New FDA Orphan Drugs: Amphotericin B Inhalation Powder, TRX4, AT2101

Yael Waknine

March 02, 2006

March 2, 2006 — The US Food and Drug Administration (FDA) has approved orphan drug status for amphotericin B inhalation powder in the prevention of pulmonary fungal infections in patients at risk for aspergillosis due to immunosuppressive therapy; a monoclonal antibody for the treatment of new-onset type 1 diabetes mellitus; and an orally active, small-molecule drug for the treatment of Gaucher disease.


Orphan Formulation of Amphotericin B Prevents Fungal Lung Infections in High-Risk Patients

The FDA approved in February orphan drug status for a new inhalation powder formulation of amphotericin B (made by Nektar Therapeutics) in the prevention of pulmonary fungal infections in patients at risk for aspergillosis due to immunosuppressive therapy.

According to a company news release, the product may potentially reduce the risk for aspergillosis as well as the subsequent high morbidity and mortality associated with the condition.

The powder is delivered using a small proprietary inhaler, thereby targeting the lungs directly with the broad-spectrum antifungal drug and potentially eliminating systemic toxicities that limit use currently available intravenous formulations.

The approval was based in part on preclinical data showing that use of inhalable amphotericin B yielded a statistically significant improvement in the survival of immunosuppressed rabbits challenged with a pulmonary dose of Aspergillus fumigatus spores.

In addition, little or no pulmonary toxicity was observed when animals were administered amphotericin B at doses 10-fold or greater than those expected for use in humans. Toxicology data revealed no systemic toxicity, and serum drug concentrations were lower than those generally considered as toxic to humans, even at the 10-fold greater doses.

Thus far, the company has conducted 2 phase 1 trials and long-term toxicity studies are underway to support pivotal trials that are expected to begin early next year.


Orphan Drug Immunotherapy (TRX4) for New-Onset Type 1 Diabetes

The FDA approved in February orphan drug status for a monoclonal antibody (TRX4 [ChAglyCD3], made by TolerRx, Inc) in the treatment of new-onset type 1 diabetes mellitus.

According to a company news release, TRX4 is a monoclonal antibody that binds to T-cell CD3 receptors, thereby functionally blocking the autoreactive T-effector cells involved in autoimmune diseases such as type 1 diabetes.

Because T-effector and T-regulatory cells are activated via separate signaling pathways, TX4 is expected to suppress autoreactive disease activity while promoting normal regulatory activity.

The approval was based in part on study data showing that a single 6-day course of the product preserved pancreatic beta-cell function and decreased the amount of insulin required to control blood glucose for a period of at least 18 months.

Adverse events associated with the regimen included transient symptoms of flu-like syndrome and transient Epstein-Barr virus reactivation.

According to the news release, a US clinical trial of type 1 diabetic patients is currently underway to select an optimal dosing regimen for use in future trials. TRX4 is also being studied for the treatment of moderate to severe psoriasis.


Orally Active Orphan Drug (AT2101) for Gaucher Disease

The FDA approved in February orphan drug status for an orally active, small-molecule drug (AT2101, made by Amicus Therapeutics, Inc) in the treatment of Gaucher disease. According to a company news release, the condition affects approximately 10,000 individuals in the developed world.

Gaucher disease is a lysosomal storage disorder related to a deficiency of the key metabolic enzyme glucocerebrosidase (GCase) that leads to cellular accumulation of glucocerebrosidase. Over time, accumulation of these Gaucher cells results in damage to the liver, spleen, bone marrow, and potentially the central nervous system.

In most patients, the enzyme deficiency is caused by a missense mutation that results in protein misfolding and degradation. By binding to GCase, AT2101 acts as a pharmacologic chaperone to restore the enzyme's proper structure and trafficking from the endoplasmic reticulum to the lysosome. Once GCase reaches the lysosome, the chaperone is displaced and enzyme activity is restored.

According to the news release, clinical studies of the drug are expected to begin during the first half of this year.

Reviewed by Gary D. Vogin, MD

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