Novel compound shows early promise for treatment of acne

The retinoic acid metabolism-blocking agent (RAMBA) Rambazole (Barrier Therapeutics) has demonstrated promising efficacy and safety as a novel oral treatment for acne in early clinical trials along with potential activity as a topically applied agent. Based on those results, this novel compound is about to proceed into further testing of its topical use in a multicenter, randomized, double-blind, vehicle-controlled study and for oral administration in a double–blind, dose-finding study.

Rambazole is a potent and highly selective inhibitor of RA 4-hydroxylase, the enzyme that mediates the intracellular breakdown of all-trans retinoic acid to the more water-soluble and less biologically active compound 4-hydroxy-retinoic acid. By blocking the activity of the RA 4-hydroxylase, Rambazole and other RAMBAs increase endogenous levels of retinoic acid in target tissues with resultant potential therapeutic benefits on acne as well as on other retinoid-responsive conditions, including psoriasis, photoaging and ichthyosis.

Rambazole is being developed by Barrier Therapeutics, Princeton, N.J. Results from a recently completed phase 2a trial performed in Belgium by Diane Roseeuw, M.D., Ph.D., showed that when administered orally, Rambazole was safe, well-tolerated and highly effective in treating moderate-to-severe acne.

"Rambazole appears to be a promising and exciting alternative to exogenous retinoic acid treatments because it may offer the benefits of those agents but with a more favorable safety profile. The potential for fewer side effects with Rambazole is an attractive feature because the development of adverse reactions with existing oral and topical retinoids is a major limiting factor in patient compliance and willingness to continue therapy," says Dr. Roseeuw, professor and chair, department of dermatology, Free University of Brussels, Belgium.

The study

The clinical trial evaluating oral Rambazole for the treatment of acne had an open-label design and enrolled males with moderate to severe disease. Dr. Roseeuw enrolled one of two cohorts of eight patients for a preliminary assessment of the drug's efficacy. After eight weeks of once-daily treatment with Rambazole 1 mg, all eight patients responded with a 50 percent or greater reduction in total acne lesion count, and the sample size was increased with enrollment of an additional nine patients.

At baseline, mean total lesion count for the overall population was 89 (range, 20-199), and after a 12-week treatment period, 16 (94 percent) of the 17 men experienced a 50 percent or greater reduction in total lesion count, while six (35 percent) were considered "cleared or almost cleared" based on achieving a 90 percent or greater reduction in total lesion count.

"Notably, both inflammatory and non-inflammatory lesions responded equally well, and onset of response was rapid. Within four weeks, about half of our patients already achieved a 50 percent or greater reduction in total lesion count," Dr. Roseeuw reports.

The study of the topical formulation of Rambazole was conducted in 15 healthy subjects who applied preparations containing vehicle, Rambazole 0.07 percent or Rambazole 0.35 percent to sites on the back. Evaluations of tissue samples obtained by punch biopsy pre- and post-treatment showed Rambazole 0.07 percent significantly up-regulated both CRABP-II and keratin 4 and down-regulated keratin 2E, while the 0.35 percent formulation had an even more pronounced effect on those markers of retinoic acid activity. There were essentially no changes noted in tissue obtained from vehicle-treated skin.

"Retinoic acid affects these proteins in a dose-dependent manner. Compared with the effects of 0.025 percent retinoic acid, the changes associated with the 0.35 percent Rambazole concentration were equal to or greater, while those of the 0.07 percent concentration of Rambazole were slightly less," reports Geert Cauwenbergh, Ph.D., chairman and chief executive officer, Barrier Therapeutics, Princeton, N.J.

Safety stands out

Experience from the clinical trials conducted so far indicate that both topical and oral Rambazole may offer a more favorable safety profile compared with currently used retinoids.