Janssen Biotech, Inc. and Janssen Biologics B.V. announced the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) and a Type II Variation to the European Medicines Agency (EMA) requesting approval of SIMPONI® (golimumab) for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy. Approximately 700,000 people in the United States and 1.1 million people in the European Union (EU) are affected by UC, a chronic inflammatory bowel disease marked by inflammation and ulceration of the colonic mucosa, or innermost lining, which may lead to bloody stools, severe diarrhea and frequent abdominal pain.
SIMPONI became the first subcutaneous anti-tumor necrosis factor (TNF)-alpha therapy to receive approvals in the U.S., Canada and the EU in 2009 for three rheumatic indications simultaneously. In May 2012, findings from a Phase 3 investigational study reported the efficacy and safety of SIMPONI subcutaneous induction therapy in the treatment of moderately to severely active UC among patients who failed or were intolerant to conventional treatments. Data from the SIMPONI Phase 3 UC maintenance study will be submitted for presentation in the future.
Both the U.S. and EU applications are supported by efficacy and safety findings from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT), which included Phase 3 multicenter, randomized, double-blind, placebo-controlled studies designed to evaluate the safety and efficacy of subcutaneous induction and every-four-week maintenance regimens of SIMPONI in adults with moderately to severely active UC. All trial patients had failed to respond to or tolerate treatment with 6-mercaptopurine (6-MP), azathioprine (AZA), corticosteroids and/or 5-aminosalicylate (5-ASA), or were corticosteroid dependent. Study participants were naive to treatment with TNF inhibitors and had a baseline Mayo score between 6 and 12 and endoscopic subscore of 2 or more.
The induction trial (PURSUIT-SC) had an adaptive design with a Phase 2 dose-finding portion followed by a Phase 3 dose-confirming component. The primary endpoint was clinical response at week 6. Secondary endpoints at week 6 included clinical remission, mucosal healing and a change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) scores. Overall, 1,065 patients were treated in the study; 774 of these patients were randomized into the Phase 3 component of the study. Patients responding to induction treatment with SIMPONI were eligible to continue in the Phase 3 PURSUIT-Maintenance study.
Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD) affecting 2.5 million individuals worldwide, is marked by the inflammation and ulceration of the colonic mucosa, or innermost lining, which may lead to bloody stools, severe diarrhea and frequent abdominal pain. Tiny open sores, or ulcers, form on the surface of the lining, where they bleed and produce pus and mucus. Symptoms of the disease may lead to loss of appetite, subsequent weight loss and fatigue. On average, people are diagnosed with UC in their mid-30s, but the disease can occur at any age. Between 25 and 40 percent of people living with UC will require surgery at some point in their life. UC is a chronic disease, and there is no cure. Although progress has been made in IBD research, researchers do not know what causes this disease.
SIMPONI is a human monoclonal antibody that targets and neutralizes excess TNF-alpha, a protein that when overproduced in the body due to chronic inflammatory diseases can cause inflammation and damage to bones, cartilage and tissue. SIMPONI is approved in 52 countries for rheumatologic indications, including the United States, where SIMPONI received FDA approval in April 2009 for the treatment of moderately to severely active rheumatoid arthritis (RA) with the medicine methotrexate, active psoriatic arthritis alone or with the medicine methotrexate and active ankylosing spondylitis, and in the European Union (EU), where SIMPONI received European Commission approval in October 2009 for the treatment of moderate-to-severe, active RA in combination with methotrexate, for the treatment of active and progressive psoriatic arthritis alone or in combination with methotrexate and for the treatment of severe, active ankylosing spondylitis. SIMPONI is available either through the SmartJect® autoinjector/prefilled pen or a prefilled syringe as a subcutaneously administered injection.
SIMPONI is currently being investigated in Phase 3 studies as a subcutaneously administered treatment for active polyarticular juvenile idiopathic arthritis (JIA) and as an intravenous (I.V.) formulation for the treatment of moderately to severely active RA.
In the European Union, SIMPONI is contraindicated in patients with active tuberculosis, severe infections such as sepsis, opportunistic infections, in patients with moderate or severe heart failure (NYHA Class III/IV), as well as in patients who are hypersensitive to SIMPONI or any of its excipients. Serious infections, including sepsis, pneumonia, tuberculosis, invasive fungal and opportunistic infections, have been observed with the use of TNF antagonists including SIMPONI. Some of these infections have been fatal. SIMPONI should not be given to patients with a clinically important, active infection.
Caution should be exercised when considering the use of SIMPONI in patients with a chronic infection or a history of recurrent infection. Patients should be monitored for signs and symptoms of infection before, during and for several months after treatment with SIMPONI. If a patient develops a new serious infection or sepsis, SIMPONI therapy should be discontinued and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate. For patients who have resided in or traveled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of SIMPONI treatment should be carefully considered before initiation of SIMPONI therapy. Patients must be evaluated for the risk of tuberculosis (TB), including latent TB, prior to initiation of SIMPONI. If active TB is diagnosed, SIMPONI must not be initiated. If latent TB is suspected or diagnosed then the benefit/risk balance of SIMPONI therapy should be carefully considered.
Treatment of latent tuberculosis infection should be initiated prior to therapy with SIMPONI. Anti-TB therapy prior to initiating SIMPONI should also be considered in patients who have several or significant risk factors for tuberculosis infection and have a negative test for latent tuberculosis. Patients receiving SIMPONI should be monitored closely for signs and symptoms of active TB during and after treatment, including patients who tested negative for latent TB infections. Use of anti-TB therapy should also be considered before the initiation of SIMPONI in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
The use of TNF blocking agents including SIMPONI has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of the virus. Some of these cases have been fatal. Carriers of hepatitis B should be appropriately evaluated and monitored prior to the initiation of, during treatment with, and for several months following discontinuation of SIMPONI. In patients who develop HBV reactivation, SIMPONI should be discontinued.
The potential role of TNF-blocking therapy in the development of malignancies is not known. Based on the current knowledge, a possible risk for the development of lymphomas, leukaemia or other malignancies in patients treated with a TNF-antagonist cannot be excluded. Caution should be exercised when considering TNF-blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy. Lymphomas have been observed in patients treated with TNF blocking agents, including SIMPONI. In controlled clinical studies, the incidence of lymphoma was higher than in control patients while the incidence of non-lymphoma malignancies was similar to controls. In an exploratory clinical trial evaluating the use of SIMPONI in patients with severe persistent asthma, more malignancies were reported in patients treated with SIMPONI compared with control patients. The significance of this finding is unknown. Based on an exploratory clinical trial with another TNF blocking agent in patients with chronic obstructive pulmonary disease (COPD), caution should be exercised when using any TNF-blocking therapy in patients with COPD, as well as in patients with an increased risk for malignancy due to heavy smoking.
Worsening and new onset congestive heart failure (CHF) have been reported with TNF blockers, including SIMPONI. Worsening of CHF and increased mortality due to CHF have been reported with another TNF blocker. SIMPONI has not been studied in patients with CHF. SIMPONI should be used with caution in patients with mild heart failure (NYHA class I/II) and must be discontinued if new or worsening symptoms of heart failure appear.
TNF-blocking agents, including SIMPONI, have been associated with cases of new onset or exacerbation of demyelinating disorders, including multiple sclerosis and peripheral demyelinating disorders. The benefits and risks of anti-TNF treatment should be carefully considered before initiation of SIMPONI therapy in patients with pre-existing or recent onset of demyelinating disorders.
There is limited safety experience of SIMPONI treatment in patients who have undergone surgical procedures, including arthroplasty. A patient who requires surgery while on SIMPONI should be closely monitored for infections, and appropriate actions should be taken.
The possibility exists for TNF-blocking agents, including SIMPONI, to affect host defenses against infections and malignancies. Treatment with SIMPONI may result in the formation of auto-antibodies and, rarely, in the development of a lupus-like syndrome.
There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF blockers. Cytopenias including pancytopenia, have been infrequently reported with SIMPONI in clinical trials. Discontinuation of SIMPONI should be considered in patients with confirmed significant hematologic abnormalities.
The concurrent administration of TNF-antagonists with anakinra or abatacept is not recommended. Concurrent administration has been associated with increased infections, including serious infections without increased clinical benefit.
Patients treated with SIMPONI may receive concurrent vaccinations, except for live vaccines.
In controlled Phase 3 clinical trials 5.8 percent of SIMPONI-treated patients had injection site reactions compared to 2.2 percent in control patients. The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema. In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following SIMPONI administration. Allergic reactions may occur after first or subsequent administration of SIMPONI. If an anaphylactic reaction or other serious allergic reactions occurs, administration of SIMPONI should be discontinued immediately and appropriate therapy initiated.
The needle cover on the syringe in the pre-filled pen is manufactured from dry natural rubber containing latex, and may cause allergic reactions in individuals sensitive to latex. SIMPONI contains sorbitol; patients with rare hereditary problems of fructose intolerance should not take SIMPONI.
Patients should be given detailed instructions on how to administer SIMPONI. After proper training, patients may self inject if their physician determines that this is appropriate. The full amount of SIMPONI should be administered at all times.
Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for at least 6 months after the last SIMPONI treatment. Women must not breast feed during and for at least 6 months after SIMPONI treatment.
SIMPONI may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of SIMPONI.
The most common adverse drug reaction (ADR) reported from controlled Phase 3 clinical trials through week 16 was upper respiratory tract infection (7.2 percent of SIMPONI-treated patients compared with 5.8 percent in control-treated patients). The most serious ADRs that have been reported for SIMPONI include serious infections (including sepsis, pneumonia, TB, invasive fungal and opportunistic infections), demyelinating disorders, lymphoma, HBV reactivation, CHF, autoimmune processes (lupus-like syndrome) and haematologic reactions. Common (greater than or equal to 1/100 to less than 1/10) ADRs include: bacterial infections, viral infections, bronchitis, sinusitis, superficial fungal infections, anaemia, allergic reactions, autoantibody positive, depression, insomnia, dizziness, paraesthesia, headache, hypertension, constipation, dyspepsia, gastrointestinal and abdominal pain, nausea, alanine aminotransferase increased, aspartate aminotransferase increased, alopecia, dermatitis, pruritus, rash, pyrexia, asthenia, injection site reaction, impaired healing and chest discomfort.
The SIMPONI Patient Alert Card provides safety information to the patient. It should be given and explained to all patients before treatment. Patients must show the Patient Alert Card to any doctor involved in his/her treatment, during and up to 6 months after SIMPONI treatment.
"We are pleased to bring forward submissions for SIMPONI as a potential therapeutic option for patients who fail to respond to conventional treatments and who face the continued debilitating effects of living with ulcerative colitis, and in some circumstances, a decision of surgery," said Jerome A. Boscia, M.D., Vice President, Head of Immunology Development, Janssen Research&Development, LLC. "We look forward to collaborating with the health authorities on these submissions seeking approval of SIMPONI as a subcutaneously administered anti-tumor necrosis factor-alpha treatment for moderately to severely active ulcerative colitis."
1. Crohn's&Colitis Foundation of America. What is Ulcerative Colitis? http://www.ccfa.org/info/about/ucp [http://www.ccfa.org/info/about/ucp]. Accessed July 11, 2012.
2. European Federation of Crohn's and Ulcerative Colitis Associations. What is IBD? http://www.efcca.org/index.php/about-efcca/what-are-ibd [http://www.efcca.org/index.php/about-efcca/what-are-ibd]. Accessed July 11, 2012. 3. World IBD Day. About Us. http://ibdday.bvsalud.org/ [http://ibdday.bvsalud.org/]. Accessed July 11, 2012.