2017-12-21艾伯维（AbbVie）近日公布了抗炎新药upadacitinib（ABT-494）作为单药疗法治疗类风湿性关节炎（RA）成人患者的一项关键III期临床研究SELECT-MONOTHERAPY（NCT02706951）的积极顶线数据。数据显示，该研究达到了全部主要终点和次要终点。

SELECT-MONOTHERAPY是一项多中心、随机、双盲、平行组研究，在接受稳定剂量甲氨喋呤（MTX）治疗缓解不足的中度至重度RA成人患者中开展，旨在评估upadacitinib单药治疗的疗效和安全性。研究中，患者以双盲方式随机分配至由甲氨蝶呤转向upadacitinib（15mg/天，30mg/天）或继续接受之前稳定剂量的甲氨蝶呤。第一阶段的主要终点是治疗14周后实现ACR20缓解和低疾病活动度（LDA）的患者比例，次要终点包括在治疗第14周时实现ACR50、ACR70和临床缓解的患者比例。目前该研究正在进行中，第二阶段是一个双盲长期扩展期，旨在评估upadacitinib（15mg/天，30mg/天）单药疗法在已完成第一阶段治疗的患者中的长期安全性、耐受性和疗效。

此次公布的数据显示，治疗14周后，与继续接受之前稳定剂量甲氨蝶呤治疗组相比，2种剂量upadacitinib（15mg/天，30mg/天）单药治疗组均达到了ACR20和LDA的主要终点，同时也达到了全部的关键次要终点。在治疗第14周，upadacitinib 15mg剂量组、30mg剂量组实现ACR20/50/70的患者比例分别为68%/42%/23%和71%/52%/33%，继续接受甲氨蝶呤的治疗组实现ACR20/50/70的患者比例为41%/15%/3%，这些结果均具有统计学显著差异（均p＜0.001）。此外，在治疗第14周，与继续接受甲氨蝶呤的治疗组相比，2种剂量upadacitinib治疗组有显著更高比例的患者达到LDA和临床缓解目标（p＜0.001）。具体而言，upadacitinib 15mg剂量组和30mg剂量组实现LDA的患者比例分别为45%和53%，实现临床缓解的患者比例分别为28%和41%，继续接受甲氨蝶呤的治疗组实现LDA和临床缓解的患者比例分别为19%和8%。

该研究中，upadacitinib的安全性与之前报道的III期SELECT研究和II期研究中一致，没有观察到新的安全信号。严重不良事件发生率，upadacitinib 15mg剂量组、30mg剂量组、甲氨蝶呤治疗组分别为5%、3%、3%。值得注意的是，该研究中15mg剂量upadacitinib治疗组发生了1例因破裂性动脉瘤导致的出血性脑卒中死亡事件，该患者之前已存在心血管风险因素，同时还有1例患者发生了肺栓塞（PE），该患者之前已存在PE风险因素。横跨整个SELECT RA项目，包括安慰剂对照期和扩展期，深静脉血栓和PE发生率仍然和RA患者群体中的背景发生率一致。

艾伯维研发执行副总裁兼首席科学官Michael Severino表示，来自SELECT-MONOTHERAPY的积极数据是支持upadacitinib作为RA疗法且无需联合背景甲氨蝶呤治疗的首个证据，同时也进一步充实了upadacitinib为RA群体提供一个有意义的治疗选择的数据集。

该研究的研究员、维也纳医科大学风湿科医师Josef S. Smolen表示，这项临床研究解决了对甲氨蝶呤缓解不足的RA患者由甲氨蝶呤转向upadacitinib单药治疗的临床影响。结果表明，2种剂量upadacitinib均能提供临床意义的缓解。这些研究结果支持了upadacitinib单药疗法作为一种治疗选择用于RA群体的潜力。

RA是一种慢性和致衰性疾病，影响全球约2370万人。甲氨蝶呤是常用于RA临床治疗的一线药物，但许多患者对该药无应答或不耐受，使得这些患者身处疾病进展的风险之中。upadacitinib是一种实验性口服选择性JAK1抑制剂，JAK1是一种激酶，在多种炎症性疾病的病理生理过程中发挥了关键作用，包括RA、克罗恩病（CD）、溃疡性结肠炎（UC）、银屑病关节炎（PsA）等。目前，艾伯维也在评估upadacitinib治疗其他免疫疾病的潜力，包括PsA、UC和AS及特应性皮炎。

3个关键研究2个曝出死亡病例：upadacitinib疗效惊艳，然前景不同乐观

今年6月，艾伯维公布了upadacitinib治疗RA的首个关键性III期临床SELECT-NEXT研究的结果。该研究在接受稳定剂量常规合成疾病修饰抗风湿疗法（csDMARDs）但病情缓解不足的中度至重度RA成人患者中开展。研究也达到了全部主要终点和次要终点。安全性方面，无一例患者死亡。基于该研究的惊艳数据，华尔街著名投资银行Jefferies分析师预测，如果upadacitinib所有临床适应症均开发成功，其销售峰值将突破35亿美元。而鉴于礼来/Incyte开发的另一款JAK抑制剂Olumiant已被FDA拒绝，因此35亿美元对于upadacitinib而言很可能低估。

然而今年9月，艾伯维公布了第二个关键III期临床SELECT-BEYOND的结果，该研究在接受生物类疾病修饰抗风湿疗法（bDMARDs）治疗缓解不足或不耐受的中度至重度RA成人患者中开展。尽管该研究也达到了全部主要终点和次要终点，但安全性方面，发生2例患者死亡，其中1例来自15mg剂量组，死亡原因不明，另一例来自30mg剂量组，该例患者出现发烧和腹泻，随后在住院期间发生心脏衰竭和肺栓塞（PE）死亡，包括该例PE在内，该研究中共发生2例PE。

SELECT RA临床项目总共包括6个III期研究，此次公布的SELECT-MONOTHERAPY是其中的第3个研究，也是第二个爆出死亡病例的研究。尽管在声明中艾伯维将患者死亡归因于既往风险因素。然而连续2次死亡事件，无疑使upadacitinib的惊艳疗效打了折扣，同时也为该药的未来前景增添了一抹黯淡之色。目前，业界正在翘首期待SELECT临床项目剩下的3个关键III期研究的数据，upadacitinib能否摆脱死亡阴云，让我们静等观望.

Company: AbbVie Inc.
Date of Approval: August 16, 2019
Treatment for: Rheumatoid Arthritis

Rinvoq (upadacitinib) is a Janus kinase (JAK) inhibitor for the treatment of adult patients with moderate to severe rheumatoid arthritis.

FDA Approves Rinvoq (upadacitinib), an Oral JAK Inhibitor for the Treatment of Moderate to Severe Rheumatoid Arthritis

NORTH CHICAGO, Ill., Aug. 16, 2019 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved Rinvoq (upadacitinib), a 15 mg, once-daily oral Janus kinase (JAK) inhibitor, for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX-IR).1 Rinvoq is expected to be available in the U.S. in late August 2019.

The FDA approval of Rinvoq is supported by data from the SELECT program, one of the largest registrational Phase 3 programs in RA with approximately 4,400 patients evaluated across all treatment arms in five studies.2-6 The studies include assessments of efficacy, safety and tolerability across a variety of RA patients, including those who failed or were intolerant to biologic disease-modifying anti-rheumatic drugs and who were naïve or inadequate responders to methotrexate. Rinvoq is not indicated for methotrexate-naïve patients.

"Despite the availability of multiple treatment options with varying mechanisms of action, many patients still do not achieve clinical remission or low disease activity—the primary treatment goals for rheumatoid arthritis," said Roy M. Fleischmann, M.D., primary investigator for SELECT-COMPARE and clinical professor at the University of Texas Southwestern Medical Center at Dallas. "With this FDA approval, Rinvoq has the potential to help additional people living with RA achieve remission who have not yet reached this goal."

Across the SELECT Phase 3 studies, Rinvoq met all primary and ranked secondary endpoints. The primary endpoints include:

· In SELECT-EARLY, 52 percent of MTX-naïve patients treated with Rinvoq 15 mg achieved ACR50 vs 28 percent treated with MTX at week 121

· In SELECT-MONOTHERAPY, 68 percent of MTX-IR patients treated with Rinvoq 15 mg achieved ACR20 vs 41 percent treated with continued MTX at week 141

· In SELECT-COMPARE, 71 percent of MTX-IR patients treated with Rinvoq 15 mg plus MTX achieved ACR20 vs 36 percent treated with placebo plus MTX at week 121

· In SELECT-NEXT, 64 percent of csDMARD-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 36 percent treated with placebo plus csDMARDs at week 121

· In SELECT-BEYOND, 65 percent of biologic-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 28 percent treated with placebo plus csDMARDs at week 121

"The discovery and development of Rinvoq is indicative of AbbVie's long-standing commitment to advancing the science for people living with immune-mediated conditions," said Michael Severino, M.D., vice chairman and president, AbbVie. "Today's FDA approval marks an important milestone in our pursuit to deliver innovative medicines that advance care for people living with rheumatoid arthritis."

Clinical Remission
Patients taking Rinvoq achieved clinical remission, a state characterized by almost no disease activity and symptoms, even without methotrexate.2-3,6 Approximately 30 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 in SELECT-COMPARE and week 14 in SELECT-MONOTHERAPY compared to six percent with placebo plus methotrexate and eight percent with methotrexate, respectively.1 In SELECT-EARLY, 36 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 compared to 14 percent with methotrexate.1 

Durable remission rates were observed up to week 26. Forty-eight percent of patients treated with Rinvoq alone in SELECT-EARLY and 41 percent of patients treated with Rinvoq plus methotrexate in SELECT-COMPARE achieved clinical remission at weeks 24 and 26, compared to nine percent with placebo plus methotrexate and 18 percent with methotrexate, respectively.1 Analysis at weeks 24 and 26 were not controlled for multiple comparisons.3,10

Radiographic Inhibition
Rinvoq significantly inhibited radiographic progression as measured by the change in modified total Sharp score (mTSS) from baseline compared to methotrexate in SELECT-EARLY (0.14 vs 0.67) and Rinvoq plus methotrexate compared to placebo plus methotrexate in SELECT-COMPARE (0.15 vs 0.78) through weeks 24 and 26, respectively.1 

Safety
The most common side effects associated with Rinvoq include upper respiratory tract infections (common cold, sinus infections), nausea, cough and pyrexia.1 Patients treated with Rinvoq are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.1 Lymphoma and other malignancies have been observed in Rinvoq-treated patients.1 Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions.1 Patients treated with RINVOQ also may be at risk for other serious adverse reactions, including gastrointestinal perforations, neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations, and embryo-fetal toxicity.1 

Ease of Use and Access
Designed to help accommodate the physical limitations of people living with RA, the packaging for Rinvoq includes a bottle cap with a wide, easy-to-grip texture and an embedded tool that punctures the foil liner to simplify medication access. This packaging design was awarded the Arthritis Foundation Ease of Use Commendation.

"Rheumatoid arthritis can have a debilitating impact on the lives of those with the chronic disease, including making it difficult to perform everyday tasks," said Cindy McDaniel, senior vice president, consumer health, Arthritis Foundation. "The Arthritis Foundation is committed to recognizing innovation that can help patients living with rheumatoid arthritis and we are proud to recognize AbbVie with our Ease of Use Commendation for the packaging design of Rinvoq."

AbbVie continues to work closely with key stakeholders to support patient access to Rinvoq, including offering a patient support program and a co-pay card that may reduce out-of-pocket costs to $5 per month for eligible, commercially-insured patients. For those with limited or no health insurance, AbbVie offers myAbbVie Assist, a patient assistance program that provides Rinvoq to qualifying patients.

About Rheumatoid Arthritis

Affecting 1.3 million Americans, rheumatoid arthritis is a complex, systemic autoimmune disease that occurs when the immune system mistakenly attacks joints, creating inflammation that causes the tissue inside of joints to thicken, damaging the bones and associated connective tissue.11-12 Pain, fatigue and stiffness are among the signs and symptoms of RA that can have an impact on daily living.13 If not properly treated, RA can lead to permanent, debilitating bone and cartilage damage.

About Rinvoq

Rinvoq is an oral, small molecule JAK inhibitor being studied for moderately to severely active rheumatoid arthritis and other immune-mediated diseases. Rinvoq is under review by the European Medicines Agency (EMA), as well as regulatory authorities in Canada and Japan, for the treatment of adult patients with moderately to severely active RA.

Use and Important Safety Information
Rinvoq is a prescription medicine used to treat adults with moderate to severe rheumatoid arthritis in whom methotrexate did not work well or could not be tolerated. It is not known if Rinvoq is safe and effective in children under 18 years of age.

What is the most important information I should know about Rinvoq?
Rinvoq is a medicine that can lower the ability of your immune system to fight infections. You should not start taking Rinvoq if you have any kind of infection unless your healthcare provider (HCP) tells you it is okay.

· Serious infections have happened in some people taking Rinvoq, including tuberculosis (TB) and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your HCP should test you for TB before starting Rinvoq and check you closely for signs and symptoms of TB during treatment with Rinvoq. You may be at higher risk of developing shingles (herpes zoster).

· Lymphoma and other cancers, including skin cancers, can happen in people taking Rinvoq.

· Blood clots in the veins of the legs or lungs and arteries are possible in some people taking Rinvoq. This may be life-threatening and cause death.

· Tears in the stomach or intestines and changes in certain laboratory tests can happen. Your HCP should do blood tests before you start taking Rinvoq and while you take it. Your HCP may stop your Rinvoq treatment for a period of time if needed because of changes in these blood test results.

What should I tell my HCP BEFORE starting Rinvoq?
Tell your HCP if you:

· Are being treated for an infection, have an infection that won't go away or keeps coming back, or have symptoms of an infection such as:

o Fever, sweating, or chills

o Shortness of breath

o Warm, red, or painful skin or sores on your body

o Muscle aches

o Feeling tired

o  Blood in phlegm

o Diarrhea or stomach pain

o Cough

o Weight loss

o Burning when urinating or urinating more often than normal

· Have TB or have been in close contact with someone with TB.

· Have had any type of cancer, hepatitis B or C, shingles (herpes zoster), or blood clots in the veins of your legs or lungs, diverticulitis (inflammation in parts of the large intestine), or ulcers in your stomach or intestines.

· Have other medical conditions including liver problems, low blood cell counts, diabetes, chronic lung disease, HIV, or a weak immune system.

· Live, have lived, or have traveled to parts of the country that increase your risk of getting certain kinds of fungal infections, such as the Ohio and Mississippi River valleys and the Southwest. If you are unsure if you've been to these areas, ask your HCP.

· Have recently received or are scheduled to receive a vaccine. People who take Rinvoq should not receive live vaccines.

· Are pregnant or plan to become pregnant. Based on animal studies, Rinvoq may harm your unborn baby. Your HCP will check whether or not you are pregnant before you start Rinvoq. You should use effective birth control (contraception) to avoid becoming pregnant while taking Rinvoq and for at least 4 weeks after your last dose.

· Are breastfeeding or plan to breastfeed. Rinvoq may pass into your breast milk. You should not breastfeed while taking Rinvoq and for at least 6 days after your last dose.

·  

Tell your HCP about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Rinvoq and other medicines may affect each other, causing side effects.

Especially tell your HCP if you take:

· Medicines for fungal or bacterial infections

· Rifampicin or phenytoin

· Medicines that affect your immune system

Ask your HCP or pharmacist if you are not sure if you are taking any of these medicines.

What should I tell my HCP AFTER starting Rinvoq?
Tell your HCP right away if you:

· Have any symptoms of an infection. Rinvoq can make you more likely to get infections or make any infections you have worse.

· Have any signs or symptoms of blood clots during treatment with Rinvoq, including:

o Swelling

o Pain or tenderness in the leg

o Sudden unexplained chest pain

o Shortness of breath

o Have a fever or stomach-area pain that does not go away, and a change in your bowel habits.

What are the common side effects of Rinvoq?
These include: upper respiratory tract infections (common cold, sinus infections), nausea, cough, and fever. These are not all the possible side effects of Rinvoq.

Rinvoq is taken once a day with or without food. Do not split, break, crush, or chew the tablet. Take Rinvoq exactly as your HCP tells you to use it.

This is the most important information to know about Rinvoq. For more information, talk to your HCP.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you are having difficulty paying for your medicine, AbbVie may be able to help. Visit AbbVie.com/myAbbVieAssist to learn more.

SOURCE AbbVie

Posted: August 2019