Non-permanent fillers: Belotero®/Esthélis® and Teosyal®

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5 Non-permanent fillers

Belotero®/Esthélis® and Teosyal®

Berthold J. Rzany, Heike Buntrock, Vanessa Hartmann, Martina Kerscher

Summary and Key Features

• Belotero®, Esthelis®, and Teosyal® are three hyaluronic acid families produced in Switzerland

• Good clinical data are available only for Belotero® Basic and Teosyal® Deep Lines

• At 6 months Belotero® Basic and Teosyal® Deep Lines still show at least a one-grade difference after treatment of the nasolabial folds

• Belotero® Basic and Teosyal® Deep Lines have a good safety profile

Introduction

Switzerland is not only the home of high mountains and chocolate but also the home of two companies that produce three hyaluronic acid (HA)-based filler families: Belotero®, Esthelis®, and Teosyal®.

Hyaluronic acid dermal fillers

HA-based dermal fillers are currently the most popular, non-permanent injectable materials available for the correction of age-related changes of the face and beyond the face (wrinkles, and volume loss). HA fillers derive from bacterial fermentation from a specific streptococcus strain (Streptococcus equi), a bacterium non-pathogenic for humans. As natural HA does not persist in tissues for more than 24 hours, it needs to be chemically stabilized by cross-linking techniques. Most HA-based fillers are stabilized by 1,4-butanediol diglycidyl ether (BDDE).

How to differentiate the different HA fillers? There are certain possibilities:

image Those with good clinical data and those without

image Those for more superficial and those for deeper injections

image Those with a few products and those with product families

image Those easy to inject and those more difficult to inject

image Cheaper ones and more expensive ones.

So let’s take these aspects and look at the fillers that will be discussed in this chapter. One small note beforehand: all of the HA gels discussed here are of non-animal origin (bacterial fermentation) and are cross-linked by BDDE.

Methods

For this chapter a Medline search was performed with the aim of identifying clinical trials on the fillers discussed here. To reduce bias only randomized controlled clinical trials (RCTs) with a study size of above 50 and case series with a study size of above 100 were included in this overview.

Belotero®

Belotero® is produced by the Swiss company Anteis SA and distributed by Merz Pharmaceuticals. The stabilizer is BDDE and according to the manufacturer two cross-linking processes are used leading to a cohesive and polydensified matrix, which is supposed to ease injection while maintaining long-lasting results. Belotero® offers three different formulations: Belotero® Soft, Belotero® Basic and Belotero® Intense (Table 5.1, Figs 5.1 and 5.2).

Table 5.1 Product overview of the Belotero® family

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Figure 5.1 (A) A 56-year-old patient at baseline and (B) 14 days and (C) 182 days after a single injection of 1 mL Belotero® Intense.

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Figure 5.2 Upper lip augmentation in a 45-year-old man: (A) before and (B) 4 months after 1.7 mL of Teosyal® Kiss.

We could find only one RCT for Belotero® Basic with an open extension phase, by Narins and colleagues. Furthermore we were able to detect two large German case series: one by Dirting et al focusing on Belotero® Basics and one by Pavicic on Belotero® Intense.

Randomized controlled trial

The aim of the trial was to compare the safety and effectiveness of Belotero® Basic with that of bovine collagen (probably Zyplast®, but name not given) in the correction of moderate to severe nasolabial folds (NLFs) in a split-face study. The study included 118 patients who were randomized to receive Belotero® Basic and bovine collagen on contralateral sides of the face. NLF severity was measured using the Wrinkle Severity Rating Scale (WSRS, 5 points). The initial treatment was evaluated after 2 weeks, and an optional touch-up to optimal cosmetic correction was permitted if needed. Subjects returned every 2 weeks (up to 24 weeks) for evaluation. Safety was assessed using spontaneous adverse event (AE) reporting. A mean volume of 1.97 mL of Belotero® Basic was injected. The mean change from screening at week 24 was 1.08 ± 0.74 as assessed by the blinded investigator. Belotero® Basic resulted in a significantly greater reduction in the mean change on the WSRS score than bovine collagen at weeks 8 (p = 0.009), 12 (p = 0.001), 16 (p = 0.001), and 24 (p = 0.001). There were no significant differences between the two groups in the proportion of AEs considered related to the injection site procedure. Most AEs were mild to moderate in severity and resolved within 7 days.

Case series

The Narins trial was extended by a 18-month open label extension phase; 94 of the 118 patients were reinjected with Belotero® Basic (now both sides, at various timepoints) and followed for a maximum of an additional 72 weeks (96 weeks with the 24 weeks from the RCT included). The mean volume injected was 0.71 mL on the Belotero® Basic treated site, and 1.04 mL on the site treated previously with the collagen. At weeks 32, 48, 72, and 96 (total study period), the severity of the NLFs showed a decrease from baseline on both sides of the face, although the mean change from baseline was greater on the side of the face that had been previously injected with Belotero® Basic than on the contralateral side previously injected with bovine collagen. The mean Global Aesthetic Improvement Scale (GAIS) score, as assessed by the treating physician, was between 2 (improved) and 3 (much improved) at all timepoints. Only one (2.9%) related adverse event (hematoma on both sides of the face) was documented. The event was described as moderate and disappeared over 3 days. It is noteworthy that at week 96 of the study 27/85 (31.8%) patients still did not require a reinjection.

A further case series on Belotero® Basic with a follow- up of 6 months could be found. In this case series by Dirting et al, 114 subjects with moderate to severe nasolabial folds (5-point WSRS) were treated with Belotero® Basic. Touch-ups were not allowed. The mean injected volume was 2 mL. After 6 months 81% of 109 subjects who finished the 6-month study showed at least a 1-point improvement on the WSRS for NLFs. Adverse events were mild with erythema and swelling in about 70% of patients.

For Belotero® Intense, the large case series by Pavicic comprised 149 patients. In contrast to the previous trials, patients could be treated in various areas. Follow- up was, however, limited to only 3 months. Efficacy was measured by the 5-point WSRS and the Global Aesthetic Improvement Scale (GAIS). Most treated folds were NLFs (83.9%) followed by marionette lines (32.9%) and mentolabial folds (20.8%). The mean WSRS score (all areas involved) improved significantly by 1.9 points from 3.98 initially to 2.07 (at 12 weeks). Satisfaction was described as excellent or good by 94% of the patients. The most common adverse events were erythema (63.8%), swelling (52.3%), and pain (49%). Induration was reported in 21.5%. These adverse events generally appeared on the treatment day and resolved over time.

Esthélis®

The Esthélis brand is also produced by Anteis SA. The Esthélis® range provides three different main products: Fortélis® Extra, Esthélis® Soft, and Esthélis® Basic (Table 5.2). In addition, as a filler for volume augmentation, Modelis® has been added to the Esthélis® range. No good clinical data – not even a case series – are available for this family of fillers. It might be probably safe to assume that they are similar to the Belotero® group of fillers.

Table 5.2 Product overview of the Esthélis® family

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Teosyal®

Teoxane is the manufacturer of the HA filler family Teosyal® (Tables 5.3 and 5.4, Figs 5.1 and 5.2). Like Belotero® only one good clinical trial has been published, by Nast and co-workers. No large case series on this product family could be found.

Table 5.3 Summary table for the Teosyal® family*

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Table 5.4 Summary table for the Teosyal® family*

  Teosyal® Ultimate Teosyal® Kiss
Hyaluronic acid concentration 22 mg/g 25 mg/g
Cross-linking ++++ +++
Syringes Pre-filled, sterile glass syringes (1 × 3 mL) Pre-filled, sterile glass syringes (2 × 1 mL)
Needle 23 G 27 G
Indications Volume augmentation and remodeling of facial contours Lip contour and volume

* Please note that Teosyal® Puresense products contain 0.3% lidocaine.

Randomized controlled trial

This was a participant- and assessor-blinded, randomized clinical trial involving 60 participants with moderate to severe NLFs (3 or higher on the 5-point, WSRS). The study was conducted in a split-face design comparing Teosyal® Deep Lines with Restylane® Perlane (a maximum of two injections was possible at baseline). Wrinkle improvement was measured before and after injection and after 1, 2, 4, and 7 months, using the WSRS and the GAIS as outcome criteria. An optional treatment was offered at the end of the study, with participants allowed to choose one of the products. Both products showed immediate, good results after injection and touch-up and demonstrated good durability over time. The initial average WSRS score for Teosyal® Deep Lines decreased from 3.17 to 1.62 (two injections) and was still 2.23 at the end of 7 months. A total of 1.36 ± 0.41 mL was injected. Participant preference for optional treatment at the end of the study favoured Teosyal® Deep Lines. Both products were well tolerated, without serious adverse events. Please note that there is an additional US trial under way, the results of which will be published hopefully in the near future.

Conclusion

Belotero Basic® and Teosyal® Deep Lines are the only products from the filler families discussed in this chapter where clinical data based on RCTs are available. Strictly speaking, only for those fillers do we have some evidence on their efficacy (how good they are at correcting wrinkles and folds), durability (how long the effect lasts), and safety (the proportion of patients who react with erythema, edema/swelling immediately after the injection). Furthermore for Belotero Intense® we have at least a 3-month case series adding evidence to the Belotero® family.

Both Belotero Basic® as well as Teosyal® Deep Lines proved to be effective and safe HA products for the correction of NLFs. When compared with collagen, Belotero Basic® proved to be superior; when compared with another HA (Restylane® Perlane), Teosyal® Deep Lines proved to be comparable if not slightly better.

How far can we go with analogous assumptions? We have randomized controlled trials on NLFs for only two products and a larger case series for more indications for another product – the latter of limited follow-up duration. Therefore, strictly speaking, we cannot say anything on the durability of the other products of the family and other indications. It might be safe to say that there might be differences. In areas with extensive facial movements HA fillers are known not to last as long as in areas with less or no movements. Last but not least is safety: it might be as well safe to assume that safety features are similar for all products of the Belotero® and the Teosyal® families. For the Esthélis® family in contrast there are no data from which to surmise anything. Some may argue that when two products are produced by one company it is likely that the products have similar characteristics, but there is a lack of scientific data to back up this reasoning.

What do we want? More randomized controlled trials or at least case series on different indications using the products of the above discussed HA fillers.

Further reading

Dirting K, Lampe H, Wolters M, et al. [Hyaluronic acid filler for correction of nasolabial grooves – results of a clinical study]. Journal der Deutschen Dermatologischen Gesellschaft [Journal of the German Society of Dermatology]. 2008;6(suppl 2):S10–S14.

Narins RS, Coleman W, Donofrio L, et al. Nonanimal sourced hyaluronic acid-based dermal filler using a cohesive polydensified matrix technology is superior to bovine collagen in the correction of moderate to severe nasolabial folds: results from a 6-month, randomized, blinded, controlled, multicenter study. Dermatologic Surgery. 2010;36(suppl 1):730–740.

Narins RS, Coleman WP, 3rd., Donofrio LM, et al. Improvement in nasolabial folds with a hyaluronic acid filler using a cohesive polydensified matrix technology: results from an 18-month open-label extension trial. Dermatologic Surgery. 2010;36(suppl 3):1800–1808.

Nast A, Reytan N, Hartmann V, et al. Efficacy and durability of two hyaluronic acid-based fillers in the correction of nasolabial folds: results of a prospective, randomized, double-blind, actively controlled clinical pilot study. Dermatologic Surgery. 2011;37:768–775.

Pavicic T. Efficacy and tolerability of a new monophasic, double-crosslinked hyaluronic acid filler for correction of deep lines and wrinkles. Journal of Drugs in Dermatology. 2011;10:134–139.

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