Pfizer's Abrocitinib and Xeljanz FDA Reviews Delayed by Three Months Amid JAK Inhibitor Safety Concerns

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On April 7, Pfizer announced that the U.S. Food and Drug Administration (FDA) had extended the priority review period for the New Drug Application (NDA) of abrocitinib, an oral anti-inflammatory agent. Abrocitinib is a next-generation oral JAK1 inhibitor indicated for the treatment of moderate-to-severe atopic dermatitis (AD) in adolescent and adult patients. The FDA has extended the Prescription Drug User Fee Act (PDUFA) target action date for the aforementioned NDA by three months, to early in the third quarter of 2021.

In addition, the FDA extended the review period for the supplemental new drug application (sNDA) for the oral anti-inflammatory drug Xeljanz/Xeljanz XR (tofacitinib) for the treatment of adult patients with active ankylosing spondylitis (AS) by 3 months, with a new target action date set for early in the third quarter of 2021.

Abrocitinib is an oral small molecule that selectively inhibits Janus kinase 1 (JAK1) and has previously been granted Breakthrough Therapy designation by the FDA for the treatment of moderate-to-severe atopic dermatitis (AD). In China, the New Drug Application (NDA) for abrocitinib has been included in the priority review program by the National Medical Products Administration (NMPA), with the indication being: for the treatment of patients aged 12 years and older with moderate-to-severe AD.

Xeljanz, approved in 2012, is the first JAK inhibitor to reach the market. In the United States, Xeljanz has been approved for four indications: treatment of adult patients with moderately to severely active rheumatoid arthritis (RA); treatment of adult patients with active psoriatic arthritis (PsA); treatment of adult patients with moderately to severely active ulcerative colitis (UC); and treatment of patients aged 2 years and older with active polyarticular course juvenile idiopathic arthritis (pcJIA). In China, Xeljanz was approved for marketing in March 2017, becoming the first JAK inhibitor for the treatment of RA in the Chinese market.

In the announcement, Pfizer did not disclose the reasons for the FDA’s delay in reviewing the NDA and sNDA for the aforementioned two drugs. Recently, the FDA also successively delayed by three months the review periods for AbbVie’s oral JAK1 inhibitor Rinvoq (two sNDAs for the treatment of adults with moderate-to-severe atopic dermatitis [AD] and adults with active psoriatic arthritis) and Eli Lilly/Incyte’s oral JAK1/2 inhibitor Olumiant (sNDA for the treatment of adults with moderate-to-severe AD).

Analysts have pointed out that the delays in the review of multiple JAK inhibitors mentioned above indicate that the FDA will conduct a rigorous review of all drugs in this class. The reason is that Pfizer, in a post-marketing RA safety study earlier this year, found that Xeljanz was associated with an increased risk of heart-related events compared to traditional TNF inhibitors.

Currently, the drug labels for Olumiant, Xeljanz, and Rinvoq all carry a boxed warning regarding the risks of serious infections, thrombosis, and cancer. As the first JAK inhibitor to enter the market, Xeljanz was required to undergo a long-term post-marketing study to further evaluate these risks. In this study, Pfizer initially linked an increased risk of major adverse cardiac events to high-dose Xeljanz. However, updated data in January revealed that the same issue applies to the low dose as well.

As the FDA considers taking action on the existing indications for Xeljanz, the agency is also closely reviewing pending applications for the entire JAK inhibitor class. For Eli Lilly and AbbVie, the agency requested additional data analyses from these companies before deciding to extend the review period.

Although the delayed review of JAK inhibitors represents a setback for the aforementioned companies, it also signifies reduced or delayed competition for Sanofi and Regeneron’s monoclonal antibody anti-inflammatory drug, Dupixent. Unlike JAK inhibitors, Dupixent’s drug label does not carry a black box warning. This safety advantage is one of the reasons why industry observers believed that Dupixent would be adopted prior to JAK inhibitors in the clinical treatment of atopic dermatitis (AD), even before the issuance of the safety warning for Xeljanz.

Atopic dermatitis (AD) is currently the largest indication for Dupixent and a “significant growth driver.” In 2020, AD propelled a 75% year-over-year increase in Dupixent sales, surpassing $4 billion. In a February report, SVB Leerink analyst Geoffrey Porges summarized that patients with AD also appeared to remain on Dupixent therapy for an extended duration, with approximately 75%–80% of patients still receiving treatment after six months—above the industry average—demonstrating the drug’s positive impact on patients’ quality of life.

Among the three marketed JAK inhibitors whose reviews were deferred, Xeljanz generated the highest revenue in 2020, reaching $2.44 billion, a year-on-year increase of 9%, primarily driven by its three major indications: rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ulcerative colitis (UC). Olumiant was approved in mid-2018 for the treatment of RA and received approval for atopic dermatitis (AD) in the European Union and Japan. Its sales reached $639 million in 2020, representing a 50% year-on-year increase, partly attributable to the Emergency Use Authorization (EUA) for its use in combination with Gilead’s antiviral drug remdesivir for the treatment of COVID-19. As for Rinvoq, it was approved by the FDA in August 2019 for the treatment of RA and achieved sales of $281 million in its first full year on the market.

Reference Source:

1.Pfizer Announces Extension of Review of New Drug Application of Abrocitinib for the Treatment of Moderate to Severe Atopic Dermatitis

2.More relief for Dupixent as FDA pushes back Lilly, Pfizer eczema decisions on safety concerns