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美国FDA批准Regeneron公司白介素-1受体阻断剂rilonacept冻干粉针（Arcalyst）上市，皮下注射长期治疗成人和12岁及以上儿童的2种冷吡啉相关的周期性综合征（Cryopyrin-Associated Periodic Syndromes，CAPS）疾病：家族冷自主炎症综合征（Familial Cold Auto-Inflammatory Syndrome，FCAS）和穆-韦二氏综合征（Muckle-Wells Syndrome，MWS）。此2种疾病的症状在成人和儿童身上均表现为关节疼痛、潮红或皮肤损伤、发热和寒战、眼睛红肿或疼痛、乏力。然而，MWS可造成更为严重的炎症，有可能引起听力丧失或耳聋。此外，一些 MWS 患者体内构成蛋白质的物质会损伤器官和组织。在美国，FCAS和MWS患者约300例。
In patients with CAPS, the most common and consistently reported adverse event associated with ARCALYST was injection-site reaction (ISR). The ISRs included erythema, swelling, pruritis, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth and hemorrhage. Most injection-site reactions lasted for one to two days. No ISRs were assessed as severe, and no patient discontinued study participation due to an ISR. 6.3 Infections During Part A, the incidence of patients reporting infections was greater with ARCALYST (48%) than with placebo (17%). In Part B, randomized withdrawal, the incidence of infections were similar in the ARCALYST (18%) and the placebo patients (22%). Part A of the trial was initiated in the winter months, while Part B was predominantly performed in the summer months. In placebo-controlled studies across a variety of patient populations encompassing 360 patients treated with rilonacept and 179 treated with placebo, the incidence of infections was 34% and 27% (2.15 per patient-exposure year and 1.81 per patient-exposure year), respectively, for rilonacept and placebo. Serious Infections: One patient receiving ARCALYST for an unapproved indication in another study developed an infection in his olecranon bursa with Mycobacterium intracellulare. The patient was on chronic glucocorticoid treatment. The infection occurred after an intraarticular glucocorticoid injection into the bursa with subsequent local exposure to a suspected source of mycobacteria. The patient recovered after the administration of the appropriate antimicrobial therapy. One patient treated for another unapproved indication developed bronchitis/sinusitis, which resulted in hospitalization. One patient died in an open-label study of CAPS from Streptococcus pneumoniae meningitis. 6.4 Malignancies [see Warnings and Precautions (5.2)]. 6.5 Hematologic Events One patient in a study in an unapproved indication developed transient neutropenia (ANC < 1 x 109/L) after receiving a large dose (2000 mg intravenously) of ARCALYST. The patient did not experience any infection associated with the neutropenia. 6.6 Immunogenicity Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with ARCALYST. Nineteen of 55 patients (35%) who had received ARCALYST for at least 6 weeks tested positive for treatment-emergent binding antibodies on at least one occasion. Of the 19, seven tested positive at the last assessment (Week 18 or 24 of the open-label extension period), and five patients tested positive for neutralizing antibodies on at least one occasion. There was no correlation of antibody activity and either clinical effectiveness or safety. The data reflect the percentage of patients whose test results were positive for antibodies to the rilonacept receptor domains in specific assays, and are highly dependent on the sensitivity and specificity of the assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies to other products may be misleading. 6.7 Lipid profiles Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Patients with CAPS treated with ARCALYST experienced increases in their mean total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. The mean increases from baseline for total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were 19 mg/dL, 2 mg/dL, 10 mg/dL, and 57 mg/dL respectively after 6 weeks of open-label therapy. Physicians should monitor the lipid profiles of their patients (for example after 2-3 months) and consider lipid-lowering therapies as needed based upon cardiovascular risk factors and current guidelines. 7 DRUG INTERACTIONS 7.1 TNF-blocking agent and IL-1 blocking agent Specific drug interaction studies have not been conducted with ARCALYST. Concomitant administration of another drug that blocks IL-1 with a TNF-blocking agent in another patient population has been associated with an increased risk of serious infections and an increased risk of neutropenia. The concomitant administration of ARCALYST with TNF-blocking agents may also result in similar toxicities and is not recommended [see Warnings and Precautions (5.1)]. The concomitant administration of ARCALYST with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacologic interactions between rilonacept and a recombinant IL-1ra, concomitant administration of ARCALYST and other agents that block IL-1 or its receptors is not recommended. 7.2 Cytochrome P450 Substrates The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as rilonacept, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of ARCALYST, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies of ARCALYST in pregnant women. Based on animal data, ARCALYST may cause fetal harm. An embryo-fetal developmental toxicity study was performed in cynomolgus monkeys treated with 0, 5, 15 or 30 mg/kg given twice a week (highest dose is approximately 3.7-fold higher than the human doses of 160 mg based on body surface area). The fetus of the only monkey with exposure to rilonacept during the later period of gestation showed multiple fusion and absence of the ribs and thoracic vertebral bodies and arches. Exposure to rilonacept during this time period was below that expected clinically. Likewise, in the cynomolgus monkey, all doses of rilonacept reduced serum levels of estradiol up to 64% compared to controls and increased the incidence of lumbar ribs compared to both control animals and historical control incidences. In perinatal and postnatal developmental toxicology studies in the mouse model using a murine analog of rilonacept (0, 20, 100 or 200 mg/kg), there was a 3-fold increase in the number of stillbirths in dams treated with 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). ARCALYST should be used during pregnancy only if the benefit justifies the potential risk to the fetus. Nonteratogenic effects. A peri- and post-natal reproductive toxicology study was performed in which mice were subcutaneously administered a murine analogue of rilonacept at doses of 20, 100, 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). Results indicated an increased incidence in unscheduled deaths of the F1 offspring during maturation at all doses tested. 8.3 Nursing Mothers It is not known whether rilonacept is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARCALYST is administered to a nursing woman. 8.4 Pediatric Use Six pediatric patients with CAPS between the ages of 12 and 16 were treated with ARCALYST at a weekly, subcutaneous dose of 2.2 mg/kg (up to a maximum of 160 mg) for 24-weeks during the open-label extension phase. These patients showed improvement from baseline in their symptom scores and in objective markers of inflammation (e.g. Serum Amyloid A and C-Reactive Protein). The adverse events included injection site reactions and upper respiratory symptoms as were commonly seen in the adult patients. The trough drug levels for four pediatric patients measured at the end of the weekly dose interval (mean 20 mcg/mL, range 3.6 to 33 mcg/mL) were similar to those observed in adult patients with CAPS (mean 24 mcg/mL, range 7 to 56 mcg/mL). Safety and effectiveness in pediatric patients below the age of 12 have not been established. When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if ARCALYST will alter bone development in pediatric patients. Pediatric patients treated with ARCALYST should undergo appropriate monitoring for growth and development. [see Use in Specific Populations (8.1)] 8.5 Geriatric Use In the placebo-controlled clinical studies in patients with CAPS and other indications, 70 patients randomized to treatment with ARCALYST were ≥ 65 years of age, and 6 were ≥ 75 years of age. In the CAPS clinical trial, efficacy, safety and tolerability were generally similar in elderly patients as compared to younger adults; however, only ten patients ≥ 65 years old participated in the trial. In an open-label extension study of CAPS, a 71 year old woman developed bacterial meningitis and died [see Adverse Reactions (6.3)]. Age did not appear to have a significant effect on steady-state trough concentrations in the clinical study. 8.6 Patients with Renal Impairment No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with renal impairment. 8.7 Patients with Hepatic Impairment No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with hepatic impairment. 10 OVERDOSAGE There have been no reports of overdose with ARCALYST. Maximum weekly doses of up to 320 mg have been administered subcutaneously for up to approximately 18 months in a small number of patients with CAPS and up to 6 months in patients with an unapproved indication in clinical trials without evidence of dose-limiting toxicities. In addition, ARCALYST given intravenously at doses up to 2000 mg monthly in another patient population for up to six months were tolerated without dose-limiting toxicities. The maximum amount of ARCALYST that can be safely administered has not been determined. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects, and appropriate symptomatic treatment instituted immediately. 11 DESCRIPTION Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human interleukin-1 receptor component (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Rilonacept has a molecular weight of approximately 251 kDa. Rilonacept is expressed in recombinant Chinese hamster ovary (CHO) cells. ARCALYST is supplied in single-use, 20-mL glass vials containing a sterile, white to off-white, lyophilized powder. Each vial of ARCALYST is to be reconstituted with 2.3 mL of Sterile Water for Injection. A volume of up to 2 mL can be withdrawn, which is designed to deliver 160 mg for subcutaneous administration only. The resulting solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Each vial contains 220 mg rilonacept. After reconstitution, each vial contains 80 mg/mL rilonacept, 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5 ± 0.3. No preservatives are present. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [Nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis. In most cases, inflammation in CAPS is associated with mutations in the NLRP-3 gene which encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds IL-1α and IL-1 receptor antagonist (IL-1ra) with reduced affinity. The equilibrium dissociation constants for rilonacept binding to IL-1β, IL-1α and IL-1ra were 0.5 pM, 1.4 pM and 6.1 pM, respectively. 12.2 Pharmacodynamics C-Reactive Protein (CRP) and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Compared to placebo, treatment with ARCALYST resulted in sustained reductions from baseline in mean serum CRP and SAA to normal levels during the clinical trial. ARCALYST also normalized mean SAA from elevated levels. 12.3 Pharmacokinetics The average trough levels of rilonacept were approximately 24 mcg/mL at steady-state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady-state appeared to be reached by 6 weeks. No pharmacokinetic data are available in patients with hepatic or renal impairment. No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady state trough concentrations were similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical study, reflecting the epidemiology of the disease. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of rilonacept. The mutagenic potential of rilonacept was not evaluated. Male and female fertility was evaluated in a mouse surrogate model using a murine analog of rilonacept. Male mice were treated beginning 8 weeks prior to mating and continuing through female gestation day 15. Female mice were treated for 2 weeks prior to mating and on gestation days 0, 3, and 6. The murine analog of rilonacept did not alter either male or female fertility parameters at doses up to 200 mg/kg (this dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). 14 CLINICAL STUDIES The safety and efficacy of ARCALYST for the treatment of CAPS was demonstrated in a randomized, double-blind, placebo-controlled study with two parts (A and B) conducted sequentially in the same patients with FCAS and MWS. Part A was a 6-week, randomized, double-blind, parallel-group period comparing ARCALYST at a dose of 160 mg weekly after an initial loading dose of 320 mg to placebo. Part B followed immediately after Part A and consisted of a 9-week, patient-blind period during which all patients received ARCALYST 160 mg weekly, followed by a 9-week, double-blind, randomized withdrawal period in which patients were randomly assigned to either remain on ARCALYST 160 mg weekly or to receive placebo. Patients were then given the option to enroll in a 24-week, open-label treatment extension phase in which all patients were treated with ARCALYST 160 mg weekly. Using a daily diary questionnaire, patients rated the following five signs and symptoms of CAPS: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of 0 (none, no severity) to 10 (very severe). The study evaluated the mean symptom score using the change from baseline to the end of treatment. The changes in mean symptom scores for the randomized parallel-group period (Part A) and the randomized withdrawal period (Part B) of the study are shown in Table 2. ARCALYST-treated patients had a larger reduction in the mean symptom score in Part A compared to placebo-treated patients. In Part B, mean symptom scores increased more in patients withdrawn to placebo compared to patients who remained on ARCALYST. Table 2: Mean Symptom Scores
** A confidence interval lying entirely below zero indicates a statistical difference favoring ARCALYST versus placebo. Daily mean symptom scores over time for Part A are shown in Figure 1. Figure 1: Group Mean Daily Symptom Scores by Treatment Group in Part A and Single-blind ARCALYST Treatment Phase from Week -3 to Week 15
16 HOW SUPPLIED/ STORAGE AND HANDLING Each 20-mL glass vial of ARCALYST contains a sterile, white to off-white, preservative-free, lyophilized powder. ARCALYST is supplied in a carton containing four vials (NDC 61755-001-01). The lyophilized ARCALYST product is to be stored refrigerated at 2° to 8°C (36° to 46°F) inside the original carton to protect from light. Do not use beyond the date stamped on the label. After reconstitution, ARCALYST may be kept at room temperature, should be kept from light, and should be used within three hours of reconstitution. ARCALYST does not contain preservatives; therefore, unused portions of ARCALYST should be discarded. Discard the vial after a single withdrawal of drug. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. The first injection of ARCALYST should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer ARCALYST, he/she should be instructed on aseptic reconstitution of the lyophilized product and injection technique. The ability to inject subcutaneously should be assessed to ensure proper administration of ARCALYST, including rotation of injection sites. (See Patient Information Leaflet for ARCALYST®). ARCALYST should be reconstituted with preservative-free Sterile Water for Injection to be provided by the pharmacy. A puncture-resistant container for disposal of vials, needles and syringes should be used. Patients or caregivers should be instructed in proper vial, syringe, and needle disposal, and should be cautioned against reuse of these items. Injection-site Reactions: Physicians should explain to patients that almost half of the patients in the clinical trials experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, pruritis, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Patients should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician. Infections: Patients should be cautioned that ARCALYST has been associated with serious, life-threatening infections, and not to initiate treatment with ARCALYST if they have a chronic or active infection. Patients should be counseled to contact their healthcare professional immediately if they develop an infection after starting ARCALYST. Treatment with ARCALYST should be discontinued if a patient develops a serious infection. Patients should be counseled not to take any IL-1 blocking drug, including ARCALYST, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of ARCALYST with other IL-1 blocking agents, such as anakinra, is not recommended. Vaccinations: Prior to initiation of therapy with ARCALYST physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ARCALYST. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=282f4099-e848-432a-bac1-e041c192a5ba Arcalyst扩大应用申请遭FDA拒绝批准 2012年7月30日，Regeneron公司药物Arcalyst用于初始降尿酸治疗（uric acid-lowering therapy）预防痛风急性发作（gout flares）的扩大应用申请遭FDA拒绝。FDA要求提供更多的临床数据，包括有关Arcalyst新剂型的化工、制造及控制信息，Regeneron在一份声明中称。 之前，FDA顾问小组对Regeneron公司仅完成的一项为期16周的研究表示了关注，最终一致投票反对批准Arcalyst用于防治痛风的扩大应用申请。 痛风是体内嘌呤代谢紊乱所导致的一种疾病，表现为高尿酸血症，尿酸盐在关节、肾及结缔组织中析出结晶。在美国，该病影响着约500万~600万人。 Arcalyst，通常称为rilonacept，已获批用于一组罕见遗传性自身炎症性（genetic auto-inflammatory）疾病的治疗，然而该适应症对于Regeneron公司的整体销售仅起到了温和的推动作用。 因此，Regeneron公司急切希望扩大Arcalyst的应用，用于在初始降尿酸治疗（uric acid-lowering therapy）中预防痛风急性发作（gout flares）。 痛风相关药品治疗 降尿酸治疗 别嘌呤醇 别嘌呤醇是最常用的降尿酸药物，但许多患者血尿酸不能降至目标值，且存在安全性问题，其最严重副作用为别嘌呤醇超敏综合征（AHS），可致死。康纳（Khanna）发现，肾损害患者AHS发病率为0.41%～0.72%，最常见表现为急性肾衰竭，未校正估计AHS发病率较无肾损害者高3～4倍，校正后，肾损害者AHS发病率仍明显高于无肾损害者，提示别嘌呤醇与急性肾衰竭可能相关。另有研究报告，肾损害、应用利尿剂和血清氧嘌呤醇>100 μmol/L与AHS发生相关，血清氧嘌呤醇30～100 μmol/L为适宜治疗范围。 尿酸酶 有报告重组A黄曲尿酸酶（拉布立酶）可用于治疗严重慢性痛风，但其抗原性强、半衰期短，因此顽固性高尿酸血症的痛风患者在应用6~12个月后，患者耐受性及药物疗效均较差。 一项双盲安慰剂对照Ⅲ期临床试验（RCT阶段）纳入治疗失败的痛风（TFG）患者，予静脉注射Pegloticase（8 mg，q2w）、Pegloticase（8 mg，q4w）或安慰剂。结果为，6个月时q2w、q4w和安慰剂组血尿酸<6 mg/dl的患者分别占42%、35%和0；治疗组痛风石明显消退，3个月和6个月时痛风石完全消失的患者分别占22%和45%。 随后为期1年的开放延长试验（OLE）纳入完成Ⅲ期临床试验的患者151例，进一步评估Pegloticase长期应用的安全性和疗效。结果为，除RCT阶段3个月后痛风发作次数和频率持续减少外，OLE与RCT阶段不良反应发生率（包括注射反应和严重不良事件）相似；疗效方面，进入OLE后患者压痛、肿胀关节数、疾病活动和疼痛的整体状况评估持续改善；RCT阶段治疗组至少1处痛风石完全消失者为32例，进入OLE后新增21例；48例RCT阶段血尿酸＜6 mg/dl的患者中有43例进入OLE后血尿酸仍＜6 mg/dl。OLE证实，TFG患者可长期耐受Pegloticase，疗程延长至1年时风险无明显增加，仍可维持症状改善及血尿酸降低。 但RCT阶段结果显示，Pegloticase治疗组产生抗Pegloticase抗体（a-PGL）的患者比例明显高于安慰剂组（88%对15%），且多数血尿酸持续＜6 mg/dl的持续有效者滴度<1:2430，而不能维持在6 mg/dl以下的短暂有效者滴度常>1:2430。a-PGL的形成加速了Pegloticase清除而失去降尿酸作用，但a-PGL仅明显降低其血药峰浓度和谷浓度。在短暂有效者中，在治疗5周和8周内失去降尿酸作用的比例分别为80%和90%，当血尿酸水平升高时血清Pegloticase测不到而a-PGL水平升高，但两者无相关性。在q2w和q4w治疗组注射反应发生率分别为26%和40%，其中当血尿酸超过6 mg/dl时出现注射反应和高滴度a-PGL（平均1:28013）者分别占91%和59%，71%患者的注射反应发生于血尿酸无反应后。q2w治疗组中，如血尿酸超过6 mg/dl时即停药可使注射反应减少91%。上述结果提示，a-PGL与血尿酸无反应和注射反应相关，多数注射反应发生在血尿酸无反应之后，因此常规监测血尿酸可预测接受Pegloticase治疗的患者不再获益及注射反应风险增加的时间。 另外，尿酸酶是否增加氧化应激值得关注。赫什菲尔德（Hershfield）等观察Pegloticase（8mg，q3w）对氧化应激的影响时发现，高基线血清异前列腺素F2（IsoP) 水平提示顽固性痛风患者的高尿酸血症与高应激状态相关，而Pegloticase治疗导致的低尿酸血症未明显降低IsoP水平，且尿酸水平与IsoP水平不相关，这提示Pegloticase可能不增加氧化应激状态。 选择性肾小管尿酸转运蛋白1（URAT1）抑制剂 RDEA594是一种新型选择性肾小管尿酸转运蛋白1（URAT1）抑制剂。临床前毒性研究显示长期应用安全性好且无明显内脏毒性。Ⅰ期临床试验显示，RDEA594（5~600 mg/d，共10 d）安全且有剂量依赖性降尿酸作用。 RDEA594Ⅱa期试验纳入21例血尿酸≥8.0 mg/dl的痛风患者，随机分为RDEA594组11例（第1周200 mg qd，第2周400 mg qd）、安慰剂组5例及开放标签别嘌呤醇组5例（300 mg qd，共2周）。RDEA594组1例患者因不宜用药退出试验。结果为，RDEA594组服药1周和2周后血尿酸降至6 mg/dl以下者分别为40%和60%，平均下降超过40%，疗效与别嘌呤醇组相当，明显优于安慰剂组，提示RDEA594 200 mg和400 mg可有效降低血尿酸水平，因此被确定用于Ⅱa期剂量-疗效研究。RDEA594组6例患者伴轻中度肾功能不全，在2周后血尿酸至少下降30%，肌酐清除率最低（53 ml/min）者下降40%，提示RDEA594对轻中度肾功能不全的痛风患者治疗有效；尿酸排泄率低的患者在RDEA594治疗后其尿酸清除率和24小时尿的尿酸水平与对照组接近，但无尿酸过度排泄，因此肾结石风险极低；患者对RDEA594耐受性好，未发生严重不良事件。目前RDEA594的Ⅱb期临床试验正在进行。 痛风发作治疗 秋水仙碱 控制痛风急性发作的传统药物主要是非类固醇类抗炎药（NSAID）、秋水仙碱和皮质类固醇。目前仅有1项关于秋水仙碱治疗急性痛风发作的随机安慰剂对照临床试验，结果为，治疗48小时后大剂量秋水仙碱（平均6.7 mg）组患者疼痛缓解明显优于安慰剂组，但均出现腹泻。 最近的AGREE研究为随机双盲安慰剂对照Ⅲ期临床试验，对184例急性痛风发作患者分别予小剂量（首剂1.2 mg，1小时后0.6 mg，共1.8 mg）或大剂量（首剂1.2 mg，此后6小时内0.6 mg/h，共4.8 mg）秋水仙碱，或安慰剂。结果为，在小剂量组、大剂量组和安慰剂组，首剂给药后24小时、32小时疼痛改善[0-10视觉模拟评分（VAS）下降≥2分]患者的比例分别为43.2%、34.6%、17.2%和45.9%、38.5%、17.2%；小剂量组与大剂量组疼痛减轻50%的时间（24 h对24.5 h）及因24小时内疼痛无改善而使用解救药的患者比例（31.3%对34.6%）相似，3组使用解救药的时间分别为70 h、36.5 h和24 h；3组腹泻发生率分别为23%、76.9%和13.6%，小剂量组总体不良反应与安慰剂组相似（36.5%对27.1%），且明显低于大剂量组。药代动力学分析发现，秋水仙碱大剂量与小剂量方案血药峰浓度相似（6.8 ng/ml对6.2 ng/ml），但药物暴露量为小剂量方案的2倍。该研究证实，额外的秋水仙碱药物暴露未增加其疗效而仅增加副作用，因此，对早期痛风发作患者不主张应用大剂量秋水仙碱，而推荐小剂量方案。 IL-1受体拮抗剂 最近研究发现，NALP3炎症小体/IL-1通路在晶体诱导的关节炎中发挥重要作用，尿酸盐晶体通过活化NALP3、促进IL-1β合成导致炎症反应。 Canakinumab(ACZ885)为全人源化IL-1β单抗。有研究对200例接受Canakinumab或醋酸曲安奈德治疗的难治性痛风性关节炎患者观察8周后发现，与醋酸曲安奈德相比，Canakinumab 150 mg可快速缓解痛风性关节炎症状，使复发的相对危险性下降94%（45.4%对3.7%），且患者耐受性好。 Rilonacept为可溶性IL-1受体融合蛋白，可每周1次皮下注射160 mg。一项多中心随机双盲Ⅱ期研究显示，与安慰剂对比，rilonacept可使人均痛风发作次数明显减少（0.79对0.15），痛风发作≥1次者明显减少（45%对15%），而副作用无明显增加，主要为感染和骨骼肌肉系统异常，未发生死亡和严重感染。该研究证实，rilonacept明显减少痛风复发，且安全性好。 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
