International Approvals: Ambrisentan, Oral-lyn, Risperdal

Yael Waknine

May 09, 2005

May 9, 2005 — The European Commission has approved orphan drug status for ambrisentan for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension; the Ecuadorian Ministry of Public Health has approved an oral insulin spray for the management of type 1 and type 2 diabetes mellitus; and Health Canada has approved a new indication for risperidone, allowing its use as monotherapy for the acute management of manic episodes associated with bipolar I disorder.

Ambrisentan Granted Orphan Drug Status for Pulmonary Arterial Hypertension in EU

On May 2, the European Commission approved ambrisentan (made by Myogen, Inc.) for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension.

Ambrisentan is a selective endothelin receptor type A (ETA) antagonist and potent inhibitor of endothelin-induced vasoconstriction.

Endothelin is thought to play a critical role in the control of blood flow and cell growth; elevated levels of the hormone are associated with several cardiovascular conditions such as PAH, chronic renal disease, hypertension, and chronic heart failure.

According to a company news release, recent studies have revealed that the two classes of endothelin receptors (ETA and ETB) play significantly different roles in regulating blood vessel diameter. The binding of endothelin to ETA receptors on vascular endothelium causes vasoconstriction, while binding to ETB receptors causes vasodilatation through nitric oxide production.

Selective ETA antagonists such as ambrisentan therefore have the potential to prevent vasoconstriction and cell proliferation while preserving the beneficial effects of ETB receptor activation.

According to the news release, potential advantages of ambrisentan over nonselective endothelin receptor antagonists include enhanced efficacy; a lower incidence of hepatotoxicity; the potential for once-daily dosing; and a lower incidence of adverse interactions with other drugs, including anticoagulants.

Two large, multinational, randomized, double-blind, placebo-controlled, phase 3 clinical trials (ARIES 1 and 2) are currently in progress to evaluate the efficacy of ambrisentan in improving exercise capacity in subjects with PAH.

Ambrisentan was granted orphan drug status by the FDA in August 2004 for the PAH indication.

Oral Insulin Spray (Oral-lyn) for Type 1 and 2 Diabetes in Ecuador

On May 3, the Ecuadorian Ministry of Public Health approved the first oral spray formulation of insulin (Oral-lyn, made by Generex Biotechnology Corp.) for the treatment of type 1 and 2 diabetes mellitus. The approval is expected to pave the way for similar approvals worldwide.

The device delivers insulin for buccal absorption with no lung deposition. According to a company news release, the oral formulation is intended to offer a safe, simple, convenient, fast, and effective alternative to prandial insulin injections.

The approval was based on the results of clinical trials involving more than 250 patients with diabetes, showing that use of the product yielded insulin and blood glucose levels consistent with those achieved by injected insulin.

Additional studies of the oral insulin formulation are ongoing worldwide, and phase 3 clinical trials are slated to begin in Europe and Canada later this year.

Risperidone (Risperdal) Monotherapy for Bipolar Mania in Canada

On April 22, Health Canada approved a new indication for risperidone (Risperdal, made by Janssen-Ortho, Inc.), allowing its use as monotherapy for the acute management of manic episodes associated with bipolar I disorder.

The approval was based on the results of three 3-week, randomized, placebo-controlled clinical trials showing that risperidone provided significant and rapid relief of manic symptoms as early as three days after therapy initiation.

In addition, results of a three-month, double-blind, placebo-controlled comparative study in 6,438 patients experiencing a manic episode showed that risperidone was similarly efficacious to haloperidol therapy in improving symptoms over a three-week initial period, while demonstrating an improved safety profile. Compared with haloperidol, risperidone therapy was associated with a decreased incidence of extrapyrimidal adverse effects such as trembling, decreased motor function/activity, and restlessness.

Treatment with risperidone was generally well tolerated at a dose range of 1 to 6 mg/day. The majority of reported adverse events were mild to moderate in intensity and included somnolence, extrapyrimidal symptoms, and hyperkinesia.

Risperidone was previously approved in Canada for the treatment of schizophrenia and inappropriate behavior caused by aggression and/or psychosis in severe dementia. It is approved by the FDA for the treatment of schizophrenia and for use alone or in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder.

Reviewed by Gary D. Vogin, MD

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