New FDA Orphan Drugs: Ceflatonin, Valortim, TQ-1018

Yael Waknine

March 31, 2006

March 31, 2006 — The US Food and Drug Administration (FDA) has approved orphan drug status for homoharringtonine in the treatment of chronic myeloid leukemia; a human antibody to Bacillus anthracis protective antigen for the treatment of anthrax infection; and a high-concentration topical capsaicin product for the treatment of postherpetic neuralgia.


Orphan Drug Homoharringtonine (Ceflatonin) for Chronic Myeloid Leukemia

On March 19, the FDA approved orphan drug status for homoharringtonine (HHT; Ceflatonin, made by ChemGenex Pharmaceuticals Ltd) in the treatment of chronic myeloid leukemia (CML).

CML is caused by an acquired genetic defect (bcr-abl mutation) that involves switching of genetic material from chromosomes 9 and 22 to create the Philadelphia chromosome. The mutation interferes with normal cell replication processes, leading to abnormal leukocyte proliferation.

The small-molecule drug is a potent inducer of apoptosis in myeloid cells and also inhibits angiogenesis. In phase 2 trials, HHT has shown clinical activity in patients who are developing resistance to tyrosine kinase inhibitor therapy.

In a single-agent study of 9 patients with accelerated-phase CML that had become resistant to imatinib mesylate, 80% of patients returned to chronic-phase CML and 67% achieved a complete hematologic response.

Results from a similar single-agent study of chronic-phase CML (n = 5) showed that all patients achieved a complete hematologic response and 40% achieved a cytogenetic response. Also, 2 patients with detectable resistance mutations achieved a complete hematologic response and their mutations (p-loop) were no longer detectable after receiving HHT therapy.

HHT has also shown both additive and synergistic effects in decreasing bcr-abl protein expression (the hallmark of CML resistance) when administered in combination with imatinib mesylate (Gleevec, made by Novartis Pharmaceuticals Corporation).

In a study of 10 patients who had a partial or complete cytogenetic response, the addition of HHT to imatinib therapy further reduced bcr-abl transcript counts. Results showed that 70% of patients achieved a significant decrease in bcr-abl counts; complete cytogenetic and molecular responses were each achieved by 20% of patients.

According to a company news release, a multinational phase 2/3 study of CML patients harboring the T215I point mutation (known to confer complete resistance to tyrosine kinase inhibitors) is expected to begin in the second quarter of 2006.

HHT was previously granted orphan drug status by the European Medicines Evaluation Agency for the treatment of CML and acute myeloid leukemia in September and October 2004, respectively. The drug is also being evaluated for use in patients with myelodysplastic syndrome.


Orphan Drug MDX-1303 (Valortim) for Inhalational Anthrax

On March 6, the FDA approved orphan drug status for MDX-1303 (Valortim, made by Medarex, Inc, and PharmAthene, Inc) in the treatment of anthrax infection.

The fully human antibody is designed to target the protective antigen of the lethal Bacillus anthracis toxin that is believed to initiate the onset of illness via cell attachment thus facilitating the entry of additional destructive toxins.

According to a company news release, animal studies suggest that MDX-1303 has the potential to provide significant protection against anthrax infection when administered prophylactically (prior to the emergence of symptoms), and it may also increase survival when administered therapeutically.

Study results showed that use of the antibody at doses as low as 1 mg/kg upon exposure effectively protected rabbits and monkeys against the lethal effects of anthrax infection. When administered to rabbits after the development of symptoms, the antibody also improved survival as late as 48 hours postexposure compared with control subjects.

MDX-1303 is currently being studied in a phase 1, open-label, dose-escalation clinical trial to evaluate its safety, tolerability, immunogenicity, and pharmacokinetics when administered as a single intravenous or intramuscular dose to healthy volunteers. Results from this trial are anticipated later this year.


Orphan Drug High-Concentration Topical Capsaicin (TQ-1018) for Postherpetic Neuralgia

The FDA approved in January orphan drug status for a high-concentration topical capsaicin product (TQ-1018, made by TheraQuest Biosciences, LLC) in the management of postherpetic neuralgia.

According to a company news release, one application of the product in conjunction with a local topical anesthetic is intended to provide pain relief lasting weeks to months.

In contrast, currently marketed low-concentration topical capsaicin products are not approved for the treatment of any painful neuropathy, and 3 or 4 daily applications only provide modest and inconsistent efficacy in alleviating the condition.

Reviewed by Gary D. Vogin, MD

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