches applied to children's growth.

The present paper describes two statistical modelling approaches that have been developed to demonstrate switchability from the original recombinant human growth hormone (rhGH) formulation (Genotropin(®) ) to a biosimilar product (Omnitrope(®) ) in children suffering from growth hormone deficiency. Demonstrating switchability between rhGH products is challenging because the process of growth varies with the age of the child and across children. The first modelling approach aims at predicting individual height measured at several time-points after switching to the biosimilar. The second modelling approach provides an estimate of the deviation from the overall growth rate after switching to the biosimilar, which can be regarded as an estimate of switchability. The results after applying these approaches to data from a randomized clinical trial are presented. The accuracy and precision of the predictions made using the first approach and the small deviation from switchability estimated with the second approach provide sufficient evidence to conclude that switching from Genotropin(®) to Omnitrope(®) has a very small effect on growth, which is neither statistically significant nor clinically relevant.

Switching to Omnitrope(®) from Other Recombinant Human Growth Hormone Therapies: A Retrospective Study in an Integrated Healthcare System.

INTRODUCTION: This study was conducted using an integrated retrospective database to evaluate the effectiveness of Omnitrope(®) (Sandoz) on children with growth hormone deficiency (GHD), idiopathic short stature (ISS), and Turner Syndrome (TS) who switched from a non-Omnitrope recombinant human growth hormone (rhGH) preparation during routine clinical care. METHODS: This was a retrospective study which identified patients with GHD, ISS, and TS during the study time period of January 1, 2006 and July 31, 2011. Patients were included if they switched to Omnitrope from another non-Omnitrope rhGH therapy during the study time period, were <18 years of age at time of switch, and on a prior rhGH therapy for at least 15 months pre-switch and on Omnitrope for 15 months post-switch. Auxological parameters (height, height standard deviation score [HSDS], height velocity [HV], and height velocity standard deviation score [HVSDS]) were evaluated during post-switch. RESULTS: One hundred and three patients were identified: GHD (n = 57), ISS (n = 26), and TS (n = 20). There was continuous growth in height for all 103 patients with an average rate of 6.52 cm over the 15-month post-switch period. Patients with GHD grew an average rate of 6.30 cm, patients with ISS grew an average rate of 6.58 cm, and patients with TS grew an average rate of 6.52 cm over the 15-month post-switch period. The average rate of HSDS was increased by 0.04 for all patients. The HV and HVSDS demonstrated the expected decline with advancing age and prolonged duration of treatment. CONCLUSIONS: The growth trajectories of rhGH-treated patients were not negatively impacted by switching to Omnitrope and growth rates remained as expected prior to the switch.

Switching From Originator to Biosimilar Human Growth Hormone Using Dialogue Teamwork: Single-Center Experience From Sweden.

INTRODUCTION: A new treatment plan was implemented at Skåne University Hospital, on economic grounds, for children requiring recombinant human growth hormone (rhGH) treatment. This involved switching patients from treatment with originator rhGHs to treatment with a biosimilar rhGH, somatropin (Omnitrope®), using a Dialogue Teamwork approach. The feasibility of using this approach to implement the switch of treatment was assessed, as well as the impact of the switch on treatment efficacy and cost of therapy. METHODS: As part of the Dialogue Teamwork approach, patients/parents received several opportunities for dialogue and sources of information, including discussions with the Head of Department, the responsible physician and a specialized endocrinology nurse. Height and height standard deviation score (HSDS) data were plotted for each individual patient (N = 98). A modeling approach was also used, to predict growth after switching to biosimilar rhGH; the predictions were then compared to the actual observed height after the switch. Costs to the clinic of rhGH therapy were calculated between May-August 2009 and May-August 2012. RESULTS: Of the 102 patients offered the switch, 98 accepted. Height and HSDS data indicated there was no negative impact on growth velocity after the switch to biosimilar rhGH. Modeling demonstrated that observed growth following the switch was consistent with predicted growth based on data before patients were switched. There were no reports of serious or unexpected adverse drug reactions following the switch to biosimilar rhGH. Following the switch, the cost to the clinic of rhGH treatment decreased from approximately 6 million SEK (May-August 2009) to approximately 4 million SEK (May-August 2012). This corresponds to an annual saving of 6 million SEK (€650,000). CONCLUSION: Patients were successfully switched from originator to biosimilar rhGH (somatropin), with no negative impact on growth, and no serious or unexpected adverse drug reactions. The switch from originator to biosimilar rhGH is associated with substantial cost savings.

Treatment of active lupus nephritis with the novel immunosuppressant 15-deoxyspergualin: an open-label dose escalation study.

INTRODUCTION: As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN). METHODS: Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of nine times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects. RESULTS: A total of 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. Five patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. Eleven out of 20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and 1 patient was not assessable. Twelve patients completed all nine cycles; in those patients, proteinuria decreased from 5.88 g/day to 3.37 g/day (P = 0.028), Selena-SLEDAI (Safety of Estrogens in Lupus Erythematosus-National Assessment-systemic lupus erythematosus disease activity index) decreased from 17.6 to 11.7. In 13 out of 20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1 g/day. CONCLUSIONS: Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00709722.

Effect of St John's wort dose and preparations on the pharmacokinetics of digoxin.

BACKGROUND AND OBJECTIVE: St John's wort preparations vary in composition, main constituents, formulation, and daily dose administered. The aim of the study was to evaluate the possible pharmacokinetic interaction of marketed St John's wort formulations and doses with digoxin. METHODS: A randomized, placebo-controlled, parallel-group study was performed in 96 healthy volunteers in 3 study parts. A 7-day loading phase with digoxin was followed by 14 days of comedication with placebo or one of 10 St John's wort products varying in dose and formulation. The pharmacokinetics of digoxin was determined before comedication and on day 14 of comedication. RESULTS: Comedication comprised traditionally used Hypericum products; 2 g powder without hyperforin, tea, juice, oil extract, and placebo had no significant interaction with digoxin nor did hyperforin-free extract (Ze 117) or low daily doses of hyperforin-containing Hypericum powder (1 g, 0.5 g). However, comedication with the high-dose hyperforin-rich extract LI 160 resulted in a reduction of digoxin area under the curve from time 0 to 24 hours (AUC(0-24)) of -24.8% (95% confidence interval [CI], -28.3 to -21.3), a reduction in digoxin maximal plasma concentration (C(max)) of -37% (95% CI, -42 to -32), and a reduction in digoxin plasma concentration at 24 hours after previous dosing (C(trough)) of -19% (95% CI, -27 to -11). Comedication with 4 g Hypericum powder with comparable hyperforin content resulted in a reduction in digoxin AUC(0-24) of -26.6% (95% CI, -37.3 to -15.9), a reduction in digoxin C(max) of -38% (95% CI, -48 to -18), and a reduction in digoxin C(trough) of -19% (95% CI, -27 to -10). Two grams of Hypericum powder with half the hyperforin content resulted in a less prominent reduction in AUC(0-24) of -17.7% (95% CI, -21.6 to -13.7), C(max) (-21%; 95% CI, -40 to -2), and C(trough) (-13%; 95% CI, -21 to -5). CONCLUSIONS: The interaction of St John's wort and digoxin varies within St John's wort preparations and doses and seems to be correlated with the dose, particularly of hyperforin.