New FDA Orphan Drugs: Amplimexon, AP23573, TQ-1017

Yael Waknine

September 06, 2005

Sept. 6, 2005 — The U.S. Food and Drug Administration (FDA) has approved orphan drug status for imexon for the treatment of ovarian cancer; a non-prodrug rapamycin analog for the treatment of soft-tissue and bone sarcomas; and an abuse-deterrent once-daily formulation of tramadol HCl for the management of postherpetic neuralgia.

Imexon (Amplimexon) for the Treatment of Ovarian Cancer

On Aug. 30, the FDA approved a new orphan drug indication for imexon injection (Amplimexon, made by AmpliMed Corp.), allowing its use in the treatment of ovarian cancer.

Imexon is an injectable formulation of a cyanoaziridine compound that functions as a potent mitochondrial oxidant, scavenging glutathione and other sulfhydryl-containing compounds and inducing apoptosis.

The approval was based on the results of preclinical efficacy studies demonstrating the product's ability to kill ovarian cancer cells at doses that can be achieved in humans.

Imexon has also demonstrated synergistic effects with common cancer therapies such as docetaxel and platinum-containing agents. According to a company news release, study results suggest that imexon may resensitize certain types of ovarian cancer to these therapies, thereby overcoming drug resistance and extending the period of clinical response.

Imexon was previously granted orphan drug designation for the treatment of metastatic malignant melanoma, multiple myeloma, and pancreatic cancer. It is currently in phase 1/2 clinical studies in combination with gemcitabine for the treatment of pancreatic cancer, and with dacarbazine for the treatment of metastatic melanoma.

In prior human trials, imexon was well-tolerated and effective, with moderate myelosuppressive effects only at the highest doses. Full doses can be used in combination with other cytotoxic drugs and in patients with compromised bone marrow function.

Rapamycin Analog (AP23573) for the Treatment of Soft-Tissue and Bone Sarcomas

On Aug. 18, the FDA approved orphan drug and fast-track 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 is also in phase 1 and 2 clinical trials for the treatment of solid tumors and hematologic cancers.

Once-Daily Secure-Release Tramadol (TQ-1017) for Postherpetic Neuralgia

On Aug. 11, the FDA approved a second orphan drug indication for an abuse-deterrent once-daily extended-release formulation of tramadol HCl (TQ-1017, made by TheraQuest Biosciences, LLC), allowing its use in the management of postherpetic neuralgia.

According to a company news release, the secure-release formulation was engineered to provide a greater margin of safety in the event of intentional or inadvertent attempts to defeat the time-release mechanism. It cannot be crushed for inhalation or to obtain rapid euphoria from high blood levels when swallowed, and extraction of tramadol using common solvents (such as alcohol) is difficult.

The product was approved in February 2005 for the management of HIV-related neuropathic pain. Short-acting tramadol, in 50-mg tablet formulation (Ultram, made by Ortho-McNeil Pharmaceuticals, Inc.), is approved by the FDA only for the management of moderate to moderately severe pain in adults.

Reviewed by Gary D. Vogin, MD

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