Upadacitinib Meets All Endpoints in Phase 3 SELECT-EARLY Rheumatoid Arthritis Study

Daily upadacitinib monotherapy 15 mg/30 mg met both primary endpoints with 52%/56% of methotrexate patients achieving ACR50 at week 12 and 48%/50% achieving clinical remission at week 24.

Michael Severino, MD

AbbVie announces positive top-line results from the SELECT-EARLY phase 3 study showing that both 15 mg and 30 mg doses of upadacitinib monotherapy met the primary endpoints of ACR50 at week 12, and clinical remission at week 24 versus methotrexate in adult patients with moderate to severe rheumatoid arthritis, methotrexate-naïve.

Additionally, all secondary endpoints were also achieved.

“SELECT-EARLY is the fifth pivotal trial that will support regulatory submissions for upadacitinib in rheumatoid arthritis later this year,” Michael Severino, MD, executive vice president, research and development, chief scientific officer, AbbVie, said in a statement. “Results from the SELECT-EARLY further support our belief that upadacitinib has the potential to be an important new treatment option for patients with rheumatoid arthritis.”

In the first phase of the SELECT-EARLY phase 3 study, patients were randomized 1:1:1 to receive upadacitinib 15 mg or 30 mg daily, or methotrexate. Additionally, it includes a Japan sub-study in which subjects were randomized 2:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg daily or methotrexate.

Primary endpoints included the percentage of patients achieving ACR50 after 12 weeks of treatment, and clinical remission after 24 weeks of treatment versus methotrexate, while secondary endpoints included the proportion of patients achieving ACR20, ACR70 and low disease activity in addition to changes in the modified total Sharp score in the Health Assessment Questionnaire-Disability-Index (HAQ-DI). Both endpoints were met.

A significantly higher proportion of upadacitinib patients in both doses achieved superior responses versus those on methotrexate at weeks 12 and 24. Results at week 12 showed that among patients receiving a daily oral dose of upadacitinib 15/30 mg, 52%/56% achieved ACR50, respectively, compared with 28% receiving methotrexate.

At week 12, 76%/77% of patients receiving 15 mg/30 mg of upadacitinib achieved ACR20, respectively, compared to 54% in the methotrexate group. ACR70 was achieved by 32%/37% of patients receiving 15 mg /30 mg of upadacitinib, respectively, compared to 14% receiving methotrexate at week 12.

Clinical remission at week 12 was achieved by 36% and 41% of patients in the 15 mg and 30 mg groups, respectively, compared to 14% of patients receiving methotrexate at week 12, while at week 24, 48%/50% of patients receiving upadacitinib 15/30 mg, respectively, versus 18% of those receiving methotrexate.

Low disease activity based on Disease Activity 28 [DAS28] C-Reactive Protein (CRP) was achieved by 53% and 55% of patients in the 15 mg and 30 mg groups, respectively, compared to 28% of patients receiving methotrexate at week 12, and by 60% and 65% of patients in the 15 mg and 30 mg groups, respectively, versus 32% of patients receiving methotrexate at week 24.

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

Following 24 weeks of treatment, both doses of upadacitinib inhibited radiographic progression, measured by the change of total Sharp score from baseline.

The safety profile of upadacitinib was consistent with previously reported results from other SELECT rheumatoid arthritis trials, and no new safety signals were reported.

Through week 24, serious adverse effects occurred in 5%/6% of patients in the 15 mg/30 mg upadacitinib groups, respectively, versus 4% in the methotrexate group, while serious infections occurred in 2%/3% of those in the 15 mg/30 mg upadacitinib groups, respectively, versus 1% in the methotrexate group.

The 6 deaths that occurred through week 24 included 3 patients that experienced major adverse cardiovascular events (MACE), with 1 in each treatment group; 1 death in the 15 mg upadacitinib group due to unrelated metastatic malignant melanoma; and 2 deaths in the 30 mg upadacitinib group, 1 due to pneumonia and sepsis and another due to peritonitis.

Four MACE occurred—1 non-fatal MACE in the 30 mg upadacitinib group and the 3 fatal events mentioned above.

In the study, there were 2 cases of adjudicated venous thromboembolic events (VTEs), 1 pulmonary embolism in the methotrexate group and 1 deep vein thrombosis in the 30 mg upadacitinib group.

SELECT-EARLY is ongoing and includes a 48-week randomized, double-blind treatment period and is followed by a long-term extension period for up to an additional 4 years.

Across the entire SELECT program, the rates of VTEs in both the placebo-controlled and extension periods remain consistent with the background rate in this patient population.

In April, AbbVie announced positive results from the SELECT-COMPARE trial in which upadacitinib also met the primary endpoints of ACR20 and clinical remission versus placebo.

Upadacitinib is currently being tested in phase 3 trials of rheumatoid arthritis, psoriatic arthritis and Crohn’s disease, and is being investigated to treat ulcerative colitis, ankylosing spondylitis, atopic dermatitis and giant cell arteritis.

Currently, upadacitinib is not approved by regulatory authorities and its safety and efficacy have not yet been established.