>>MONROVIA, Calif., Jan. 29, 2015 /PRNewswire/ -- Xencor, Inc. ( XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of autoimmune diseases, asthma and allergic diseases and cancer, today 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 (RA), including multiple DAS28-CRP remissions and ACR50 and ACR70 responses. XmAb5871 is a first-in-class monoclonal antibody containing Xencor's proprietary XmAb immune inhibitor Fc domain that targets Fc?RIIb to inhibit B-cell function.
"XmAb5871's reduction of RA disease activity demonstrates for the first time that its unique mechanism of action targeting Fc?RIIb can be effective at treating an autoimmune disease, and builds on the potent, reversible B-cell inhibition we observed in our Phase 1a clinical trial," said Paul Foster, M.D., chief medical officer of Xencor. "We have begun translational and mechanistic studies of XmAb5871 in the rare autoimmune disorder IgG4-RD and during 2015 we plan to initiate an open-label pilot clinical trial in IgG4-RD to assess control of disease activity as measured by the IgG4-RD Responder Index (Carruthers, et al., 2012, Int J Rheum)."
In the Phase 2a cohort of the trial, 15 XmAb5871 treated patients and eight placebo treated patients were evaluable for RA 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.
"XmAb5871 is our most advanced wholly-owned program and provides us with a number of therapeutic development opportunities where B-cell inhibition shows promise. We are very encouraged by these results, and anticipate a dialogue with the FDA on our clinical development plans in IgG4-RD and other indications," said Bassil Dahiyat, Ph.D., president and chief executive officer of Xencor.
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.
The Company continues to conduct an analysis of safety, pharmacokinetics, immunogenicity and efficacy data and full study results are expected to be presented at an upcoming medical conference in 2015.
Conference Call and Webcast
Xencor will host a conference call today at 8:30 a.m. ET to discuss this data. The live call may be accessed by dialing (855) 433-0932 for domestic callers or (484) 756-4280 for international callers, and providing the conference ID number 76049183. A live webcast of the conference call will be available online from the investors section of the Company's website at www.xencor.com. The webcast will be archived on the company website for 30 days.
About the Phase 1b/2a Study of XmAb®5871
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).
About XmAb®5871
XmAb5871 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 Fc?RIIb, a receptor that inhibits B-cell function. XmAb5871 is the first drug candidate that Xencor is aware of that targets Fc?RIIb 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.
About Xencor's XmAb® Immune Inhibitor Technology
Fc?RIIb (IIb), also called CD32b, is a receptor for Fc domains on B cells and other immune cells. When engaged, the IIb receptor blocks immune activation pathways and traffics bound soluble antigens out of circulation. Xencor has discovered a series of Fc domain variants with up to a 400-fold increase in binding affinity to Fc?RIIb derived from just two amino acid changes. These XmAb Immune Inhibitor Fc domains greatly heighten the properties of IIb receptor engagement and have potential as building blocks for drug candidates in autoimmune, allergic and inflammatory diseases.<<
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Hard to tell from this if any endpoints were hit. Stock was weak for the day, but seems to be trading back up after hours, which seems a bit odd.
Also some early results for 7195:
>>MONROVIA, Calif., Jan. 29, 2015 /PRNewswire/ -- Xencor, Inc. ( XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of asthma and allergic diseases, autoimmune diseases and cancer, today reported top-line interim results from a Phase 1a study for XmAb®7195. The data show rapid reduction of circulating free IgE levels to below the limit of detection in 90% of XmAb7195 treated subjects that had detectable free IgE pre-dose, including those at the lowest dose evaluated of 0.3 mg/kg. Total IgE levels were also reduced in a parallel fashion. A dose limiting toxicity of transient, asymptomatic thrombocytopenia was observed at the 3.0 mg/kg dose. Two subjects with high pre-dose IgE levels (above 400 IU/mL) were treated with XmAb7195, one each at 0.75 mg/kg and 3.0 mg/kg doses, and both had reduction of free IgE levels to below the limit of detection lasting for at least one week. XmAb7195 is an anti-IgE monoclonal antibody containing Xencor's proprietary XmAb Immune Inhibitor Fc domain that targets Fc?RIIb, which results in rapid clearance of free and total IgE and inhibition of the function of IgE expressing B cells. >>
"These results demonstrate for the first time that XmAb7195's first-in-class mechanism of action which targets IgE and Fc?RIIb can be effective at reducing both free and total IgE from the circulation in humans," said Paul Foster, M.D., chief medical officer of Xencor. "XmAb7195 was very potent, reducing IgE to the assay detection limit at even our lowest dose of 0.3 mg/kg. In addition, for the two subjects enrolled who happened to have IgE above 400 IU/mL, one each at 0.75 mg/kg and 3.0 mg/kg, it reduced free IgE below the detection limit for at least a week. These data will help us determine a dose regimen with acceptable activity and safety profiles as we proceed with future clinical development."
XmAb7195 has been administered to 30 subjects in Part 1 of the study in single doses ranging from 0.3 to 3.0 mg/kg. 29 of 30 (97%) subjects had detectable free IgE levels pre-dose. Of these, 26 subjects (90%) had reduction of free IgE levels to below the detectable limit of the assay (<10 ng/mL) at the end of the XmAb7195 infusion with reduction lasting for at least one week following a single infusion. Total IgE was reduced to below the limit of detection (<2.0 IU/mL) in 26 of 30 (87%) subjects with detectable total IgE pre-dose. Total IgE reduction differentiates XmAb7195 from other anti-IgE therapeutic antibodies, which actually increase total IgE levels. Because total IgE assays, unlike free IgE assays, are readily available to clinicians, the effect of XmAb7195 on total IgE levels could enable for the first time simple monitoring, and potentially adjustment, of treatment effect.
"IgE is a key mediator of allergic symptoms whose reduction is correlated to clinical response in allergic asthma, and these results support our clinical development plans for XmAb7195 to treat allergic diseases. While this study explores two of the three mechanisms of XmAb7195, the rapid clearance via FcgRIIb-expressing cells and the binding to soluble IgE, assessing its third mechanism, the suppression of IgE production by immune cells, will require longer duration studies" said Bassil Dahiyat, Ph.D., president and chief executive officer of Xencor. "In addition to continuing the high IgE subject portion of this study, we are planning a multi-dose Phase 1b study and are developing a subcutaneous formulation of XmAb7195."
Dosing through the first three cohorts (0.3, 1.0 and 3.0 mg/kg) resulted in observations of two apparent dose-related toxicities: urticaria and thrombocytopenia. There were no other adverse events that occurred in more than two XmAb7195 treated subjects. There were no serious adverse events reported and no subject discontinued the trial early.
As a result of the laboratory finding of transient, asymptomatic thrombocytopenia in all six subjects receiving XmAb7195 in the 3.0 mg/kg dose cohort, thrombocytopenia was deemed a dose limiting toxicity and the two remaining cohorts were subsequently enrolled at a reduced dose of 0.75 mg/kg. The decrease in platelet count was transient with a nadir by 24 hours post-dose, recovery starting by 48 hours post-dose and near full platelet count recovery by study day eight in all cases, at which time serum drug concentrations still exceeded levels that eliminate detectable IgE. There was no apparent relationship of thrombocytopenia to known polymorphisms of Fcg receptors IIa or IIb. No evidence of thrombocytopenia has been observed in any of the clinical trials of XmAb5871, an anti-CD19 antibody with the identical XmAb Immune Inhibitor Fc domain as that of XmAb7195.
Moderate urticaria was reported in a total of seven XmAb7195 treated subjects with an apparent correlation of dose with frequency of occurrence. In all cases regardless of dose, the signs/symptoms of urticaria were mild, non-diffuse and easily treated with oral antihistamine, and the study drug infusions were continued to completion without worsening of symptoms.
The Company continues to conduct an analysis of safety, pharmacokinetics, immunogenicity and efficacy data of Part 1 of the Phase 1a study and continues to enroll patients in Part 2 of the study.
Conference Call and Webcast
Xencor will host a conference call today at 8:30 a.m. ET to discuss this data. The live call may be accessed by dialing (855) 433-0932 for domestic callers or (484) 756-4280 for international callers, and providing the conference ID number 76049183. A live webcast of the conference call will be available online from the investors section of the Company's website at www.xencor.com. The webcast will be archived on the company website for 30 days.
About the Phase 1a Study of XmAb®7195
The Phase 1a study is a randomized, double-blind, placebo-controlled, single ascending dose trial being conducted in two parts. In the completed Part 1, healthy subjects were enrolled into five consecutive dose cohorts of eight subjects each, randomized to receive a single intravenous (IV) administration of XmAb7195 or matching placebo (6:2). In the ongoing Part 2, otherwise healthy subjects with a history of allergic rhinitis and/or allergic conjunctivitis and/or atopic dermatitis with elevated serum IgE (> 300 IU/mL), will be enrolled into three consecutive dose cohorts of eight subjects each, randomized to a single IV administration of XmAb7195 or matching placebo (6:2). The primary and secondary objectives of the study are to determine the safety and tolerability profile of single-dose IV administration of XmAb7195 and to characterize the pharmacokinetics (PK) and immunogenicity of single-dose IV administration of XmAb7195 respectively. Exploratory objectives include the determination of the effect of XmAb7195 on serum free and total IgE and the effect on basophil surface IgE and basophil FceRI expression levels.
About XmAb®7195
XmAb7195 is a first-in-class monoclonal antibody that targets IgE with its variable domain and that uses Xencor's XmAb immune inhibitor Fc domain to target Fc?RIIb, a receptor that inhibits B cell function. Xencor has demonstrated in multiple animal models that XmAb7195 rapidly reduces free and total IgE and blocks production of IgE by immune cells. Its three mechanisms of action offer a unique approach to IgE reduction for the potential treatment of allergic disease.<<
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Cheers, Tuck |
