Biomedtracker: 開発中医薬品をFDA承認確率で評価, ターゲット市場の実像をつかむ
The Pharma Intelligence analyst team will be covering the 2021 ASCO virtual meeting from June 4-8, 2021.
Pfizer’s Xeljanz (tofacitinib) is set to lead the Janus kinase (JAK) inhibitors to market in psoriatic arthritis (PsA) following positive Phase III data, particularly in joint inflammation; however, it will face several challenges upon launch. With less impressive skin findings, Datamonitor Healthcare believes Xeljanz will be a suitable treatment option for patients with heavy joint involvement and minimal skin disease, or for patients who are not concerned about their skin symptoms.
Pfizer unveiled Phase III data from the OPAL Beyond (ClinicalTrials.gov identifier: NCT01882439) and OPAL Broaden (ClinicalTrials.gov identifier: NCT01877668) trials in PsA at the European League Against Rheumatism (EULAR) congress, which took place in Madrid, Spain, on 14–17 June 2017. Pfizer filed the lower dose tested in the studies (5mg twice daily) with the US Food and Drug Administration (FDA) in May 2017, and approval is likely to be granted in Q1 2018. Xeljanz is already marketed in rheumatoid arthritis (RA), following FDA approval in 2012 and European Medicines Agency approval in 2017. Pfizer is also investigating the JAK inhibitor in other autoimmune indications, including ulcerative colitis and atopic dermatitis.
In the OPAL Beyond trial, 5mg and 10mg twice-daily doses of Xeljanz were tested against placebo in PsA patients who were inadequate responders to at least one anti-tumor necrosis factor (TNF) biologic either due to lack of efficacy or an adverse event. Xeljanz met the primary endpoint of ACR20, with response rates of 50% and 47% observed in the 5mg and 10mg treatment groups, respectively, compared to 24% in the placebo arm. Significant improvements as measured by ACR20 and the Health Assessment Questionnaire Disability Index (HAQ-DI) score were observed as early as week two. In addition, improvements in other PsA domains, including dactylitis and enthesitis, were also observed in the trial, and were significant after three months of treatment with both doses. Xeljanz’s efficacy in the management of skin symptoms was less impressive, with the PASI 75 response rate in the 5mg group not meeting statistical significance after three months of treatment.
In the OPAL Broaden trial, 5mg and 10mg twice-daily doses of Xeljanz were tested in patients who were naïve to TNF inhibition. The study included Humira (adalimumab; AbbVie/Eisai) as a comparable control. At month three, Xeljanz 5mg and 10mg showed statistically significant improvements compared to placebo as measured by the primary endpoint of ACR20. ACR20 responses were reached by 50% of patients on the 5mg dose and by 61% of patients on the 10mg dose vs 52% in the Humira arm and 33% in the placebo arm. Response rates achieved statistical significance as early as week two, and were maintained to 12 months. Improvements in dactylitis and enthesitis were observed, but were not significant after three months for the 5mg dose. Philip J Mease, the lead author of the study, presented the non-responder imputation (NRI) analysis for PASI 75 scores, which classifies missing values as non-responders. Mease stressed that PASI 75 response rates were statistically significant after three months with both Xeljanz doses.
In both trials, no unexpected safety signals were observed, and the frequency and type of reported adverse events (AEs) were consistent with the AEs observed in the RA studies, meaning that Xeljanz’s safety profile appears to be comparable to the safety profiles of the leading TNF inhibitors. Although skin findings were disappointing in the two trials after three months, with the Xeljanz 5mg twice-daily dose not meeting the PASI 75 endpoint, Mease noted that “most patients who visit a rheumatologist have minimal skin involvement.” Additionally, he highlighted that after 12 months in the NRI analysis, the 5mg twice-daily dose reached a PASI 75 response of 56%, which was comparable to the response rate observed in the Humira arm.
With Phase III trials in both TNF-naïve and TNF-experienced patients, Pfizer is aiming to ensure use across multiple lines of therapy. However, it may flounder in both settings. Xeljanz will struggle to establish a place early in the PsA treatment algorithm, despite the convenience of its oral formulation. Branded anti-TNF biologics currently dominate the early treatment setting in PsA, and will be difficult to displace due to their proven efficacy and preferential formulary placement, while the growing availability of anti-TNF biosimilars complicates the picture further. The reduction in the cost of anti-TNFs following the launch of biosimilars will negatively impact Xeljanz’s uptake, as payers are likely to enforce step therapy, requiring treatment with an anti-TNF before Xeljanz can be used.
Celgene’s oral phosphodiesterase 4 (PDE4) inhibitor Otezla (apremilast) is also expected to pose a threat to Xeljanz. Celgene reported that Otezla achieved global sales of $1.0bn in 2016. Despite its modest efficacy compared to the leading anti-TNFs, Otezla has seen strong uptake since its 2014 launch in PsA. Key opinion leaders attribute Otezla’s uptake to its strong tolerability and safety profile, and note that this will give the PDE4 inhibitor a competitive edge over Xeljanz, which carries a black box warning for an increased risk of serious infections and malignancies.
“Well, there may be some competition [between Xeljanz and Otezla], but I think one of the stronger points that apremilast has is the safety profile […]. So, there may be less efficacy but definitely better safety, so that is why it is a better drug to start with.” US key opinion leader
Aside from having a more favorable safety profile, Otezla also benefits from an attractive price tag. The annual treatment cost for Otezla is approximately 30% lower than the leading biologics Enbrel (etanercept; Amgen/Pfizer/Takeda) and Humira. Xeljanz’s pricing in PsA will be dictated by its price in RA, which is in line with or higher than the key anti-TNFs once discounts are factored in. Indeed, payers are currently restricting patient access to Xeljanz in RA based on its high cost.
Xeljanz will also face competition in late lines of therapy. Novartis’s interleukin 17 (IL-17) inhibitor Cosentyx (secukinumab) and the Phase III IL-17 agent Taltz (ixekizumab; Eli Lilly), which mainly target late lines of therapy, have demonstrated strong efficacy in both joint and skin manifestations. Indeed, Cosentyx is now the preferred agent in the post-TNF setting and benefits from long-term data showing high and sustained responses.
By Tara Hansen
The FDA Oncology Center of Excellence’s ‘industry-wide evaluation’ of accelerated approvals has already led to withdrawals of four PD-1/PD-L1 inhibitor indications, with the Oncologic Drugs Advisory Committee set to review another six in late April. Over the next two years, an additional five indications may be up for review.