Pfizer’s Two JAK Inhibitors, Abrocitinib and Tofacitinib, Face U.S. FDA Review Delays Amid Safety Concerns

July 22, 2021 /BioonBIOON/ --Pfizer(Pfizer) recently announced that the U.S. Food and Drug Administration (FDA) has notified the company that it will not by the Prescription Drug User Fee Act (PDUFA) target date onNext-generation oral JAK1 inhibitor abrocitinib(100 mg, 200 mg) New Drug Application (NDA) for the treatment of moderate-to-severe atopic dermatitis (AD) in adults and adolescents (≥12 years of age), regardingOral JAK inhibitor Xeljanz/Xeljanz XR (tofacitinib)A regulatory review decision has been made on the Supplemental New Drug Application (sNDA) for the treatment of active ankylosing spondylitis (AS) in adults.

FDAIt was noted that the agency is reviewing Pfizer's post-marketing study ORAL Surveillance, which is evaluating oral tofacitinib versus TNF inhibitors for the treatment of moderate-to-severe rheumatoid...Rheumatic ArthritisSafety in adult patients with (RA). The review of the study results was one of the factors contributing to the delay in the regulatory review of the aforementioned drug. According to the notice dated April 7, 2021,FDAThe PDUFA target date had previously been extended to early third quarter 2021.

Pfizer Global Product Development Inflammation andImmunologyDr. Michael Corbo, Chief Development Officer, stated: “We remain confident in the benefit-risk profiles of abroctinib and Xeljanz, both of which have already been supported by robustClinical Trialdemonstrated in the study. For many patients with moderate-to-severe atopic dermatitis or active ankylosing spondylitis, treatment options are limited. We look forward toFDAnews, as we work to bring these important potential treatment options to the right patients.”

Notably, in addition to Pfizer's aforementioned two JAK inhibitors,FDARecently, that is also correct.AbbVie's Oral JAK1 Inhibitor Rinvoq (upadacitinib)sNDA for the treatment of moderate-to-severe AD in adult patients,Eli LillyOral JAK1 inhibitor Olumiant(Chinese brand name: Aileming, generic name: baricitinib) A delay notice has been issued for the sNDA for the treatment of adult patients with moderate-to-severe AD.

All these delays are related toFDARelated to the ongoing safety review of JAK inhibitors.JAK inhibitors are a promising class of therapeutics that can be used to treat variousAutoimmunitydisease, but this class of drugs has been questioned due to safety concerns.

In January this year, Pfizer announcedPost-marketing Safety Study ORAL Surveillance(A3921133, NCT02092467) preliminary co-primary endpoint results. The data showed that the study did not meet the pre-specified non-inferiority criteria: for major adverse cardiovascular events (MACE) and malignantTumor(excluding non-Melanomain terms of skin cancer [NMSC]),Xeljanz has a lower safety profile than TNF inhibitors.

Unlike other tofacitinib studies, the ORAL Surveillance studySpecifically to assess cardiovascular events and malignanciesTumorrisk of, therefore requiring subjects to be aged 50 years or older, and to have at least one additional cardiovascular risk factor at screening (e.g., current smoking,Hypertension, high cholesterol levels,Diabetes mellitus, history of myocardial infarction, family history of coronary artery disease, and extra-articular rheumatoid arthritis disease). Additionally, all subjects were also required to have an inadequate response to background methotrexate therapy to be eligible for enrollment in the study.Currently, Pfizer is continuing to work with the United StatesFDAand in collaboration with other regulatory authorities, review all results and analyses.

ORAL Surveillance Study Preliminary Co-Primary Endpoint Results (Click image to view larger version)

Abrocitinib is an oral small molecule that selectively inhibits Janus kinase 1 (JAK1).. Inhibition of JAK1 is believed to modulate multiple cytokines involved in the pathophysiology of atopic dermatitis (AD), including interleukin (IL)-4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin (TSLP). In the United States,FDAIn February 2018, abrocitinib was granted Breakthrough Therapy Designation (BTD) for the treatment of moderate-to-severe atopic dermatitis (AD).

The application for abrocitinib for the treatment of moderate-to-severe atopic dermatitis (AD) is based on data from the robust Phase 3 JADE global clinical development program. In this program, compared with placebo, abrocitinib demonstrated statistically significant superiority in skin clearance, disease extent, and severity, with rapid improvement in pruritus (as early as Week 2). Abrocitinib also exhibited a consistent safety profile across the trials and was generally well tolerated.

The active pharmaceutical ingredient of Xeljanz/Xeljanz is tofacitinib, an oral JAK inhibitor that selectively inhibits JAK kinases and blocks the JAK/STAT signaling pathway. This cytokine-stimulated signal transduction pathway is involved in numerous important biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation.

Xeljanz was approved in the United States in 2012, becoming the first JAK inhibitor to reach the market., the drug is administered orally twice daily. Currently, Xeljanz is approved in the United States for four indications: (1) treatment of moderately to severely active rheumatoidRheumatic arthritis(RA) adult patients; (2) treatment of adult patients with active psoriatic arthritis (PsA); (3) treatment of adult patients with moderate to severe ulcerative colitis (UC); (4) treatment of pediatric patients aged ≥2 years and adolescents with active polyarticular-course juvenile idiopathic arthritis (pcJIA).

Since 2012, Xeljanz has been approved in more than 50 countries worldwide.Clinical TrialStudies have been conducted, including over 20 trials in patients with RA, and it has been prescribed to more than 300,000 adult patients worldwide (the majority of whom have RA). (Bioon.com)

Original Source:Pfizer Provides Update on U.S. FDA Review of Abrocitinib and XELJANZ® Filings