New FDA Orphan Drugs: Zactima, Surfaxin, IL-21

Yael Waknine

November 08, 2005

Nov. 8, 2005 — The U.S. Food and Drug Administration (FDA) has approved orphan drug status for ZD6474 for the treatment of follicular, medullary, anaplastic, and locally advanced and metastatic papillary thyroid cancer; lucinactant for the treatment of bronchopulmonary dysplasia in premature infants; and interleukin 21 for the treatment of advanced or aggressive melanoma.

Orphan Drug ZD6474 (Zactima) for the Treatment of Rare Forms of Thyroid Cancer

On Oct.31, the FDA approved orphan drug status for ZD6474 (Zactima, made by AstraZeneca) for the treatment of follicular, medullary, anaplastic, and locally advanced and metastatic papillary thyroid cancer.

ZD6474 is an orally active selective inhibitor of the vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. RET tyrosine kinase activity is an important growth driver in certain thyroid tumors

Because the agent combines the action of gefitinib (Iressa, made by AstraZeneca) and erlotinib HCl (Tarceva, made by OSI Pharmaceuticals, Inc.) with an additional ability to deprive tumors of their blood supply via VEGFR-2–mediated antiangiogenic effects, it is expected to show activity across a wide range of solid tumors.

In phase 2 studies of locally advanced or metastatic non–small cell lung cancer (NSCLC), patients treated with 300 mg of ZD6474 once daily achieved a significant improvement in progression-free survival (PFS) compared with gefitinib (hazard ratio [HR], 0.632; 95% confidence interval, 0.44 - 0.90; P < .011).

According to a company news release, this dose is currently being studied in a phase 2 trial of thyroid cancer; adverse events observed thus far are consistent with those observed in previous trials and most commonly include diarrhea, rash, and nausea/vomiting. Asymptomatic QTc prolongation has also been reported.

ZD6474 is currently being reviewed by the European Medicines Evaluation Agency for orphan drug status in the treatment of medullary thyroid cancer.


Orphan Drug Lucinactant (Surfaxin) for Bronchopulmonary Dysplasia in Premature Infants

On Oct. 28, the FDA approved orphan drug status for lucinactant (Surfaxin, made by Discovery Laboratories, Inc.) for the treatment of bronchopulmonary dysplasia (chronic lung disease [CLD]) in premature infants.

The protein B–based agent is designed to mimic the surface-active properties of human lung surfactant. Data from clinical trials have demonstrated its efficacy for removing inflammatory and infectious infiltrate from patients' lungs when used by lavage, and as lung surfactant replacement therapy.

Administration of lucinactant in bolus form through an endotracheal tube is currently being evaluated in a phase 2, double-blind, controlled trial of up to 210 very-low-birthweight premature infants born at risk for developing CLD.

According to a company news release, the study is designed to determine the safety and tolerability of lucinactant administration in a total of five doses during the first 10 days of the infant's life as a therapeutic approach for the prevention of CLD. Primary end points include the proportion of infants on mechanical ventilation/oxygen and the incidence of death or CLD.

The product was previously deemed approvable by the FDA in February 2005 for the prevention and treatment of respiratory distress syndrome in infants. This indication is also currently under review for approval by the European Medicines Evaluation Agency (EMEA).

Lucinactant has also been granted orphan drug status by the FDA and the EMEA for the treatment of acute lung injury and acute respiratory distress syndrome in adults; phase 2 studies for this indication are currently in progress.


Orphan Drug Interleukin 21 (IL-21) for the Treatment of Advanced Melanoma

On Oct. 5, the FDA approved orphan drug status for interleukin 21 (IL-21, made by ZymoGenetics, Inc.) for the treatment of advanced or aggressive melanoma.

According to a company news release, the IL-21 receptor was first discovered by screening DNA sequence databases using a computer algorithm based on cytokine receptor structural similarities. It appears to be expressed in bone marrow cells and defined subsets of B cells, T cells, and natural killer cells that circulate in blood.

IL-21 was subsequently identified through receptor activity and found to be structurally similar to interleukin 2, an approved therapy for several cancers.

The approval was based on the results of animal studies demonstrating the cytokine's ability to increase the activity of natural killer cells and disease-specific cytotoxic T cells, thereby suppressing tumor growth and significantly decreasing the number of metastases.

IL-21 is currently being evaluated in phase 1b clinical trials of melanoma and renal cell carcinoma.

Reviewed by Gary D. Vogin, MD

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