Pipeline of injectable fat treatments set to deliver paradigm shift

Los Angeles - The product development pipeline will deliver game-changing injectable fat treatments in the very near future, according to one dermatologist.

"When we look at the next five years in the injectable arena, perhaps there will be some novel twists on toxins and fillers. But what will be a paradigm shift is the ability to legitimately reduce fat with injections," says Adam M. Rotunda, M.D., who has a Mohs Micrographic Surgery practice in Newport Beach, Calif., and is assistant clinical professor of dermatology, David Geffen School of Medicine, University of California, Los Angeles.

Coined in 1952, the term mesotherapy, representing injectable treatments for a wide variety of conditions, morphed into its current meaning as a fat loss technique in the mid-1990s, Dr. Rotunda says. At that time, physicians began injecting the intravenous anti-hyperlipidemic medication Lipostabil (an EU-approved phosphatidylcholine-sodium deoxycholate/PC-DC formulation; Sanofi-Aventis), into the skin to treat xanthelasma.

Subsequently, he says, Brazilian dermatologist Patricia Rittes, M.D., discovered that injecting PC-DC subcutaneously around the eyes would reduce the fat deposits there.

"However, nobody asked and then investigated how it worked, or why," Dr. Rotunda says. Without this understanding, injection of PC-DC (also known as "lipodissolve" and injection lipolysis) began to develop a bad name as physicians without adequate training in how, where and why to inject began treating body areas they perhaps should not have, he adds.

Beyond a pipe dream
Around 2003, "My mentor and colleague Michael S. Kolodney, M.D., Ph.D., said, 'Let's take this drug to the lab and figure out what's happening and why it's happening.'" Together, he says, they isolated deoxycholate (the active ingredient in PC-DC), patented its use for localized fat loss and found that some pharmaceutical companies were highly interested in the technology. Dr. Kolodney is program director and chief, division of dermatology, at Harbor-UCLA Medical Center, Torrance, Calif.

"These days," Dr. Rotunda says, "development of deoxycholate injections is occurring through Food and Drug Administration oversight, using rigorous investigative studies to create a novel medication you may potentially use in your practices. This is a quite a change - from what once amounted to just a pipe dream of injectable fat treatments to what currently is in the pipeline."

Through research and experience, Dr. Rotunda says he discovered that the varying quality and stability of DC sold by compounding pharmacies made this route "not the best way to go. These days, I turn patients away from treatment and inform them to wait for a commercially available product. They find me one way or the other, but I am not comfortable using a compounded formulation knowing that there are nonanimal and purified (pharmaceutical grade) forms of the drug that are being used in clinical trials."

Moreover, he says, "The FDA will not limit your practice of medicine. But if you advertise that you're using a product that's not FDA-approved, there will be untoward consequences."

Current concepts
At present, two injectable fat drugs are undergoing FDA clinical trials. LIPO-102 (salmeterol xinafoate, fluticasone propionate; Lithera) induces fat cell lipolysis, the hydrolysis of intracellular triglyceride, Dr. Rotunda says. "Essentially, all fat cells have this capacity. The medication stimulates the beta2-receptor, as well as the steroid receptors on the fat cell, to shrink it."

In phase 2b clinical trials, LIPO-102 produced very encouraging data in treatments of the anterior abdomen, Dr. Rotunda says.

"But we've yet to figure out whether these results are long-lasting."

The procedure causes no inflammation or downtime, he explains.

Kenneth Locke, Ph.D., chief scientific officer of Lithera, adds, "In our last clinical trial, we found that the salmeterol xinafoate component of LIPO-102 was responsible for most of its activity (fat reduction). Consequently, we have decided to move forward with the single agent salmeterol xinafoate - named LIPO-202. We will be conducting a phase 2b dose-ranging trial of LIPO-202 in August."

ATX-101 (sodium deoxycholate, Kythera) causes adipocytolysis, Dr. Rotunda says. "It's an ablative mechanism - chemical destruction of fat. The cell is removed after injection and won’t return" because macrophages engulf fat cells dissolved by the injection.

ATX-101's data are impressive, Dr. Rotunda says. Additionally, "Kythera now has MRI studies to confirm that there is, in fact, objective evidence of fat dissolution."

Researchers are testing ATX-101 in the submental area. As such, "This is not liposuction. Best results are seen on relatively small areas of fat. The treatment would not be successful for the abdomen of a 'robust' male or female. That, I believe, is another reason why deoxycholate (in combination with PC) went so astray years ago," he says, adding that nondermatologists were injecting it in inappropriate areas and were erroneously promoting it as an alternative to liposuction.

Regarding next steps, Kythera has partnered with Bayer to pursue European approval.

"Bayer recently completed two pivotal phase 3 trials of ATX-101 in Europe for the reduction of submental fat. Early data from this study (available at www.kytherabiopharma.com) are consistent with the phase 2 data, demonstrating statistically significant improvements in submental fat reduction and improvement in subject satisfaction in the treatment groups versus placebo,” Dr. Rotunda says.

“Bayer is about two years away from EU approval." In the United States, Kythera has initiated its pivotal phase 3 clinical program, with planned enrollment of 1,000 patients, for ATX-101 in the United States and Canada, Dr. Rotunda says. The company expects to report results from these trials in 2013, he says.

Disclosures: Dr. Rotunda is a shareholder in Kythera and a consultant for Kythera and Lithera.