Pfizer Announces Positive Phase 3 Results for Xeljanz (Tofacitinib) in Juvenile Idiopathic Arthritis

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Recently, at the 2019 Annual Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARP) held in Atlanta, Pfizer announced the results of the pivotal Phase III clinical study A3921104 (NCT02592434) evaluating Xeljanz (tofacitinib) for the treatment of patients aged 2 to less than 18 years with juvenile idiopathic arthritis (JIA).

Data show that in patients with polyarticular course juvenile idiopathic arthritis (pcJIA), treatment with Xeljanz, compared with placebo, significantly reduced the incidence of disease flares, delayed the time to flare, improved disease signs/symptoms and physical function, and achieved sustained clinically meaningful improvements in disease activity. The safety profile was consistent with that observed in adult patients with rheumatoid arthritis (RA). Based on these study results, Pfizer plans to submit a new indication application to the U.S. FDA in 2020 for the use of Xeljanz in the treatment of pcJIA.

Study A3921104 is a randomized, double-blind, placebo-controlled withdrawal study comprising two parts. During the open-label lead-in period, all patients received 18 weeks of treatment with Xeljanz. At the end of the 18-week lead-in period, only patients who achieved at least JIA ACR30 response were randomized in a 1:1 ratio to enter a 26-week double-blind, placebo-controlled withdrawal phase, where they either continued receiving Xeljanz or discontinued Xeljanz and received placebo until the end of the study at Week 44. The study evaluated the efficacy and safety of Xeljanz administered as 5-mg tablets or 1-mg/mL oral solution twice daily (BID), with dosage adjusted according to patient body weight: <40 kg, 2–4 mg BID; ≥40 kg, 5 mg BID.

The primary endpoint was the incidence of disease flares over 44 weeks of treatment. The key secondary endpoints were the JIA ACR50/30/70 response rates at Week 44 and the change from the Phase II baseline in the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). In this study, a disease flare was defined as a worsening of ≥30% in at least three of the six variables comprising the Juvenile Idiopathic Arthritis (JIA) core set (the outcome assessment tool used in JIA clinical trials).

During the lead-in period, a total of 225 patients were enrolled and received treatment with Xeljanz, including those with polyarticular-course juvenile idiopathic arthritis (pcJIA, n=184), psoriatic arthritis (PsA, n=20), or enthesitis-related arthritis (ERA, n=21). At Week 18 of treatment, 173/225 (76.9%) patients entered Part 2 (pcJIA, n=142; PsA, n=15; ERA, n=16).

The data showed that the study met its primary endpoint: in patients with pcJIA, the incidence of disease flare in the Xeljanz treatment group was significantly lower than that in the placebo group by Week 44 in Part 2 of the study (29.2% vs. 52.9%; p=0.0041; Figure 1a). The JIA ACR50/30/70 response rates (Figure 1b) and the change from baseline in Part 2 for CHAQ-DI (Figure 1c) were all higher in the Xeljanz treatment group than in the placebo group, with specific data as follows: JIA ACR30 response rate (70.0% vs. 47.1%; p=0.0060), JIA ACR50 response rate (65.7% vs. 47.1%; p=0.0267), JIA ACR70 response rate (54.3% vs. 37.1%; p=0.0418), and CHAQ-DI (-0.09 vs. +0.03; p=0.0292).

In Part 2, the time to disease flare (defined as an increase in disease activity during the course of the disease) was delayed in the Xeljanz treatment group compared with the placebo group (p=0.0037; Figure 1d). At Week 44, assessed by the change from the baseline of Part 1 in JIA ACR core set variables, Xeljanz demonstrated greater efficacy than placebo in reducing signs and symptoms of pcJIA (Figure 1e). From early time points in Part 2 onward, disease activity (assessed using JADAS27-CRP) worsened in the placebo group, whereas it remained stable in the Xeljanz treatment group (Figure 1f).

In the study, the safety profile of Xeljanz-treated patients was similar to that of placebo-treated patients (Table 2), with adverse event rates of 77.3% and 74.1%, respectively, and serious adverse event rates of 1.1% and 2.4%, respectively. The most common adverse events were upper respiratory tract infection, headache, nasopharyngitis, nausea, fever, disease exacerbation, vomiting, and JIA. No deaths, major adverse cardiovascular events (MACE), malignancies, thrombosis, opportunistic infections, or tuberculosis cases occurred. During the entire study period, two cases of herpes zoster and four cases of serious infection occurred in the Xeljanz treatment group.

Xeljanz is an oral JAK inhibitor that selectively inhibits JAK kinases and blocks the JAK/STAT pathway, a cytokine-stimulated signal transduction pathway identified in recent years that participates in many important biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation.

In the United States, Xeljanz was approved in 2012, becoming the first JAK inhibitor to reach the market. The drug has been approved for three indications: treatment of adult patients with moderately to severely active rheumatoid arthritis (RA); treatment of adult patients with active psoriatic arthritis; and treatment of adult patients with moderately to severely active ulcerative colitis. Currently, Pfizer is advancing an extensive clinical program to evaluate Xeljanz for the treatment of various immune-mediated inflammatory diseases.

Clarivate: Competitive Landscape of JAK Inhibitors

Currently, Xeljanz is the leader in the JAK inhibitor field. According to Pfizer’s performance report released in late October, Xeljanz generated $1.634 billion in sales during the first nine months of this year, representing a 34% increase compared to the same period in 2018. Sales grew by 25% in the U.S. market and by 69% in international markets.

However, safety concerns surrounding the high-dose (10 mg) formulation of Xeljanz have persisted. In particular, during the first half of this year, both the U.S. FDA and the European EMA issued safety warnings and restrictions on 10 mg Xeljanz due to pulmonary embolism and an imbalance in mortality rates, which will undoubtedly adversely affect the commercial prospects of Xeljanz. On the other hand, Eli Lilly’s Olumiant, AbbVie’s Rinvoq, and Gilead’s filgotinib, which is expected to be launched, will all exert greater competitive pressure on Xeljanz. Notably, Rinvoq and filgotinib have demonstrated a favorable safety profile in clinical studies.

Reference Source:

1、PFIZER ANNOUNCES RESULTS OF PHASE 3 STUDY FOR XELJANZ® (TOFACITINIB) IN JUVENILE IDIOPATHIC ARTHRITIS AHEAD OF PRESENTATION AT 2019 AMERICAN COLLEGE OF RHEUMATOLOGY/ASSOCIATION OF RHEUMATOLOGY PROFESSIONALS ANNUAL MEETING

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