Pfizer Inc. (NYSE: PFE) today announced that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the 100 mg and 200 mg doses of abrocitinib, an oral, once-daily, Janus kinase 1 (JAK1) inhibitor, for marketing authorization to treat moderate to severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. The CHMP also adopted a positive opinion recommending marketing authorization for XELJANZ® (tofacitinib) 5 mg and 10 mg, administered twice daily, for the treatment of adults with active ankylosing spondylitis (AS) who have responded inadequately to conventional therapy.
"The CHMP's positive recommendation brings us closer to our goal of helping people living with moderate to severe atopic dermatitis in Europe find relief," said Michael Corbo, PhD, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development. "We look forward to working with the European Commission and hope to soon provide abrocitinib to people in Europe and eventually to more people worldwide who are living with this debilitating disease, many of whom have limited treatment options today."
"Atopic dermatitis can be a debilitating condition that impacts the daily lives of millions of people," said Dr. Diamant Thaci, Comprehensive Center for Inflammation Medicine, University of Luebeck, Germany. "Abrocitinib has shown significant efficacy, including relief from the hallmark chronic itch, rapid improvements in skin clearance, extent and severity of disease versus placebo, and a favorable risk-benefit profile. If approved, abrocitinib may become an important new treatment option for patients living with moderate to severe atopic dermatitis."
Based on these CHMP recommendations, a decision by the European Commission, which authorizes marketing approval in the European Union, is expected on the abrocitinib and XELJANZ applications later this year. If granted by the European Commission, the centralized marketing authorizations would be valid in all EU Member States as well as in Iceland, Liechtenstein, and Norway.
The recommendation for abrocitinib is based on the results of five Phase 3 studies and a long-term extension study from a robust clinical trial program including more than 3,100 patients.
The recommendation for XELJANZ is based on data from a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of XELJANZ twice daily versus placebo in 269 adult patients living with active AS.
About Abrocitinib
Abrocitinib is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of atopic dermatitis, including interleukin IL-4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin (TSLP).
CIBINQO® (abrocitinib) received marketing authorization from the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Japanese Ministry of Health, Labour and Welfare (MHLW) in September 2021.
About XELJANZ
XELJANZ is approved in the European Union in four indications: adults with moderately to severely active rheumatoid arthritis (RA) after disease modifying antirheumatic drug (DMARD) failure or intolerance, adults with active psoriatic arthritis (PsA) after DMARD failure or intolerance, adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent, and active polyarticular juvenile idiopathic arthritis (JIA) and juvenile PsA in patients two years of age and older who have responded inadequately to previous therapy with DMARDs. Limitations of Use below.
XELJANZ has been studied in more than 50 clinical trials worldwide and prescribed to more than 300,000 adult patients (the majority of whom were RA patients) worldwide since 2012.i,ii.
In June 2021, the Committee for Medicine Products for Human Use of the European Medicines Agency adopted a recommendation from the Pharmacovigilance Risk Assessment Committee (PRAC) following its review of XELJANZ in the European Union, which states that in patients over 65 years of age, patients who are current or past smokers, patients with other cardiovascular (CV) risk factors, and patients with other malignancy risk factors, XELJANZ should only be used if no suitable treatment alternatives are available. The CHMP-endorsed PRAC recommendation is applicable to all EU member states and has been implemented in the XELJANZ summary of product characteristics.
Pfizer is also continuing to work with the U.S. Food and Drug Administration (FDA) and other regulatory agencies to review the full results and analysis of the ORAL Surveillance data. Most recently in September 2021, the FDA issued a Drug Safety Communication (DSC) related to XELJANZ®/XELJANZ XR® and two other arthritis medicines in the same drug class, based on its completed review of the ORAL Surveillance trial.
About Atopic Dermatitis
AD is a chronic skin disease characterized by inflammation of the skin and skin barrier defects.iii,iv Lesions of AD are characterized by erythema (skin turning red or purple depending on normal skin color), itching, induration (hardening)/papulation (formulation of papules), and oozing/crusting.iii,iv
AD affects up to 10% of adults worldwide.v The prevalence of AD in adults in the European Union is approximately 5-10%.vi,vii
About Ankylosing Spondylitis
AS is a chronic, inflammatory disease that affects men and women in early adulthood. The first symptoms usually occur before the age of 30 and seldom onset after the age of 45.viii,ix Symptoms of AS include pain and stiffness in the back and hips. Over time, some patients may experience fusion of the vertebrae in the spinal column.ix AS can cause severe, chronic pain for those living with the disease and can negatively impact health-related quality of life.ix An estimated average of 0.19% of adults in the European Union live with AS.x
FDA-APPROVED INDICATIONS
Rheumatoid Arthritis
- XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Psoriatic Arthritis
- XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Ulcerative Colitis
- XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or who are intolerant to TNF blockers.
- Limitations of Use: Use of XELJANZ in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Polyarticular Course Juvenile Idiopathic Arthritis
- XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older.
- Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
IMPORTANT SAFETY INFORMATION
SERIOUS INFECTIONS
Patients treated with XELJANZ* are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.
If a serious infection develops, interrupt XELJANZ until the infection is controlled.
Reported infections include:
- Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
- Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
- Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.
The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections, or with chronic or recurrent infection.
In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.
The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection.
MORTALITY
Rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study. XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.
MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with XELJANZ.
Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.
Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.
Malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily dosing in the UC long-term extension study.
Other malignancies were observed in clinical studies and the post-marketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
THROMBOSIS
Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. RA patients who were 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing safety study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death. Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis. For patients with UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer.
GASTROINTESTINAL PERFORATIONS
Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).
HYPERSENSITIVITY
Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.
LABORATORY ABNORMALITIES
Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter.
Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.
Anemia: Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.
Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.
Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.
VACCINATIONS
Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.
PATIENTS WITH GASTROINTESTINAL NARROWING
Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.
HEPATIC and RENAL IMPAIRMENT
Use of XELJANZ in patients with severe hepatic impairment is not recommended.
For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily, reduce to XELJANZ 5 mg once daily.
For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily.
ADVERSE REACTIONS
The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with RA with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in RA patients.
Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials for UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.
USE IN PREGNANCY
Available data with XELJANZ use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.
* Unless otherwise stated, "XELJANZ" in the Important Safety Information refers to XELJANZ, XELJANZ XR, and XELJANZ Oral Solution.
Please see full Prescribing Information, including BOXED WARNING for XELJANZ available at: www.xeljanzpi.com.
