The FDA ( U.S. Food and Drug Administration ) approved Humira ( Adalimumab ) for first-line treatment of recent onset moderate to severe rheumatoid arthritis ( RA ).
The approval offers RA patients an important therapeutic option early in the course of their disease, when there is a critical window of opportunity to intervene before the potential crippling effects of joint destruction and long-term disability set in.
In 2002, Humira was approved to treat patients with moderately to severely active rheumatoid arthritis, who have had insufficient response to one or more disease-modifying anti-rheumatic drugs ( DMARDs ).

The approval for the expanded indication is based on clinical and radiographic data from the two-year PREMIER study of 799 Methotrexate-naive patients with active recent onset moderate to severe rheumatoid arthritis ( defined as disease of less than three years duration ).
On average, patients had less than nine months of disease duration from the time of diagnosis.

The trial compared three arms, Humira monotherapy, Methotrexate monotherapy, and the two drugs combined in treating this patient population.

The study showed Humira in combination with Methotrexate was superior to Methotrexate alone on several efficacy endpoints, including the two primary endpoints – inhibition of joint damage and improvement in signs and symptoms at one year – and a secondary endpoint, achievement of clinical remission measure of DAS28 < 2.6 at one year.

The Disease Activity Score ( DAS ) measures disease activity responses in rheumatoid arthritis by assessing tender and swollen joint count, general health status and an inflammatory marker.

" Mounting evidence suggests that early and aggressive treatment of moderate to severe rheumatoid arthritis can achieve favorable outcomes, since joint damage can occur quickly, even in the first year, " said Arthur Kavanaugh, UCSD Center for Innovative Therapy, La Jolla, California, and PREMIER investigator. " Humira ( Adalimumab ) has been shown to slow the progression of rheumatoid arthritis when initiated in patients early in their treatment. For many patients, this means reduction in signs and symptoms, but more importantly, significant inhibition of joint damage."

The PREMIER study showed patients taking Humira in combination with Methotrexate experienced significantly less joint damage as measured by the change in modified Total Sharp Score, or mTSS, than those on Methotrexate alone. Modified Total Sharp Score assesses bone erosion and joint space narrowing on X-rays.
A smaller change in mTSS reflects less progression of joint damage.

Also, approximately twice as many patients on the Humira-Methotrexate regimen experienced no further joint destruction compared to those on Methotrexate alone ( 61 percent vs. 34 percent ) after two years.
No joint destruction was defined as < 0.5 units change from baseline in mTSS.

After one year, patients on Methotrexate alone had four times the disease progression as those in the Humira-Methotrexate regimen, with a mean change in mTSS of 5.7 vs. 1.3 respectively, and after two years, patients on MTX alone had five times more disease progression than those on the Humira-Methotrexate regimen, with a mean change in mTSS of 10.4 vs. 1.9 respectively.

In this trial, Humira in combination with Methotrexate significantly improved the signs and symptoms of rheumatoid arthritis.

After one year, 62 percent of patients on the Humira-Methotrexate regimen achieved ACR50 ( a 50 percent or greater improvement in signs and symptoms of rheumatoid arthritis ) compared to 46 percent on Methotrexate alone and 41 percent on Humira alone.

After two years, 59 percent of patients on the Humira-Methotrexate regimen achieved ACR50 compared to 43 percent on Methotrexate alone and 37 percent on Humira alone.

PREMIER is the first rheumatoid arthritis trial to measure ACR50 as a primary endpoint. American College of Rheumatology ( ACR ) scores measure the percentage of improvement in tender and swollen joint count and several other clinical measures.

Forty-three percent of patients on the Humira-Methotrexate regimen achieved a measure of clinical remission as defined by DAS28 < 2.6 at one year vs. 21 percent of patients on Methotrexate only, and nearly one in two patients on the combination therapy achieved clinical remission at two years compared with one in four patients on Methotrexate alone ( 49 percent vs. 25 percent ).

Additionally, almost half of patients on the Humira-Methotrexate regimen achieved major clinical response, defined as achieving and maintaining an ACR70 response for six or more continuous months, compared to Methotrexate alone ( 49 percent vs. 28 percent ).

Also, 27 percent of patients on the Humira-Methotrexate regimen achieved ACR90 at two years, a 90 percent or greater improvement in signs and symptoms, compared to 13 percent on Methotrexate alone.

In this trial, all treatment arms had a comparable overall rate of adverse events.
Among patients taking Humira, the most common adverse events were nasopharyngitis, headache, nausea, diarrhea, joint pain, and pharyngitis.

Important safety information

Cases of tuberculosis ( TB ) have been observed in patients receiving Humira.

Serious infections and sepsis, including fatalities, have been reported with the use of TNF-blocking agents, including Humira.
Many of these infections occurred in patients also taking other immunosuppressive agents that in addition to their underlying disease could predispose them to infections.
Treatment with Humira should not be initiated in patients with active infections.

The combination of Humira and Anakinra is not recommended.

TNF-blocking agents, including Humira, have been associated in rare cases with demyelinating disease and severe allergic reactions. Infrequent reports of serious blood disorders have been reported with TNF-blocking agents.

More cases of malignancies have been observed among patients receiving TNF blockers, including Humira, compared to control patients in clinical trials.
These malignancies, other than lymphoma and non-melanoma skin cancer, were similar in type and number to what would be expected in the general population.
There was an approximately four fold higher rate of lymphoma in combined controlled and uncontrolled open label portions of Humira clinical trials.
The potential role of TNF-blocking therapy in the development of malignancies is not known.

The most frequent adverse events seen in the placebo-controlled clinical trials in rheumatoid arthritis ( Humira vs. placebo ) were injection site reactions ( 20 percent vs. 14 percent ), upper respiratory infection ( 17 percent vs. 13 percent ), injection site pain ( 12 percent vs. 12 percent ), headache ( 12 percent vs. 8 percent ), rash ( 12 percent vs. 6 percent ) and sinusitis ( 11 percent vs. 9 percent ).

Discontinuations due to adverse events were 7 percent for Humira and 4 percent for placebo.

Source: Abbott, 2005


XagenaMedicine2005