Barry Gumbiner

Clinical considerations for the development of biosimilars in oncology

Despite availability of biologic therapies, limited patient access to many of the most-effective cancer treatments affects overall health outcomes. To address this issue, many governments have enacted legislation for the approval of biosimilars. The term “biosimilar” refers to a biologic product that is developed to be highly similar, as opposed to identical, to a licensed biologic product (the reference or innovator product), such that, per US Food and Drug administration draft guidelines, “no clinically meaningful differences [exist] between the biological product and the reference product in terms of safety, purity, and potency.” This article presents some considerations about the development of biosimilars in cancer treatment through an overview of biosimilars from a clinical perspective. Topics covered include the development requirements and unique regulatory requirements for biosimilars, labeling considerations, potential limitations to the uptake of biosimilars, and review of some biosimilars in development for oncology indications.

A phase I pharmacokinetics trial comparing PF‐05280586 (a potential biosimilar) and rituximab in patients with active rheumatoid arthritis

Aims Pharmacokinetic (PK) similarity was assessed among PF‐05280586 (a proposed biosimilar) vs. rituximab sourced from the European Union (rituximab‐EU) and the United States (rituximab‐US). Pharmacodynamics (PD), overall safety and immunogenicity were also evaluated. Methods Patients with active rheumatoid arthritis on a background of methotrexate and inadequate response to one or more tumour necrosis factor antagonist therapies were randomized to intravenous PF‐05280586, rituximab‐EU or rituximab‐US 1000 mg doses on study days 1 and 15. Results A total of 220 patients were randomized to receive study treatment as assigned. Of these, 198 met per‐protocol population criteria for inclusion in the PK data analysis. PF‐05280586, rituximab‐EU and rituximab‐US exhibited similar PK profiles following administration of assigned study drug on days 1 and 15. The 90% confidence intervals of test‐to‐reference ratios for C max, AUCT, AUC0–∞ and AUC2‐week were within the bioequivalence margin of 80.00–125.00% for comparisons of PF‐05280586 with rituximab‐EU, PF‐05280586 with rituximab‐US, and rituximab‐EU with rituximab‐US. All treatments resulted in a rapid and profound reduction in CD19+ B cells and sustained profound B cell suppression up to week 25. The incidence of antidrug antibody (ADA) response (n = 7, 10 and 9 for PF‐05280586, rituximab‐EU and rituximab‐US, respectively), time to ADA emergence and ADA titres were similar across treatments. None of the ADA‐positive samples was positive for neutralizing activity. No clinically meaningful differences in adverse events were identified. Conclusions The study demonstrated PK similarity among PF‐05280586, rituximab‐EU and rituximab‐US. In addition, all treatments showed comparable CD19+ B cell depletion PD responses, as well as safety and immunogenicity profiles.

Comparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar, and rituximab

Aims To evaluate potential differences between PF‐05280586 and rituximab sourced from the European Union (rituximab‐EU) and USA (rituximab‐US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF‐05280586. Methods A randomised, double‐blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti‐tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab‐EU and rituximab‐US responses using longitudinal nonlinear mixed effects models. Results The analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group‐to‐group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF‐05280586 vs. rituximab‐EU or rituximab‐US lie outside the reference ranges were low. Conclusions No clinically meaningful differences were detected in DAS28 or ACR response between PF‐05280586 and rituximab‐EU or rituximab‐US as the differences were within the pre‐specified reference ranges. TRIAL REGISTRATION Number: NCT01526057.

A Phase I Randomized Study of a Specifically Engineered, pH‐Sensitive PCSK9 Inhibitor RN317 (PF‐05335810) in Hypercholesterolemic Subjects on Statin Therapy

This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF‐05335810), a specifically engineered, pH‐sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low‐density lipoprotein cholesterol (LDL‐C) ≥ 80 mg/dl) 18–70 years old receiving statin therapy. Subjects were randomized to: single‐dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s.c. 1, 3, or i.v. 1 mg/kg); or multiple‐dose RN317 (s.c. 300 mg every 28 days; three doses). Of 133 subjects randomized, 127 completed the study. RN317 demonstrated a longer half‐life, greater exposure, and increased bioavailability vs. bococizumab. RN317 was well tolerated, with no subjects discontinuing because of treatment‐related adverse events. RN317 lowered LDL‐C by up to 52.5% (day 15) following a single s.c. dose of 3.0 mg/kg vs. a maximum of 70% with single‐dose bococizumab s.c. 3.0 mg/kg. Multiple dosing of RN317 produced LDL‐C reductions of ∼50%, sustained over an 85‐day dosing interval.

FRI0309 A Phase I Pharmacokinetics TRIAL Comparing PF-05280586 (A Potential Biosimilar) and Rituximab in Subjects with Active Rheumatoid Arthritis with Active Disease in TNF Failures (Reflections B328-01)

Background PF-05280586, a proposed biosimilar to rituximab, has the same primary amino acid sequence as rituximab with similar physicochemical and in vitro functional properties. Objectives This study was designed to demonstrate pharmacokinetic (PK) similarity of PF-05280586 to rituximab sourced from the US (rituximab-US) and EU (rituximab-EU), and between rituximab-US and rituximab-EU. Safety was also evaluated. Methods In this double-blind trial (NCT01526057), 220 subjects with active rheumatoid arthritis on a background of methotrexate who had an inadequate response to one or more TNF antagonist therapies were randomized 1:1:1 to one course of IV PF-05280586, rituximab-US or rituximab-EU 1000 mg on Days 1 and 15 (with stable background regimen of methotrexate). The primary analysis was the PK similarity testing using full PK profiling. PK similarity for a given test-to-reference comparison was considered demonstrated if the 90% CI of the test-to-reference ratio of the AUC from time 0 to infinity (AUC0–∞) and maximum concentration (Cmax) were within 80.00–125.00%. Results Baseline demographics for 198 subjects evaluable for PK were similar among 3 treatment arms. The 3 study drugs exhibited similar disposition profiles and PK parameters. The 90% CI for the ratios of Cmax, AUC from time 0 to 2 weeks (AUC0–2wk) and to the last measurable time point (AUCT), and AUC0–∞ were within 80.00–125.00% for the comparisons of PF-05280586 to rituximab-US and rituximab-EU, and rituximab-EU to rituximab-US. A similar number of subjects discontinued for safety reason. 8 subjects reported serious adverse events of which 2 were considered treatment-related (rituximab-US: grade 2 atrial flutter [resolved]; rituximab-EU: grade 2 thrombocytopenic purpura [resolved although the subject was permanently discontinued from the study]). Conclusions This study demonstrates PK similarity of PF-05280586 to both rituximab-US and rituximab-EU and rituximab-EU to rituximab-US. All 3 treatments were generally well tolerated, with a low incidence of treatment-related AEs and discontinuations due to AEs. Disclosure of Interest D. Yin Employee of: Pfizer Inc., J.-C. Becker Employee of: Pfizer Inc., L. Melia Employee of: Pfizer Inc., R. Li Employee of: Pfizer Inc., B. Gumbiner Employee of: Pfizer Inc., D. Thomas Employee of: Pfizer Inc., G. Spencer-Green Employee of: Pfizer Inc., X. Meng Employee of: Pfizer Inc. DOI 10.1136/annrheumdis-2014-eular.5444

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects

PURPOSE Monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) elicit significant reductions in serum LDL-C levels. However, little is known about their effects on lipoprotein particles. The purpose of this analysis was to evaluate the effect of PCSK9 inhibition with bococizumab (RN316/PF-04950615), a humanized monoclonal antibody to PCSK9, on LDL, VLDL, and HDL particle concentration and size in hypercholesterolemic subjects. METHODS Data from 3 double-blind, placebo-controlled, randomized studies were analyzed. In study 1, a total of 67 hypercholesterolemic subjects received IV placebo or bococizumab 0.25, 0.5, 1, or 1.5 mg/kg weekly for 4 weeks. In studies 2 and 3, a total of 135 hypercholesterolemic subjects taking statins received IV placebo or bococizumab 0.25, 1, 3, or 6 mg/kg monthly for 12 weeks. Lipoprotein particle concentration and size were measured by using nuclear magnetic resonance spectroscopy. FINDINGS Overall, the majority of subjects were men (51.9%) aged >50 years of age and of white ethnic origin. In total, 189 subjects with both baseline and 2-week posttreatment data were included in the analysis. After PCSK9 inhibition with bococizumab 0.5, 1, 1.5, 3, and 6 mg/kg, concentrations of total LDL, total small LDL, and small VLDL particles decreased significantly versus baseline and placebo (P < 0.05), whereas concentrations of HDL particles increased (P < 0.05). The size of the LDL, VLDL, and HDL particles increased after PCSK9 inhibition. Reductions in LDL-C and total LDL particle concentrations were highly correlated. IMPLICATIONS The effect of inhibiting PCSK9 with bococizumab on lipoprotein particle concentration and size are consistent with the general mechanism of PCSK9 inhibitors in blocking PCSK9-mediated downregulation of LDL receptors. PCSK9 inhibition has the potential to provide a clinical benefit through the modulation of atherogenic lipoprotein particles in addition to LDL-C lowering, and this effect will likely be assessed in future analyses of data from cardiovascular outcomes trials of PCSK9 monoclonal antibodies that are currently being conducted. ClinicalTrials.gov identifiers: NCT01243151, NCT01342211, and NCT01350141.

EFFECTS OF RN316 (PF-04950615), A HUMANIZED IGG2ΔA MONOCLONAL ANTIBODY BINDING PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9, ON LIPOPROTEIN PARTICLES IN HYPERCHOLESTEROLEMIC SUBJECTS

RN316 binds to Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), preventing PCSK9-mediated down-regulation of the low density lipoprotein (LDL) receptor (R), improving LDL cholesterol (C) clearance from serum, and reducing LDL-C levels. High concentrations of small LDL particles contribute to

A Mechanism‐Based Pharmacokinetic/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, and Its Application in Early Clinical Development

Bococizumab (RN316/PF‐04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low‐density lipoprotein receptor, leading to improved clearance and reduction of low‐density lipoprotein cholesterol (LDL‐C) in plasma. A mechanism‐based drug‐target binding model was developed, accounting for bococizumab, PCSK9, and LDL‐C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies. First, simulations performed with this model demonstrated that the conventional method of the area‐under‐the‐curve ratio for bioavailability determination underestimated the subcutaneous bioavailability of bococizumab due to its target‐mediated disposition. Second, a covariate model component for statin effects on bococizumab PK/PD was characterized, including a description of the decreased baseline LDL‐C, increased baseline PCSK9, and increased LDL‐C lowering with concomitant use of statins. Last, the impact of the dosing regimens with and without a dose holiday on bococizumabs LDL‐C–lowering effectiveness was shown to be predictable due to the well‐characterized PK‐PD relationship.

Single and multiple ascending-dose study of glucagon-receptor antagonist RN909 in type 2 diabetes: a phase 1, randomized, double-blind, placebo-controlled trial

PurposeThis first-in-human study assessed safety, immunogenicity, pharmacokinetics, and pharmacodynamics of RN909, a monoclonal antibody antagonist of the glucagon receptor, in type 2 diabetes (T2DM) subjects.MethodsThis study enrolled 84 T2DM subjects receiving stable metformin regimens. Forty-four subjects were randomized to receive single escalating doses of RN909 (0.3 to 6 mg/kg subcutaneously (SC), or 1 mg/kg intravenously (IV)), or placebo; 40 subjects were randomized to receive multiple escalating doses (50 to 150 mg SC) or placebo every 4 weeks for 12 weeks.ResultsRN909 was well tolerated; treatment-related elevated liver function tests (LFTs) were observed in 4/33 (12.1%) and 5/32 (15.6%) subjects treated with single and multiple doses, respectively, versus 1/10 (10%) and 0 in the respective placebo groups. RN909 dose-normalized AUCinf increased more than dose-proportionally following single SC doses, and after multiple doses, accumulation ratios ranged from 1.3 to 3.4. The incidence of antidrug antibodies (ADA) was 33% after single doses and 50% after multiple doses. RN909 produced dose-dependent, durable fasting plasma glucose (FPG)-lowering at day 29 (mean change −20.6 to −97.5 mg/dL) and day 85 (mean change; −27.2 to −43.5 mg/dL) after single and multiple doses, respectively. HbA1c also was reduced after single (mean change −0.30% to −1.44%), and multiple doses (−0.83% to −1.56%).ConclusionRN909 was well tolerated after single and multiple doses in T2DM subjects, with diarrhea and elevated LFTs the most frequent adverse events. The appearance of ADA did not affect pharmacokinetics or efficacy. Robust lowering of FPG and HbA1c was observed.