GlaxoSmithKline (GSK) has launched a Phase III program for the rheumatoid arthritis candidate it is developing under license from MorphoSys—triggering a milestone payment to MorphoSys of €22 million ($24.9 million), the companies said.

Otilimab, an anti-granulocyte macrophage colony-stimulating factor (anti GM-CSF) monoclonal antibody, is indicated for patients with moderate to severe rheumatoid arthritis who have had an inadequate response to disease-modifying antirheumatic drugs (DMARD) or targeted therapies.

GSK agreed to oversee development and commercialization of otilimab when it licensed rights to the drug in 2013 from MorphoSys for up to €445.5 million (up to $503 million), of which €22.5 million ($25.4 million) was paid upfront.

The safety and efficacy of two doses of otilimab—90 mg and 150 mg subcutaneous weekly injection—will be evaluated in the ContRAst Phase III program, consisting of three pivotal trials comparing the drug to two marketed arthritis therapies, and an extension study, GSK said.

The first pivotal trial, contRAst-1 (201790), is designed to compare otilimab with placebo and Pfizer’s Xeljanz® (tofacitinib), all in combination with methotrexate (MTX), over 52 weeks in approximately 1500–1700 patients with moderately to severely active RA who have an inadequate response to MTX (NCT03980483).

The second pivotal study, contRAst-2 (201791), is intended to compare otilimab with placebo and with Xeljanz 5 mg capsules twice daily, all in combination with conventional synthetic DMARDs, over 52-weeks in approximately 1500–1800 patients with moderately to severely active RA who have an inadequate response to conventional synthetic DMARDs or biologic DMARDs (NCT03970837).

JAK inhibitor challenges

Xeljanz is a JAK inhibitor approved for indications in rheumatoid arthritis as well as psoriatic arthritis and ulcerative colitis. On February 29, the FDA warned the public of increased risk of blood clots in the lungs and death in rheumatoid arthritis patients dosed in an ongoing safety trial with a 10 mg twice daily dose of Xeljanz approved in the dosing regimen for patients with ulcerative colitis. The trial—required as a condition of Xeljanz’ approval—is expected to be completed by year’s end, the FDA said at the time.

Another JAK inhibitor for arthritis faced a challenging approval process last year: Eli Lilly won FDA approval only for its 2 mg dose of Olumiant® (baricitinib), co-developed with Incyte, in adults with moderate-to-severe rheumatoid arthritis, and not the 4 mg dose, following safety concerns.

However, Gilead Sciences said Monday it will file an NDA for the selective JAK1 inhibitor filgotinib as a treatment for rheumatoid arthritis later this year. The FDA is now priority-reviewing another selective JAK1 inhibitor for moderate-to-severe rheumatoid arthritis, AbbVie’s upadacitinib (ABT-494), for which the company expects a decision in the third quarter.

The third pivotal trial in the ContRAst Phase III program, contRAst-3 (202018), is designed to evaluate otilimab with placebo and with the Sanofi Genzyme/Regeneron Pharmaceuticals co-marketed Kevzara® (sarilumab), all in combination with conventional synthetic DMARDs, over 24-weeks in approximately 500–600 patients with moderately to severely active RA who have an inadequate response to biological DMARDs and/or JAK inhibitors.

Kevzara is an interleukin-6 (IL-6) receptor antagonist indicated for adults with moderately-to-severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more DMARDs.

“The unique Phase III studies, designed in consultation with regulators, will help us understand how this potential new medicine could benefit appropriate patients living with rheumatoid arthritis,” Hal Barron, MD, GSK’s CSO and president, R&D, said in a statement.

The long-term extension study will further assess the efficacy and safety of otilimab for up to four years in eligible patients who complete the pivotal studies, according to GSK.

Mixed Phase II results

Otilimab—formerly called GSK3196165, and originally known as MOR103—advances to Phase III nine months after generating mixed results in the Phase II BAROQUE study (Bringing Anti-GM-CSF to Rheumatoid Arthritis: A New Approach to Overcoming an InadeQUate ResponsE to MTX).

GSK trumpeted what it termed encouraging results from BAROQUE (NCT02504671) in October 2018 during a presentation at the American College of Rheumatology (abstract 1938). The pharma giant said otilimab surpassed placebo in the proportion of patients who achieved efficacy (16% to 3%) in the study’s primary endpoint of disease activity score with C-reactive protein (CRP) [DAS28(CRP)<2.6] at Week 24. However, GSK acknowledged at the time that “this did not reach statistical significance.”

Otilimab fared better in other endpoints that included DAS28(CRP) change from baseline, with GSK saying it saw “a rapid onset of efficacy, as early as Week 1” for all doses of the drug candidate above 22.5 mg, reaching statistical significance at Week 12.

GSK also cited positive results in “major” secondary endpoints that included a “particularly marked” improvement in patient-based measures (swollen and tender joint counts, pain and clinical disease activity index [CDAI]).

“The rapid onset and marked benefit on clinically meaningful endpoints such as pain and swollen tender joint counts, represents a potentially important advance for patients with rheumatoid arthritis who are in need of new treatment options,” Barron stated at the time.

BAROQUE was a dose-ranging study designed to compare the efficacy of five doses of otilimab (22.5 mg, 45 mg, 90 mg, 135 mg, or 180 mg) with placebo, in combination with MTX, in 222 patients with active moderate-to-severe RA despite prior treatment with MTX.

The study’s secondary endpoints included the DAS28(CRP) score, ACR response criteria (ACR20/50/70), EULAR response, global disease assessment, HAQ-DI score, simple disease activity index (SDAI), CDAI and functional assessment of chronic illness therapy (FACIT)-fatigue score.

MorphoSys said separately it will raise its 2019 investor guidance as a result of the milestone payment from GSK. MorphoSys increased its range of projected revenues to between €65 million and €72 million ($73 million to $81 million), up from its earlier forecast of between €43 million and €50 million ($48.5 million and $56 million).

MorphoSys also raised its guidance range for earnings before interest and taxes (EBIT) to between €105 million and €115 million ($118.5 million and about $130 million), from its previous range of between €127 million to €E137 million ($143 million to about $155 million).

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