International Approvals: Humira, Atripla, Januvia

Yael Waknine

January 14, 2008

January 14, 2008 — The European Commission (EC) has approved adalimumab injection for the treatment of moderate-to-severe plaque psoriasis and efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablets for the treatment of HIV infection. Health Canada has approved sitagliptin phosphate tablets in combination with metformin and diet/exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Adalimumab (Humira) for Moderate-to-Severe Plaque Psoriasis in EU

On December 20, the European Commission (EC) approved a new indication for adalimumab subcutaneous injection (Humira, Abbott Laboratories), allowing its use for the treatment of moderate-to-severe plaque psoriasis.

Psoriasis is a chronic, noncontagious autoimmune skin disease for which there is currently no cure. The disease affects an estimated 125 million people worldwide, 25% of whom have moderate to severe symptoms.

The approval was based in part on data from a pivotal 16-week Comparative Study of Humira vs Methotrexate vs Placebo in Psoriasis Patients (CHAMPION; N = 271), showing that 80% of adalimumab-treated patients achieved a 75% improvement in the extent and severity of psoriasis symptoms, as measured by the 72-point Psoriasis Area and Severity Index score (PASI 75).

In contrast, only 35.5% of those receiving standard methotrexate therapy and 18.9% of patients receiving placebo achieved PASI 75 (P < .001 for both). Similarly, 17% of patients in the adalimumab group achieved PASI 100 vs 7% and 2% of those in the methotrexate and placebo groups, respectively.

Patient response to adalimumab was rapid, with a mean PASI improvement of 57% achieved at week 4 relative to baseline. Results of the Physician's Global Assessment, a secondary endpoint, showed that 73% of patients receiving adalimumab vs 30% of those receiving methotrexate and 11% of placebo patients achieved psoriasis assessments of "clear" or "minimal" (P < .001 for both).

"This is the first psoriasis study to feature a head-to-head comparison between a biologic agent and a standard systemic treatment," the company notes in a news release.

These findings were supported by those of the 52-week Randomized Controlled EValuation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis study (REVEAL; N = 1200), showing that 71% and 20% of adalimumab-treated patients achieved PASI 75 and PASI 100 at 16 weeks, respectively, compared with 6.5% and 1% of those receiving placebo.

At 16 weeks, patients who had achieved PASI 75 were randomly assigned to receive placebo or continue adalimumab therapy. Results at 52 weeks showed that significantly fewer patients in the adalimumab group lost response, as defined by a less than 50% improvement in PASI score relative to baseline and worsening of psoriasis (minimum 6-point increase in PASI score) vs that achieved at week 33 of the year-long study (5% vs 28%).

"Patients taking Humira for psoriasis experienced rapid, significant skin clearance and maintained improvement for up to a year," says Eugene Sun, MD, vice president of Global Pharmaceutical Clinical Development at Abbott in a company news release. Adverse events most commonly reported included nasopharyngitis, upper respiratory tract infection, and headache.

The recommended regimen of adalimumab for patients with moderate-to-severe plaque psoriasis is 80 mg at week 0, followed by 40 mg every other week starting at week 1. Adverse events observed in the studies were similar to that observed in other trials of the drug and most commonly included injection site reaction, hepatic events, nasopharyngitis, arthralgia, and headache.

Adalimumab previously was approved by the EC and US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn's disease. The plaque psoriasis indication is currently under consideration by the FDA.

Once-Daily Efavirenz/Emtricitabine/Tenofovir Tablets (Atripla) for HIV in EU

On December 17, the European Commission approved efavirenz 600 mg/emtricitabine 200 mg plus tenofovir disoproxil 245 mg (equivalent to 300 mg of tenofovir disoproxil fumarate; Atripla, filed as a 3-way joint venture between Bristol-Myers Squibb, Gilead Sciences, and Merck Sharp & Dohme Ltd) for once-daily use alone or with other antiretroviral agents in the treatment of HIV-1 infection in adults with virologic suppression to HIV-1 (RNA levels < 50 copies/mL) on their current combination antiretroviral therapy for more than 3 months.

Its use in the European Union is limited to patients who have not have experienced virological failure on any prior antiretroviral therapy and who are known not to harbor virus strains with mutations conferring significant resistance to any of the 3 components.

The approval was based on data from a 48-week, open-label, randomized, active-controlled, multicenter study (N = 487) showing that once-daily use of the efavirenz/emtricitabine/tenofovir product was noninferior to efavirenz plus twice-daily lamivudine/zidovudine (Combivir, GlaxoSmithKline) for achieving a viral load of fewer than 400 copies/mL (84% vs 73%).

Efavirenz/emtricitabine/tenofovir tablets previously were approved by the US Food and Drug Administration and Health Canada in July 2006 and October 2007, respectively. In the United States, the tablets are marketed by Bristol-Myers Squibb as Sustiva.

Sitagliptin Phosphate ( Januvia) for Type 2 Diabetes in Canada

On December 14, Health Canada approved sitagliptin phosphate tablets (Januvia, Merck Frosst Canada Ltée) as an add-on therapy to improve glycemic control in patients with type 2 diabetes for whom diet and exercise plus metformin do not provide adequate control. The recommended dose is 100 mg/day.

"Many Canadians with type 2 diabetes continue to face challenges in optimizing their diabetes control. The introduction of sitagliptin provides an important and innovative new option for the management of type 2 diabetes, which will be welcome news for patients and health care providers across Canada," says Daniel Drucker, MD, professor of medicine and director of Toronto's Banting and Best Diabetes Centre in a company news release.

Sitagliptin represents a new class of oral drugs called dipeptidyl peptidase 4 inhibitors. These agents serve to increase the body's active incretin hormone levels, which trigger the pancreas to increase insulin and signal the liver to stop glucose production. Adding sitagliptin to an insulin sensitizer such as metformin therefore addresses the 3 key defects of diabetes: insulin resistance, beta-cell dysfunction, and alpha-cell dysfunction.

The approval was based on data from a 24-week study of 701 patients, showing that the addition of sitagliptin 100 mg to metformin yielded a significant decrease from baseline in hemoglobin A1c (Hb A1c) relative to metformin alone (−0.7; P < .001); more than twice as many sitagliptin-treated patients achieved an HbA1c goal of 7% or less (47% vs 18%; P < .001).

Significant decreases in postprandial and fasting plasma glucose levels were likewise observed (−51 and −25 mg/dL, respectively; P < .001 for both).

"One in 2 Canadians being treated for type 2 diabetes does not achieve the targeted HbA1c level (average blood sugar level over 3 months) of less than or equal to 7% as per the Canadian Diabetes Association Guidelines," the company says in the news release.

Sitagliptin previously was approved by the US Food and Drug Administration for use as initial therapy in combination with metformin, add-on therapy with a sulfonylurea (glimepiride) when the single agent alone does not provide adequate glycemic control, and add-on therapy to glimepiride and metformin when dual therapy does not achieve adequate control.

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