Abbott's HUMIRA(R) (Adalimumab) Approved in the European Union for the Treatment of Crohn's Disease
- Category: Antibodies
- Published on Friday, 08 June 2007 04:00
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ABBOTT PARK, IL, USA | June 7, 2007 | Abbott (NYSE: ABT) announced today that it has received marketing authorization from theEuropean Commission for the use of HUMIRA(R) (adalimumab) as a treatmentfor severe Crohn's disease. HUMIRA is the first self-administered biologicfor the treatment of Crohn's disease and offers an effective and convenienttreatment option that can help enable patients to maintain control of theirdisease. This announcement follows FDA approval for the Crohn's diseaseindication, which Abbott received in February, and is the fourth approvedindication for HUMIRA in the United States and the European Union.
Crohn's disease is a serious, chronic, inflammatory disease of thegastrointestinal (GI) tract that affects more than 1 million people inNorth America and Europe. It affects people of all ages, but it isprimarily a disease of young adults, with onset typically before age 40.There is no medical or surgical cure for Crohn's disease and few treatmentoptions exist for patients suffering with this chronic condition.
"Crohn's can have a devastating impact on patients, many of whom areyoung and active, making it difficult to carry out normal day-to-dayactivities," said Rod Mitchell, chairman, European Federation of Crohn's &Ulcerative Colitis Associations. "The unpredictable nature of the diseasecan seriously impact their quality of life and self-esteem. For the halfmillion people across Europe suffering from Crohn's, this approval offershope to help them regain control of their disease."
Common symptoms of Crohn's disease include diarrhea, cramping,abdominal pain, weight loss, fever, and in some cases, rectal bleeding.Complications include intestinal obstruction, fistulas (ulcers that formtunnels to surrounding tissues), and malnutrition. Over the course of theirdisease, as many as 75 percent of patients with Crohn's disease willundergo surgery at least once for complications or disease resistant totreatment. Of those who undergo surgery to remove a portion of theintestines (resection), half will experience a relapse within five years.
"After I was diagnosed with Crohn's, the unpredictable symptoms madeworking and relationships difficult. I was afraid to leave the house," saidRocio Lopez, a HUMIRA clinical trial patient. "With HUMIRA, my Crohn'ssymptoms are under control and I have more freedom to live my life."
"The approval of HUMIRA in Crohn's disease means that an underservedpatient population now has a clinically effective treatment option thatthey can administer themselves," said Eugene Sun, M.D., vice president,Global Pharmaceutical Clinical Development at Abbott. "For the thousands ofpeople across Europe with Crohn's disease, HUMIRA represents a new,effective, and convenient treatment option."
HUMIRA for Crohn's Disease
The approval was based on data from three pivotal trials of HUMIRA inmore than 1,400 adult patients with moderately to severely active Crohn'sdisease. The CLASSIC I, CHARM and GAIN trials supporting the indication forCrohn's disease evaluated the efficacy and safety of HUMIRA in a diversegroup of moderate to severe adult Crohn's disease patients, from those whowere naive to anti-tumor necrosis factor alpha (TNF-alpha) therapy, topatients who had previously lost response or were unable to tolerateinfliximab, an anti-TNF agent for treatment of Crohn's disease.
In each trial, clinical remission was measured by a Crohn's DiseaseActivity Index (CDAI) score of less than 150. CDAI is a weighted compositescore of eight clinical factors that evaluate patient wellness, includingdaily number of liquid or very soft stools, severity of abdominal pain,levels of general well being and other measures.
Key outcomes include:
-- The CLASSIC I induction trial evaluated HUMIRA for the induction of clinical remission. Of 299 anti-TNF naive patients, 36 and 24 percent of patients receiving HUMIRA (160 mg at week zero followed by 80 mg at week two and 80 mg at week zero followed by 40 mg at week two, respectively) achieved clinical remission at week four compared to 12 percent treated with placebo (p<0.001 for 160 mg/80 mg dose group and p=0.06 for 80mg/40mg dose group).
-- The CHARM trial studied HUMIRA for the maintenance of clinical remission. CHARM was a 56-week trial that enrolled 854 patients with moderate to severe Crohn's disease. After a four-week open label induction phase during which all subjects received 80 mg HUMIRA at week zero followed by 40 mg HUMIRA at week two, 58 percent of patients (n=499) demonstrated clinical response to HUMIRA (a CDAI decrease equal to or greater than 70 from baseline). These patients were randomized to receive either HUMIRA 40 mg every other week (eow), HUMIRA 40 mg weekly, or placebo. Of those who continued on HUMIRA 40 mg every other week (n=172), 40 percent were in clinical remission at week 26 (p<0.001) and 36 percent were in remission at week 56 (p<0.001), versus 17 percent and 12 percent of patients in the placebo group, respectively. For those who continued taking HUMIRA 40 mg weekly, 47 percent were in clinical remission at week 26 and 41 percent were in remission at week 56 (p<0.001).
-- In GAIN, a four-week induction trial of 325 patients who lost response or were intolerant to infliximab, three times as many patients taking HUMIRA achieved clinical remission at week four versus placebo (21 percent versus 7 percent, p less than or equal to 0.001).
The safety profile of HUMIRA in the Crohn's clinical trials was similarto that seen in HUMIRA clinical trials for rheumatoid arthritis (RA).Adverse events reported by >5 percent of HUMIRA treated patients with agreater incidence than patients taking placebo include injection siteirritation, injection site pain, injection site reaction, nausea, jointpain, inflammation of the nose and pharynx, abdominal pain, headache andfatigue.
In the EU, the recommended HUMIRA induction dose for adult patientswith severe Crohn's disease is 80 mg at week 0 followed by 40 mg at week 2.If there is a need for a more rapid response to therapy, patients can take160 mg at week 0 (dose can be administered as four injections in one day oras two injections per day for two consecutive days) followed by 80 mg atweek 2, with the awareness that the risk for adverse events is higherduring induction.
Serious infections, sepsis, rare cases of tuberculosis (TB), andopportunistic infections, including fatalities, have been reported with theuse of TNF antagonists, including HUMIRA. Many of the serious infectionshave occurred in patients on concomitant immunosuppressive therapy that, inaddition to their RA could predispose them to infections. Patients must bemonitored closely for infections, including tuberculosis, before, duringand after treatment with HUMIRA. Treatment should not be initiated inpatients with active infections until infections are controlled. HUMIRAshould not be used by patients with active TB or other severe infectionssuch as sepsis and opportunistic infections. Patients who develop newinfections while using HUMIRA should be monitored closely. HUMIRA should bediscontinued if a patient develops a new serious infection until infectionsare controlled. Physicians should exercise caution when considering use ofHUMIRA in patients with a history of recurring infection or with underlyingconditions that may predispose patients to infections.
TNF-blocking agents have been associated with reactivation of hepatitisB (HBV) in patients who are chronic carriers of the virus. Some cases havebeen fatal. Patients at risk for HBV infection should be evaluated forprior evidence of HBV infection before initiating HUMIRA.
The combination of HUMIRA and anakinra is not recommended.
TNF antagonists, including HUMIRA, have been associated in rare caseswith demyelinating disease and serious allergic reactions. Rare reports ofpancytopenia including aplastic anemia have been reported with TNF-blockingagents. Adverse events of the haematologic system, including medicallysignificant cytopenia have been infrequently reported with HUMIRA.
More cases of malignancies including lymphoma have been observed amongpatients receiving a TNF antagonist compared with control patients inclinical trials. The size of the control group and limited duration of thecontrolled portions of studies precludes the ability to draw firmconclusions. Furthermore, there is an increased background lymphoma risk inrheumatoid arthritis patients with long-standing, highly active,inflammatory disease, which complicates the risk estimation. During thelong-term open-label trials with HUMIRA, the overall rate of malignancieswas similar to what would be expected for an age, gender and race matchedgeneral population. With the current knowledge, a possible risk for thedevelopment of lymphomas or other malignancies in patients treated with aTNF antagonist cannot be excluded.
In clinical studies with another TNF antagonist, a higher rate ofserious congestive heart failure (CHF) related adverse events includingworsening CHF and new onset CHF have been reported. Cases of worsening CHFhave also been reported in patients receiving HUMIRA. Physicians shouldexercise caution when using HUMIRA in patients who have heart failure andmonitor them carefully. HUMIRA should not be used in patients with moderateor severe heart failure.
The most frequently reported adverse event (greater than or equal to1/10 patients) at least possibly causally related to HUMIRA is injectionsite reaction (including pain, swelling, redness or pruritus). Other commonadverse events (reported by greater than or equal to 1/100 patients) atleast possibly causally related to HUMIRA include lower respiratoryinfections (including pneumonia, bronchitis), viral infections (includinginfluenza, herpes infections), candidiasis, bacterial infection (includingurinary tract infections), upper respiratory infection, lymphopenia,dizziness (including vertigo), headache, neurologic sensation disorders(including paraesthesias), infection, irritation or inflammation of theeye, cough, nasopharyngeal pain, diarrhoea, abdominal pain, stomatitis andmouth ulceration, nausea, hepatic enzymes increased, rash, dermatitis andeczema, pruritus, hair loss, musculoskeletal pain, pyrexia, fatigue(including asthenia and malaise)
In addition to Crohn's disease, HUMIRA is approved for the treatment ofRA, psoriatic arthritis (PsA), and ankylosing spondylitis (AS) in Europeand the United States. HUMIRA resembles antibodies normally found in thebody. It works by blocking tumor necrosis factor alpha (TNF-alpha), aprotein that, when produced in excess, plays a central role in theinflammatory responses of autoimmune diseases. To date, HUMIRA has beenapproved in 67 countries and more than 180,000 people worldwide arecurrently being treated with HUMIRA. Clinical trials are currently underway evaluating the potential of HUMIRA in other immune-mediated diseases.
In Europe, HUMIRA, in combination with methotrexate (MTX), is indicatedfor the treatment of moderate to severe, active RA in adult patients whenthe response to disease-modifying anti-rheumatic drugs (DMARDs) includingMTX has been inadequate, and for the treatment of severe, active andprogressive RA in adults not previously treated with MTX. HUMIRA can begiven as monotherapy in case of intolerance to MTX or when continuedtreatment with MTX is inappropriate. HUMIRA has been shown to reduce therate of progression of joint damage as measured by x-ray and to improvephysical function, when given in combination with MTX. Additionally, HUMIRAis indicated for the treatment of active and progressive PsA in adults whenthe response to previous DMARD-therapy has been inadequate and for thetreatment of severe, active AS in adults who have had an inadequateresponse to conventional therapy.
Abbott is a global, broad-based health care company devoted to thediscovery, development, manufacture and marketing of pharmaceuticals andmedical products, including nutritionals, diagnostics and devices. Thecompany employs 65,000 people and markets its products in more than 130countries.
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