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Commentary on: Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials

Commentary on: Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From... “Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials” is a follow up of the data obtained in the Refine Phase 3 clinical trials.1 The results from that clinical trial ultimately led to the approval of ATX-101 (deoxycholic acid injection; Kybella [United States] and Belkyra [Canada, Australia, and Europe]; Kythera Biopharmaceuticals, Inc., Parsippany, NJ [an affiliate of Allergan]) as a nonsurgical treatment for excess submental fat (SMF).2 Both REFINE-I3 and REFINE-II4 trials were Phase III clinical trials aimed at evaluating efficacy and safety of the drug. Briefly, adults with moderate or severe SMF who were unhappy with their appearance, were randomized to either ATX-101 or a placebo for up to 6 treatment sessions. The severity of the SMF was graded by both the clinician and patient; the clinician evaluated the submental fat severity using a standardized photonumeric chart and the patient graded their dissatisfaction with their appearance. Endpoints in the study included patients who received a grade 1 or more improvement of their appearance based on both clinician and patient evaluation. While the REFINE trials demonstrated efficacy and safety of ATX-101, in this study Dayan et al aim to further characterize the treatment profile and safety of the treatments between individual treatments. Given the total treatments allotted in the REFINE trials was 6 depending on satisfaction and SMF improvement endpoints, the numbers needed to treat and volumes were heterogeneous for the patient population. This study aims to clarify optimal treatment durations and intertreatment safety profiles. A total of 1022 patients from the REFINE studies were pooled together for evaluation. Their findings help confirm what many clinicians who work regularly with the product encounter: the usual treatment course is typically longer than one session and lasting about 4 treatments. A total of 67% of the ATX-101 treated patients who were treated with less than 6 treatments stopped treatment due to satisfaction with results within 4 treatments. However, most patients enrolled in the ATX-101 trial, received 6 treatments (60%). This compared favorably to placebo, in which 81% received all 6 treatments, suggesting that placebo did not result in a satisfactory result in more participants. Drug volumes per treatment decreased for both ATX-101 and placebo, although more significantly for ATX-101. Patient’s self-reported improvement using line drawings as reference showed significant improvement per treatment session over placebo. Adverse events were typical and self-limited. ATX-101 had more significant adverse events at the first treatment as compared to placebo but these decreased significantly after each treatment time point. Typical adverse events following treatment with ATX-101 included edema/swelling, pain, ecchymosis, most notable after the first treatment decreasing with subsequent treatments. There was a 4% instance of temporary marginal mandibular paresis and interestingly a 0.4% instance in the placebo group. These resolved after a mean duration of 42 days in the treatment group and 85 days in the placebo group. The study clarifies the need for individualized treatment when using ATX-101 for submental fat. While the study demonstrated that frequently less than 6 treatments of ATX-101 will elicit a measurable clinical response, there was enough “demand for more” to ensure that patient clinical response and personal preferences will play a significant role in satisfactory endpoints. As demonstrated in this study, clinical improvement frequently did not correlate with patient satisfaction, and there were significant patients continuing treatment despite distinct clinical levels of improvement. The study explains clearly that clinical changes are occurring after each treatment time and the patient response should be assessed carefully. Clearly the fact that the patients were receiving the product without cost could be perceived as a motivator to continue with treatment. Clinical trends were clarified nicely in this study. The initial treatments with ATX-101 resulted in frequent but self-limited adverse events (ecchymosis, bruising, swelling) for the patients and these early treatments tended to be the worst for the patient. As the fat was resorbed over the treatment course, drug volume required, and adverse events tended to diminish. The trend and “expected” treatment response will help clinicians counsel patients, helping to manage their anxieties. Additionally, the study defined the follow up as 4 weeks for consistency. After using the product, we acknowledge that many patients have some subtle signs of a resolving inflammatory response at 4 weeks. Delaying secondary treatments for 6 to 8 weeks intervals could allow for ongoing contour change and may have an impact on how much product is needed and how many treatments each patient may require. This study failed to show evidence of skin laxity following the treatment of SMF with ATX-101. Whether this was appropriate patient selection, scarring, or neocollangeneis remains to be seen and deserves further attention. Finally, further investigation comparing different modalities and patient satisfaction and efficacy would be of interest. We physicians appreciate providing our patients with a number of options to help them achieve their goals. The introduction ATX-101 and other modalities has provided us the tools to tailor treatment of SMF for our patients. Most clinicians are interested in using a product such as ATX-101 for “off face” indications. The cost of the product makes justification of its use even “off label” prohibitive. Disclosures Dr Kenkel was a consultant for Kythera from 2014-2016, focusing on the anatomic considerations with the product. Dr Lahar declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Dayan SH , Schlessinger J , Beer K , et al. Efficacy and safety of ATX-101 by treatment session: pooled analysis of data from the phase 3 REFINE trials . Aesthet Surg J . 2018 ; 38 ( 9 ): 998 - 1010 . 2. Center for Drug Evaluation and Research . Application Number: 206333Orig1s000 . https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206333orig1s000sumr.pdf. Accessed March 27, 2018 . 3. Jones DH , Carruthers J , Joseph JH , et al. REFINE-1, a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental fat reduction . Dermatol Surg . 2016 ; 42 ( 1 ): 38 - 49 . Google Scholar CrossRef Search ADS PubMed 4. Humphrey S , Sykes J , Kantor J , et al. ATX-101 for reduction of submental fat: a phase III randomized controlled trial . J Am Acad Dermatol . 2016 ; 75 ( 4 ): 788 - 797.e7 . Google Scholar CrossRef Search ADS PubMed © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aesthetic Surgery Journal Oxford University Press

Commentary on: Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials

Aesthetic Surgery Journal , Volume 38 (9) – Sep 1, 2018
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Publisher
Oxford University Press
Copyright
© 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: [email protected]
ISSN
1090-820X
eISSN
1527-330X
DOI
10.1093/asj/sjy086
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Abstract

“Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials” is a follow up of the data obtained in the Refine Phase 3 clinical trials.1 The results from that clinical trial ultimately led to the approval of ATX-101 (deoxycholic acid injection; Kybella [United States] and Belkyra [Canada, Australia, and Europe]; Kythera Biopharmaceuticals, Inc., Parsippany, NJ [an affiliate of Allergan]) as a nonsurgical treatment for excess submental fat (SMF).2 Both REFINE-I3 and REFINE-II4 trials were Phase III clinical trials aimed at evaluating efficacy and safety of the drug. Briefly, adults with moderate or severe SMF who were unhappy with their appearance, were randomized to either ATX-101 or a placebo for up to 6 treatment sessions. The severity of the SMF was graded by both the clinician and patient; the clinician evaluated the submental fat severity using a standardized photonumeric chart and the patient graded their dissatisfaction with their appearance. Endpoints in the study included patients who received a grade 1 or more improvement of their appearance based on both clinician and patient evaluation. While the REFINE trials demonstrated efficacy and safety of ATX-101, in this study Dayan et al aim to further characterize the treatment profile and safety of the treatments between individual treatments. Given the total treatments allotted in the REFINE trials was 6 depending on satisfaction and SMF improvement endpoints, the numbers needed to treat and volumes were heterogeneous for the patient population. This study aims to clarify optimal treatment durations and intertreatment safety profiles. A total of 1022 patients from the REFINE studies were pooled together for evaluation. Their findings help confirm what many clinicians who work regularly with the product encounter: the usual treatment course is typically longer than one session and lasting about 4 treatments. A total of 67% of the ATX-101 treated patients who were treated with less than 6 treatments stopped treatment due to satisfaction with results within 4 treatments. However, most patients enrolled in the ATX-101 trial, received 6 treatments (60%). This compared favorably to placebo, in which 81% received all 6 treatments, suggesting that placebo did not result in a satisfactory result in more participants. Drug volumes per treatment decreased for both ATX-101 and placebo, although more significantly for ATX-101. Patient’s self-reported improvement using line drawings as reference showed significant improvement per treatment session over placebo. Adverse events were typical and self-limited. ATX-101 had more significant adverse events at the first treatment as compared to placebo but these decreased significantly after each treatment time point. Typical adverse events following treatment with ATX-101 included edema/swelling, pain, ecchymosis, most notable after the first treatment decreasing with subsequent treatments. There was a 4% instance of temporary marginal mandibular paresis and interestingly a 0.4% instance in the placebo group. These resolved after a mean duration of 42 days in the treatment group and 85 days in the placebo group. The study clarifies the need for individualized treatment when using ATX-101 for submental fat. While the study demonstrated that frequently less than 6 treatments of ATX-101 will elicit a measurable clinical response, there was enough “demand for more” to ensure that patient clinical response and personal preferences will play a significant role in satisfactory endpoints. As demonstrated in this study, clinical improvement frequently did not correlate with patient satisfaction, and there were significant patients continuing treatment despite distinct clinical levels of improvement. The study explains clearly that clinical changes are occurring after each treatment time and the patient response should be assessed carefully. Clearly the fact that the patients were receiving the product without cost could be perceived as a motivator to continue with treatment. Clinical trends were clarified nicely in this study. The initial treatments with ATX-101 resulted in frequent but self-limited adverse events (ecchymosis, bruising, swelling) for the patients and these early treatments tended to be the worst for the patient. As the fat was resorbed over the treatment course, drug volume required, and adverse events tended to diminish. The trend and “expected” treatment response will help clinicians counsel patients, helping to manage their anxieties. Additionally, the study defined the follow up as 4 weeks for consistency. After using the product, we acknowledge that many patients have some subtle signs of a resolving inflammatory response at 4 weeks. Delaying secondary treatments for 6 to 8 weeks intervals could allow for ongoing contour change and may have an impact on how much product is needed and how many treatments each patient may require. This study failed to show evidence of skin laxity following the treatment of SMF with ATX-101. Whether this was appropriate patient selection, scarring, or neocollangeneis remains to be seen and deserves further attention. Finally, further investigation comparing different modalities and patient satisfaction and efficacy would be of interest. We physicians appreciate providing our patients with a number of options to help them achieve their goals. The introduction ATX-101 and other modalities has provided us the tools to tailor treatment of SMF for our patients. Most clinicians are interested in using a product such as ATX-101 for “off face” indications. The cost of the product makes justification of its use even “off label” prohibitive. Disclosures Dr Kenkel was a consultant for Kythera from 2014-2016, focusing on the anatomic considerations with the product. Dr Lahar declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Dayan SH , Schlessinger J , Beer K , et al. Efficacy and safety of ATX-101 by treatment session: pooled analysis of data from the phase 3 REFINE trials . Aesthet Surg J . 2018 ; 38 ( 9 ): 998 - 1010 . 2. Center for Drug Evaluation and Research . Application Number: 206333Orig1s000 . https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206333orig1s000sumr.pdf. Accessed March 27, 2018 . 3. Jones DH , Carruthers J , Joseph JH , et al. REFINE-1, a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental fat reduction . Dermatol Surg . 2016 ; 42 ( 1 ): 38 - 49 . Google Scholar CrossRef Search ADS PubMed 4. Humphrey S , Sykes J , Kantor J , et al. ATX-101 for reduction of submental fat: a phase III randomized controlled trial . J Am Acad Dermatol . 2016 ; 75 ( 4 ): 788 - 797.e7 . Google Scholar CrossRef Search ADS PubMed © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Aesthetic Surgery Journal – Oxford University Press

Published: Sep 1, 2018

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