Top-line results from North American phase 3 clinical trials show that a series of injections with ATX-101 is safe, well-tolerated, and results in clinically meaningful and statistically significant reductions in submental fat or “double chin.”
Chicago - Top-line results from North American phase 3 clinical trials show that a series of injections with ATX-101 is safe, well-tolerated, and results in clinically meaningful and statistically significant reductions in submental fat or “double chin.”
The findings from the two placebo-controlled, double-blind trials, REFINE-1 and REFINE-2, were presented by Jean D. Carruthers, M.D., F.R.C.S.C., F.R.C., REFINE-1 investigator and clinical professor, department of ophthalmology, University of British Columbia, Vancouver, at the annual meeting of the American Society for Dermatologic Surgery. She reported ATX-101 2 mg/cm2 (purified synthetic version of deoxycholic acid, Kythera Biopharmaceuticals) demonstrated meaningful results in the population of study patients who were being treated with the drug for moderate-to-severe submental fat.
“There is currently no FDA (Food and Drug Administration)-approved injectable drug to reduce fat under the chin,” says Derek H. Jones, M.D., associate professor of dermatology, University of California, Los Angeles, and founder and medical director or Skin Care and Laser Physicians of Beverly Hills. He was also a REFINE-1 investigator. “It’s very exciting that the top-line data demonstrate an excellent safety and effectiveness profile. If approved, ATX-101 could address an unmet need in patients who desire a nonsurgical option to safely and effectively contour the area under the chin.”
The two studies included more than 1,000 patients with moderate-to-severe submental fat enrolled at 70 centers in the United States and Canada. Eligibility was determined using three validated scales: the five-point Clinician-Reported Submental Fat Rating Scale (CR-SMFRS), the five-point Patient-Reported Submental Fat Rating Scale (PR-SMFRS), and the seven-point Subject Self Rating Scale (SSRS).
To be randomized to treatment, patients had to have a score of two or three on both the CR-SMFRS and PR-SMFRS and a score of zero to two on the SSRS. Patients were allowed to receive up to six treatments, which were administered at approximately monthly intervals. Overall, about half of patients received the maximum number of injections.
Efficacy was evaluated at three months after the last treatment using a co-primary endpoint requiring a ≥1-grade improvement from baseline on both the CR- and PR-SMFRS scores. This clinically meaningful change was achieved in 70.3 percent of ATX-101 treated subjects in the REFINE-1 trial and 66.9 percent in REFINE-2, versus 18.7 percent and 22.4 percent in placebo, respectively (p<0.001).
A two-grade improvement in both rating scales - an FDA-preferred endpoint intended to drive the placebo responder rate very low - was achieved by 13.4 percent of ATX-101 treated subjects in REFINE-1 and 18.7 percent of ATX-101 treated subjects in REFINE-2 versus 0 percent and 3.2 percent for placebo, respectively (p<0.001).
Consistent with the subjective ratings, MRI measurements of the volume of submental fat also showed significantly higher responder rates in patients treated with ATX-101 compared with the controls in both REFINE-1 (46.6 percent vs. 5.4 percent) and REFINE-2 (40.0 percent vs. 5.1 percent).
In addition, study subjects were asked to rate the visual and psychological impacts of their submental fat using the Patient-Reported Submental Fat Impact Scale (PR-SMFIS), and ATX-101 was associated with a statistically significant greater score improvement than placebo (p<0.001). Overall patient satisfaction with ATX-101 treatment approached 90 percent.
“We consider the ATX-101 phase 3 study results a real success and we could not be happier,” says Frederick Beddingfield, III, MD, PhD, Chief Medical Officer, KYTHERA Biopharmaceuticals, Calabasas, Calif.
“The consistency of all of the efficacy endpoints gives confidence that ATX-101, if approved, could have true benefit, and the high patient satisfaction rate is very encouraging, because at the end of the day, patient satisfaction is what drives decisions on aesthetic interventions,” he says.
Analyses of the full dataset are ongoing as Kythera prepares to submit its data package to the FDA for product approval.
The safety analyses showed adverse events in both the ATX-101 and control groups mostly represented the types of local reactions that would be expected with any injection. They included swelling, pain, bruising, numbness and redness. These adverse events were mostly transient, local to the treatment area and mild-to-moderate in severity, although rates of numbness and hard lumps, both temporary, were somewhat higher in the ATX-101 group. However, there were no serious adverse events, and less than 4 percent of patients withdrew from the study because of an adverse event.
“The safety experience with ATX-101 in the phase 3 clinical trials is excellent and consistent with what we expected based on its prior use. Our global database now includes use in more than 1,500 patients,” Dr. Beddingfield says.
Follow-up of patients in the phase 3 trials is continuing and will provide information about the durability of the treatment benefit. Available data from earlier studies indicate that more than 90 percent of treatment responders continue to show improvement at two years after their last ATX-101 injection while more than 80 percent are sustaining benefit after four years.
“This type of durability represents a different paradigm for injectable cosmetic treatments,” Dr. Beddingfield notes. “Whereas benefit with temporary fillers or neurotoxin injections is achieved with fewer initial treatment sessions, maintenance of improvement requires patients return at much more frequent intervals.”
Histological studies from European investigators show that ATX-101 treatment results in targeted destruction of fat cells followed by removal of the cellular debris by normal host mechanisms and tissue remodeling. These observations are consistent with the durable results and data showing that submental skin laxity is improved or unchanged in 90 percent of treated patients.
Ongoing analyses of data collected in the phase 3 trials are expected to offer insight into how many monthly treatments patients typically need to achieve acceptable improvement. Dr. Beddingfield notes that while about half of patients in the studies received the maximum number of six injections, real-world practice represents a different situation.
“The goal of the clinical trials was to establish a treatment benefit and so investigators were encouraged to administer the maximum number of treatments as appropriate for each patient. In addition, patients generally had no reason to stop treatment before receiving all six injections,” he says.
Disclosures: Drs. Carruthers and Jones are ATX-101 clinical trial investigators and consultants for Kythera.