BBI Contributing Editor

The whirlwind in facial injectables and dermal fillers has just begun, according to several experts. Last month's FDA approval of Botox opened the floodgates for competing injectable drugs. And bovine collagen is increasingly being challenged by a number of other fillers, including bioengineered human collagen and hyaluronic acid derivatives.

"Filler substances are evolving at a ridiculously rapid rate," observed Arnold Klein, MD, a professor of dermatology and medicine at the University of California at Los Angeles (UCLA; Westwood, California). For instance, Cosmoderm from Inamed (Santa Barbara, California) is a collagen made from bioengineered human tissue. "It's not from cadavers," said Klein, who is the skin-test monitor for a study of Cosmoderm. "Hopefully it will have all the properties of a bovine product, without having to worry if a patient is allergic."

Perlane and Restylane are two pending hyaluronic products from Q-Med Esthetics (Sweden). Klein also is an investigator for the hyaluronic acid filler Hylaform, a viscoelastic gel from Genzyme Biosurgery (Cambridge, Massachusetts). "I think hyaluronic agents can help a lot in rolling out the lip, for example. The lip is the No. 1 site for soft tissue augmentation," he noted. But using a permanent filler in the lips or in a mechanical line "gives me a great deal of fear."

Similarly, "the biggest problem is not what filler agent you use," Klein said. "Patients get fed up because practitioners don't have proper injection techniques." One reason why Botox, a botulinum toxin type A from Allergan (Irvine, California), has become so widely popular "is that the technique is not as critical as it is with other filler agents," said Klein, who has spent the better part of 20 years attempting to teach physicians how to inject collagen.

According to William Beeson, MD, an assistant clinical professor at the Indiana University School of Medicine (Indianapolis, Indiana), "Botox is really a quick pick-me-up. Many patients are looking for something fast with minimal recovery time. They also want something reasonable in cost, not uncomfortable and safe. Botox really fits the bill for all these parameters." In short, "my patients have just been elated with Botox," Beeson said. "In my 20 years of practice, I've never had a treatment that has been so uniformly accepted by patients. They love their Botox."

The consumer's love affair with Botox will likely accelerate now that the FDA has formally approved the drug for cosmetic use. Currently, these injections account for about 20% of the 8.5 million annual cosmetic procedures performed in the U.S. "Once you treat someone with Botox, it is extremely unusual for someone not to continue treatment," said Beeson, who finds duration of effect between three to seven months. Furthermore, "the more that someone is treated, the longer the interval between treatments."

Botox is most effective in treating the brow furrow (the wrinkle between the eyebrows). And at Beeson's practice, an increasing percentage of patients are male, now representing 25% to 30%. "We see Botox demand really increasing exponentially," he said. "There are a significant number of people who want to look refreshed without the downtime. Botox is also an extremely important adjunctive procedure to bring patients into my practice and keep them happy."

Although Botox appears to be the rage, "we're still quite excited about autologous fat transfer," said Neil Sadick, MD, a clinical professor of dermatology at Cornell University Weill Medical College (New York). "This involves removing fat from one part of the body and injecting it into another." The technique is natural and there is no allergy. "It also lasts longer than any other filler, with the exception of a permanent filler such as silicone or Artecoll [from Artes Medical, San Diego, California], which is not FDA-approved," Sadick added.

In addition to culture-derived human collagen, which allows for an unlimited amount of collagen, "culture-derived fat is being investigated," according to Sadick. On the other hand, hyaluronic acid derivatives offer minimal allergy potential and "are smoother to inject, but have not been FDA-approved."

As for Botox, "public advertising will greatly help its growth, despite any bad press," Sadick noted. A competing botulinum toxin type B is on the horizon, however. Myobloc from Elan Pharmaceuticals (South San Francisco, California) may give Botox a run for its money in the U.S., once the appropriate dosage is determined. "Myobloc has a more rapid onset, but it does not last as long as Botox," said Sadick, who is involved with FDA studies of Myobloc. Onset is from 24 to 48 hours, compared to two to four days with Botox. "Myobloc also has a more diffuse freezing effect for a more natural look," he said.

Myobloc's effect "lasts 10 to 11 weeks vs. Botox's 12 to 16 weeks. But it really depends on the patient. Does she want more quick onset or more longevity?" Sadick said. "I think Botox is still the standard at this time."

For the average professional who has some motion-derived wrinkles (for example, the brow), along with deep wrinkles when the face is at rest, "desirable treatment involves not having to keep performing skin tests. These people want treatment today," said Jean Carruthers, MD, a clinical professor of ophthalmology at the University of British Columbia (Vancouver, British Columbia), where the hyaluronic acid Restylane is approved for use. "Because this viscoelastic acid naturally occurs in our joints, skin tests are not required." Carruthers often injects Botox and Restylane at the same time.

In a study of 38 patients randomized into two groups (Botox and Restylane vs. Restylane only), the combination group showed better results. "With Restylane only, patients looked fabulous at rest, but they could still frown. Because of the filler, they also had a bulkier look to their brow," Carruthers said. In contrast, "the Botox smooths out the muscle action and also allows the brows to lift a little bit." As the facial cosmetic arena progresses, "we increasingly realize that you can't do everything with just one tool," she said. "It's like using both a knife and a fork for eating. You need combinations sometimes to give you the flexibility and the polish."

Last December, Inamed signed a letter of intent outlining an agreement whereby it would gain exclusive rights to develop, market and sell a botulinum A toxin called Dysport in the U.S., Canada and Japan. The manufacturer, Beaufour Ipsen, "is the fifth-largest pharmaceutical firm in France," said Peter Nicholson, vice president of corporate communications and investor relations at Inamed. "We'll also have our own trademark for the product." Nicholson noted that both Dysport and Botox are available in Europe, where they each command about a 50% market share overall. "I wouldn't say there are advantages or disadvantages of Dysport over Botox," he said. The respective market shares indicate that "physicians probably don't see a big difference either."

Eventually, Botox and Dysport are expected to compete head-on in the U.S. "We have a very strong franchise in the facial aesthetics business," Nicholson said. Specifically, "we have the only collagen product available in the U.S. We think that adding a botulinum toxin to our product portfolio will give us a unique position in that we will be the only company here — or elsewhere — to offer both a botulinum product that is used above the nose (around the eyes and on the brows) and a collagen product that is used below the nose (around the lips and the mouth)."

McGhan Medical (also Santa Barbara) is a wholly owned subsidiary of Inamed that produces the highly purified bovine dermal collagen products Zyderm and Zyplast. "There were nearly 50% more cosmetic procedures performed in the U.S. last year compared to the year before," Nicholson said. "So any stigma that might ever have been associated with a cosmetic treatment is rapidly falling by the wayside. These kinds of procedures are moving into the mainstream."

BioNuvia, a wholly owned subsidiary of Advanced Tissue Sciences (both headquartered in La Jolla, California), helped Inamed develop the human collagen alternatives Cosmoderm and Cosmoplast, both of which are under regulatory review. "These two products may provide a viable alternative for people that have sensitivity to bovine collagen. The hope is that these products will be approved without the requirement for a skin test," said Kerry Vail, vice president and general manager of BioNuvia.

According to Vail, many physicians perform between one and three skin tests before injecting bovine collagen. However, "Patients prefer cosmetic treatments that provide instant gratification," she said. In fact, "30% to 40% of patients walk away even after undergoing a skin test, never to return for an actual injection. The goal is for human collagen to optimize the procedure for both the physician and the patient."

Cosmoderm and Cosmoplast are created by a patented, 3-D tissue engineering process "that is built on a strong foundation of science for burn and wound healing," Vail said. "We really expect the market to expand with this alternative." Combination therapies may also hold promise. "This might consist of human collagen, hyaluronic acid and human growth factors," she added.

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