美国FDA批准罕用药物rilonacept冻干粉针上市

   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。 CAPS 疾病为遗传性疾病， 50 %的病例系 CIAS 1 基因内基因突变造成。本品剂量规格：利洛纳塞 220 mg/20 mL 玻瓶。

　Nlonacept 系一靶向性白介素 -1 受体阻断剂，后者是成 CAPS 炎症的关键诱发剂。 Nlonacept 通过作用于与白介素 1β （ IL-1β ）结合的水溶性德考义（ decoy ）受体及防止其与细胞表面受体相互作用来阻滞 IL-1β 的信号传递。 Nlonacept 还与 IL-1α 和 IL-1 受体阻断剂（ IL-1ra ）结合来降低其亲和性。其与 IL-1β 、 IL-1α 和 IL-1ra 结合的解离平衡常数分别为 0.5 pM 、 1.4 pM 和 6.1 pM 。对 CPS 患者每周皮下注射利洛纳塞 160 mg 长达 48 周平均稳态血药浓度约为 24 μg/mL ， 6 周达到稳态血药浓度。

　在本品关键的临床开发计划中，采用由每日评价潮红、发热 / 寒战感觉、关节疼痛、眼睛红肿或疼痛和乏力综合症状记分测定药物的疗效。以本品治疗的患者症状的总记分较安慰剂对照组改善。持续使用本品可保持改善症状。本品最常见的不良反应是注射部位反应和上呼吸道感染。

In February 2008, the U.S. Food and Drug Administration (FDA) approved ARCALYST Injection for Subcutaneous Use for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 and older.

In September 2009, Regeneron received marketing authorization in the European Union from the European Commission based upon a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) for rilonacept for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS) with severe symptoms, including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 and older. The authorization for approval of rilonacept in the E.U. under exceptional circumstances is permissible for products for which a company can demonstrate that comprehensive data cannot be provided, for example because of the rarity of the condition. Each year, Regeneron will need to provide the EMEA with any new information that may become available for review.

Cryopyrin-Associated Periodic Syndromes (CAPS)-a rare, hereditary condition

CAPS are generally caused by mutations in the NLRP-3 (previously known as CIAS1) gene and resultant alterations in the protein, cryopyrin, which it encodes. Cryopyrin, active in circulating, infection-fighting, white blood cells, controls the production of a protein called interleukin-1 (IL-1). As part of the body's infection-fighting defense system, IL-1 circulates throughout the body and can trigger inflammatory reactions when it binds to inflammatory cells. Researchers have found that alterations in the cryopyrin protein lead to over-production of IL-1, resulting in an inflammatory response and the symptoms of CAPS. Most, but not all, patients with CAPS have the NLRP-3 gene mutation.

The incidence of CAPS has been reported to be approximately 1 in 1,000,000 people in the United States and Europe.

Important Safety Considerations Regarding ARCALYST

IL-1 blockade may interfere with immune response to infections. Serious, life-threatening infections have been reported in patients taking ARCALYST. ARCALYST should be discontinued if a patient develops a serious infection. Taking ARCALYST with tumor necrosis factor inhibitors is not recommended because this may increase the risk of serious infections. Treatment with ARCALYST should not be initiated in patients with active or chronic infections. Patients should not receive a live vaccine while taking ARCALYST. It is recommended that patients receive all recommended vaccinations prior to initiation of treatment with ARCALYST. Patients should be monitored for changes in their lipid profiles and provided with medical treatment if warranted. Hypersensitivity reactions associated with ARCALYST administration have been rare.

Rilonacept治疗痛风的疗效评估

近期在美国风湿病协会年会上进行交流的一项研究指出，Rilonacept (IL-1 Trap)能有效缓解反复发作的慢性痛风患者的疼痛及病情的严重程度。 Rilonacept是一种用于治疗炎症状态的新药，通过阻断白介素-1与细胞表面受体的结合来缓解疾病。由于白介素-1在痛风的发病机制中也扮演了一定的角色，因此推测Rilonacept应该对此症也有作用。为了进一步评估反复发作的慢性痛风患者在Rilonacept治疗后的病情变化情况以及Rilonacept的安全性，研究人员共随访了10名参加一项多中心、非随机、单盲、对照研究的患者，平均年龄为62岁，平均痛风病史13年。患者在接受每周1次的皮下注射安慰剂治疗2周后给予Rilonacept每周1次共6周。通过疼痛程度的评估来界定痛风的活动情况，同时还评估了总病情变化、疼痛的关节数及C反应蛋白的变化情况。结果显示，在第3~8周的治疗期，约有70%的患者疼痛缓解程度达到50%以上，疼痛缓解75%以上的患者比例为60%。治疗6周后，C反应蛋白水平平均降低了59%左右。未发现死亡或其他严重的不良反应事件，注射部位的轻至中度反应是最常见的药物相关性副反应