Rheumatoid Arthritis- TNF and Enbrel- Part II
6/24/08)- The FDA announced on its Web site that it would require Amgen Inc. to enhance the warning label for its rheumtoid arthritis drug Enbrel for children because a staff reviewal of the agency's adverse-event reporting database found cases of serious adverse events tied to pediatric patients who took Enbrel.
These events which included malignancies, infections and neurological problems are similar to those experienced by adults. Many of these events were life threatening and resulted in deaths and hospitalizations.
Enbrel is currently approved for usage in treating rheumatoid arthritis in adults and children, and psoriasis in adults. The company is seeking FDA approval for usage in treating children with moderate-to-severe psoriasis
(6/17/08)- A biologic therapy for rheumatoid arthritis being developed by Johnson & Johnson and Schering-Plough showed efficacy in three late-stage clinical studies, the results of which were presented at the European League Against Rheumatism meeting recently in Paris.
The treatment, called golimumab, is an anti-TNF, which reduces inflammation and combats some immune-system diseases.
These studies showed the medicine, injected under the skin once a month, improved physical functioning and disease symptoms in different patients, including those who had been treated with other standard and anti-TNF medications.
The drug is awaiting approval in Europe, and the companies are expected to file for approval with the FDA later this month.
(6/17/08)- A biologic therapy for rheumatoid arthritis being developed by Johnson & Johnson and Schering-Plough showed efficacy in three late-stage clinical studies, the results of which were presented at the European League Against Rheumatism meeting recently in Paris.
The treatment, called golimumab, is an anti-TNF, which reduces inflammation and combats some immune-system diseases.
These studies showed the medicine, injected under the skin once a month, improved physical functioning and disease symptoms in different patients, including those who had been treated with other standard and anti-TNF medications.
The drug is awaiting approval in Europe, and the companies are expected to file for approval with the FDA later this month.
(6/9/08)- The tumor necrosis factor (TNF)-blockers, represent one of the most successful classes of drugs ever developed using biotechnology. The drugs act to reduced inflammation by blocking the TNF protein, and they are used to treat various immune diseases such as rheumatoid arthritis, psoriasis and Crohn's disease.
Since they block part of the immune system, it has been known that they might contribute to higher risk of cancers and infections. The labels for these drugs contain a warning to that effect.
The FDA announced that it would investigate how much of an increase risk for cancer that these drugs do present to children. The drugs involved are:
The agency said that it had received reports of 30 cases of cancer over a 1-year period of time among children and young adults treated by these drugs. The FDA also stated that the benefits of the drugs exceeded the risks as of now, so that there was no need to presently discontinue usage of these drugs.
(9/28/07)- The Recombinant DNA Advisory Committee, a committee that was set up by the National Institute of Health to help oversee gene therapy clinical trials has determined that it is still to early to prove whether an experimental gene therapy treatment for rheumatoid arthritis contributed to the death of a 36-year old woman in July.
Jolee Mohn, who had a 5-year-old daughter, died on July 24 at the University of Chicago Medical Center, three weeks after trillions of genetically engineered viruses were injected into her right knee as a test of an experimental treatment for rheumatoid arthritis. The type of virus used as the gene carrier has widely been considered safe and is being used in 35 other trials.
Autopsy data presented at the committee meeting suggested that the main cause of death was a fungal infection, histoplasmosis that had gone out of control destroying her organs. The autopsy results indicated that the virus did not directly kill her, but the question has arisen as to whether or not the gene therapy suppressed her immune system.
The gene therapy was meant to cause cells in her knee joint to produce an anti-inflammatory protein identical to the one in Enbrel, the rheumatoid arthritis drug. Enbrel can leave patients more susceptible to infections. Ms. Mohr was also taking regular injections of Humira, a drug similar to Enbrel that has also been linked to infections, including histoplasmosis. She was also on two other immune-suppressing drugs.
Studies found that the genetically engineered virus had spread to Ms. Mohr's liver and spleen. That raised the possibility that the immune-suppressing protein was produced outside the joint. Her rheumatologist had recruited her for the trial, which may have led her to believe that she might have been helped directly by the trial, even though its main purpose was to gather information.
(8/7/06)- Abbott Laboratories said that it had received approval from the FDA for the use of its drug Humira to treat arthritis of the spine and spinal joints. Humira is Abbott's top selling drug, garnering $1.4 billion in sales last year.
Humira has previously been approved to treat rheumatoid arthritis and psoriatic arthritis. Abbott had previously announced that it would seek approval from the FDA to treat Crohn's disease. For more on this matter see our item dated 5/31/06.
Crohn's disease is an ailment affecting the gastrointestinal system. Humira's approval to be sold as a medication to treat ankylosing spondylitis or arthritis of the spine is another example of how one drug can help in the treatment of several diseases.
The company will start selling Humira for treatment of spinal arthritis as soon as possible.
(5/31/06)- Johnson & Johnson's Remicade, known generically as infliximab, received approval from the FDA to market the drug for treating children with active Crohn's disease, a chronic bowel inflammation. At the same time the FDA will require that the drug's label warn of the possibility of lymphoma. Remicade is in a group of drugs that suppress tumor necrosis factor-alpha (TNF). Other drugs in this class include Enbrel from Amgen and Humira from Abbott Laboratories. All carry warning about the possibility of malignancies or serious infections.
Remicade has been therefore cleared for usage among children who have moderate to severe Crohn's disease symptoms. Safety and effectiveness were not studied in children younger than 6.
Researchers at the Mayo Clinic however have concluded that J&J's Remicade and Abbott's Humira can trigger serious infections, and may even contribute to cancer in some patients. Their findings show that the cancer risk may include tumors such as skin, lung and breast cancers, rather than limited to lymphomas.
The Mayo researchers concluded that tuberculosis infections occurred in one of every 59 patients treated with those drugs for three months to a year. An additional cancer struck one in every 154 patients treated with the drugs for 6 months to a year. The risk of the cancer occurring increased with the higher dosages of the drugs. The makers of the drugs disputed these findings.
(12/25/05)- The FDA has granted approval to Bristol-Myers Squibb to sell its anti-TNF rheumatoid arthritis drug Orencia. Please see our item below dated 9/10/05 for the advisory panel's decision on this matter. Bristol said it hoped to begin to market the drug in February using a special sales force that has extensive experience in rheumatoid arthritis.
Orencia is administered as a 30-minute intravenous infusion on a monthly basis. The company has not indicated yet what the cost for the drug will be. Orencia will compete with Enbrel by Amgen, Remicade by J&J, and Humira from Abbott, which are the other approved anti-TNF drug treatments for rheumatoid arthritis.
Clinical tests showed that Orencia worked in a significant number of patients who did not respond to other anti-TNF agents or another commonly used drug, methotrexate, There are about 2 million rheumatoid arthritis patient sufferers in this country, of which about 250,000 are on anti-TNF therapy.
(9/10/05)- An FDA advisory panel voted in favor of recommending to the FDA that Bristol-Myers rheumatoid arthritis drug Orencia was effective, but at the same cautioned that it might lead to a slightly higher risk of infections. The drug was found to be effective in easing the symptoms of rheumatoid arthritis, slowed joint damage from the disease and improved patients' physical functions.
In three studies, at least half of the patients taking Orencia showed signs of improvement after six months, and in one of the trials, 68% showed improvement. On the other hand anywhere from 20% to 40% of the patients taking placebos showed improvement.
Bristol is seeking FDA approval to market the drug to patients with moderate to severe rheumatoid arthritis who have not responded to other treatments, including Abbott Lab's Humira and Johnson & Johnson's Remicade. The drug is designed to inhibit certain aspects of T-cell functioning, which are involved with inflammation and disease progression. T-cells are involved in the body's immune system, and suppressing them increases the risk of infection and some types of cancer.
Data presented by the FDA during the panel meeting suggested that those on Orencia had a higher rate of infections such as pneumonia and bronchitis, compared with those taking the placebos. The infection rate was higher among patients on other rheumatoid arthritis drugs known as TNF-inhibitors when combined with Orencia.
Bristol said that if the FDA does approve the drug, the label would include a warning to not prescribe it on top of the TNF drugs such as Humira and Remicade, as well as Enbrel, which is marketed by Amgen Inc. and Wyeth. The company further stated that it would conduct additional studies as to the infection and cancer rates, as well as create a patient registry.
(3/31/03)-It seems as if the sales of Abbott Laboratories' rheumatoid arthritis drug Humira is rapidly growing its share of the market. Miles D. White told analysts at a meeting in New York that he expected sales of the drug to be more than $250 million, up from a previous estimate of $200 million in 2003. Mr. White estimated that sales from the drug would grow to over $500 million in 2004, making the drug one of the most important products in Abbott's drug line in the next five years.
The rheumatoid arthritis drug Humira, was originally called D2E7. A European advisory panel has recommended approval for Humira to be sold in the European countries, but final approval to sell the drug there is still pending. Abbott developed the medication along with Cambridge Antibody Technology Group of Britain. Abbott acquired rights to the drug when it bought the Knoll Pharmaceutical unit of German's BASF AG. Humira is administered through injection every other week. The drug works the same way as the other two drugs do by blocking an inflammartory protein called TNF-alpha.
Humira requires only one injection every two weeks as opposed to Enbrel which must be injected twice a week, and Remicade which is given by intravenous infusion every two months, or sometimes more frequently. Please keep in mind that since Remicade is given intravenously in the doctor's office, it is reimbursable by Medicare.
Abstracts for the European Congress of Rheumatology's (EULAR) annual meeting held in Stockholm from June 12-15 have been posted on the organization's website. There are seven late-stage abstracts that pertain to Abbott's Humira (D2E7) (Adalimumab).
The studies suggest that D2E7 is very safe and also indicate that it is the first fully human anti-TNF monoclonal antibody that is effective in reducing the symptoms of the disease. The therapeutic benefits also appear to be very durable, with patients continuing to benefit from the drug for at least 2 1/2 years after therapy.
With Remicade from Johnson & Johnson and Enbrel from American Home Products having achieved annual sales of about $1.5 billion there is a huge market out there for this type of product. The company submitted data on D2E7 based on 23 clinical trials involving 2,300 patients to the FDA seeking marketing approval for the drug.
D2E7 like Remicade and Enbrel is a so called anti-TNF-alpha drug because it blocks the effects of a pro-inflammatory protein, called Tumor Necrosis Factor, that is secreted by the cells of the immune system. People with high levels of the protein suffer from rheumatoid arthritis. D2E7 was initially developed by Cambridge Antibody Technology Group PLC and licensed to Knoll Pharmaceuticals before Abbott acquired the company.
Roughly two million Americans suffer from rheumatoid arthritis, and the approval of Humira brings another participant into the battle with Amgen's Enbrel and Johnson & Johnson's Remicade. Abbott has set the wholesale price of Humira at $13,500 for a year's treatment, the same as Enbrel. Remicade costs upwards of $13, 940 a year to administer.
In a particularly aggressive stance to gain market share of this market Abbott is offering its new drug Humira free to seniors who lack prescription drug benefits. "The program is directed at people who couldn't afford the drug and don't have insurance, " said Abbott's chairman and chief executive, Miles D. White, in an interview.
Genentech Inc. of South San Francisco, Ca. And Xoma Ltd of Berkeley, Ca. jointly announced that they were halting further tests on people with rheumatoid arthritis with their biologically engineered drug Raptiva. The companies had determined that the drug failed to effectively help the patients in the trial study group.
Amgen announced that the FDA has requested a review of the safety of TNFa inhibitors. The review will be held at a meeting on March 4-5 and will focus specifically of the incidence of lymphomas in patients taking TNFa inhibitors. The review could result in stronger warnings being added to TNFa inhibitor products specifically warning about lymphoma. Embrel, Remicade and Humira already contain warnings against lymphoma/malignancies on their labels.
Remicade has to be administered intravenously and therefore, even if administered in a doctor's office rather than in an outpatient clinic, is reimbursable through Medicare. Embrel and Humira are both administered as injections, so they do not qualify for Medicare reimbursement.
Amgen announced that it is finally making inroads towards decreasing the amount of patients waiting to use Enbrel for the treatment of rheumatoid arthritis. Production problems had limited the availability of the drug. Amgen has completed its purchase of Immunex for $10 billion and thus will have both Kinert and Enbrel in the battle against rheumatoid arthritis.
The company also announced that a clinical study showed that giving Enbrel once a week with two injections of 25 mg was just as effective as the current regimen of a 25 mg injection given twice a week. The company also stated that it is developing a single injection given once weekly. Amgen initiated this trial to counter one of the primary perceived advantages of Abbott's fully human anti-TNF monoclonal antibody called D2E7 or Humira.
Amgen has received final approval to market Kinert, its treatment for rheumatoid arthritis. Kinert is being priced somewhat comparable to Immunex's Enbrel, with a wholesale acquisition cost (WAC) of $924 for a four week supply or about $12,000 per year. Amgen expects to launch the product early next year. The Food and Drug Administration has recommended widening the use of Enbrel to include patients just beginning to suffer from rheumatoid arthritis as well as those who have especially severe cases of the disease.
The drug has been so successful in fighting arthritis that there is a 40,000 patient waiting list for it. At present about 350,000 patients are using the drug. The drug had slightly over $760 million in sales last year making it the fastest biotech launched drug in history. This injectable drug costs about $12,000 per year to use. The company is seeking to allow the label to contain the claim that it can inhibit the destruction of a patient's joints. Weighed against this cost is the fact that methotrexate, the standard therapy now in use costs about $1,500 per year and comes in pill form. Enbrel had previously been approved for patients in advanced stages of the disease that have failed to respond to other medications.
On the negative side however is the fact that Immunex announced that Enbrel had failed in clinical trials to treat chronic heart failure and asthma. Immunex had thought that the drug could be used to treat these diseases as well as rheumatoid arthritis. Immunex announced at the same time that Enbrel had been effective in treating psoriatic arthritis, a joint condition that afflicts some people suffering from the skin disease psoriasis. The company will apply to the FDA in the middle of this year for approval to sell the drug for that condition which is said to afflict about 250,000 patients in the U.S.
The production problem for Enbrel is one that the biotech industry faces compared to the non-biotech industry. It takes between 4 to 5 years to build and certify a plant to make a biotech drug whereas it only takes from 1 to 2 years to build and certify a non-biotech drug plant. The growing and harvesting of the cells needed for a biotech drug is much more complicated and expensive for this type of drug compared to a non-biotech drug. In order to be able to meet the present demand for Enbrel, Immunex would have had to have started construction of the plant in 1996, which was 2 years before the company won approval of the drug from the FDA.
Remicade, made by Centocor Ind., a subsidiary of Johnson & Johnson is another new drug that is showing great promise in the battle against arthritis. It must be taken in combination with another drug methotrexate, which may potentially cause lung and liver damage. Knoll Pharmaceutical Co., a unit of BASF AG of Germany is finishing a large clinical trial for a drug called D2E7 that doctors say may be as effective as Enbrel. Knoll is in the process of being acquired by Abbott Labs which expects to start selling the drug in 2003.
According to Dr. Arthur Kavanaugh, professor at the University of California at San Diego and an investigator in the study, Abbott Laboratories' experimental drug for rheumatoid arthritis proved as effective as Amgen's Enbrel and Johnson & Johnson's Remicade in treating the disease.
Remicade is administered in the doctor's office and Medicare covers it. Injectible drugs are normally not covered by Medicare. Centocor, the subsidiary of Johnson & Johnson that sells Remicade came under some negative publicity recently because of the fact that its web site extolled the financial benefits to doctors for administering Remicade versus the other rheumatoid arthritis drugs.
Another promising new drug in the battle against rheumatoid
arthritis is Celltech's CDP 870 which for a fee is being
co-developed by Pharmacia. It is also a monoclonal antibody
therapy that is an anti-tumor necrosis factor and is a PEGylated
compound (which makes it longer lasting). This drug is currently
in Phase IIb dosing trials, which means that it is at least 2
years away from being launched. Amgen's Kineret is expected to be
approved by year end when it may be another major drug in the
battle against rheumatoid arthritis.
This article presents the highlights of an international
roundtable on anti-tumor necrosis factor (TNF) therapies for
rheumatoid arthritis held in Lausanne, Switzerland, on February
19 and 20, 1999. Experts in rheumatology discussed the emerging
role of anti-TNF therapies as well as the dominant drug in RA
therapy, methotrexate, and the future role of combination
therapy.
It is known that the cytokine TNF-a
plays a critical role in the inflammation of the lining
(synovium) of the joint that leads to joint destruction and
chronic pain. The anti-TNF agents bind to TNF having the effect
of neutralizing it and thus substantially improving the symptoms
of the disease. More is known about the mechanism of action of
anti-TNF agents than is known about the action of traditional
agents such as methotrexate (MTX), yet the latter has been used
for twenty years and is the most studied drug in clinical trials
for rheumatoid arthritis.
According to Michael E. Weinblatt, MD, Professor of Medicine,
Harvard Medical School and Brigham & Women’s Hospital,
Boston, MA, methotrexate consistently outperforms all other drugs
for RA in comparative trials. It has been shown to be superior to
oral gold, cyclosporine A, and azathriopine. Etanercept, the p75
TNF receptor, is being compared with MTX in a large US trial of
patients with early-onset RA. "Methrotrexate has the highest
long-term retention rate of any disease-modifying antirheumatic
drug (DMARD)," Dr. Weinblatt said. This means that
individuals stay on the drug for long periods of time without any
untoward effects. He believes the most effective dose is about 18
mg per week. However, one of the participants reported that in
his clinic about 20% of patients can’t take more than 7.5 mg
of methotrexate a week because of the adverse effects i.e. oral
ulcers, unacceptable hair loss even with folic acid.
James R. O’Dell, MD, Professor and Chair of Rheumatology and
Program Director, Department of Internal Medicine, University of
Nebraska Medical Center, Omaha, Nebraska reported on combination
therapies in the battle against RA. He said, "until we get a
lot of additional data, combination therapy is going to continue
to be an art." He indicated that 99% of the US
Rheumatologists surveyed use combination therapy to treat
patients who aren’t responding as well as the physician
would like. The American College of Rheumatology defines success
of treatment as a 50% reduction in the number of tender and
swollen joint counts.
The problem with many of the past studies is that they do not
distinguish between those with early RA (average disease
duration, 4 months) and those who have suffered the disease for a
long time or have had trials of medications prior to entering the
study. Individual pharmacological response variation to
medication is related to underlying genetic variations.
There are several other new drugs in the pipeline in connection
with the fight against rheumatoid arthritis. Johnson &
Johnson's Remicade won approval in 1999 as a secondary treatment
after other drugs have failed to work. Aventis's Arave has been
approved in connection with the slowing of the erosion of the
bone and cartilage associated with the disease.
Candidates for anti-TNF include:
In general, participants at this conference felt that anti-TNF therapies are new additions for the
treatment of RA, but there are questions regarding dosages,
toxicities, long-term effects, and appropriate target
populations. While anti-TNF agents can alter symptoms, there is
little known about whether they can alter the course of the
disease as measured by the impact on bone erosion.
Dr. Peter Lipsky, a leading expert in the field of arthritis
research, was asked the question: "Is there any evidence
that aggressive treatment of early rheumatoid arthritis produces
a better long-term outcome than treating patients with
established disease?" His response was: "That is our
anticipation, but again, it needs to be tested, especially with
these new powerful agents." Researchers still need to
determine the characteristics of an individual that indicate
response to a medication.
In announcing it's quarterly earning report on July 12th, 1999
Amgen Inc. also announced some interesting news in the battle
against rheumatoid arthritis. The company stated that it expects
to file a request with the FDA for approval by year's end for its
RA drug IL-1RA. The FDA had reviewed the results of two large
studies that had been conducted using the drug and found that
there would be no need for the final testing phase of a drug
called the "Phase III" testing. This is an extremely
rare occurrence and seems to indicate that the testing of the
efficacy of the drug has gone exceedingly well. The drug has been
previously tested for a different medical condition. Another drug
in the fight against RA is Naproxen.
Although these articles deal with Rheumatoid Arthritis we feel that it is important to report to you the results of a study done on a popular operation on the knee for osteoarthritis. This operation is done on at least 225,000 middle-age and older Americans at a cost of more than a billion dollars to Medicare, the Department of Veterans Affairs and private insurers.
The operation is called arthroscopic surgery for the pain and stiffness caused by osteoarthritis. Investigators at the Houston Veterans Affairs Medical Center and Baylor College of Medicine reported that while the patients often said they felt better after the surgery, their improvement was just wishful thinking. Tests of knee functions revealed that the operation had not helped, and those who got a placebo surgery instead of the arthroscopic surgery felt just as good as those who got the surgery.
There were 180 participants in the study who were randomly assigned to have the operation or to have placebo surgery. After they recovered from the operation, most patients said their knee pains had improved, and they continued to say that they were better for the two years that the researchers followed their progress.
FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "Selecting a Nursing Home"
See: Rheumatoid Arthritis Part I-General
Overview-Part A
See: Rheumatoid Arthritis-Part
III-Vioxx, Celebrex and the Elderly who Have Ulcers.
See: Rheumatoid Arthritis-Part IV-General
Overview-Part B
Harold Rubin, MS, ABD, CRC, Guest Lecturer
Allan Rubin
updated June 17, 2008
To e-mail: hrubin12@nyc.rr.com or rubin@brainlink.com