Background Analysis: US FDA Advisory Committee to Review Eli Lilly’s Baricitinib for Rheumatoid Arthritis – APR 23, 2018 (AAC)

Announcement

The US FDA has scheduled an Arthritis Advisory Committee (AAC) meeting for Monday, April 23, 2018. The Committee will discuss new drug application (NDA) 207924 for baricitinib tablets, submitted by Eli Lilly and Company (Eli Lilly), for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. The discussion will include: efficacy, safety, including the risk of thromboembolic adverse events, dose selection, and overall risk benefit considerations. Note that, in 2009, Eli Lilly and Incyte Pharmaceuticals (Incyte) entered into a global license and collaboration agreement to develop baricitinib and follow-on compounds for inflammatory and autoimmune diseases.

Indication Background

Description of Indication

Rheumatoid arthritis (RA) is a chronic autoimmune condition, where the body’s immune system attacks its own tissue. RA is characterized by pain, joint swelling, stiffness, joint destruction and disability. In severe cases, it attacks internal organs. Over long periods of time, the inflammation associated with rheumatoid arthritis can cause bone erosion and joint deformity.

The prevalence of RA in the US is estimated at 1.29 million people, or 0.6% of the population. Onset is most frequent during middle age and women are affected 2.5 times as frequently as men.

RA is generally diagnosed through clinical symptoms, X-ray analysis, and blood tests, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), although a significant minority of patients with RA are seronegative, and test negative for RF and ACPA blood tests.

RA is often treated with a drug from the disease-modifying anti-rheumatic drug (DMARD) class. Small molecule DMARDs include hydroxychloroquine, leflunomide, methotrexate (MTX), and sulfasalazine. Biologic DMARDs include abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab.

Product Background

Description of Product

Baricitinib is an immunosuppressant. It is a selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2. JAKs are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in hematopoiesis, inflammation and immune function. The JAK enzymes play an important role in the process of inflammation and damage of the joints that occurs in rheumatoid arthritis. Baricitinib acts by blocking the enzymes to reduce the inflammation and other symptoms of the disease.

Clinical Trials of Proposed Indication

Eli Lilly said that the original NDA submission for RA contained the results of four phase 3 clinical trials, which met their primary endpoints. Approximately 3,100 patients were enrolled across the full spectrum of RA patients, from treatment-naive to highly-treatment refractory.

The clinical trials were:
RA-BEGIN (ClinicalTrials.gov Identifier: NCT01711359), was a randomized, double-blind, active-controlled study to evaluate the efficacy and safety of baricitinib in patients with moderately to severely active RA who had limited or no treatment with DMARDs. In this study, 584 patients were randomized 4:3:4 to MTX monotherapy, baricitinib 4 mg once daily, or baricitinib 4 mg once daily plus MTX for up to 52 weeks. The primary outcome evaluated non-inferiority of baricitinib 4 mg monotherapy compared with MTX monotherapy for ACR 20 (American College of Rheumatology 20, which measures a twenty percent improvement on a scale that includes usually 28 designated joints) response at week 24. The ACR 20 response rate at week 24 was higher in the baricitinib monotherapy group compared with MTX monotherapy (77% versus 62%, p < 0.01).

RA-BEAM (ClinicalTrials.gov Identifier: NCT01710358), was a randomized, double-blind, placebo- and active-controlled study evaluating baricitinib in patients with moderately to severely active RA who had an inadequate response to methotrexate. Patients were randomized 3:3:2 to placebo, baricitinib 4 mg once daily, or adalimumab 40 mg bi-weekly with background MTX. Nonresponders were rescued at week 16 and patients on placebo were switched to baricitinib 4 mg at week 24. An ACR 20 response was achieved at 12 weeks by 40% of patients in the placebo group, 61% in the adalimumab arm, and by 70% in the baricitinib group (p < 0.001 for comparisons versus placebo).

RA-BUILD (ClinicalTrials.gov Identifier: NCT01721057), was a randomized, double-blind, placebo-controlled study to evaluate baricitinib in patients with moderately to severely active RA who had an inadequate response to conventional DMARDs. In this trial, 684 RA patients were randomized 1:1:1 to placebo or baricitinib 2 mg or 4 mg once daily for 24 weeks. Placebo-treated patients were switched to active treatment at 16 weeks. Significantly higher ACR 20 response rates compared with placebo were observed in both baricitinib groups 40% versus 66% and 62% respectively (p < 0.001 for both).

RA-BEACON (ClinicalTrials.gov Identifier: NCT01721044), was a randomized, double-blind, placebo-controlled study evaluating baricitinib in patients with moderately to severely active RA who had an inadequate response to tumor necrosis factor (TNF) inhibitors. In RA-BEACON, 527 RA patients were randomized 1:1:1 to placebo or baricitinib 2 mg or 4 mg once daily, in addition to background non-biologic DMARDs for 24 weeks. Significantly higher ACR 20 response rates compared with placebo were observed in both baricitinib groups: 27% for placebo versus 49% and 55% for the baricitinib groups respectively (p < 0.001 for both).

Thromboembolic events, diagnosed as deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in five patients receiving baricitinib in two out of the seven completed phase 2 or phase 3 trials in RA. Eli Lilly said that, although an imbalance was observed during the placebo controlled period of the RA clinical trials, the rate of these events in the overall baricitinib clinical program was consistent with that seen among the general population of treated RA patients.

Regulatory Background

US Regulatory Background

Unknown 2018 – PDUFA date

Unknown 2017-2018 – Resubmission of NDA for baricitinib for treatment of moderate-to severe rheumatoid arthritis

April 14, 2017 – Eli Lilly and Incyte Pharmaceuticals announced the receipt of a complete response letter (CRL) from the FDA.

January 13, 2017 – FDA extended the review period for baricitinib

January 19, 2016 – Eli Lilly and Incyte announced the submission of an NDA for baricitinib for treatment of moderate-to-severe rheumatoid arthritis

Ex-US Regulatory Background

July 2017 – Baricitinib approved in Japan for the treatment of rheumatoid arthritis

June 2017 – Baricitinib approved in Switzerland and in Kuwait

February 13, 2017 – Baricitinib (Olumiant) granted market authorization by the European Commission, valid throughout the European Union

Baricitinib remains under review in other markets.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Eli Lilly and Company Drug Name: baricitinib Drug Class: janus kinase (JAK) inhibitor Indication: rheumatoid arthritis

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.