Chandrasekhar Udata

Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR‐623, a Novel Liver X‐Receptor Agonist, in Healthy Participants

Liver X‐receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate—binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR‐623 is a synthetic ligand for LXRs α and β that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending‐dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR‐623 in healthy participants. LXR‐623 was absorbed rapidly with peak concentrations (Cmax) achieved at approximately 2 hours. The Cmax and area under the concentration‐time curve increased in a dose‐proportional manner. The mean terminal disposition half‐life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose‐dependent increase in ABCA1 and ABCG1 expression. The effect of LXR‐623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic‐pharmacodynamic analysis, yielding EC50 estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system—related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of “target engagement” by an LXR agonist in humans.

SAT0142 Immunogenicity Assessment of PF-06438179, A Potential Biosimilar to Infliximab, In Healthy Volunteers

Background PF-06438179 is being developed as a potential biosimilar to Remicade® (infliximab) in a stepwise approach following globally accepted regulatory guidelines. PF-06438179 was shown to have an identical primary amino acid sequence and similar physicochemical, in vitro and in vivo functional properties to infliximab reference products sourced from the European Union (infliximab-EU) and United States (infliximab-US). Objectives PF-06438179 was evaluated for immunogenicity in a Phase I pharmacokinetic (PK) similarity study; safety was also evaluated. Methods In this double-blind trial (NCT01844804), 146 healthy volunteers received a single 10-mg/kg IV dose of PF-06438179 (n=49), infliximab-EU (n=48) or infliximab-US (n=49). All subjects provided informed consent. Safety and immunogenicity were evaluated over 12 weeks and PK over 8 weeks. Serum samples for detecting anti-drug antibodies (ADA) and neutralizing antibodies (NAb) were collected up to 12 weeks postdose. ADA samples were analyzed using 2 validated electrochemiluminescent immunoassays, 1 each to detect ADA against PF-06438179 and reference drugs (infliximab-EU or -US). A tiered approach of screening, confirmation and titer quantitation was used. Samples were tested first for ADA against the dosed product and confirmed ADA-positive samples were tested for ADA cross-reactivity using the alternate ADA assay. ADA-positive samples were analyzed for NAb using a validated semi-quantitative cell-based assay against the dosed product and for NAb cross-reactivity using the alternative NAb assay. Cross-reactivity was also examined using the alternate ADA assay for the week 12 samples that tested negative against the dosed product. Results Samples for immunogenicity assessment were collected from 146 subjects. No subject tested positive for ADA at baseline. Six out of 37 (16.2%), 14/43 (32.6%) and 11/39 (28.2%) subjects in the PF-06438179, infliximab-EU and infliximab-US groups, respectively, had ≥1 ADA-positive sample through Day 85. Of these 31 subjects, 27 (6/6 PF-06438179; 10/14 infliximab-EU; 11/11 infliximab-US) also tested positive for cross-reactivity by alternative assay, suggesting that ADA were likely developed against epitopes shared among study drugs. Of the 31 subjects who tested ADA positive, 26 tested positive for NAb (5/6 PF-06438179; 12/14 infliximab-EU; 9/11 infliximab-US). Cross-reactivity was further demonstrated by negative ADA samples, which were confirmed by alternative assay. Overall safety profiles were similar across the three cohorts and no infusion related reactions were reported. Conclusions The three study drugs had comparable immunogenicity profiles, however, a lower incidence of ADA response was observed in the PF-06438179 group. The majority of ADA-positive subjects also developed NAb. PF-06438179 demonstrated PK similarity and comparable safety profiles to infliximab-EU and -US in healthy subjects. An ongoing global, comparative study assessing the efficacy and safety of PF-06438179 and infliximab-EU in subjects with active rheumatoid arthritis who had an inadequate response to methotrexate will include a comparative assessment of immunogenicity. Disclosure of Interest C. Udata Employee of: Pfizer Inc, D. Yin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C.-H. Cai Employee of: Pfizer Inc, S. Hua Employee of: Pfizer Inc, S. Salts Employee of: Pfizer Inc, M. Rehman Employee of: Pfizer Inc, A. AL-Sabbagh Employee of: Pfizer Inc, J. McClellan Employee of: Pfizer Inc, X. Meng Employee of: Pfizer Inc

A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01)

ABSTRACT Background: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US. Methods: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios for PK parameters, Cmax, AUCT, and AUCinf, were within the 80.00–125.00% pre-specified equivalence window. Results: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration–time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for Cmax, AUCT, and AUCinf were within 80.00–125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups. Conclusions: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles. Trial registration: CT.gov identifier NCT01844804

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.