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Preclinical Pharmacology
Atacicept treatment of normal mice (100 μg i.p. 3 times a week for 2 weeks) blocked the transition of immature T1 B cells to the T2 precursors of mature splenic B cells and reduced the levels of circulating Ig (2). Atacicept was found to block the development of specific B-cell populations in the periphery by neutralizing BAFF and APRIL and to inhibit disease progression in mouse models of rheumatoid arthritis and systemic lupus erythematosus (SLE) (2, 6).
Atacicept treatment (i.p. injection 3 times a week for 3 weeks) of DBA/1 mice with collagen-induced arthritis (CIA) reduced serum antibody titers. Histological assessment of treated animals showed undamaged articular cartilage, reduced inflammation and decreased hypertrophy of the synovium, accompanied by a decrease of inflammatory cells in the soft tissues around
the joints (2).
In vivo, the effects of atacicept on the progression of SLE were assessed in the NZBWF1 (also referred to as NZB/NZW F1) mouse strain, which develops chronic spontaneous autoimmune disease and is used as a model of SLE (6). Symptoms characteristic of SLE include high titers of anti-dsDNA antibodies, proteinuria and glomerulonephritis. Administration of atacicept to 15- to 21-week-old female NZBWF1 mice (100 μg 3 times a week for 5 weeks) significantly reduced the proportion of animals with proteinuria ≥ 100 mg/dl for up to 10 weeks following the last treatment compared to animals treated with Fc control protein or phosphate-buffered saline (PBS; vehicle control). A survival rate of 100% at 38 weeks of age was observed in the atacicept-treated animals compared to 47% survival for the Fc-treated group at 12 weeks following the last treatment. No significant differences were observed in anti-dsDNA autoantibody production in the different treatment groups. However, a significant 53% reduction in the percentage of peripheral blood B cells at 28 weeks of age was observed in atacicept- treated compared to Fc-treated mice. This decrease in B cells persisted until 31 weeks of age (5 weeks following the last treatment) and returned to control levels by 37 weeks of age (6).
In a mouse model of chemically induced autoimmunity, atacicept treatment (100 μg 3 times a week for 2 weeks) reduced autoantibody production in HgCl2- induced autoimmunity in the mercury-susceptible mouse strain A.SW (9). Treatment with atacicept during the induction phase of mercury-induced autoimmunity significantly reduced anti-nucleolar autoantibody (ANoA) IgG1 levels, whereas pretreatment with atacicept prevented total serum IgE induction. A dramatic reduction in B-cell numbers undergoing T1–T2 transition during splenic Bcell development was also observed.
The effects of atacicept exposure on the ability of mice to clear influenza virus were also evaluated (10, 11). C57Bl/6 mice were treated with either vehicle control, dexamethasone (positive control) or atacicept (0.05, 0.50 and 5.0 mg/kg) s.c. 3 times a week from within 1 week prior to infection with mouse-adapted human influenza A/Port Chalmer/1/73 (H3N2) virus through 21 days postinfection. Atacicept-treated mice displayed a dosedependent reduction in spleen weight and influenza-specific IgM and IgG production in the lung and serum compared to vehicle control animals. Animals exposed to atacicept displayed a decrease in the number of B but not T cells in the peripheral blood. However, unlike treatment with dexamethasone, atacicept had no effect on viral clearance and animal survival.
Myelomatous SCID-hu mice (an animal model of multiple myeloma) were generated with either high or low TACI gene expression (TACI-high and TACI-low). Following the establishment of myeloma growth, the mice were treated i.p. with atacicept (5 or 10 mg/kg 3 times a week). Atacicept reduced tumor burden in animals bearing TACI-high multiple myeloma cells and delayed growth or showed no effect in mice with TACI-low multiple myeloma cells (12, 13). Ex vivo, myeloma plasma cells from patients with active myeloma were co-cultured with osteoclasts for 5-7 days in the absence or presence of atacicept (1-10 μg/ml) and atacicept inhibited osteoclastinduced survival of myeloma cells by > 35% (13).
Pharmacokinetics and Metabolism
The preclinical safety, pharmacokinetics (PK) and pharmacodynamics (PD) of atacicept were evaluated in a recent study carried out in mice and cynomolgus monkeys (14). Atacicept administered s.c. to mice (single dose or repeated dosing 3 times a week for 2, 4 and 26 weeks) and monkeys (single dose or repeated dosing twice a week for 4, 13 and 39 weeks) was generally deemed safe and well tolerated. Single doses of 1 mg/kg atacicept resulted in 76% and 92% bioavailability, respectively, in mice and monkeys. Bioavailability levels remained high at doses ranging from 1 to 15 mg/kg. The time to maximum serum concentrations (tmax) was 4-16 h and 6-8 h, respectively, and the mean serum half-life (t1/2) was 40-50 h and 140-190 h, respectively, in mice and monkeys. Repeated atacicept administration was associated with decreased serum concentrations of IgG (up to 50% reduction) and IgM (> 99% reduction). The concentrations of circulating mature B cells were also reduced by up to 60%. These effects of atacicept were dose-related
and reversible over a follow-up period of 25 weeks.
The safety, PK and PD of atacicept were also assessed in four phase I clinical trials performed in healthy volunteers (15), patients with rheumatoid arthritis (16) and patients with SLE (17).
In the first study, a single s.c. dose of atacicept (2.1, 70, 210 or 630 mg) or placebo was administered to healthy male volunteers and the participants were monitored for a period of 7 weeks. The main PK evaluations based on the 70-, 210- and 630-mg doses revealed consistent multiphasic free drug PK profiles at the three different dose levels. A fairly rapid absorption phase was followed by a 1-2-week distribution phase and a long terminal phase. The median tmax was 16 h for all three doses (12-36 h) and the AUC increased in an approximately dose-dependent manner. A dose-dependent effect on the levels of IgM was also observed following doses of 70, 210 and 630 mg, whereas placebo and 2.1 mg atacicept had no effect. The greatest reduction in IgM levels (23%; range: 12-25%) was observed in the 630-mg group at 35 days postdose. The concentration of serum IgM remained low even 47 days postadministration when serum atacicept levels were unquantifiable and recovered to approximately 10% of baseline values at 100-150 days postadministration. No treatment-related effects on IgG levels or lymphocyte subpopulations were observed (15).
In the second study, the PK and biological activity of atacicept were evaluated in patients with moderate to severe active rheumatoid arthritis (16). Atacicept was administered s.c. either as a single dose or repeated doses at 2-week intervals in six escalating-dose cohorts (single-dose cohorts 1, 3 and 5 receiving 70, 210 and 630 mg, respectively, and repeated-dose cohorts 2, 4 and 6 receiving 3 x 70 mg, 3 x 210 mg and 7 x 420 mg, respectively). PK profiles of atacicept in all cohorts were nonlinear. Following the first dose, the PK profiles of free drug displayed a multiphasic behavior with a rapid absorption phase followed by a distribution phase lasting 2 weeks and a prolonged terminal phase (median tmax = 24 h for all cohorts; median t1/2 range = 104 h [cohort 6] to 1070 h [cohort 3]; median Cmax range = 419 ng/ml [cohort 1] to 5530 ng/ml [cohort 5]; median AUC range = 34.8 mg.h/l
[cohort 1] to 643 mg.h/l [cohort 5]). The biological activity of atacicept as estimated by the production of nonspecific Ig antibodies was deemed to be dose-related. The highest atacicept doses (cohorts 4, 5 and 6) caused a significant > 50% reduction in serum IgM levels, whereas statistically significant reductions in IgA (~40%) and IgG (~20%) were only observed in cohort 6.
Six cohorts of 8 patients each with SLE were treated with atacicept (single doses of 0.3, 1, 3 or 9 mg/kg s.c. in cohorts 1-4; 1 or 3 mg/kg s.c. weekly x 4 in cohorts 5 and 6) in one phase I study, and another evaluated single i.v. doses of 3, 9 or 18 mg/kg and two doses of 9 mg/kg 3 weeks apart. Pharmacokinetics were nonlinear but consistent and predictable across doses, routes and schemes of administration. Pharmacokinetic profiles for free and total drug were multiphasic, with a median terminal half-life of 30-83 days. Bioavailability following s.c. administration was 28-40% (17).
Clinical Studies
The maximum tolerated and the optimal biological doses of atacicept in patients with refractory or relapsed multiple myeloma or active, previously treated Waldenström’s macroglobulinemia were evaluated in an open-label, dose-escalation phase I/II study (18-20). One cycle of 5 weekly s.c. injections of atacicept (2, 4, 7 or 10 mg/kg) was administered to eligible patients (12 multiple myeloma and 4 Waldenström’s macroglobulinemia patients). Only subjects who demonstrated at least stable disease following the first cycle were allowed to continue to the extension phase of the trial. This phase comprised either two additional cycles separated by a 4-week washout period or 15 weekly injections of 10 mg/kg. Preliminary data from this study revealed no dose-limiting toxicity (DLT) or serious adverse events (SAE) associated with atacicept administration. After the first cycle, 5 multiple myeloma patients and 3 Waldenström’s macroglobulinemia patients had stable disease, and of 8 patients entering the extension phase, 4 with multiple myeloma and 1 with Waldenström’s macroglobulinemia had stable disease. The majority of patients exhibited a decrease in polyclonal immunoglobulins and plasmocytes.
A phase I open-label, dose-escalation clinical study of atacicept was carried out between October 2005 and July 2006 in patients with relapsed and refractory non- Hodgkin’s lymphoma (NHL) to address overall safety and maximum tolerated dose (MTD) (4, 21). Atacicept was administered s.c. weekly for 5 weeks to 4 patient cohorts receiving doses of 2, 4 or 7 mg/kg (n = 4 patients per dose cohort) and 10 mg/kg (n = 3 patients). Atacicept was well tolerated up to 10 mg/kg and showed biological activity; IgA, IgG and IgM concentrations displayed a mean dose-related reduction of 15-40% from baseline levels after 4 weeks of atacicept. The most common AEs associated with atacicept (occurring in ≥ 20% of patients) were fatigue (47%) and injection-site bruising (20%). None of the participants achieved a complete or partial response; 26.7% had stable disease at day 56 following 2 mg/kg atacicept treatment and 73.3% had progressive disease.
Preliminary results were reported from an open-label, dose-escalation phase I trial in patients with refractory orrelapsed B-cell chronic lymphocytic leukemia (B-CLL) administered atacicept i.v. once weekly for 5 weeks at doses of 1, 4, 10, 15, 20 or 27 mg/kg. No dose-limiting toxicity and no treatment-related SAEs were observed. Stable disease was attained by 3 of 6 patients treated at 10 and 15 mg/kg, 1 of whom was refractory to fludarabine and remained stable for over 6 months (22).
The safety and tolerability of atacicept were also addressed in a phase Ib trial in patients with mild to moderate SLE (23). Atacicept or placebo was administered to six cohorts of patients. Single-dose cohorts (cohorts 1-4) received one s.c. injection of 0.3, 1, 3 and 9 mg/kg of atacicept. In the repeated-dose cohorts (cohorts 5 and 6) weekly doses of 1 and 3 mg/kg of atacicept, respectively, were administered for a period of 4 weeks. The patients were followed for up to 6 weeks (single-dose cohorts) or 9 weeks (repeated-dose cohorts). Preliminary results from this study demonstrated biological activity for atacicept, with dose-dependent reductions of Ig levels and total B-cell numbers, which were more prominent in the repeated-dose cohorts (IgM, IgA and IgG reduction of ~ 50%, ~33% and ~16%, respectively, in cohort 6; total Bcell reductions of ~40-50% in cohorts 5 and 6). No effect on the numbers of T cells, natural killer (NK) cells or monocytes was observed. Treatment with atacicept was well tolerated with fairly rapid absorption (tmax ~24 h; initial distribution phase = 7-14 days). Atacicept was accompanied by mild injection-site reactions but no SAEs.
A multicenter, placebo-controlled, dose-escalating phase Ib study was recently carried out in patients with rheumatoid arthritis (24). Participants (N = 73) were divided into six escalating-dose cohorts receiving s.c. injections of atacicept or placebo as either single (70, 210 or 630 mg) or repeated doses (3 x 70 mg, 3 x 210 mg, 7 x 420 mg) administered at 2-week intervals. The study comprised 10 weeks of trial assessment followed by a single assessment at 3 months after the final dose. Overall, atacicept was well tolerated, with 44% of all patients exhibiting AEs, 56% of which were classified as mild or unrelated to the study medication. Local injectionsite symptoms were reported in 24 of 73 patients, the most frequent of which was mild to moderate erythema. The results of hematology, biochemistry, urine, coagulation, vital sign and electrocardiogram (EKG) assessments did not suggest any potential safety concerns. Ataciceptrelated decreases in Ig (especially IgM) and rheumatoid factor (RF) levels were observed, which were more evident in the cohort treated with 7 doses of 420 mg (IgM decreased by 45%; RF decreased by 41-44%). Pilot information on clinical outcomes was also collected in this study, including DAS28 (Disease Activity Score 28-joint assessment) scores and ACR20 (American College of Rheumatology 20% improvement criteria) responses. DAS28 scores indicated an improvement in rheumatoid arthritis signs and symptoms, especially in the highest repeated dose cohort (mean DAS28 = 6.4 ± 1.3 and 5.1 ± 1.4 at baseline and on day 85 in atacicept-treated patients). During the 3-month atacicept treatment period, 32% of patients attained an ACR20 response or better based on self-assessment of pain and overall disease activity.
The efficacy of atacicept in the treatment of B-cell malignancies and autoimmune conditions is currently being assessed in several ongoing phase II/III clinical trials (25-30).
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1楼2010-02-12 22:21:01
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dujuan521

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ald(金币+1): 2010-02-18 00:19
楼主太强了啊！佩服
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baoobao

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ald(金币+2): 2010-02-16 21:19
临床前药理学
Atacicept正常小鼠的治疗（100微克的IP 3倍，2周周）阻塞不成熟的T1 B细胞成熟脾B细胞前体的T2过渡和降低循环免疫球蛋白（2）的水平。 Atacicept发现阻止在周边的中和活化因子和4月，抑制类风湿关节炎和系统性红斑狼疮（SLE）小鼠模型红斑狼疮疾病进展的具体乙的发展，细胞群（2，6）。

Atacicept治疗（腹腔注射3次，每周3个星期）的数据库管理员/ 1小鼠胶原性关节炎（中央情报局）降低血清抗体滴度。经过处理的动物组织学评估显示关节软骨损坏，减少炎症，降低了滑膜肥厚，由炎症细胞周围的软组织着下降关节（2）。
在体内，对SLE的进展的atacicept影响评估的NZBWF1（也称为NZB /新西兰白兔F1）的小鼠品系，其中慢性自发开发自身免疫性疾病，是作为一个系统性红斑狼疮（6）模型。系统性红斑狼疮的症状特点，包括高滴度的抗dsDNA抗体，蛋白尿，肾小球肾炎。对atacicept政府15 - 21周龄雌性小鼠NZBWF1（100微克为5周，每周3次），大大降低蛋白尿≥100毫克/长达10周的动物分升以下的比例在过去的治疗相比，动物与FC治疗控制蛋白质或磷酸盐缓冲液（PBS;车辆控制）。甲在38岁周的100％，成活率在atacicept观察治疗的动物相比，47％存活的Fc治疗组12周后的最后治疗。无显着性差异反在不同的治疗组双链DNA抗体的生产。然而，一个重要的53％，而外周血B细胞百分率为28岁的周后观察atacicept处理相比，财务处理的小鼠。这在B细胞减少，一直持续到31岁的周月（5周之后的最后处理），返回控制37岁（6）周水平。
在化学诱导的自身免疫小鼠模型，atacicept治疗（100微克为2周，每周3次），减少抗体生产氯化汞诱导的自体免疫汞敏感小鼠品系答：西南（9）。治疗期间汞诱导期与atacicept大大减少诱发自身免疫抗细胞核抗体，而与atacicept预处理（野牛）IgG1水平，防止血清总IgE诱导。甲B中大量减少细胞数量进行T1，脾B细胞发展过程中过渡T2还观察。
对小鼠的能力明显流感病毒的atacicept暴露的影响进行了评价（10，11）。 C57BL / 6小鼠的治疗或车辆管制，地塞米松（阳性对照）或atacicept（0.05，0.50和5.0毫克/千克）资深大律师每周3次从一周前，用鼠标感染适应人类流感的A /港口Chalmer/1/73（H3N2型）通过21天postinfection病毒。 Atacicept处理的小鼠表现出了脾脏的重量及流感特异性IgM和IgG肺和血清生产dosedependent相比，减少了车辆控制动物。动物暴露于atacicept展现了在B数量减少，但不是在外周血T细胞。然而，与地塞米松治疗，atacicept并没有对病毒的清除和动物生存的影响。
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2楼2010-02-14 16:51:03
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baoobao

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ald(金币+1): 2010-02-16 21:19
药代动力学和代谢
在临床前安全性，药代动力学（TGTL.PK）的药效学（PD）的进行了评价的atacicept在最近的一项研究进行小鼠和猕猴（14）。南卡罗来纳州Atacicept管理对小鼠（单剂量或重复用药2，4和26个星期，每周3次）和猴（单剂量或重复用药4次，第13和39周周），一般被视为安全和耐受性良好。单剂量的1毫克/千克atacicept导致了76％和92％生物利用度，分别在老鼠和猴子。生物利用度水平仍然很高，1至15毫克不等剂量/公斤。以最大的血药浓度（最高温度），时间为4-16 h和6-8小时，分别平均血清半衰期（t1 / 2为）为40〜50 h和140-190小时，分别在老鼠，猴子。反复atacicept与管理是降低血清中IgG浓度（高达50％减少）及IgM（“减少了99％）。循环成熟B细胞的浓度也降低了60％。对atacicept这些作用剂量relatedand超过后续25周内逆转。
这项安全性，PK和帕金森的atacicept还评估了4期临床试验在健康志愿者进行（15），类风湿关节炎（16）和系统性红斑狼疮（17）患者。
在第一项研究中，一个单一的南卡罗来纳剂量atacicept（2.1，70，210或630毫克）或安慰剂，研究人员让健康男性志愿者和参加者为7周期间监测。主要激酶评价的基础上的70 - ，210 -和630毫克的剂量显示一致多相免费药品激酶配置在三个不同的剂量水平。阿较快吸收阶段之后是1 - 2周分布相和长期的终端阶段。中位数最高温度为16对所有的三剂（12-36小时）和哥伦比亚联合自卫军ħ增加了约剂量依赖性。阿剂量的抗体水平依赖效应还指出以下70，210和630毫克剂量，而安慰剂和2.1毫克atacicept，没有效果。在IgM水平下降幅度最大（23％;范围：12-25％）中观察到630毫克组在服药后35天。该抗体的血药浓度维持在低水平，即使在47天postadministration血清atacicept水平难以估量，并追回在100-150天postadministration约10％的基准值。无治疗相关的抗体水平或淋巴细胞亚群的影响观察（15）。
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3楼2010-02-14 16:51:22
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baoobao

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ald(金币+1): 2010-02-16 21:21
在第二项研究中，PK的和atacicept生物活性进行了评价患者有中度至重度活动期类风湿关节炎（16）。 Atacicept是南卡罗来纳州管理无论是作为单剂量或重复剂量2在6周的时间间隔不断升级剂量组群（单剂量组群1，第3和第5接收70，210和630毫克，分别重复剂量组群2，4和6接收3 × 70毫克，3 × 210毫克和7 × 420毫克，分别）。型材的atacicept激酶在所有组群的非线性。第一剂后，自由PK的药物配置表现出的快速吸收的分销阶段持续2周，长期终端阶段（中位数最高温度= 24的所有同伙H级;中位数t1 / 2为范围= 104期多相行为ħ [队列6]到1070 ħ [队列3];中位数Cmax分别范围= 419纳克/毫升[队列1] 5530纳克/毫升[队列5];中位数曲线下面积范围= 34.8 mg.h /升[队列1] 643 mg.h /升[队列5]）。在atacicept生物活性，由非特异性免疫球蛋白抗体的产量估计被认为是剂量相关。最高（同伙4，5和6）造成重大的“50％，血清IgM水平降低，而在IgA显着性降低，（〜40％）和IgG（〜20％）仅在队列6观察atacicept剂量。
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