2017年12月14日,辉瑞（Pfizer）公司宣布，美国FDA批准XELJANZ 5mg BID（每日两次）和XELJANZ XR（tofacitinib）11mg QD（每日一次）的疗法，用于治疗具有活跃银屑病关节炎（psoriatic arthritis，PsA）的成年患者，这些患者对氨甲蝶呤（methotrexate）或者其他缓解疾病的抗风湿药物（DMARDs）的反应不足或是不耐受。XELJANZ/XELJANZ XR是首个且唯一获美国FDA批准，用于治疗中度至严重类风湿性关节炎（RA）和活跃PsA的Janus激酶（JAK）抑制剂。

　银屑病关节炎是一种慢性自身免疫炎性疾病，可能影响外周关节、肌腱、韧带或皮肤。 PsA的症状可能包括诸如关节僵硬和疼痛、脚趾和/或手指肿胀、运动范围缩小等等，给患者生活带来极大不便，亟需有能为他们改善病情的新药出现。
　辉瑞公司开发的XELJANZ就是一种治疗这种疾病的新药。它是种新颖的口服JAK抑制剂，旨在抑制细胞中的JAK信号通路，而JAK通路被认为在PsA的炎症反应中发挥了重要作用。通过抑制这些JAK通路，XELJANZ就能抑制细胞信号传导、相关基因表达和激活，从而改善病情。
　这次FDA批准XELJANZ用于治疗活跃PsA的成年患者的决定，是基于临床3期OPAL（Oral Psoriatic Arthritis Trial）研究结果，这项研究包含两个关键试验，分别是OPAL Broaden和OPAL Beyond。两项试验结果已经于2017年10月发表在《新英格兰医学杂志》（NEJM）上，除此之外，还有个尚在进行的长期延长试验OPAL Balance。OPAL Broaden是一项为期12个月的研究，受试者是对非生物（nonbiologic）的DMARDs反应不足，且未用过肿瘤坏死因子抑制剂（TNFi）的活跃PsA成年患者。试验包含有每两周接受40mg  adalimumab的对照组，但该试验不支持XELJANZ和adalimumab之间的劣效或优异性比较。OPAL Beyond则是一项为期6个月的对活跃PsA成年患者的研究，他们使用过TNFi但对其反应不足。根据银屑病关节炎分类标准（CASPAR），所有患者的活跃PsA至少持续6个月，至少有3个疼痛关节和至少有3个肿胀关节，以及活跃斑块型银屑病。在这两项研究中，所有患者都需要接受稳定、单独的背景剂量非生物DMARD。
　这两项关键性研究均达到了两个主要疗效终点：与安慰剂治疗组相比，接受XELJANZ 5mg BID与非生物DMARD联合治疗的患者在三个月时，在美国风湿病学会20（ACR20）的指标以及健康评估问卷——残疾指数（HAQ-DI）上都显示出有统计学意义的改善。在OPAL Broaden中，接受XELJANZ 5mg BID的患者有50％在3个月时达到ACR20缓解，而接受安慰剂的患者是33％（p≤0.05）。在OPAL Beyond中，接受XELJANZ 5mg BID的患者有50％在3个月时达到ACR20缓解，而接受安慰剂的患者是24％（p≤0.05）。值得一提的是，在这两项研究中，相对于对照组，用药组ACR20缓解的显著提高在第二周就可以观察到，达到了研究的次要终点（OPAL Broaden：用药组22% vs.对照组6% [p=0.0003]；OPAL Beyond：用药组27% vs. 对照组13% [p=0.0046]）。
　用XELJANZ治疗活跃银屑病关节炎患者时观察到的安全性特征与在类风湿性关节炎患者中观察到的安全性一致。XELJANZ 5mg BID患者最常见的不良事件是鼻咽炎、上呼吸道感染、头痛和腹泻。
　“银屑病关节炎是一种复杂而渐进的疾病，具有难以预测的病程，”辉瑞公司炎症与免疫学部全球主席Angela Hwang表示：“XELJANZ的批准是给患者带来新疗法的重要一步，也是辉瑞公司坚定不移地致力于改进患者护理的明证。”
“银屑病关节炎是一种严重而致人虚弱的慢性疾病，应该尽早诊断和治疗，”美国国立银屑病基金会（National Psoriasis Foundation）的主席兼首席执行官Randy Beranek先生说：“作为一个为银屑病关节炎患者呼吁的组织，针对这种疾病的新疗法。”
The US Food and Drug Administration (FDA) has approved tofacitinib (Xeljanz/Xeljanz XR, Pfizer) for treatment of adults with active psoriatic arthritis (PsA) who have failed to respond adequately or are intolerant to methotrexate or other disease-modifying antirheumatic drugs (DMARDs), according to a company news release.
Tofacitinib, a selective oral Janus kinase (JAK) inhibitor, interrupts signaling of several cytokines involved in immune response. It was first approved by the FDA in 2012 for adults with moderately to severely active rheumatoid arthritis (RA) who have not responded adequately to, or are intolerant of, methotrexate.
The FDA approval of tofacitinib for PsA was based on data from the phase 3 Oral Psoriatic Arthritis Trial (OPAL) clinical development program, which consisted of two studies, OPAL Broaden and OPAL Beyond, as well as an ongoing long-term extension trial, OPAL Balance.
The findings from OPAL Broaden and OPAL Beyond were published in October in the New England Journal of Medicine and were reported by Medscape Medical News at that time.
Both studies met their two primary efficacy endpoints, demonstrating statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire–Disability Index score at 3 months in patients receiving Xeljanz 5 mg twice daily in combination with a nonbiologic DMARD, compared to those receiving placebo.
In OPAL Broaden, 50% of patients taking tofacitinib 5 mg twice daily achieved an ACR20 response, compared to 33% of patients taking placebo (P ≤ .05), at 3 months. In OPAL Beyond, 50% of patients achieved an ACR20 response with tofacitinib 5 mg twice daily, compared to 24% of patients taking placebo (P ≤ .05), at 3 months.
In both studies, statistically significant improvements in ACR20 response were also seen with tofacitinib compared to placebo at 2 weeks, a secondary endpoint (OPAL Broaden: 22% and 6% [P = .0003], respectively; OPAL Beyond: 27% and 13% [P = .0046], respectively).
The safety profile of tofacitinib observed in patients with PsA was consistent with the safety profile observed in rheumatoid arthritis patients. The most common adverse events (>3% of patients) were nasopharyngitis, upper respiratory tract infection, headache, and diarrhea.
The tofacitinib label cautions that patients treated with the drug are at increased risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. If a serious infection develops, tofacitinib should be interrupted until the infection is controlled. Full prescribing information is available online.
"As a practicing rheumatologist, I've seen the significant physical impact psoriatic arthritis has on people living with the disease, and many patients are looking for additional therapeutic options," OPAL study investigator Philip Mease, MD, from the Swedish Medical Center, University of Washington, Seattle, said in the company release. "I'm pleased that Xeljanz is now available for use in the treatment of this chronic condition."
"Psoriatic arthritis is a serious and debilitating chronic illness that should be diagnosed and treated early," Randy Beranek, president and CEO, National Psoriasis Foundation, said in the release. "As an organization that advocates for people living with psoriatic arthritis, we welcome the availability of new therapies for treating this disease."
Xeljanz(Tofacitinib)
XELJANZ Rx
Generic Name and Formulations:
Tofacitinib 5mg; tabs.
Company:
Pfizer Inc.
Indications for XELJANZ:
Moderately-to-severely active rheumatoid arthritis (RA) in adults who have had an inadequate response or intolerance to methotrexate (MTX), as monotherapy or in combination with MTX or other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs). Active psoriatic arthritis in adults who have had an inadequate response or intolerance to MTX or other DMARDs, in combination with nonbiologic DMARDs.
Adult:
5mg twice daily. Switching from immediate-rel to XR tabs: start XR tabs the day following the last immediate-rel 5mg dose. Moderate-to-severe renal impairment or moderate hepatic impairment; concomitant potent CYP3A4 inhibitors, or drugs that result in both moderate CYP3A4 and potent CYP2C19 inhibition: 5mg once daily. Concomitant potent CYP3A4 inducers: not recommended. Dose adjustments: see full labeling.
Children:
Not established.
Warnings/Precautions:
Increased risk of serious or fatal infections (eg, TB, bacterial, viral, invasive fungal, or other opportunistic pathogens). Avoid in active, serious, or localized infections. Chronic, recurrent, or history of serious or opportunistic infections. Travel to, or residence in, areas with endemic TB or mycoses. Conditions that predispose to infection. Test/treat latent TB infection prior to and per applicable guidelines during therapy. Monitor closely if new infection, active TB (even if initial latent test is negative), reactivation of herpes virus or hepatitis occurs; interrupt treatment if serious or opportunistic infection, or sepsis develops. History of chronic lung disease or in those who develop interstitial lung disease. Known malignancy. History of GI perforations. Specifically XR tabs: pre-existing severe GI narrowing. Lymphopenia. Monitor lymphocytes at baseline, then every 3 months; neutrophils and hemoglobin at baseline, after 4–8 weeks, then every 3 months thereafter. Do not initiate therapy if lymphocytes <500cells/mm3, ANC <1000cells/mm3, or hemoglobin <9g/dL. Severe hepatic impairment: not recommended. Routinely monitor liver enzymes; interrupt therapy if drug-induced liver injury suspected. Monitor lipids 4–8 weeks following initiation. Perform periodic skin exam in those with skin cancer risk. Update immunization based on current guidelines prior to initiating therapy. Diabetes. Elderly. Pregnancy. Females of reproductive potential should use effective contraception during and for ≥4wks after last dose. Nursing mothers: not recommended.
Interactions:
Concomitant live vaccines, biologic DMARDs or potent immunosuppressants (eg, azathioprine, cyclosporine): not recommended. Potentiated by potent CYP3A4 inhibitors (eg, ketoconazole), or drugs that result in both moderate CYP3A4 and potent CYP2C19 (eg, fluconazole) inhibition. Antagonized by potent CYP3A4 inducers (eg, rifampin); see Adults.
See Also:
XELJANZ XR
Pharmacological Class:
Janus kinase (JAK) inhibitor.
Adverse Reactions:
Upper respiratory tract infections, headache, diarrhea, nasopharyngitis; serious or opportunistic infections, TB, malignancies (eg, lymphoma), cytopenias, liver enzyme or lipid elevations, non-melanoma skin cancer.
Metabolism:
Hepatic (CYP3A4, 2C19).
Elimination:
Renal.
Generic Availability:
NO
How Supplied:
Tabs—28, 60, 180; XR tabs—14, 30
XELJANZ XR(Tofacitinib)
XELJANZ XR Rx
Generic Name and Formulations:
Tofacitinib 11mg; ext-rel tabs.
Company:
Pfizer Inc.
Select therapeutic use: Arthritis/rheumatic disorders
Indications for XELJANZ XR:
Moderately-to-severely active rheumatoid arthritis (RA) in adults who have had an inadequate response or intolerance to methotrexate (MTX), as monotherapy or in combination with MTX or other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs). Active psoriatic arthritis in adults who have had an inadequate response or intolerance to MTX or other DMARDs, in combination with nonbiologic DMARDs.
Adult:
Swallow whole; do not crush, split, or chew. 11mg once daily. Concomitant potent CYP3A4 inducers: not recommended. Dose adjustments: see full labeling.
Children:
Not established.
Warnings/Precautions:
Increased risk of serious or fatal infections (eg, TB, bacterial, viral, invasive fungal, or other opportunistic pathogens). Avoid in active, serious, or localized infections. Chronic, recurrent, or history of serious or opportunistic infections. Travel to, or residence in, areas with endemic TB or mycoses. Conditions that predispose to infection. Test/treat latent TB infection prior to and per applicable guidelines during therapy. Monitor closely if new infection, active TB (even if initial latent test is negative), reactivation of herpes virus or hepatitis occurs; interrupt treatment if serious or opportunistic infection, or sepsis develops. History of chronic lung disease or in those who develop interstitial lung disease. Known malignancy. History of GI perforations. Specifically XR tabs: pre-existing severe GI narrowing. Lymphopenia. Monitor lymphocytes at baseline, then every 3 months; neutrophils and hemoglobin at baseline, after 4–8 weeks, then every 3 months thereafter. Do not initiate therapy if lymphocytes <500cells/mm3, ANC <1000cells/mm3, or hemoglobin <9g/dL. Severe hepatic impairment: not recommended. Routinely monitor liver enzymes; interrupt therapy if drug-induced liver injury suspected. Monitor lipids 4–8 weeks following initiation. Perform periodic skin exam in those with skin cancer risk. Update immunization based on current guidelines prior to initiating therapy. Diabetes. Elderly. Pregnancy. Females of reproductive potential should use effective contraception during and for ≥4wks after last dose. Nursing mothers: not recommended.
Interactions:
Concomitant live vaccines, biologic DMARDs or potent immunosuppressants (eg, azathioprine, cyclosporine): not recommended. Potentiated by potent CYP3A4 inhibitors (eg, ketoconazole), or drugs that result in both moderate CYP3A4 and potent CYP2C19 (eg, fluconazole) inhibition. Antagonized by potent CYP3A4 inducers (eg, rifampin); see Adults.
See Also:
XELJANZ
Pharmacological Class:
Janus kinase (JAK) inhibitor.
Adverse Reactions:
Upper respiratory tract infections, headache, diarrhea, nasopharyngitis; serious or opportunistic infections, TB, malignancies (eg, lymphoma), cytopenias, liver enzyme or lipid elevations, non-melanoma skin cancer.
Metabolism:
Hepatic (CYP3A4, 2C19).
Elimination:
Renal.
Generic Availability:
NO
How Supplied:
Tabs—28, 60, 180; XR tabs—14, 30
1):https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831
2):https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68e3d6b2-7838-4d2d-a417-09d919b43e13