Emerging Therapies for the Treatment of Rosacea

Newly approved agent is the first to specifically treat erythema
Payer Perspectives in Dermatology - Rosacea
Caroline Helwick

Rosacea is a common skin condition that leads to persistent erythema, transient flushing, and/or acne-like eruptions across the face. Although effective treatments exist for the pimples and pustules associated with rosacea (ie, papulopustular rosacea), the effective relief of erythema in rosacea (ie, erythematotelangiectatic rosacea) is an unmet medical need.

This treatment gap will soon be narrowed, thanks to the development of novel therapies that are specifically designed to address the problem of redness. In addition, other agents in the pipeline should further improve the arsenal of treatments for the papules and pustules of rosacea.

New Therapies in Development for Erythema
Treating the central facial erythema associated with rosacea (ie, erythematotelangiectactic rosacea) has been challenging. A new topical agent that acts as a vasoconstrictor, brimonidine gel 0.33% (Mirvaso, Galderma Laboratories), was approved on August 26, 2013, by the US Food and Drug Administration (FDA). This is the first and only FDA-approved topical treatment specifically developed and indicated for the facial erythema of rosacea (see article, FDA Approves Mirvaso, First and Only Treatment Available for Erythema in Rosacea).

Another agent currently in the pipeline for redness is oxymetazoline hydrochloride cream (Allergan), an alpha-1A adrenergic receptor agonist and alpha-2A adrenergic receptor partial agonist, which therefore works similarly to brimonidine gel 0.33%. This drug candidate is in phase 2 clinical trials.1

In 2 randomized, placebo-controlled phase 2 trials of patients with erythematous rosacea, statistically significant improvements in facial erythema were demonstrated over 8 hours and over 12 hours compared with placebo, with a favorable safety profile. There was also a significant improvement (P <.05) in the reduction of the combined clinician’s erythema assessment and patient’s self-assessment end point.2

The manufacturer has indicated that a dose-finding trial is under way involving more than 350 patients with rosacea. Scheduled to be completed in late 2013, the study was designed to optimize the drug’s concentration in preparation for phase 2 testing and to further characterize the duration of oxymetazoline’s clinical effect.3

Other Promising Compounds in Early-Phase Trials
Several other compounds are in phase 2 testing for the treatment of erythematotelangiectatic rosacea. BFH-772 (Novartis) is a topical ointment that appears to inhibit skin-cell activity and constrict blood vessels and to possibly have an anti-inflammatory effect as well.4

Laropiprant (Merck) is an active human prostaglandin D2 receptor-1 antagonist that may be anti-inflammatory.5

Aganirsen (Gene Signal) is an antisense oligonucleotide that blocks a protein required for the formation and growth of new blood vessels.6

Improved Compounds for Papulopustular Rosacea
Although effective treatments exist for the other main type of rosacea, papulopustular rosacea, several compounds could improve this therapeutic landscape as well.

Omiganan pentahydrochloride (Cutanea Life Sciences) is a topical cationic antimicrobial peptide with rapid bactericidal activity against microorganisms colonizing the skin and possibly contributing to the inflammatory lesions seen in this type of rosacea. It is an aqueous-based topical gel “designed to provide cosmetic elegance with minimal irritation.”7 The drug has a unique mechanism of action involving disruption of the cytoplasmic membranes of the microorganism, resulting in its depolarization and death.8,9

Ivermectin 1% cream (Galderma Laboratories) is a new topical formulation of the acaricidal compound, ivermectin for the treatment of papulopustular rosacea. The exact mechanism of action of ivermectin is not known. Several phase 3 clinical trials with ivermectin have been initiated to investigate the safety and efficacy of the drug for an extended period of time in patients with papulopustular rosacea, including a trial that compares ivermectin with azelaic acid 15% gel for up to 40 weeks, and a study that compares the safety and efficacy of ivermectin with metronidazole 0.75% cream in patients with papulopustular rosacea.10 That study is estimated to be completed in October 2013.

Carbamide peroxide (Elorac) is also in phase 3 clinical trials for the treatment of rosacea (as well as acne). It is thought to work in patients with papulopustular rosacea by inhibiting inflammatory mediators, toll-like receptor activation, and proinflammatory cytokines.11

SGT-VD-54 (Sol-Gel Technologies), which is in phase 2 development, uses the Sol-Gel drug delivery technology to optimize its delivery. Sol-Gel microcapsules are hydrophilic and are freely dispersed in water, thereby increasing the solubility of the active ingredients. The exact mechanism of action of SGT-VD-54 is not known.12

Sarecycline hydrochloride (Paratek Pharmaceuticals) is an oral tetracycline-based drug candidate that is a new chemical entity; it is expected to be more clinically useful and effective than tetracycline alone. In addition to its antimicrobial properties, sarecycline downregulates inflammatory cytokine production. The drug is in phase 2 trials.13

Apremilast (Celgene) is an oral agent that modulates multiple anti-inflammatory pathways and is being tested in phase 2 trials of patients with moderate-to-severe inflammatory rosacea.14

Topical foam formulations of 2 established drugs for the treatment of patients with rosacea are in late-stage development. Minocycline foam (Foamix Ltd) contains the broad-spectrum antibiotic minocycline, and thus inhibits numerous bacterial species and inflammation. It is currently in phase 2 trials.15

Azelaic acid foam 15% (Intendis GmbH) is in phase 3 clinical trials. A new phase 3 clinical trial of patients with papulopustular rosacea is randomizing patients to azelaic acid foam 15% or to vehicle foam, administered twice daily for 12 weeks.16

Incobotulinumtoxin A (De Nova) is being evaluated in a randomized phase 2 study versus saline injections to the cheek region in patients with rosacea.17

Summary
In 2013, approximately a dozen new therapies are currently in various clinical evaluation phases for the treatment of patients with rosacea, and another half dozen or so are in preclinical and laboratory testing.18 These novel compounds are expected to provide clinically meaningful improvements in the treatment of patients with rosacea—the papulopustular type, for which some effective treatments are already available, and more important, for the treatment of erythematotelangiectatic rosacea, thereby filling an unmet medical need by addressing the erythema component of rosacea, where current approaches fall short. The recent approval of brimonidine gel 0.33%—the first treatment for this common condition in rosacea—is an exciting and promising development for patients with rosacea, as well as for their physicians.

References
  1. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 50.
  2. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 57.
  3. Pascoe D. Allergen dose finding trials for AGN-199201 oxymetazoline. Rosacea Support Group. November 30,2012. http://rosacea-support.org/allergan-dose-finding-trials-for-agn-199201-oxymetazoline.html. Accessed August 29, 2013.
  4. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 46.
  5. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 37.
  6. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 38.
  7. Products in development. Cutanea Life Sciences. www.cutanealife.com/cls001.html. Accessed August 29, 2013.
  8. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pgs. 35-36.
  9. PR Newswire Association. Omiganan phase II rosacea study demonstrates promising results: partner plans to advance to phase III. Press release. October 17, 2007. www.drugs.com/clinical_trials/omiganan-phase-ii-rosacea-study-demonstrates-promising-results-2281.html. Accessed August 30, 2013.
  10. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 52.
  11. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 47.
  12. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 53.
  13. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 45.
  14. ClinicalTrials.gov. Open Label Pilot Study of Apremilast in Treatment of Rosacea.
  15. http://clinicaltrials.gov/show/NCT01045551. Accessed August 30, 2013.
  16. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 43.
  17. ClinicalTrials.gov. Safety and Efficacy of Azelaic Acid Foam, 15% in Papulopustular Rosacea. http://clinicaltrials.gov/ct2/show/NCT01555463?term=azelaic+acid+foam&rank=2. Accessed August 30, 2013.
  18. ClinicalTrials.gov. A Double-Blinded, Randomized Placebo Controlled Pilot Study Comparing the Efficacy and Safety of IncobotulinumtoxinA Versus Saline Injections to the Cheek Region in Patients with Rosacea. http://clinicaltrials.gov/ct2/show/NCT01614743?term=Incobotulinumtoxin+A&rank=26. Accessed August 30, 2013.
  19. Global Markets Direct. Rosacea—pipeline review, H1 2013. GMDHC3389IDB. March 2013; pg. 8.
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