International Approvals: Procoralan, H101, AP2573

Yael Waknine

November 21, 2005

Nov. 21, 2005 — The European Commission has approved ivabradine tablets for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers; the Chinese State Food and Drug Administration has approved an oncolytic adenovirus for use with chemotherapy in the treatment of late-stage refractory nasopharyngeal cancer; and the European Medicines Evaluation Agency has approved orphan drug status for a non-prodrug rapamycin analog in the treatment of soft-tissue and bone sarcomas.


Ivabradine (Procoralan) for Chronic Stable Angina in EU

On Nov. 15, the European Commission approved ivabradine (Procoralan film-coated tablets, made by Servier Laboratories, Inc.) for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. The approval allows use of the drug in 27 member states of the European Union.

Ivabradine is a selective inhibitor of cardiac pacemaker I f (funny) current, a sinoatrial node modulator that induces dose-dependent heart rate reduction both at rest and during exercise without modifying myocardial contractility, atrioventricular conduction, and ventricular repolarization duration.

The approval was based on data from four double-blind, randomized trials that compared the antianginal and anti-ischemic efficacy of ivabradine with placebo, atenolol, and amlodipine in 3,222 patients. Results obtained using a standardized exercise tolerance test showed that twice-daily administration of ivabradine, 5 and 7.5 mg, significantly decreased the incidence of anginal episodes.

No serious adverse events were attributed to ivabradine therapy. Unlike beta-blockers, ivabradine therapy was not associated with negative inotropic effects, sexual disturbances, rebound phenomena, bronchoconstriction, or peripheral vasoconstriction. Dose-related, reversible, and often transient visual symptoms were most commonly reported and rarely resulted in drug discontinuation.

Long-term data in patients treated with ivabradine for at least one year (n = 713) revealed sustained reductions in heart rate, with no rebound effect upon discontinuation. No influences on glucose or lipid metabolism were observed.

The recommended starting dose for ivabradine is 5 mg twice daily, followed by up-titration to 7.5 mg twice daily.

According to a company news release, ivabradine is also being studied in a 33-country morbidity-mortality trial (BEAUTIFUL) of more than 10,000 patients with left ventricular dysfunction. Future studies will explore use of the drug for other indications, such as heart failure and acute coronary syndrome.


Oncolytic Gene Therapy (H101) for Head and Neck Cancer in China

On Nov. 17, the Chinese State Food and Drug Administration approved an oncolytic adenovirus (H101, made by Shanghai Sunway Biotech Co., Ltd.) for use in combination with chemotherapy in the treatment of late-stage refractory nasopharyngeal cancer.

H101 is a recombinant human type-5 adenovirus in which the E1B-55kDs gene has been deleted, enabling it to selectively replicate in and lyse p53-mutated tumor cells while leaving normal cells unaffected. It is administered via intratumoral injection.

The approval was based on data from a multicenter, randomized, phase 3 clinical trial, showing that the addition of H101 therapy yielded a 27% increase in overall response rates (complete or partial) compared with fluorouracil plus cisplatin-based chemotherapy alone.

The most commonly reported adverse events related to the gene therapy included fever, injection site reactions, and influenza-like symptoms.

Further studies are planned to evaluate use of the adenovirus for additional indications, including non-small cell lung cancer and osteogenic sarcoma.


Rapamycin Analog (AP23573) Granted Orphan Drug Status for Sarcomas in EU

On Nov. 15, the European Medicines Evaluation Agency approved orphan drug status for a non-prodrug rapamycin analog (AP23573 injection, made by ARIAD Pharmaceuticals, Inc.) for the treatment of soft-tissue and bone sarcomas.

The small-molecule drug potently inhibits the molecular target of rapamycin (mTOR), a critical downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, thereby inhibiting cell cycle progression, cell growth, and proliferation.

Preliminary results of an ongoing phase 2 clinical trial have shown the drug to decrease overall 2-fluoro-2-deoxy-D-glucose (FDG) uptake by more than 25% in nine patients (39%) with tumor-associated uptake; a decrease of less than 25% was observed in the remaining 14 patients. Symptomatic improvements in pain, cough, and dyspnea were noted in 13 patients.

Most adverse events were mild or moderate in severity and included mucositis, anemia, thrombocytopenia, and maculopapular rash.

The mTOR inhibitor was previously approved for these orphan drug indications and granted fast-track status by the U.S. Food and Drug Administration in August 2005. According to a company news release, it is also being studied in phase 1 and 2 clinical trials for the treatment of solid tumors and hematologic cancers.

Reviewed by Gary D. Vogin, MD

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