International Approvals: PTC 124, Nelarabine, Rectogesic

Yael Waknine

July 11, 2005

July 11, 2005 — The European Commission has approved orphan drug PTC 124 for the treatment of Duchenne muscular dystrophy and cystic fibrosis caused by nonsense mutations and approved the orphan drug nelarabine for the treatment of acute lymphoblastic leukemia; the U.K.'s Medicines and Healthcare Products Regulatory Agency has approved nitroglycerine 0.4% ointment for the treatment of chronic anal fissures.

Orphan Drug (PTC 124) for DMD and CF in the European Union

On July 7, the European Commission approved two indications for orphan drug PTC 124 (made by PTC Therapeutics, Inc.), allowing its use in the treatment of Duchenne muscular dystrophy (DMD) and cystic fibrosis (CF) caused by nonsense mutations.

According to a company news release, an estimated 10% of CF and 15% of DMD patients have these diseases as a consequence of nonsense mutations in the CF conductance regulator and dystrophin gene, respectively, that prematurely halt protein translation.

The single-molecule drug selectively modulates RNA use to allow bypass of the point mutation for the production of full-length, functional proteins. As such, it has the potential to address the underlying cause of disease, in contrast with current measures that may only temporarily slow disease progression or provide palliative benefit.

The approvals were based on the results of phase 1 studies in healthy volunteers showing that the drug is orally bioavailable and generally well tolerated, achieves target plasma concentrations that have been associated with activity in preclinical models, and does not induce ribosomal readthrough of normal stop codons.

Pharmacokinetic modeling of phase 1 data has led to the development of dosing regimens for use in phase 2 studies that are expected to begin in the U.S. later this year. The company is also working with patient advocacy groups and other organizations to develop studies in other regions of the world.

PTC 124 was previously granted fast-track status by the U.S. Food and Drug Administration for the CF indication and orphan drug indications in the treatment of CF and DMD on Dec. 9, 2004, and Jan. 27, 2005, respectively.

Potential indications currently under evaluation include hemophilia, neurofibromatosis, retinitis pigmentosa, epidermolysis bullosa, and lysosomal storage disorders.

Orphan Drug (Nelarabine) for ALL in the European Union

On June 16, the European Commission approved orphan drug designation for nelarabine (made by GlaxoSmithKline Research & Development, Ltd.) in the treatment of acute lymphoblastic leukemia (ALL).

Nelarabine is a prodrug of arabinosylguanine with T-cell selectivity. The nucleoside analog is converted into arabinosylguanine nucleotide triphosphate, which inhibits DNA synthesis and induces apoptosis.

Although the approval was based on data from studies in experimental models, results of a clinical study in 2003 showed that nelarabine therapy induced a response in more than half of pediatric patients with leukemia treated after first relapse and in more than a quarter of those treated after multiple relapses.

In the study, 153 patients younger than 21 years with refractory or relapsed T-cell lymphoblastic leukemia or non-Hodgkin's lymphoma received 650 mg per m2 of nelarabine daily as a one-hour intravenous dose for five consecutive days every three weeks.

Among 33 evaluable patients who were refractory to initial therapy or in first relapse, 53% responded to nelarabine therapy, including 16 patients (48%) who had a complete remission or return of their bone marrow to normal cell counts.

Among 30 patients whose disease had relapsed or not responded to two or more prior therapies, 8 (26%) responded, and 7 (23%) achieved complete remission.

The principle dose-limiting adverse events associated with nelarabine therapy were neurologic in nature.

Nelarabine was granted orphan drug designation by the U.S. Food and Drug Administration on Aug. 10, 2004, for the treatment of ALL and lymphoblastic lymphoma and has recently been granted fast-track status for these indications.

Nitroglycerin 0.4% Ointment (Rectogesic) for Anal Fissures in the U.K.

On May 27, nitroglycerin 0.4% ointment (Rectogesic, also known as Cellegesic, made by Cellegy Pharmaceuticals, Inc.) was launched in the U.K. The ointment was approved on Aug. 25, 2004, by the U.K.'s Medicines and Healthcare Products Regulatory Agency for the topical treatment of pain associated with chronic anal fissure.

The approval allows the U.K. to act as a reference member state for the European Union's Mutual Recognition Procedure that facilitates reciprocal drug approvals in member countries. The product is currently being considered for approval by the U.S. Food and Drug Administration.

Reviewed by Gary D. Vogin, MD

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