New FDA Orphan Drugs: Lestaurtinib, TRX4, and EPI-A0001

Yael Waknine

April 11, 2006

April 11, 2006 — The US Food and Drug Administration (FDA) has approved orphan drug status for CEP-701 in the treatment of acute myeloid leukemia; the monoclonal antibody ChAglyCD3 for new-onset type 1 diabetes mellitus; and EPI-A001 for the treatment of inherited mitochondrial respiratory chain diseases.

Orphan Drug CEP-701 (Lestaurtinib) for Acute Myeloid Leukemia

On April 4, the FDA approved orphan drug status for CEP-701 (lestaurtinib, made by Cephalon, Inc) in the treatment of acute myeloid leukemia (AML).

CEP-701 is an orally bioavailable indolocarbazole derivative with antineoplastic properties. It inhibits autophosphorylation of FMS-like tyrosine kinase 3 (FLT3), resulting in inhibition of FLT3 activity and induction of apoptosis in tumor cells that overexpress FLT3.

According to a company news release, nearly one third of AML patients have a mutation in the gene for FLT3, which is linked to an increased risk for relapse and reduced survival.

Preliminary results from an ongoing phase 2 trial in patients with relapsed AML have shown that CEP-701 given in sequence with induction chemotherapy significantly increased the proportion of patients who achieved a second complete remission within 42 days compared with chemotherapy alone (46% vs 27%, respectively). The drug was administered in an oral dose of 80 mg twice daily beginning 2 days after the end of chemotherapy for a duration of up to 113 days.

Study results also showed that susceptibility of leukemia cells at baseline may be a marker for clinical response. Patients whose cells were susceptible to CEP-701 at baseline and had an 85% or greater inhibition of FLT3 activity showed significant response compared with those having low baseline sensitivity or FLT3 plasma levels.

CEP-701 was generally well-tolerated in the study; gastrointestinal events such as nausea and dyspepsia were most commonly reported.

CEP-701 is also being investigated in a phase 2 trial of patients with advanced multiple myeloma and phase 1 trials of patients with prostate cancer and young patients with recurrent or refractory high-risk neuroblastoma.

Orphan Drug ChAglyCD3 (TRX4) for New-Onset Type 1 Diabetes

On February 14, the FDA approved orphan drug status for ChAglyCD3 (TRX4, made by TolerRx, Inc) in the treatment of new-onset type 1 diabetes mellitus.

ChAglyCD3 is a monoclonal antibody that binds to the CD3 receptor on T cells. It is designed to block the function of autoreactive T-effector cells while promoting regulatory T-cell activity, thereby improving immunologic tolerance.

The approval was based on data from a clinical study showing that a single 6-day course of ChAglyCD3 preserved the function of insulin-producing pancreatic beta cells, thereby reducing the amount of insulin needed to control blood glucose levels for at least 18 months.

Adverse events related to use of the study dose were transient and included flu-like syndrome and Epstein-Barr virus activation. A US clinical trial has recently been initiated for the purpose of determining the optimal dosing regimen for use in future trials.

According to a company news release, other potential indications for ChAglyCD3 currently under investigation include moderate to severe psoriasis and cutaneous lupus erythematosus.

Orphan Drug EPI-A0001 for Mitochondrial Respiratory Chain Diseases

On April 4, the FDA approved orphan drug status for EPI-A0001 (made by Edison Pharmaceuticals, Inc) in the treatment of inherited mitochondrial respiratory chain diseases.

There are currently no approved drugs for these highly debilitating diseases, which frequently affect the nervous system as well as skeletal and cardiac muscle. Often classified as mitochondrial encephalomyopathies, they are caused by genetic errors in the synthesis of inner mitochondrial membrane proteins that are needed for energy production.

According to a company news release, the approval was based on preclinical data demonstrating the drug's safety and efficacy in targeting mitochondrial electron shuttling and energy production.

Reviewed by Gary D. Vogin, MD


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