New FDA Orphan Drugs: Bronchitol, Prestara, GTI-2040

Yael Waknine

July 27, 2005

July 27, 2005 — The U.S. Food and Drug Administration (FDA) has approved orphan drug status for a dry powder formulation of mannitol to facilitate mucus clearance in patients with cystic fibrosis; prasterone to prevent loss of bone mineral density in patients with systemic lupus erythematosus receiving glucocorticoid therapy; and an antisense drug for the treatment of acute myeloid leukemia.

Orphan Drug Formulation of Mannitol (Bronchitol) for Improving Mucus Clearance in CF

On July 20, the FDA approved an expanded indication for an orphan drug formulation of mannitol (Bronchitol, made by Pharmaxis Ltd.), allowing its use to facilitate mucus clearance in patients with cystic fibrosis (CF) at risk for bronchiectasis. The original orphan drug indication approved in February 2005 allowed its use for the treatment of bronchiectasis.

The dry powder formulation is administered via inhaler and is thought to increase mucus clearance by reducing its viscosity and stimulating cough. The product mimics the action of salt in healthy lungs to draw out and restore surface liquid and also has a direct action on cilia.

The original approval was based on the results of phase 2 clinical studies showing the product to be safe, well-tolerated, and effective for stimulating mucus hydration/clearance, thereby improving quality of life in patients with chronic obstructive lung diseases. Data from pilot studies have suggested that its benefits may extend to patients with CF.

Longer-term studies in CF patients are currently underway to assess the efficacy of dry powder mannitol for improving quality of life; reducing the number of bacterial infections and the need for physiotherapy and hospitalization; improving oxygen delivery from the lungs, exercise capacity, and quality of sleep; and achieving overall improvements in lung function.

Orphan Drug Prasterone (Prestara) to Prevent BMD Loss in Patients With Lupus

On June 22, the FDA approved an expanded indication for orphan drug prasterone (Prestara, made by Genelabs Technologies, Inc.), allowing its use for the prevention of loss of bone mineral density (BMD) in patients with systemic lupus erythematosus receiving glucocorticoid therapy. Prasterone is a synthetic form of dehydroepiandrosterone.

The original indication approved in 2004 allowed use of prasterone in patients with lupus. Although results of a phase 3 trial that year (GL02-01) showed a trend toward increased BMD at the lumbar spine at six months' posttherapy (compared with a decrease in the placebo group), the difference did not reach statistical significance (mean, +0.003 vs -0.005 g/cm 2; P = .293).

However, data from a subsequent 12-month trial (GL95-02) showed a significant mean increase of 0.015 g per cm 2 in BMD at the lumbar spine in prasterone-treated patients compared with a decrease of 0.010 g per cm 2 in those administered placebo ( P = .002).

Analysis of possible discrepancies between the studies revealed that the shorter duration of the GL02-01 trial combined with higher baseline BMD measurements and concurrent use of calcium and vitamin D supplements may have played a role in the study's failure to demonstrate the efficacy of prasterone.

Adverse events related to use of prasterone included acne, facial hair growth, hormonal changes, and a reduction in high-density lipoprotein cholesterol.

To further evaluate the efficacy and safety of prasterone in preserving BMD in lupus patients, the company is conducting an open-label 12-month extension of the GL02-01 trial (GL03-01) that will be completed this August. Some patients will have had as much as 18-months' exposure to the drug (six months from original trial plus the 12-month extension), with BMD assessments performed at six-month intervals.

Antisense Oligonucleotide (GTI-2040) Granted Orphan Drug Status for AML

On May 4, the FDA approved a new orphan drug indication for an antisense 20-mer phosphorothioate oligonucleotide (GTI-2040, made by Lorus Therapeutics, Inc.) for the treatment of acute myeloid leukemia (AML).

The antisense oligonucleotide targets the messenger ribonucleic acid for the R2 subunit of ribonucleotide reductase, which is required for DNA synthesis and cell proliferation. Elevated levels of R2 due to deregulation are thought to cooperate with oncogenes to enhance tumor growth and metastatic potential.

The approval was based on data from phase 1 studies showing that the antisense drug significantly inhibited growth in a broad range of solid tumors.

According to a company news release, the product may also improve the efficacy of standard therapy (typically cytarabine) by decreasing drug resistance, a key factor in the poor prognosis of AML.

Phase 2 trials of the drug are currently in progress for a variety of solid tumors, including cancers of the breast, lung, prostate, and colon. Thus far, it has shown significant antitumor activity in non–small-cell lung cancer and metastatic renal cell carcinoma when combined with docetaxel and capecitabine, respectively.

GTI-2040 was previously granted orphan drug status by the FDA in 2004 for the treatment of renal cell carcinoma.

Reviewed by Gary D. Vogin, MD


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