NEWS - FDA approves Orencia (abatacept) for rheumatoid arthritis

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FDA Approves Orencia® (abatacept) For Rheumatoid Arthritis Treatment

Category: Arthritis News

Article Date: 26 Dec 2005

Bristol-Myers Squibb Company (NYSE: BMY) announced today that the U.S. Food

and Drug Administration (FDA) has approved Orencia® (abatacept), the first

selective modulator of a co-stimulatory signal required for full T-cell

activation, for the treatment of rheumatoid arthritis (RA).

Orencia is indicated for reducing the signs and symptoms of RA, inducing

major clinical response, slowing the progression of structural damage, and

improving physical function in adult patients with moderately to severely

active RA who have had an inadequate response to one or more

disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX)

or tumor necrosis factor (TNF) antagonists. Orencia may be used as

monotherapy or concomitantly with DMARDs other than TNF antagonists. Orencia

should not be administered concomitantly with TNF antagonists and is not

recommended for use concomitantly with anakinra.

" Bristol-Myers Squibb is committed to discovering and developing innovative

medications that address areas of significant unmet need, " said R.

Dolan, chief executive officer, Bristol-Myers Squibb. " There is clearly a

need for more therapies for rheumatoid arthritis, and Orencia has the

potential to help many people with this serious disease. Orencia is our

first internally-discovered biologic and it further diversifies our

pharmaceutical portfolio. "

Orencia was studied in patients with an inadequate response to DMARDs.

Specifically, it is the first approved agent to demonstrate efficacy and

safety in patients with an inadequate response to TNF antagonists, as well

as those with an inadequate response to MTX. Methotrexate is the most widely

used non-biologic DMARD for RA and TNF antagonists are the most widely used

biologic therapies for RA. Orencia is also the first in a new class of

agents for the treatment of RA that selectively modulates a co-stimulatory

signal required for full T-cell activation.

" In clinical trials, Orencia significantly reduced the signs and symptoms of

rheumatoid arthritis among patients who had inadequate response to DMARDs

such as methotrexate and/or anti-TNF therapy when compared to placebo, " said

Mark Genovese, M.D., associate professor of medicine at the Stanford

University School of Medicine, Palo Alto, CA. " Rheumatoid arthritis is a

very serious disease and it is critical that we continue to add therapies to

our armamentarium. "

Orencia Clinical Development Program

The efficacy and safety profiles of Orencia have been studied through a

rigorous clinical trial program that included more than 2,600 patients. More

than 3,800 person-years of experience were included across the

placebo-controlled and open-label extension periods of the clinical trials.

The Phase III trial program included three major double-blind randomized

placebo-controlled studies: AIM (Abatacept in Inadequate responders to

Methotrexate), which compared Orencia in combination with MTX to MTX alone;

ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders),

which compared Orencia in combination with non-biologic DMARDs to

non-biologic DMARDs alone in patients with an inadequate efficacy response

to the TNF antagonists etanercept and infliximab; and ASSURE (Abatacept

Study of Safety in Use with other RA thErapies), which studied the safety of

Orencia compared to placebo when used in combination with a variety of

biologic and non-biologic DMARDs.

In both pivotal Phase III efficacy studies (AIM and ATTAIN), Orencia

demonstrated significant and sustained improvement of the signs and symptoms

of RA as measured by American College of Rheumatology (ACR) 20, 50, and 70

scores, with significant difference from placebo by day 15 for ACR 20 in

some patients, which was the first follow-up visit after the first dose. In

both trials, significant improvements in physical function were noted as

compared to placebo. Health-related quality of life was assessed by the

SF-36 questionnaire; improvements were observed in the patients treated with

Orencia as compared to placebo in all eight domains* of the SF-36. ACR

responses and improvements in physical function were maintained up to three

years in a Phase II trial of patients with inadequate response to MTX.

Additionally, a significant proportion of patients taking Orencia plus MTX

achieved a major clinical response, defined as maintaining an ACR 70 score

for six consecutive months, compared to those treated with MTX alone in AIM

(14 percent versus 2 percent; p-value less than 0.001).

In AIM, structural damage was slowed in patients treated with Orencia plus

MTX, compared to those treated with MTX alone.

Important Safety Information about Orencia

Concurrent therapy with Orencia and a biologic DMARD is not recommended. In

controlled clinical trials, patients receiving concomitant Orencia and TNF

antagonist therapy experienced more infections (63 percent) and serious

infections (4.4 percent) compared to patients treated with only TNF

antagonists (43 percent and 0.8 percent, respectively), without an important

enhancement of efficacy.

Caution should be exercised in patients with a history of infection or

underlying conditions which predispose them to infections. Treatment with

Orencia should be discontinued if a patient develops a serious infection.

Patients should be screened for tuberculosis and if positive, should be

treated with standard medical practice prior to therapy with Orencia.

Less than 1 percent of patients treated with Orencia experienced

hypersensitivity reactions, including two cases of anaphylaxis or

anaphylactoid reactions. Other events potentially associated with drug

hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred

in less than 0.9 percent of patients treated with Orencia and generally

occurred within 24 hours of an infusion with Orencia. Appropriate medical

support measures for the treatment of hypersensitivity reactions should be

available.

Live vaccines should not be given concurrently with Orencia or within three

months of its discontinuation.

Chronic obstructive pulmonary disease (COPD) patients treated with Orencia

developed adverse events more frequently than those treated with placebo,

including COPD exacerbations, cough, rhonchi, and dyspnea. Use of Orencia in

patients with rheumatoid arthritis and COPD should be undertaken with

caution and such patients should be monitored for worsening of their

respiratory status.

Orencia should be used during pregnancy only if clearly needed. Rats treated

every three days with abatacept during early gestation throughout the

lactation period showed no adverse effects in the offspring at doses up to

45 mg/kg. At a dose of 200 mg/kg, alterations of immune function consisted

of a 9-fold increase in the T-cell dependent antibody response in female

pups and inflammation of the thyroid in one female out of 10 male and 10

female pups evaluated. Whether these findings indicate a risk for

development of autoimmune diseases in humans exposed in utero to abatacept

has not been determined.

Nursing mothers should discuss with their healthcare practitioner the

risk/benefit of continued breast-feeding or discontinuation of the drug.

The most serious adverse reactions were serious infections (3 percent

Orencia versus 1.9 percent placebo) and malignancies (1.3 percent Orencia

versus 1.1 percent placebo).

The overall frequency of malignancies was similar in patients treated with

Orencia and placebo-treated patients. However, more cases of lung cancer

were observed in patients treated with Orencia (0.2 percent) than

placebo-treated patients (0 percent). A higher rate of lymphoma was seen

compared to the general population; however, patients with RA, particularly

those with highly active disease, are at a higher risk for the development

of lymphoma. The potential role of Orencia in the development of

malignancies in humans is unknown.

The most frequent adverse events occurring in greater than or equal to 10

percent of patients treated with Orencia were headache, upper respiratory

tract infection, nasopharyngitis, and nausea.

Orencia Prescribing Information

http://www.orencia.com

Dosing and Administration

Orencia (a fully human soluble fusion protein) is administered as a

30-minute intravenous infusion at a fixed dose based on weight range

approximating 10 mg/kg at day 0, 2 weeks, 4 weeks, and every four weeks

thereafter. Infusion reactions were experienced in 9 percent of patients

treated with Orencia and in 6 percent of patients treated with placebo. The

most frequently reported events (1 percent to 2 percent) were dizziness,

headache, and hypertension. In clinical trials, premedications were not

required. However, appropriate medical support measures for the treatment of

hypersensitivity reactions should be available for immediate use in the

event of a reaction.

Orencia Supply Information

Orencia is expected to be available for initial commercial use by the end of

February 2006. As previously stated, in order to increase production

capacity and meet expected long-term demand for Orencia, Bristol-Myers

Squibb expects to submit a supplemental biologics license application (sBLA)

to the FDA for a third-party manufacturing facility shortly. During this

period between BLA and sBLA approval, a single distributor will be used. For

more information, healthcare providers and patients can call 1-800-ORENCIA

(673-6242) or visit www.orencia.com.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, chronic, autoimmune disease

characterized by inflammation in the lining of joints (or synovium), causing

joint damage with chronic pain, stiffness, and swelling1. RA causes limited

range of motion and decreased function as a result of affected joints losing

their shape and alignment.1

RA affects about 1 percent of the world's population2, including more than

two million people in the United States3. The condition is more common in

women than in men, who account for 75 percent of patients diagnosed with

RA.3

Bristol-Myers Squibb is a global pharmaceutical and related health care

products company whose mission is to extend and enhance human life.

Bristol-Myers Squibb Forward Looking Statement

This press release contains " forward-looking statements " as that term is

defined in the Private Securities Litigation Reform Act of 1995 regarding

ORENCIA supply. Such forward-looking statements are based on current

expectations and involve inherent risks and uncertainties, including factors

that could delay, divert or change any of them, and could cause actual

outcomes and results to differ materially from current expectations. No

forward-looking statement can be guaranteed. There can be no guarantee that

the sBLA for a second ORENCIA manufacturing facility will be approved.

Forward-looking statements in this press release should be evaluated

together with the many uncertainties that affect Bristol-Myers Squibb's

business, particularly those identified in the cautionary factors discussion

in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended

December 31, 2004 and in our Quarterly Reports on Form 10-Q. Bristol-Myers

Squibb undertakes no obligation to publicly update any forward-looking

statement, whether as a result of new information, future events or

otherwise.

*The eight domains are: physical functioning, role-limitations due to

physical problems, energy/fatigue, emotional well-being, role-limitations

due to emotional problems, social functioning, pain and general health.

1 - Guidelines for the management of rheumatoid arthritis; 2002 update.

Arthritis & Rheumatism. 2002;46(2):328-346.

2 - Lee DM and Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358:903-911.

3 - American College of Rheumatology Web site. Rheumatoid arthritis.

Accessed December 20, 2005.

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