Triple-Blind, Prospective, Internally Controlled Comparative Study Between AbobotulinumtoxinA and OnabotulinumtoxinA for the Treatment of Facial Rhytids

OnabotulinumtoxinA (ONA) has been used since the early 1980s for reducing muscle spasms in medical illnesses [1]. Over the past 20 years, ONA has been recognized by regulatory authorities in approximately 80 countries worldwide as an effective treatment for 21 different medical uses including strabismus, blepharospasm, cervical dystonia, and severe primary axillary hyperhidrosis. Its use as a cosmetic agent was recognized in the mid-1980s and after a decade of ‘off-label’ use, efficacy and tolerability in the treatment of glabellar frown lines was demonstrated in two large, multicenter, randomized, double-blind placebo-controlled trials, known as Glabellar Lines I and II studies [1]. These trials led to FDA approval, in April 2002, of ONA for the temporary reduction of moderate to severe glabellar lines due to muscular hypertrophy at a dose of 20 units (U) for adults aged ≤65 years [2].

AbobotulinumtoxinA (ABO), another formulation of botulinum toxin A, has been used worldwide since 1990 and is approved in 76 countries for therapeutic use. It was first approved for esthetic use outside the United States in 2001 and is currently marketed in 27 countries for esthetic use before being studied for use in glabellar lines in the US. After a series of trials, ABO was approved for the treatment of glabellar lines by the FDA in April of 2009 [3]. The derivation of ONA and ABO from botulinum toxin A is responsible for similar effects on the musculature. Both agents act by inhibiting the calcium-mediated release of acetylcholine from the nerve ending, causing temporary muscle paralysis. The weight of the core neurotoxin is the same at 150 kDa with both agents; however, they differ in molecular weight of the botulinum toxin/hemagglutinin complex. ONA is a 925-kDa protein and ABO has been reported as a 400–600 kDa protein, but the specific weight has not been disclosed by the manufacturer (Ipsen Ltd, United Kingdom) [4, 5]. Differences in the molecular weight of the protein complex have been reported to theoretically cause ABO to migrate more than ONA, with a possibility that there would be a greater incidence of eyelid/eyebrow ptosis with ABO when injected supraorbitally in the corrugators, though this effect has not been reported in the trials [6].

Slight differences in the properties of ABO and ONA may result in differences in efficacy. It is the opinion of many physicians, along with feedback from their patients, that ABO has a slightly greater efficacy (earlier onset and longer duration of effect) than ONA, though this information is largely anecdotal [7]. There have been several reports on the efficacy and safety of ONA and ABO, yet the literature contains few studies comparing these two drugs [7‐12]. Additionally, comparative studies are lacking evaluating treatment in facial wrinkles other than in the frown region. A difference in efficacies might suggest that one agent is a more suitable option for patients and clinicians seeking to prolong treatment intervals yet maintain a continuous effect of reduced wrinkle appearance.

In this prospective clinical study, we report the results of a comparison of efficacy parameters, particularly onset and duration, and the safety of ONA and ABO in the treatment of rhytids in the glabellar and crow’s feet areas.

This was a prospective, comparative, triple-blinded, single-center, randomized, internally controlled clinical trial.

Ninety-three patients were treated with ABO and ONA over a period of 2 months (87 women and 6 men). Most patients were Caucasian with an average age of 47 years. Thirty-six patients received treatment with ONA and ABO in two areas (glabella and crow’s feet areas). Fifty-seven patients received treatment with ABO and ONA in one area (either glabella or crow’s feet areas). Eight patients did not continue follow-up visits and were removed from the study, leaving 35 patients treated in 2 areas and 50 patients treated in 1 area, for a total of 59 patients treated in the glabellar area and 61 patients treated in the crow’s feet area. No patients discontinued visits due to adverse effects from the treatment.

Differences were observed in the time to onset of improvement of wrinkles between the two sides/agents, such that a larger number of patients had a quicker onset of action with ABO than with ONA. After 3 months, ABO was active for a larger percentage/number than ONA for the glabellar and crow’s feet regions, although there was an increase in the number of patients who reported no difference between the two treatments at this time. Response rates for ABO and ONA were equivalent in both regions up to approximately 3 months; however, the response rates were higher at 4 and 5 months with ABO. Patient satisfaction findings were generally consistent with evaluator assessments at each time point.

Rapid onset was observed with ONA in a short-term 14-day study [16]. Beer et al. evaluated the onset of action of ONA and found that 48% of patients reported improvement by day 1, 77% by day 2, 93% by day 3, 98% by day 4, and 100% thereafter. In the current study, ABO and ONA were administered in the glabellar region at a ratio of 2.5:1 (20 U for ABO vs 8 U for ONA) and in the crow’s feet region at a ratio of 3:1 (30 U for ABO vs 10 U for ONA). Three studies by Lowe et al. compared the efficacy of ABO and ONA for upper facial lines. In one study, injecting glabellar lines at doses of ONA (30 U) and ABO (75 U; 2.5:1 ratio) showed similar efficacy. In another study, ONA (256 U total) was significantly more effective than ABO (64 U total) (dose ratio of 4:1) for upper face lines. However, an objective measurement by computerized photographic numerical assessment showed greater efficacy in the crow’s feet region with ABO vs ONA when a 3:1 dose ratio (96 U:32 U) was used [17].

Both ABO and ONA have the same pharmacology and act by inhibiting the calcium-mediated release of acetylcholine from the nerve ending, causing temporary muscle paralysis. Side effects can occur and range from mild due to the injection itself or severe due to the effects of the toxin such as difficulty swallowing, difficulty breathing, double or blurred vision, change of voice, or muscle weakness. The safety profile was similar for both products with mild adverse events reported, which resolved within one week. One (of 85) patients developed brow ptosis on the side that was injected with ABO. Brow ptosis is said to develop by diffusion of the toxin into the frontalis from the corrugator muscle. More dilute concentration is preferable in order to increase spread and field of effect (as in the forehead), whereas lower volumes are preferred in smaller muscle groups to avoid migration into unplanned areas [18]. On the other hand, more concentrated solutions reduce reliability in delivering a specific unit dose, and more dilute solutions lead to greater spread of the toxin [18]. In our study, ABO was given as a dilution of 300 U in 3 ml for the glabellar and crow’s feet areas and ONA was reconstituted with 2.5 ml in a 100 U vial for the glabellar area and 3 ml for the crow’s feet area. For the glabellar region, we recommend adjusting the amount of diluent (1.5–2.5 ml) for both ABO and ONA to result in a more concentrated solution in order to decrease the migration of treatment into the levator and frontalis muscle and prevent brow ptosis.

In our study, we sought to achieve the minimal efficacious dose that would produce optimal benefits with the lowest risk. At doses of 20 and 30 U ABO for the unilateral glabellar and unilateral crow’s feet regions, respectively, onset of action based on patient self-assessment was shown to be significantly quicker than with ONA at 8 U in the unilateral glabellar and 10 U in the crow’s feet regions. Other studies compared the efficacies of ABO and ONA in different patients and thus do not account for variations between individuals, such as muscle mass and severity of wrinkles [17]. The current study was an internally controlled, prospective study with blinding of the patients as well as the evaluators and thus established better measures to compare clinical efficacy (Fig. 7).

We used three injections for the corrugator unilaterally although in clinical practice, two injections are used for this muscle. The dose of ABO recommended by the label (50 U for the frown on both sides, 10 U per injection point, 5 injection points) gives 20 U for each corrugator, which is the same dose used in our study. We spread the dose over three points instead of two for the purpose of better anatomic treatment of the corrugator and to have the patient serve as their own internal control in order to objectively measure the differences in efficacy between the two treatments. The findings from our study, which establishes key parameters (onset of action, duration of effect, doses, and side effects) for ABO and ONA, allows the patient to opt for the more beneficial and economic product with little risk of adverse effects, a desirable faster onset with a longer duration between treatments.

The major limitation of the study was that we could not inject the glabellar muscle as is done in practice in order to make comparisons between the two treatments in the frown region.

In conclusion, our experience with ABO demonstrated a greater duration of activity and more rapid time to onset in a larger number of patients in comparison with ONA when used at a dose ratio of 2.5:1 in the glabellar region and 3:1 in the crow’s feet region. The safety profile was similar for both products. These findings suggest that ABO is a safe effective alternative to ONA when injected for treatment of wrinkles in the glabellar and crow’s feet areas. For the glabellar area, we recommend more concentrated forms, more injection areas, and more superficial injections to decrease the incidence of brow or eyelid ptosis and to decrease the migration of treatment.