Commentary on Overview of ATX-101 (Deoxycholic Acid Injection)

Explorers know a Great Circle is sometimes the shortest course between distant points. —Fred Chaffin Jr. It is been a long arduous journey. Developing and proving efficacy for the endogenous detergent, deoxycholic acid, proverbially and literally ended where it began. In 2004, when the compound was buried in near obscurity, my colleagues and I predicted, “Just as filler substances have gained popularity in the field of cosmetic medicine, detergent substances may have an analogous role in eliminating unwanted tissue.”1 More than a decade later, Kybella (Allergan, plc, Dublin, Ireland) entered the marketplace as the first injectable treatment for the reduction of localized fat. Knowing this, reading the history of deoxycholic acid (ATX-101) and its new-found role in dermatology2 gives me deep gratitude to my mentors for their inspiration and guidance; the indebtedness I have for the team at Kythera, the biotech start-up that saw ATX-101 through its regulatory path to FDA approval, cannot be overstated. I am amazed by the staggering odds overcome by the Kythera team as it took ATX-101 from “lab to bedside.” I am also touched with sentimentality as I recall my dermatology residency. During that time, my co-inventor and mentor, Michael S. Kolodney, MD, PhD, and I discovered how deoxycholic acid profoundly affects fat (Figure 1). Kybella proves that persistence, good fortune, and venture capital can change the (dermatology) world.Figure 1.: In May 2003, Adam M. Rotunda, MD, then first year UCLA dermatology resident and Michael S. Kolodney, MD, PhD, then Assistant Professor of Dermatology, isolated deoxycholic acid from a popular but unregulated and controversial fat-dissolving injection, phosphatidylcholine/deoxycholic acid (also known as PC/DC or Lipodissolve). The discovery of the bile detergent's lytic effect on fat in the laboratory led to human studies confirming that injections of it alone, and not the phospholipid (as it was previously believed), reduces fat.The history of Kybella predates Kythera's stellar R&D and our 2003 laboratory work. Like other pioneering, minimally invasive cosmetic therapies,3 Kybella began with the observations of astute and curious clinicians. Here are some of that history. In 1988, an Italian physician named Sergio Maggiori4 reported at the fifth International Meeting of Mesotherapy that a commercially available formulation called Lipostabil visibly reduced xanthelasma after intralesional injection. Lipostabil is an intravenously administered formulation of lecithin-derived phosphatidylcholine approved in Germany for the treatment of hyperlipidemia and atherosclerosis. In the mesotherapy tradition, Dr. Maggiori demonstrated that application of a systemic lipid-lowering therapy could similarly reduce a cutaneous lipid accumulation. Inspired by this work, the Brazilian dermatologist, Patricia Rittes, MD5 (Figure 2), treated patients desiring minimally invasive eyelid rejuvenation; she injected the medication subcutaneously and in 2001 reported her encouraging outcomes Dermatologic Surgery.5 Glynis Ablon, MD (Figure 3), a volunteer UCLA-attending dermatologist at the West Los Angeles VA Hospital, read the article and obtained IRB approval for a self-funded study investigating a compounded formulation similar to Lipostabil. Remarkably, she replicated Dr. Rittes' protocol and findings, and her important study changed the aesthetic landscape as we know it today.Figure 2.: Patricia Rittes, MD, Brazilian dermatologist and pioneer of subcutaneous phosphatidylcholine/deoxycholic acid injections. Her 2001 publication in Dermatologic Surgery demonstrated lower eyelid fat pad reduction with the substance. Pilot study by Rittes confirmed that Sergio Maggiori's cutaneous injections of Lipostabil as a treatment for xanthelasma could be applied for cosmetic use.Figure 3.: Glynis Ablon, MD, Associate Clinical Professor of Dermatology at UCLA, obtained IRB approval to replicate the study by Dr. Rittes using a compounded phosphatidylcholine/deoxycholic acid formulation. Her validating work encouraged the subsequent involvement of Rotunda and Kolodney.While a resident at UCLA, from 2002 to 2005, most of the first year was dedicated to serving patients at the West LA VA dermatology clinic. Moved by Dr. Ablon's teaching, zest, and passion for dermatology, I asked if I could spend some time with her in her Redondo Beach, CA, solo practice. She agreed. Several weeks later, following an afternoon of observation, I noticed a pile of photographs and papers. The raw data of her phosphatidylcholine-eyelid study were hiding, literally, in the corner of her practice's kitchen. I was intrigued by the before and after photographs and her explanation that “phosphatidylcholine injections melted the fat.” I could not deny the coincidence. When I was younger, I was passionate about bodybuilding. Along with other nutritional supplements, I regularly ingested lecithin, a soy derivative rich in phosphatidylcholine, with the belief that it would help reduce my body fat. Dr. Ablon's remark about phosphatidylcholine made me feel as though I was meant to be at that very place for a reason: the connection between fat, phosphatidylcholine, my past, and now a run-in with these photographs seemed to make the next step inevitable. “Can I help you write the paper?” I inquired. Several months later, we found our article in the “Controversies” section of Dermatologic Surgery.6 In the page that followed was a commentary by no one other than Jean Carruthers, MD, FRCSC, who cited caution for physicians seeking to inject this intriguing but unregulated product near the eyes. Indeed, the publication was a sure-fire way to find myself sitting uncomfortably in the chairman's office! Despite the growing controversial use of phosphatidylcholine (PC) injections (spawned perhaps by our report, in addition to study by Rittes and others like Hexsel and colleagues7), there was little, if any, science on the subject. At that time, there was no reason to doubt that PC itself was responsible for reducing subcutaneous fat, just as it reduces systemic lipids with Lipostabil. However, no one could definitively speak with convincing data as to whether PC, or some other ingredient in the formulation (and there were several, including a bile-derived detergent named deoxycholic acid), was responsible for the fat loss. Enter Michael S. Kolodney, MD, PhD. I admired Mike, then Assistant Professor of Dermatology, for his teaching and constant reminders, calling upon the residents at UCLA to question the status quo. He inspired us to ask “why and how?” about even the most basic therapies and diseases. He was a paradigm of the physician–scientist, and I felt honored to learn from and work with him. I recall feeling a bit embarrassed when I saw Mike for the first time after the eyelid publication, especially since it involved an aesthetic product, which I knew Mike was not particularly fond of. True to form, he approached me and admonished, “Adam, you can't just start injecting this s**t into patients. You have to figure out how it works. Meet me in my lab.” The next several months expanded into years. Our first task was to isolate the compounded formulation's most likely active ingredient. Detergents like bile acids destroy cell membranes. Therefore, we isolated deoxycholic acid and determined that this ingredient—not the innocuous phospholipid—profoundly destroyed fat. We then subjected a number of lipomas to the substance8 and, eventually, injected fatty necks (now known as “submental fat”) as a way to complete our story.9 Despite some unnerving criticism along the way, Mike and I kept to our path. Kythera's commercial interest in our work validated our efforts. Because of that constructive partnership and more than 10 years of committed effort by Kythera and many clinical investigators, patients in the United States, Canada, and likely soon worldwide may find Kybella beneficial. Clinical experience, patient feedback, and evolution in our field will determine what place, if any, Kybella plays in your practice. To many, the Kybella story is of passing interest. But to those affected by its discovery, I implore us to acknowledge the true heroes—the curious and devoted clinicians by the names of Maggiori, Rittes, and Ablon—who paved the way.

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