Topical Botox Current Evidence
Originally approved for the treatment of eye muscle disorders like blepharospasm and strabismus, Botox has become an increasingly popular cosmetic procedure. According to the American Society of Plastic Surgeons (ASPS), botox injections were the single most popular minimally invasive cosmetic procedure performed in the United States in 2015. The ASPS report found that 7.3 million injections were given in 2015, up 3% from the year prior.
Although cosmetic BoNTA has demonstrated an acceptable safety profile, adverse events occur,and misplaced injections may cause unwanted effects in nontarget areas. For example, eyelid and brow ptosis and partial lip ptosis have been reported after injection of BoNTA into the upper face and periocular areas, respectively, and injection into the pretarsal portion of the orbicularis oculi muscle has resulted in dry eyes. There have also been complications involving pupillary reactions and light sensitivity.Limitations of injections include pain, erythema, swelling, bruising, tenderness, and potential infection from needle use.
The patient’s medical regimen is potentially affected by being advised to avoid aspirin, nonsteroidal antiinflammatory drugs, and vitamin E before injection to reduce the risk of bleeding and bruising. Bruising is of particular concern in the lateral canthus and orbicularis oculi region, where the blood vessels are superficial and the skin is thin.
Research conducted among consumers concluded that many consumers are needle averse and would still prefer a more noninvasive alternative that would provide the same benefits as BoNTA injections. It was observed that in US alone of the 11 million target demographic for BoNTA treatments, but less than 10 percent have actually received treatment. Providing an attractive option to current injections would expand the market considerably. A safe, targeted alternative may be found in topical BoNTA.
The target consumer market can be organized into the following three categories: 1) past users of BoNTA injections who would like a less painful, cheaper option; 2) consumers with no past history of injections because of the expense and/or pain associated with them; and 3) consumers currently undergoing regular injections who would welcome a more comfortable way to maintain each treatment
NANOPARTICLE TECHNOLOGY AND BoNTA CREAM
Nanotechnology allows the potential to deliver molecules into the skin, which ordinarily do not penetrate the corneal layer.
This ability to enhance penetration of active ingredients offers many benefits. At least two companies, Transdermal Corp., Birmingham, Michigan, and Revance Therapeutics, Newark, California, have made sufficient progress on topical delivery of BoNTA for clinical trials. Transdermal Corp., formed in August 2008, has developed an FDA-approved topical BoNTA cream based on commercially viable ionic nanoparticle technology (InParT).
This transdermal noninvasive drug delivery technique preserves the bioactivity of molecules without denaturing them. The cream (CosmeTox) contains BoNTA and is intended for the softening of facial rhytides and a reduction in hyperhidrotic conditions. Active ingredients in the cream allow for greater toxin stability at room temperature for extended periods of time. Topical BoNTA allows for deeper delivery of the active molecules into the skin in order to encourage the same effect of injected BoNTA—inhibiting the release of ACh and blocking neuromuscular transmission.The stabilized toxin cream is applied topically onto the skin and dosed by the quantity of cream applied. Using nanospheres and absorption enhancers, the toxin is delivered into the skin without any known skin damage or systemic toxicity. The cream also behaves in a similar fashion as an injectable in that when it is applied, it stays local for targeted delivery.
A further study was also conducted to test the efficacy of topical BoNTA cream (CosmeTox) on facial wrinkles. The study involved 4 to 7 weeks of treatment with 12 weeks of follow-up evaluation. Within the first two weeks of treatment, the BoNTA group reported subjective improvements in their appearance, including less wrinkling, but also noticed a fading of dark circles under their eyes as well as a hyperpigmentation reduction in treatment areas. The active ingredient cream was compared to a placebo on 40 female subjects. The active ingredient cream contained a concentration of 2U/mL BT and the vehicle control contained no BT. They were assessed by Facial Line Outcomes and Self Perception of Age questionnaires. The Facial Lines Outcome scores were improved and maintained for the duration of the study period of almost three months. The Self Perception of Age was also reduced in the majority of subjects. At Week 4, more than 85 percent of the BoNTA cream group rated their wrinkles as improved by at least 75 percent.
RT001 Botulinum Toxin Type A Topical Gel Revance Therapeutics, Inc., Newark, CA contains an albumin-free 150-kDa BoNTA and a novel peptide that enables transcutaneous flux of the BoNTA. RT001 raised a lot of hopes with successful Phase 2 trials.
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.
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).
Phase 3 Trial Design – REALISE 1
The Phase 3 trial was a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the safety and efficacy of DaxibotulinumtoxinA Topical Gel (RT001) for the treatment of moderate to severe lateral canthal lines. A total of 450 adult patients were enrolled at seven sites in the United States and were randomized 1:1 to a single treatment of either RT001 or placebo topical gel applied to lateral canthal lines on both sides of the face using Revance’s proprietary applicator.
In a press release “We are disappointed with the results of the REALISE 1 trial. The data was unambiguous, and we do not plan to continue development of RT001 topical for crow’s feet. Based on these results, we have also decided not to pursue the current clinical development plan for RT001 in axillary hyperhidrosis. We are grateful to all the patients and investigators for their participation in the REALISE 1 trial,” said Dan Browne, President and Chief Executive Officer at Revance.
” As of today the development of tropical botox RT001 has been shelved by Revance after non satisfactoryPhase 3 trial and long acting DaxibotulinumtoxinA for Injection (RT002) has entered phase 3 trials.”
Considering the non chemoimmobilization effects of botox and its role in anti scaring and rejuvenation it remains a potential area of research. The newer non invasive delivery modes of Botox need to be explored further.