By Lisa Seachrist
BETHESDA, Md. — An FDA advisory panel unanimously endorsed Centocor Inc.'sAvakine (infliximab) monoclonal antibody for the treatment of Crohn's disease.
The Gastrointestinal Drugs Advisory Committee agreed Avakine could be used to treatmoderate to severe Crohn's disease in patients for whom conventional therapy isinadequate and in patients who have draining fistulae. In addition, the panel specified thatit should be for short-term use.
Avakine was the first biological agent ever reviewed by the committee.
"This is the first step for Crohn's patients; these people really have very little," said DavidHolveck, CEO of the Malvern, Pa.-based Centocor. "We are getting a narrow claim forAvakine and will be building it out in the future for both Crohn's and [rheumatoidarthritis]. With this, Centocor will start to be a biopharmaceutical company and not just abiotech company."
Crohn's disease is an autoimmune disorder that causes inflammation of the mucosal liningin the gastrointestinal tract. It affects approximately 1 million people in the U.S. andEurope, and symptoms include diarrhea, fever, abdominal pain, and weight loss.
As the disease progresses, the inflammation may lead to fistulae, which are deep ulcertracts that burrow through the bowel wall into surrounding tissues and out the surface ofthe skin. The fistulae can become infected, bleed, and lead to surgical removal of theaffected tissues. Often large amounts of the small and large intestines must be removed.
Patients Stress Need For New Therapy
Patients testified to the panel that the emotional and social suffering caused by Crohn's hadcolored their lives since their diagnoses. Current therapies which attempt to quell the flare-ups of the disease include prednisone, methotrexate and other anti-inflammatorymedications. These therapies, however, inadequately control the disease and cause seriousside effects.
Avakine works by blocking the action of tumor necrosis factor (TNF) alpha, a cytokineimplicated as an overstimulator of the immune system in several inflammatory diseases,including Crohn's disease and rheumatoid arthritis. The drug binds to TNF alpha on thecell membrane, neutralizes TNF alpha in the bloodstream and destroys TNF alphaproducing cells.
Centocor presented pivotal trial data from 108 patients with moderate to severe Crohn'sdisease that was resistant to treatment. The researchers measured severity of disease andclinical response based on a scale called the Crohn's Disease Activity Index (CDAI), whichranges from zero to 600. The company defined a positive result as a reduction of CDAI of70 or greater. Remission was defined as a CDAI score less than 150.
Patients with a CDAI score between 220 and 400 received either a placebo or a two-hourinfusion of Avakine at five, 10 or 20 milligrams per kilogram. Four weeks later, 81 percentof patients given the 5 milligram dose, 50 percent of those given the 10 milligram dose and64 percent of those given the 20 milligram dose experienced a clinical response as definedby a drop in their CDAI. By comparison, only 17 percent of the placebo patientsexperienced a clinical response.
Remission at week 4 was achieved by 50 percent of the patients taking Avakine comparedwith 4 percent of those on placebo. The company determined that the results essentiallyshowed there was no dose response for Avakine, and follow-up treatment showed thatAvakine maintained the response.
A second study tested Avakine's ability to treat fistulae in 94 patients whose conditionwould not respond to standard therapy. Two-thirds of the patients receiving threeinfusions of Avakine at either 5 milligrams or 10 milligrams per kilogram experiencedclosure of at least 50 percent of their fistulae compared with 26 percent of placebopatients.
Centocor reported that three patients experienced an infusion reaction which includedhypotension and chest tightness and approximately 10 percent of patients developedantibodies against Avakine.
The FDA had questions about the long-term risks associated with taking Avakine, whichmay include infection, malignancies, cardiovascular events and lupus-related symptoms. Inaddition, the agency maintained that the fistulae healing response was lost when thepatients stopped receiving Avakine.
Panel member Lee Simon, a rheumatologist at Harvard Medical School, in Boston,expressed concern that Avakine could trigger other autoimmune diseases because severalpatients developed auto-antibodies against double stranded DNA.
"We don't know what happens long term," Simon said. "We cannot think about biologicdrugs in the same way we think about other drugs."
However, panel patient representative Sidney Getz countered that all the drugs Crohn'ssufferers take have significant risks. "I don't think you would find any Crohn's patient thatwouldn't take the risk to have 2 months of remission," Getz said.
"I think this drug is a big deal to this patient population," said Anthony Butler, an analystwith Lehman Bros. in New York. "Should it be approved a $200 million to $250 millionmarket would be available to Centocor. It's really a whole new class of drugs."
Analyst Likens Product's Impact To That Of Avonex
Mike King, an analyst with Vector Securities, told BioWorld Today Avakine is asbig for Crohn's disease as Avonex (from Biogen Inc., of Cambridge, Mass.) was for themultiple sclerosis community.
"This disease is terrible and there are no good treatments for it," King said. "And, likemultiple sclerosis, it affects more women than men and hits younger people. This drug isthe breakthrough drug for Crohn's disease."
Should the FDA follow the recommendation of the committee, which it is not bound todo, Butler said the Crohn's data may establish safety for use in rheumatoid arthritispatients. An ongoing Phase III Avakine trial in rheumatoid arthritis is expected to becompleted in August.
Because Avakine was granted expedited review, the agency must make its decision on thedrug by June 30.
Trading in Centocor's stock (NASDQ:CNTO) was halted Thursday during the panelhearing. Shares closed Wednesday at $41.375. *