New FDA Orphan Drugs: CTCE-9908, PEAC, Arimoclomol

Yael Waknine

July 20, 2005

July 20, 2005 — The U.S. Food and Drug Administration (FDA) has approved orphan drug status for a cytostatic drug for the treatment of osteosarcoma, an orally administered galenic version of valproic acid for the treatment of familial adenomatous polyposis, and arimoclomol for the treatment of amyotrophic lateral sclerosis.

Orphan Drug (CTCE-9908) to Inhibit Growth and Metastasis of Osteogenic Sarcoma

The FDA approved in July orphan drug status for a cytostatic drug (CTCE-9908, made by Chemokine Therapeutics Corp.) in the treatment of osteogenic sarcoma. The agent is designed to inhibit the growth and spread of cancer, with the potential for use with existing therapy (chemotherapy, surgery, and radiation) to improve treatment outcomes.

CTCE-9908 is an analog of a chemokine known as stromal cell-derived factor 1 (SDF-1) and acts as a competitive antagonist at CXCR4 receptors commonly found on the surfaces of stem cells and various common cancers.

SDF-1 regulates stem cell activity, and researchers believe that its action on cancer cells may promote their migration to SDF-1–rich areas such as the bone marrow, liver, and lungs, with subsequent angiogenesis and metastasis.

High CXCR4 expression has been found to correlate positively with tumor progression, a high metastatis rate, and a low survival rate. CXCR4 receptors are also thought to play a major role in resistance to chemotherapy and contribute to treatment failure.

The CXCR4 antagonist has been shown in preclinical trials to significantly inhibit the development of lung metastases in mice with osteosarcoma, as demonstrated by a 67% decrease in the number of visible lung nodules.

Results of a phase 1 dose-escalation trial in 24 healthy patients (including women of nonchildbearing potential) revealed no serious toxicities associated with CTCE-9908 injections of 0.5, 2, and 5 mg per kg body weight.

A phase 1b/2 study in adults with several types of cancer is scheduled to begin later this year.

Orphan Drug Version of Valproic Acid (PEAC) for Familial Adenomatous Polyposis

The FDA approved in July orphan drug status for an orally administered galenic version of valproic acid (VPA; PEAC minitablets, made by TopoTarget A/S) in the treatment of familial adenomatous polyposis (FAP), a condition that indicates a genetic predisposition for colon cancer.

The product is designed to inhibit a key subset of histone deacetylase (HDAC) isoenzymes that are implicated in colon cancer, thereby exerting an antiproliferative effect.

In normal cells, posttranslational acetylation of histones results in an open chromatin structure in which genes are active. By deacetylating histones, HDAC causes the formation of a condensed and compact chromatin structure in which genes are silenced. Abnormal recruitment and activation of HDACs has been shown to repress transcription and lead to neoplastic transformation.

The HDAC inhibitor represents a new therapeutic approach to FAP. Current treatment consists of prophylactic surgical removal of the colon to avoid progression of polyps to malignant cancer.

Phase 2 trials of the VPA-based therapy are scheduled to begin later this year. The drug was previously granted orphan drug status by the European Commission in 2004.

Orphan Drug (Arimoclomol) Stimulates Protein Repair in ALS

On March 29, the FDA approved orphan drug status for a small molecule drug (arimoclomol, made by CytRx Corp.) in the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease).''

Arimoclomol is thought to exert its action through the activation of "molecular chaperones" that stimulate a normal cellular protein repair pathway, thereby amplifying the natural "stress response." According to a company news release, the drug was well-tolerated in phase 1 clinical trials.

Because aggregates of damaged protein are thought to play a role in many diseases, the company believes that its small molecule "chaperone" coinduction technology could show therapeutic efficacy for other indications in addition to ALS.

A phase 2 trial of the orphan drug in ALS is expected to begin later this year, pending FDA approval.

Reviewed by Gary D. Vogin, MD


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