Date: 2015-06-10
Type of information: Presentation of results at a congress
phase: 1b/2a
Announcement: presentation of results at The European League Against Rheumatism (EULAR) 2015 annual meeting taking place in Rome, Italy
Company: Xencor (USA - CA)
Product: XmAb®5871
Action
mechanism: monoclonal antibody. XmAb®5871 is a first-in-class monoclonal antibody that targets CD19 with its variable domain and that uses Xencor\'s XmAb immune inhibitor Fc domain to target FcγRIIb, a receptor that inhibits B-cell function. XmAb5871 is the first drug candidate that Xencor is aware of that targets FcγRIIb inhibition. Xencor has demonstrated in multiple animal models and in initial human clinical trials that XmAb5871 inhibits B-cell function without destroying these important immune cells.
Disease: rheumatoid arthritis
Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases
Country:
Trial
details: The Phase 1b/2a study was a randomized, double-blind, placebo-controlled trial in patients with active rheumatoid arthritis (RA) on a background of stable non-biologic disease modifying anti-rheumatic drug (DMARD) therapy. The trial was designed to determine the safety and tolerability profile of biweekly, multiple-dose, intravenous administration in patients with RA and to characterize the pharmacokinetics and immunogenicity of intravenously administered XmAb5871 in patients with RA at multiple doses. A secondary outcome measure was RA disease response as measured by changes in Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at week 13 for the Phase 2a part of the trial. Patients received six biweekly intravenous administrations of XmAb5871. In the Phase 1b multiple ascending dose part, a total of 30 patients were randomized to placebo or XmAb5871 in dose cohorts of 0.3, 1.0, 3.0 and 10.0 mg/kg. In the Phase 2a part, 27 patients were randomized to XmAb5871 at 10.0 mg/kg or placebo (2:1).
Latest
news: * On June 10, 2015, Xencor, a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of autoimmune diseases, asthma and allergic diseases, and cancer, reported complete data results from a Phase 1b/2a study of XmAb®5871 in patients with rheumatoid arthritis (RA). XmAb5871 was generally well tolerated and showed trends in improvement in RA disease activity by multiple disease activity measures and across multiple dose groups. These data will be presented during a poster session Friday, June 12th at the European League Against Rheumatism (EULAR) 2015 Annual Meeting in Rome, Italy. "These data demonstrate clear signs of disease modifying activity in a patient population with active disease while on non-biologic disease modifying anti-rheumatic drug (DMARD) therapy," said Bassil Dahiyat, Ph.D., president and chief executive officer of Xencor. "XmAb5871 has a novel mechanism of action that inhibits B-cell function without killing B-cells. This potent yet reversible B-cell inhibition differs from other B-cell targeting treatments and has potential clinical application across a number of autoimmune diseases, including IgG4-related disease (IgG4-RD) for which we expect to initiate an open-label pilot study later this year." The two-part study was designed as a Phase 1b multiple center, randomized, placebo-controlled, double-blinded, multiple ascending dose clinical study (Part A) followed by Phase 2a cohort extension (Part B) at the top dose examined in Part A. The study enrolled patients with active RA on stable non-biologic DMARD therapy. Patients were randomized to receive ascending IV infusions of XmAb5871 (0.3, 1.0, 3.0 and 10.0 mg/kg) or placebo 14 days apart for six doses (Part A), followed by an expansion cohort at 10.0 mg/kg or placebo 14 days apart for six doses (Part B). Safety: XmAb5871 was safe and generally well tolerated. The most common AEs in the XmAb5871 group were vomiting, headache and nausea. Nausea and vomiting occurred primarily during the first infusion, were generally of mild to moderate intensity and were self-limiting. Two subjects in the study experienced infusion-related reactions with hypotension (both at 10 mg/kg) and were discontinued. The nature and severity of these infusion reactions were consistent with those reported for other monoclonal antibody therapies. Two SAEs occurred in two XmAb5871 treated patients, both in the 10 mg/kg group: one infusion-related reaction with hypotension occurring during the second infusion, and one deep venous thrombosis with onset 22 days (> 6 half-lives) after the last infusion. Efficacy: The primary objective of the study was to determine safety and tolerability of multiple-dose XmAb5871. However a secondary objective of the study was to evaluate the effect of XmAb5871 on RA disease response as measured by changes in DAS28-CRP at Day 85 (2 weeks following the last dose) in Part B of the study. 15 XmAb5871-treated and 8 placebo-treated patients in Part B of the study completed all six infusions and disease activity assessments at Day 85. 33.3% of patients who received 10.0 mg/kg XmAb5871 in Part B achieved low disease activity or remission on Day 85 (13.3% and 20% respectively) compared to 0% in the placebo group. This difference was also seen when evaluating across both parts of the study; 41.7% of patients who received any dose of XmAb5871 in Part A or B had low disease activity or remission on Day 85 (16.7% low and 25.0% remission) as compared to only 6.7% of patients in the placebo group (0% low and 6.7% remission). ACR responses we also enhanced in XmAb5871 treated patients. In Part B, 86.7%, 40.0% and 20.0% of patients in the XmAb5871 treated group achieved an ACR20, ACR50 and ACR70 response, respectively, compared to 62.5%, 12.5% and 0% for the placebo group. In Part A and Part B together, there were increased numbers of ACR20, ACR50 and ACR70 responders in the XmAb5871 treated cohorts compared to placebo (77.8% vs. 46.7%, 33.3% vs. 13.3% and 13.9% vs. 0%). Similar trends in improvement in DAS28-ESR scores and EULAR response criteria were observed. RA Disease Activity Measures: The improvement of RA disease activity was measured by composite scores that combine information from swollen joints, tender joints, inflammatory biomarkers and clinical status. Disease activity scores have been developed by the American College of Rheumatology (ACR) and EULAR (DAS28). The ACR criteria measure improvement in clinical and laboratory disease activity parameters and are combined to form a composite score and are expressed as percentages of clinical response that are known as ACR20, ACR50, and ACR70. An ACR20 score represents at least a 20% improvement in these criteria and is considered a modest improvement in a patient's disease. An ACR50 and ACR70 represent a minimal 50% and 70% improvement in the response criteria, respectively, and each is considered evidence of a substantial improvement in a patient's disease. The DAS28, or the Disease Activity Score, considers 28 tender and swollen joint counts, clinical status and levels of an inflammatory biomarker, typically either C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). The DAS28 yields a score on a scale from 0 to 10 indicating current RA disease activity. The DAS28-CRP incorporates CRP as the inflammatory biomarker and the DAS28-ESR incorporates the ESR as the inflammatory biomarker. The EULAR response criteria classify individual response into 4 categories based on DAS28 scores; remission is ≤2.6, low disease activity is ≤ 3.2, moderate disease activity is ≤ 5.1, and high disease activity is >5.1. * On May 11, 2015, Xencor announced that data from the Phase 1b/2a study of XmAb®5871 will be featured in a poster presentation at The European League Against Rheumatism (EULAR) 2015 annual meeting taking place in Rome, Italy. (Abstract # FRI0161 A Phase 1b/2a Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of XmAb®5871 in Patients with Rheumatoid Arthritis). * On January 29, 2015, Xencor reported top-line results from a Phase 1b/2a study for XmAb®5871. In addition to the study's primary objective of characterizing safety and tolerability, the data showed promising activity in patients with rheumatoid arthritis , including multiple DAS28-CRP remissions and ACR50 and ACR70 responses. In the Phase 2a cohort of the trial, 15 XmAb5871 treated patients and eight placebo treated patients were evaluable for rheumatoid arthritis disease activity at the protocol specified disease activity assessment time point of two weeks following the sixth biweekly infusion. 33% of patients (5 of 15) that received all six biweekly doses of XmAb5871 achieved DAS28-CRP remission or low disease activity versus zero on placebo. Three ACR70 responses (20%) and six ACR50 responses (40%) occurred in the XmAb5871 group compared to zero and one (13%) respectively in the placebo group. Biweekly administration of XmAb5871 for 12 weeks was generally well tolerated. The most common XmAb5871 treatment related adverse events (AEs) observed were predominantly mild to moderate gastrointestinal toxicities (nausea, vomiting, diarrhea) occurring during the first infusion of XmAb5871. These gastrointestinal AEs did not typically recur on subsequent infusions and no infusions were discontinued due to these AEs. Other treatment related AEs experienced in more than two XmAb5871 treated patients were pyrexia (fever) and headache. Treatment related serious adverse events (SAEs) occurred in two patients that received XmAb5871: infusion related reaction and venous thrombosis. Two patients in the placebo treated group also reported SAEs.
