Rod Franklin

September 27, 2011

September 27, 2011 (Denver, Colorado) — The most recent phase 2 studies on a topically delivered botulinum toxin type A (BoNTA) lend clinical support to an investigational product that physicians might use one day to essentially wipe away crow's feet wrinkles around the eyes, according to a consultant for the developer.

Addressing members here at Plastic Surgery 2011: American Society of Plastic Surgeons (ASPS) Annual Meeting, Michael Kane, MD, a plastic surgeon in private practice in New York City, emphasized the exacting efficacy standards that were observed in 2 randomized trials that tested a gel known as RT001, which employs a novel macromolecule delivery system to relax muscles in the sensitive periorbital area.

"We're actually getting a very large payload to go through cell membranes and skin cells, allowing for penetration down to the muscle," the New York surgeon reported. "Throughout phase 2 we've had 11 clinical trials, and over 550 patients have been treated with the drug. We've had no treatment-related serious adverse events, and we've had a 115-day duration of effect."

RT001, under development by California-based Revance Therapeutics, was well tolerated in a double-blind placebo-controlled study of 90 patients and in a study of 180 patients that compared the compound's individual components. The product is now scheduled for its end-of-phase 2 review.

In the BoNTA gel is a peptide carrier that penetrates skin to relax the orbicularis oculi muscle. Although it can be topically applied, RT001 won't be sold over the counter; it requires the assistance of a physician. If approved, it will be marketed as a painless alternative for people who would otherwise be treated with injectable botulinum toxin A (Botox).

Two efficacy scales — the Global Assessment of Lateral Canthal Line Severity and the Patient Severity Assessment — have been used in phase 2 research to quantify the degree of muscle rest achieved (the primary end point). To be categorized at the most stringent level of efficacy, it was necessary for physicians and patients to record a crow's feet severity reduction of at least 2 points in their respective rating systems.

"This was very different from earlier neurotoxin studies," Dr. Kane said. "It's a very strenuous new end point for neurotoxins that the FDA [US Food and Drug Administration] likes these days."

Investigators with the 90-patient study enrolled participants at 3 sites, and randomized them to active treatment or placebo for a single treatment of RT001. A reduction in severity of 1 point was demonstrated in 89% of the RT001 group and 28% in the control group (P < .0001). A reduction of at least 2 points was demonstrated in 44% of the RT001 group and in 0% of the control group (P < .0001).

"The one thing about having that stringent end point for the response is that it really knocks your placebo down," Dr. Kane observed. "It went down to 0 in this study."

The larger study involved 5 sites. Patients were randomized to either a single treatment of RT001 or to 1 of 3 control treatments: BoNTA alone, the transport peptide alone, or the gel placebo alone.

RT001 met the primary end point of an improvement of at least 2 points in lateral canthal line severity on both sides of the face (measured by the investigator). The results were statistically significant (P < .0001), compared with each component of RT001 individually and all the components combined. RT001 also met the more stringent end point of an improvement of at least 2 points on both the investigator assessment and the patient's self-assessment (P < .0001).

No serious adverse events related to RT001 have been reported. Brow elevation, classified as an adverse event in some study locations, has been one of the most frequent observations. But Dr. Kane opined that such an effect should not be viewed categorically as undesirable.

"If you're getting toxin into the muscle, you would expect that brow to come up," he said. "I wouldn't personally classify that as an adverse event."

In an interview with Medscape Medical News, Alan Matarasso, MD, ASPS spokesperson and plastic surgeon in New York City, agreed with that assessment.

"You do have a zone where the toxin will have an effect. Raising the brow is usually not considered an adverse event, even though it may have been for this study," he said. "Many people want [botulinum toxin A] to raise the brow. If, in fact, the patient doesn't like the raising of the brow, that can be addressed. I think that brow elevation is, for lack of a better term, a 'soft' adverse event."

Dr. Kane added that no evidence was found suggesting a risk for migration of BoNTA to other muscle areas in the face.

"One thing the FDA looks at involves all these little tests of different muscles in the area to see if there was evidence of drift of the toxin, and there was not," he said. "We only noted the effects in the orbicularis oculi."

Dr. Kane reports being a shareholder and consultant for Revance Therapeutics, and a consultant and speaker for numerous other companies. Dr. Matarasso has disclosed no relevant financial relationships.

Plastic Surgery 2011: American Society of Plastic Surgeons (ASPS) Annual Meeting. Presented September 21, 2011.

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