Clapton Dias

Effects of an Anti-TSLP Antibody on Allergen-Induced Asthmatic Responses

BACKGROUND Thymic stromal lymphopoietin (TSLP) is an epithelial-cell-derived cytokine that may be important in initiating allergic inflammation. AMG 157 is a human anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents receptor interaction. METHODS In this double-blind, placebo-controlled study, we randomly assigned 31 patients with mild allergic asthma to receive three monthly doses of AMG 157 (700 mg) or placebo intravenously. We conducted allergen challenges on days 42 and 84 to evaluate the effect of AMG 157 in reducing the maximum percentage decrease in the forced expiratory volume in 1 second (FEV1). We also measured the fraction of nitric oxide in exhaled air, blood and sputum eosinophils, and airway hyperresponsiveness. The primary end point was the late asthmatic response, as measured 3 to 7 hours after the allergen challenge. RESULTS AMG 157 attenuated most measures of allergen-induced early and late asthmatic responses. The maximum percentage decrease in the FEV1 during the late response was 34.0% smaller in the AMG-157 group than in the placebo group on day 42 (P=0.09) and 45.9% smaller on day 84 (P=0.02). In addition, patients receiving AMG 157 had significant decreases in levels of blood and sputum eosinophils before and after the allergen challenge and in the fraction of exhaled nitric oxide. There were 15 adverse events in the AMG-157 group, as compared with 12 in the placebo group; there were no serious adverse events. CONCLUSIONS Treatment with AMG 157 reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge. These findings are consistent with a key role for TSLP in allergen-induced airway responses and persistent airway inflammation in patients with allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined from these data. (Funded by Amgen; ClinicalTrials.gov number, NCT01405963.).

Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins.

OBJECTIVES The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy. BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling. METHODS Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3. RESULTS In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b). CONCLUSIONS In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.

EFFECTS OF AMG 145, A FULLY HUMAN MONOCLONAL ANTIBODY AGAINST PCSK9, ON LOW-DENSITY LIPOPROTEIN CHOLESTEROL IN SUBJECTS TAKING STATINS: A PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, ASCENDING MULTIPLE-DOSE STUDY

Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates surface expression of the low density lipoprotein (LDL) receptor (LDL-R), increasing circulating LDL cholesterol (LDL-C). Statins increase LDL-R and PCSK9 levels. AMG 145, a fully human monoclonal antibody against PCSK9, has been

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects with Hepatic Impairment

Evolocumab binds PCSK9, increasing low‐density lipoprotein cholesterol (LDL‐C) receptors and lowering LDL‐C. Target‐mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL‐C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open‐label, parallel‐group study evaluated the pharmacokinetics of evolocumab in hepatic‐impaired (Child‐Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140‐mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL‐C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere‐Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration –34%; mean area under the concentration‐time curve (AUC) –47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL‐C reductions in the healthy, mild, and moderate groups were –57% (–64% to –48%), –70% (–75% to –63%), and –53% (–61% to –43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment.

Rationale for Sponsor-unblinded Phase 1 Trials: Challenging the Double-blind Paradigm

Randomized, double-blind, phase 1 clinical trials conceal study treatment assignment from the subject, the investigator, and the sponsor while the trial is ongoing. We make a case for unwinding the sponsor because there is much to gain and little to lose at this very early phase of clinical development. Some of the advantages of unblinding include a direct assessment of treatment-related safety signals with the option to make appropriate trial design modifications and speeding up early drug development. The disadvantage includes the increased risk of the study investigator becoming inadvertently unblinded to individual subject treatment assignments on a few subjects. We make the case that on balance the benefits of sponsor unblinding outweigh the risks. Phase 1 trials for which unblinding may not be appropriate are also mentioned.