Biosimilars and biobetters as tools for understanding and mitigating the immunogenicity of biotherapeutics.

In this article, we review key steps for the development of biosimilars and biobetters and related bioanalytical challenges, with a focus on how they are associated with immunogenicity. We analyze the factors that can impact antidrug antibody (ADA) responses and their correlations with preclinical and clinical outcomes to provide relevant insights and to answer questions, including what types of aggregate are immunogenic. We also address strategies for developing less-immunogenic biotherapeutics. Using interferon-ß (IFN-ß) as a case study, we explore the correlation between aggregation and immunogenicity. We dissect and integrate with clinical data the IFN-ß preclinical immunogenicity and aggregation predictions and discuss the feasibility of developing an IFN-ß with lower aggregation and/or immunogenicity.

Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data.

CONTEXT: HIV patients treated with antiretroviral therapy (ART) often develop increased visceral adipose tissue (VAT). OBJECTIVE: Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin in ART-treated HIV patients with excess abdominal fat. DESIGN AND SETTING: Two multicenter, international studies were conducted; a 26-wk randomized, placebo-controlled primary intervention phase was followed by a 26-wk safety extension. PATIENTS: A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1 fashion to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc daily. At wk 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P, n = 135) for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n = 197). INTERVENTIONS: Tesamorelin (GHRH(1-44)) at a dose of 2 mg or identical placebo, sc, was given daily. MAIN OUTCOME MEASURE: We evaluated percent change in VAT by computed tomography scan at wk 26. RESULTS: At wk 26, VAT decreased significantly in tesamorelin-treated patients (-24 +/- 41 vs. 2 +/- 35 cm(2), tesamorelin vs. placebo, P < 0.001; treatment effect, -15.4%). No significant changes were observed in abdominal sc adipose tissue (-2 +/- 32 vs. 2 +/- 29 cm(2), P = 0.08; treatment effect, -0.6%). Treatment with tesamorelin resulted in significant decreases in triglycerides (-37 +/- 139 vs. 6 +/- 112 mg/dl, P < 0.001; treatment effect, -12.3%) and cholesterol to high-density lipoprotein ratio (-0.18 +/- 1.00 vs. 0.18 +/- 0.94, P < 0.001; treatment effect, -7.2%) vs. placebo. Tesamorelin improved body image [belly appearance distress (P = 0.002)], patient rating of belly profile (P = 0.003), and physician rating of belly profile (P < 0.001). Mean IGF-I increased 108 +/- 112 vs.-7 +/- 64 ng/ml (P < 0.001 vs. placebo). At wk 52, decreases in VAT [-35 +/- 50 cm(2) (-17.5 +/- 23.3%)], waist circumference (-3.4 +/- 6.0 cm), triglycerides (-48 +/- 182 mg/dl), cholesterol (-8 +/- 38 mg/dl), and non-high-density lipoprotein (-7 +/- 38 mg/dl) were maintained (all P < 0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was generally well tolerated. No clinically meaningful differences were observed between groups in glucose parameters at wk 26 and 52. CONCLUSIONS: Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk, preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without clinically meaningful changes in glucose parameters.