Many potential indications for botulinum toxin formulations have yet to be realized

Vancouver, British Columbia - The emergence of new formulations of botulinum toxin and other neuromodulators in the pipeline awaiting approval by the Food and Drug Administration signal a need for clinicians to stay abreast of the various uses and potential adverse events.

Since the start of its therapeutic use in the medical arena decades ago, the utilities for botulinum toxin have been expanding for clinical as well as cosmetic indications.

“Botulinum toxin has shown to be a very useful therapeutic tool in medicine employed for the treatment of varying indications including eye disorders, pain and neuromuscular disorders, but perhaps its most popular applications are seen in the field of aesthetic medicine for the treatment of frown lines,” says Alastair Carruthers, M.D., clinical professor, department of dermatology and skin science, Vancouver, British Columbia. “Despite its extensive use for numerous medical and aesthetic indications, I believe that we have only scratched the surface of its potential.”

Currently, four botulinum toxin serotype A (BoNTA) and B (BoNTB) formulations are approved by the FDA, namely onabotulinumtoxinA (Botox, Allergan), abobotulinumtoxinA (Dysport, Medicis), incobotulinumtoxinA (Xeomin, Merz) and rimabotulinumtoxinB (Myobloc, Solstice Neurosciences). Of these, the BoNTA preparations are the most widely used worldwide and the only ones FDA-approved for aesthetic use.

Formulation nuances

Dr. Carruthers and colleagues recently performed a comprehensive review of the current evidence regarding the FDA-approved botulinum toxin formulations. They found that there are very fine nuances that discern the different neuromodulators. According to Dr. Carruthers, these small differences can give clinicians the opportunity to personalize and individualize treatment approaches according to the intended treatment indication.

All botulinum toxin serotypes demonstrate the same basic mechanism of action, Dr. Carruthers says; however, the intracellular targets vary among them. While BoNTA cleaves synaptosomal-associated protein 25, BoNTB cleaves a vesicle-associated membrane protein, or synaptobrevin. The effects of botulinum toxin intoxication are not permanent in nature and, similarly, neither are the effects of botulinum toxin injection, with facial cosmetic treatment results lasting anywhere from three to six months or longer, Dr. Carruthers says.

Each commercially available BoNTA formulation is unique and the most basic difference among them is seen in complex size and structure, he says. While onabotulinumtoxinA and abobotulinumtoxinA are formulated complexes and differ from one another in size and composition, incobotulinumtoxinA is unique in that it is the first BoNTA formulated with no complexing proteins.

Botulinum toxin treatments are generally considered to be safe and adverse events are extremely rare, particularly at the doses in which they are given cosmetically and when a precise injection strategy is employed, according to Dr. Carruthers.

Ongoing research

Although incobotulinumtoxinA is free of complexing proteins, it still remains to be seen whether the product’s supposed decreased immunogenicity is of an advantage compared to onabotulinumtoxinA and abobotulinumtoxinA, which have complexing proteins in their formulation.

“I believe there are only five cases of resistance that have been reported with BoNTA with complexing proteins following cosmetic treatment, but when you look at the millions of BoNTA treatments performed around the world, five cases could be considered negligible. It may take decades before we see another five such cases, or other issues with any of these complexing and noncomplexing protein BoNTA formulations,” he says.

According to Dr. Carruthers, all toxins diffuse upon injection because diffusion is a natural process to attain equilibrium. Although the conventional wisdom is that smaller complexes allow for a greater diffusion, past studies have shown mixed results in terms of how differing toxin formulations spread following injection regardless of complex size.

“Further research is necessary to clarify the differences between study results and the nuances of how formulations may differ in terms of spread,” Dr. Carruthers says.

Bright future

The future of botulinum toxin therapies is very exciting, as new and innovative toxin delivery modalities are developed, such as the topical RT001 cream (Revance Therapeutics), which has yet to be approved by the FDA. This uncomplexed BoNTA topical product has been shown to traverse intact skin and achieve a result, Dr. Carruthers says, that could open doors for novel clinical applications, such as the reduction of redness, oiliness and sweating after a brief application of the neurotoxin.

“A topical neurotoxin that can target the sweat glands, sebaceous glands and vasculature could help to treat numerous dermatologic conditions. Although I don’t think that this is going to significantly impact the injectable market, such a topical modality may expand the market dramatically,” Dr. Carruthers says.

Injectable neurotoxins have been shown to be effective in the treatment of headaches and migraines, and topical neurotoxin products such as Revance have also been shown to improve this condition, representing a novel treatment option for patients.

Other evolving indications for neurotoxin therapy in medicine could be the treatment of depression. According to Dr. Carruthers, there is an increasing number of studies being reported demonstrating that the use of botulinum toxin in frown lines can help improve depression in many affected individuals. Other changes being made to the botulinum toxin molecule could result in radical changes in the treatment of pain syndromes in the future. Novel neurotoxin formulations in the works could significantly help alleviate the pain typically associated with those syndromes, he says.

“I have had experience with all of the available neurotoxins and though there are fine differences among them, I find them all to be effective. As we get to know these products better and learn from personal experiences and future studies, we may begin to distinguish areas for which one may be more suitable than the other for a given indication,” Dr. Carruthers says.

Disclosures: Dr. Carruthers is a consultant and researcher for Merz and Allergan.