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AbbVie’s upadacitinib succeeds in phase 3 trial in rheumatoid arthritis

Published 07 June 2018

AbbVie said that the phase 3 SELECT-EARLY trial evaluating two doses of upadacitinib (15 mg and 30 mg) as monotherapy in the treatment of rheumatoid arthritis met the primary endpoints of ACR50a at week 12 and clinical remissionb at week 24 versus methotrexate (MTX).

Additionally, all ranked secondary endpoints were met.

The ongoing study evaluates upadacitinib, an investigational oral JAK1-selective inhibitor, as a monotherapy treatment compared to methotrexate monotherapy in adult patients with moderate to severe rheumatoid arthritis who were methotrexate-naïve.

Upadacitinib is not approved by regulatory authorities and its safety and efficacy have not been established.

AbbVie research and development executive vice president and chief scientific officer Michael Severino said: "SELECT-EARLY is the fifth pivotal trial that will support regulatory submissions for upadacitinib in rheumatoid arthritis later this year.

"Results from SELECT-EARLY further support our belief that upadacitinib has the potential to be an important new treatment option for patients with rheumatoid arthritis."

Rheumatoid arthritis, which affects an estimated 23.7 million people worldwide, is a chronic and debilitating disease.

Methotrexate is commonly used as a first-line therapy in rheumatoid arthritis, but many patients do not respond to or cannot tolerate methotrexate.18-20 Early intervention with an effective treatment is critical to control the disease and prevent permanent joint damage and impaired physical function.

Amsterdam Rheumatology and Immunology Center ARC director Ronald van Vollenhoven said: "It is very encouraging that approximately half of patients achieved the desired clinical target of remission in six months with upadacitinib monotherapy at either dose. Outcomes from this trial address the need for additional monotherapy options early in the disease.

"Results suggest upadacitinib as a monotherapy has the potential to control rheumatoid arthritis and reduce the risk of permanent bone and joint damage for methotrexate-naïve patients."

A significantly higher proportion of upadacitinib patients in both doses achieved superior responses compared to patients on methotrexate at week 12 and 24.

Results at week 12 showed that of patients receiving an oral once-daily dose of upadacitinib 15/30 mg, 52/56 percent achieved ACR50, respectively, compared with 28 percent of patients receiving methotrexate.

At week 24, clinical remission (based on Disease Activity 28 [DAS28] C-Reactive Protein [CRP]) was achieved by 48/50 percent of patients receiving upadacitinib 15/30 mg, respectively, compared to 18 percent of patients receiving methotrexate.

At week 12, 76/77 percent of patients receiving 15/30 mg of upadacitinib, achieved ACR20, respectively, compared to 54 percent in the methotrexate group.

Additionally, ACR70 was achieved by 32/37 percent of patients receiving 15/30 mg of upadacitinib, respectively, compared to 14 percent receiving methotrexate at week 12.

Clinical remission was achieved by 36 percent and 41 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 14 percent of patients receiving methotrexate at week 12.

Low disease activity (LDA)c based on DAS28(CRP) was achieved by 53 percent and 55 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 28 percent of patients receiving methotrexate at week 12.

At week 24, 79/60/44 percent of patients receiving the 15 mg dose of upadacitinib and 78/66/50 percent of patients receiving the 30 mg dose of upadacitinib achieved ACR20/50/70 response, compared to 59/33/18 percent of patients receiving methotrexate.

Low disease activity was achieved by 60 percent and 65 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 32 percent of patients receiving methotrexate at week 24.

Following 24 weeks of treatment, both doses of upadacitinib monotherapy significantly inhibited radiographic progression as measured by the change in modified total Sharp score (mTSS) from baseline, compared to methotrexate.

The inhibition of joint damage is important for rheumatoid arthritis patients as this can lead to permanent loss of function and subsequent disability.

In this study, the safety profile of upadacitinib was consistent with previously reported results from the other SELECT trials in rheumatoid arthritis.1-8 No new safety signals were detected.

Through week 24, serious adverse events occurred in 5/6 percent of patients in the 15 mg/30 mg upadacitinib groups, respectively, compared to 4 percent in the methotrexate group.1 Serious infections occurred in 2/3 percent of patients in the 15 mg/30 mg upadacitinib groups, respectively, compared to 1 percent in the methotrexate group.1 There were six deaths through week 24, three of which were major adverse cardiovascular events (MACE) with one in each treatment group (methotrexate, 15 mg upadacitinib and 30 mg upadacitinib, respectively).

There was one death in the 15 mg upadacitinib group due to metastatic malignant melanoma in a patient with a history of melanoma prior to study entry, and two deaths in the 30 mg upadacitinib group, one due to pneumonia and sepsis and another due to peritonitis.

There were four MACE, including the three fatal events mentioned above. One additional non-fatal MACE in the 30 mg upadacitinib group was reported.

There were two cases of adjudicated venous thromboembolic events (VTE) in the study, one pulmonary embolism in the methotrexate group, one deep vein thrombosis in the 30 mg upadacitinib group and none in the 15 mg upadacitinib group.

To date, across the SELECT rheumatoid arthritis program (with more than 3,300 patient years of exposure to upadacitinib) the rates of VTEs in both the placebo-controlled and extension periods remain consistent with the background rate in the rheumatoid arthritis patient population.

Further results from SELECT-EARLY will be presented at a future medical meeting and published in a peer-reviewed publication.

AbbVie plans global regulatory submissions for upadacitinib in rheumatoid arthritis in the second half of 2018.

Source: Company Press Release.