Topical toxin appears to be promising in phase II data
NEW YORK – A topical, noninjectable form of botulinum toxin asserted its ability to effectively treat crow’s feet through impressive data from a recently completed phase II clinical trial released here.
Seventy-five patients at four study sites were treated with the novel topical toxin or placebo to the crow’s feet area. On a four-point static scale, a significant number of participants showed two point moves, according to Michael Kane, M.D., a principal investigator in the trial who released aggregate data from the study at the American Society for Aesthetic Plastic Surgery annual meeting.
“As one of the study centers, I was not unblinded as to which of my patients had toxin and which were [treated with] placebo. But, clearly, by looking at the patients, there were those whose crow’s feet got a lot better and some whose didn’t,” Dr. Kane, a plastic surgeon in private practice in New York City, tells Cosmetic Surgery Times. “The difference was night and day, both at rest and smiling. The people who showed significant difference, unsurprisingly, had lateral brow elevation, as well. Obviously, the toxin was working on the muscle.”
TRANSDUCTION TRANSFORMATION
The concept of simply applying a topical to eliminate wrinkles is not new, but proving the theory has yet to be conclusively accomplished. Yet, researchers involved with the development of the topical form of botulinum toxin think they are close. Its developers at Revance Therapeutics, Inc., a privately held company based in Mountain View, Calif., claim that the topical allows large macromolecules to cross the skin and other barrier membranes enabling local, targeted delivery. Delivered through the firm’s proprietary TransMTS™ (Macromolecule Transport Technology), the neurotoxin is based on a single, straight-chain, peptide that allows skin to be a gateway for drug delivery, rather than a barrier.
“Adding a peptide as a separate component within the [toxin] formulation allows the toxin to cross the skin,” explains Jacob Waugh, M.D., co-founder & chief scientific officer, Revance. “The peptide forms an ionic bond with the toxin and the peptide also has a Protein Transduction Domain (PTD), which is responsible for transcutaneous flux. It is essentially a quite broad and powerful transduction.”
Although the topical toxin’s technology is fairly obscure and complex, the use of two pathways on both the dead and living layers of the skin allows for a significant result, according to Dr. Waugh. Currently, there have been 600 crow’s feet areas treated via the TransMTS™ technology, with a fairly low local irritation rate and no evidence of adjacent paralysis above placebo grade, say the developers.
“TransMTS technology relies on the fluidity of the dead skin, that essentially is the equivalency of the typical topical that loads the stratum corneum, but more interesting is the second pathway that [also] happens on the living cells,” Dr. Waugh details.
“Basically, it’s a variation the cell uses to take a drink, then it dumps the drink back out on the other side of the cell.”
The key to TransMTS technology, say its developers, is a protein carrier featuring protein transduction domains that hold on to the cell membrane and allow larger molecules to pass through it undisturbed. The transport technology is also currently being studied for early applications of new cardiovascular disease drugs. Additionally, three different cancer drug trials are being investigated based on the system’s ability to transport molecules, according to the firm.
ADVANTAGE: EYE
While TransMTS technology may benefit additional medical innovations including insulin and other compounds, a phase III trial is underway to establish the neurotoxin adjunct’s effectiveness and advantages when treating crow’s feet. An area greatly sensitive to injections, a topical toxin may be a relief to most patients.
“I don’t think there’s much question regarding [the topical toxin’s] clinical effect for lateral crow’s feet,” says Richard Glogau, M.D., clinical professor of dermatology at the University of California and participant in the phase II clinical trial. “Yet, they [will need to] keep continuing to improve the formulation due to a delivery problem with the gel vehicle,” he adds.
The gel that allows the combination of the peptide and the toxin to get through the skin and the mechanics of using the gel present challenges in terms of getting it to stay where it is applied, according to Dr. Glogau, who completed a recent study for primary axillary hyperhidrosis with the topical form of botulinum toxin type A.
In that study, researchers used the topical agent to treat 12 patients in a randomized, blinded, vehicle-controlled study that also showed promising results: A 65 percent mean reduction of sweating on 10 axillae treated with the BTX-A (200 U) was observed after four weeks of treatment, compared with a 25 percent mean reduction in sweating on the vehicle controlled axillae. Although the topical toxin displayed its ability to reach the bottom of the dermis when treating hyperhidrosis, the one-time dosage upon which the crow’s feet trials’ results are based may be problematic says one investigator.
“It’s a very artificial situation, and I think that anything in dermatology ends up being a serial treatment — patients are looking for long-term effect,” Dr. Glogau says. “Yet, I think the neurotoxin is realistic in its abilities.”
“My one concern is that the topical toxin will be thought of as just the same as an injectable toxin, but in reality it’s another tool,” Dr. Waugh says. “Yet, it can be used to do some of the things that injectables can’t do.”
REFERENCE
Glogau RG. Topically applied botulinum toxin type A for the treatment of primary axillary hyperhidrosis: results of a randomized, blinded, vehicle-controlled study. Dermatol Surg. 2007;33(1 Spec No.):S76-S80.
DISCLOSURE
Dr. Kane is a paid consultant to Revance Therapeutics with an ownership equity interest comprising stock options whose value is less than $50,000 during the time of the study and for one year following completion of the study. Dr. Kane does not have a proprietary or financial interest in a product, patent, trademark, copyright, or licensing agreement, and has not received significant payments from Revance exclusive of the costs of conducting the clinical study or any financial arrangements whereby the value of the compensation could be influenced by the outcome of the study or tied to sales of the product.
Aug 1, 2009
Cosmetic Surgery Times
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