While there are at least eight forms of botulinum toxin A in various stages of testing around the world, only four are available or in testing in the United States. at this time. They are Botox and Reloxin (Medicis), PurTox (Mentor Corporation) and NT201 (Merz Pharmaceuticals). These forms of botulinum toxin A are in various stages of trials, and it appears likely that the first to the U.S. market will be Reloxin, which filed with the FDA in early December 2007.
There is also a topical form of a peptide under very early development, which won’t be covered in this review.
Reloxin Basics
Molecular Structure
Reloxin, like Botox, is a 900-KD molecule. This rather large molecule is one that includes the basic 150-KD subunit as well as the protein structure surrounding it to create the larger molecule known as botulinum toxin. The basic configuration and its subtle changes make each form of botulinum toxin slightly different, allowing for differentiations between time of onset, duration of action and diffusion characteristics.
Like Botox, Reloxin is a type A botulinum, distinct from Myobloc, the other botulinum toxin previously tested, which was a type B. There are several other types of botulinum toxins currently in testing, with subtypes ranging from A through G. However, at this time, only A and B have been significantly developed.
Usage, Packaging, and Storage
Known as Dysport in Europe and other countries, where it is marketed by Ipsen, Reloxin has been in use since 1991.
It has both medical and cosmetic uses in various countries and, per the package insert, once reconstituted has an 8-hour length of usage, versus 4 hours for Botox. Additionally, it can be stored in the refrigerator rather than the freezer. Lastly, the vial contains lactose within it, while Botox has glucose.
When Reloxin comes to market, it appears it will have 300 units per vial as compared to Botox, which will be discussed later in this article.
Unit conversion rates are a very important concept when it comes to understanding this product, as this will determine its effectiveness and price comparison to Botox once it is on sale in the US.
Diffusion Characteristics
One of the potential differences between Botox and Reloxin relates to diffusion characteristics of the material once injected. Since the two products have different, although similar, protein structures, there are potential differences in diffusion rates operating before attachment to the presynaptic membrane, which may allow attachments to more areas or retention of an attachment prior to being degraded.
Diffusion characteristics may also allow Reloxin to potentially treat a larger area than an equivalent number of units of Botox.
While there are theoretical concerns about a higher incidence of adverse effects, none of the studies so far have shown any higher incidence of ocular adverse events compared to Botox and, in fact, have shown decreased adverse events when compared to the Botox approval studies. Whether this is a true correlation is difficult to say, as the studies were done at a different time and are not head-to-head in nature.
Diffusion characteristics can also have positive effects on outcome, especially in areas such as the off-label forehead areas, since Botox frequently has challenges reaching the entire forehead due to its lower diffusion rate. Additionally, a smoother look can be helpful in certain areas, and diffusion characteristics might aid in this goal.
Reconstitution and Comparison of Strengths to Botox
While there are no hard and fast rules regarding reconstitution and comparison of strengths, the prevailing wisdom based on studies performed in Europe by various investigators is that a 3:1 ratio of Reloxin to Botox is a good estimate.
Several studies showed that 2.5:1 was ineffective in certain situations, while 4:1 ratios led to adverse events. The studies performed were done with frontal muscles and showed less activity in the 2.5:1 ratio, but increased muscle weakness in the hand when used for hyperhidrosis in the higher ratio of 4:1.
It would seem then that the 300 unit vial that is proposed at this time for Reloxin will be more than likely an equivalent to the dose of Botox and can be reconstituted in the same way as with Botox for an equivalent effect. This should make the transition to the use of Reloxin smoother in those practices that wish to do so.
Side Effects
The side effect profile of Reloxin, in studies to date, shows a fairly similar profile to Botox. There are the expected ocular events (8% vs. 0% placebo), and other, non-statistically significant events, such as headache and injection site pain. No significant serious adverse events were noted in the one study that has been released so far.
Potential Competition in this Area
There has been a history of competition in the cosmetic marketplace and this area will be one more opportunity for competition. Allergan, the maker of Botox, has enjoyed a year in which they had the availability of both a filler, Juvéderm, and Botox. During this period, Medicis has been continuing to market the Restylane family of fillers (Restylane and Perlane), but hasn’t had a neurotoxin to complete the marketing package. The introduction of Reloxin will put these two competitors on even footing, but it should be noted that Allergan may have a challenge in marketing Botox if Reloxin is priced lower, because of certain Medicare-based price structures that can’t be changed easily.
Several countries in Western Europe, as well as Brazil, Iran, Russia and the Ukraine, have been exposed to the two products, Dysport and Botox, and appear to be using a fair amount of both products after several years of competition. While no exact numbers have been released, it appears that the two competitors are at parity in many of the countries where both are available. Many hope that the competition in the U.S. market will bring more options and benefits to the dermatologists and consumers.
Other Compounds in Development
As of press time, both PurTox and NT201 were in early Phase III trials. These botulinum toxin options are similar in some ways to both products in the market, but offer certain differences as well, including a different purification process for PurTox and a less bulky molecule (150KD) for NT201. As these products come closer to the marketplace, this publication will inform its dermatology readership of trial information and comparisons.
The Near Future
During the next year it is likely that Reloxin will enter the marketplace and fill a void as a competitor to Botox. It will be interesting to see what this will do to change and improve options for patients.
Fall Clinical Dermatology 2007
Acne Case Reports
2007 ADVANCES IN COSMETIC &
MEDICAL DERMATOLOGY
“MAUI DERM” CONFERENCE
July 2007 CME Supplement
2007 Winter Dermatology Conference Hawaii®
2006 4th Annual Fall Conference Supplemental Proceedings