FDA panel backs injectable treatment for chin fat

SILVER SPRING, MD – A less-invasive alternative to liposuction and other cosmetic treatments for submental fat will likely become available in the United States in the wake of a Food and Drug Administration advisory panel’s unanimous support for approval of deoxycholic acid as an injection into subcutaneous fat under the chin.

At a meeting on March 9, the FDA’s dermatologic and ophthalmic drugs advisory committee voted 17-0 that the efficacy and safety data on 1% deoxycholic acid (DCA) injection supported approval for the proposed indication, “the improvement in the appearance of moderate to severe convexity or fullness associated with submental fat” in adults.

The product is a synthetic version of naturally occurring DCA, an endogenous secondary bile acid that “serves to emulsify and solubilize dietary fat,” and for cosmetic use, “disrupts cell membranes of adipocytes, causing destruction of fat cells,” according to the manufacturer, Kythera Biopharmaceuticals.

The regimen proposed by Kythera is up to six treatment sessions with 4-week intervals between sessions. Each session would involve up to 50 injections, with 0.2 mL of DCA solution per injection, administered subcutaneously using a grid to control spacing of injections. The product would be the first drug approved for treatment of submental fat.

A pair of phase III studies including about 1,000 adults (median age, 48-49 years) randomized patients to treatment with DCA or placebo saline injections of 6 or fewer treatments, one month apart. The effects were evaluated with validated Clinician-Reported and a Patient-Reported Submental Fat Rating Scales (CR-SMFRS and PR-SMFRS), which Kythera developed in consultation with the FDA. On the CR-SMFRS, a 5-point rating scale ranged from 0 (no localized submental fat evident) to 4 (extreme submental convexity).

Most patients enrolled were rated as 2 (moderate, with prominent localized submental fat) or 3 (severe, with marked localized submental fat); the company is not seeking an indication for extreme submental convexity. On the PR-SMFRS, patients had five options to check off, based on how much fat they thought they had under their chin when looking in a mirror, ranging from “no chin fat at all” to a “very large amount of fat.”

The coprimary efficacy endpoints were those who had at least a 2-grade improvement on both scales, or at least a 1-grade improvement in both scales, 12 weeks after the first treatment.

In the two studies, 70% and 66% of those treated with DCA achieved at least a 1-grade improvement in both scales, vs.19% and 22%, respectively, in the placebo group. The difference was statistically significant. In addition, 13% and 19% of those treated with DCA in the two studies had at least a 2-grade improvement in both scales at that time, vs. 0-3% of those in the placebo group, also statistically significant differences.

One issue raised at the meeting was that the scales were somewhat subjective. A more objective secondary endpoint used MRI volumetric measurements to evaluate results in 449 patients from both studies; this measure determined that 40%-46% of those treated with DCA achieved at least a 10% reduction in MRI volume of submental fat, vs. 5% of those on placebo.

Most patients in the placebo and DCA groups experienced adverse events that were mostly mild and were related to the injections. The rate of moderate adverse events was 17% in the DCA-treated patients and 10% in the placebo group. Injection site reactions more common in the DCA group vs. placebo included pain (70% vs. 31%), numbness (66% vs. 6%), edema (60% vs. 29%), and swelling (33% vs. 16%). There were 11 cases of dysphagia, all of which resolved, except for 1 patient who withdrew from the study and was not available for follow-up. There have been no cases of glandular injuries, including salivary or thyroid injuries, according to the company.

In a safety database of almost 2,000 patients, including 1,050 treated with DCA, the rate of marginal mandibular nerve injuries has been 4% in those treated with DCA. The nerve injuries lasted a median of 45 days (1-298 days) and all resolved. The rate of dysphagia was 2% among those on DCA , lasting a median of 3 days, vs. fewer than 1% among those on placebo, according to the FDA reviewers. One patient did not resolve, but the company noted that this patient dropped out of the study and was not followed. There were no cases of anaphylactic reactions; injection site urticaria was rare and resolved.

In addition, the potential risk of marginal mandibular nerve injuries, issues raised during the meeting included the concerns that the treatment would be used by clinicians who were not adequately trained to provide the treatment or not adequately familiar with the anatomy of the treated area. Other concerns include potential use of the product in areas that include the periorbitum, as well as off-label use of large amounts in different parts of the body, such as the abdomen or thighs. The company said that the product will not be provided to clinicians who have not gone through the planned training program and that it was better suited to small areas of the body.

While there are some questions that still need to be answered and concerns about off-label use and the need for proper training, the panel agreed this was safe and effective if used properly with appropriate training and appropriate precautions, said the panel chair, Dr. Lynn A. Drake of the department of dermatology, Massachusetts General Hospital, Boston.

DCA should not be used off label, a concern that could be at least partially addressed in the label, and “without appropriate training, this product could be misused and mishandled and cause damage,” she added. In addition, because of some “very novel” aspects to this treatment, postmarketing data are needed, addressing questions that include whether it causes scarring that could affect surgery and other interventions in the future, she said.

The FDA usually follows the recommendations of its advisory panels. None of the panel members had relevant disclosures.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD – A less-invasive alternative to liposuction and other cosmetic treatments for submental fat will likely become available in the United States in the wake of a Food and Drug Administration advisory panel’s unanimous support for approval of deoxycholic acid as an injection into subcutaneous fat under the chin.

At a meeting on March 9, the FDA’s dermatologic and ophthalmic drugs advisory committee voted 17-0 that the efficacy and safety data on 1% deoxycholic acid (DCA) injection supported approval for the proposed indication, “the improvement in the appearance of moderate to severe convexity or fullness associated with submental fat” in adults.

The product is a synthetic version of naturally occurring DCA, an endogenous secondary bile acid that “serves to emulsify and solubilize dietary fat,” and for cosmetic use, “disrupts cell membranes of adipocytes, causing destruction of fat cells,” according to the manufacturer, Kythera Biopharmaceuticals.

The regimen proposed by Kythera is up to six treatment sessions with 4-week intervals between sessions. Each session would involve up to 50 injections, with 0.2 mL of DCA solution per injection, administered subcutaneously using a grid to control spacing of injections. The product would be the first drug approved for treatment of submental fat.

A pair of phase III studies including about 1,000 adults (median age, 48-49 years) randomized patients to treatment with DCA or placebo saline injections of 6 or fewer treatments, one month apart. The effects were evaluated with validated Clinician-Reported and a Patient-Reported Submental Fat Rating Scales (CR-SMFRS and PR-SMFRS), which Kythera developed in consultation with the FDA. On the CR-SMFRS, a 5-point rating scale ranged from 0 (no localized submental fat evident) to 4 (extreme submental convexity).

Most patients enrolled were rated as 2 (moderate, with prominent localized submental fat) or 3 (severe, with marked localized submental fat); the company is not seeking an indication for extreme submental convexity. On the PR-SMFRS, patients had five options to check off, based on how much fat they thought they had under their chin when looking in a mirror, ranging from “no chin fat at all” to a “very large amount of fat.”

The coprimary efficacy endpoints were those who had at least a 2-grade improvement on both scales, or at least a 1-grade improvement in both scales, 12 weeks after the first treatment.

In the two studies, 70% and 66% of those treated with DCA achieved at least a 1-grade improvement in both scales, vs.19% and 22%, respectively, in the placebo group. The difference was statistically significant. In addition, 13% and 19% of those treated with DCA in the two studies had at least a 2-grade improvement in both scales at that time, vs. 0-3% of those in the placebo group, also statistically significant differences.

One issue raised at the meeting was that the scales were somewhat subjective. A more objective secondary endpoint used MRI volumetric measurements to evaluate results in 449 patients from both studies; this measure determined that 40%-46% of those treated with DCA achieved at least a 10% reduction in MRI volume of submental fat, vs. 5% of those on placebo.

Most patients in the placebo and DCA groups experienced adverse events that were mostly mild and were related to the injections. The rate of moderate adverse events was 17% in the DCA-treated patients and 10% in the placebo group. Injection site reactions more common in the DCA group vs. placebo included pain (70% vs. 31%), numbness (66% vs. 6%), edema (60% vs. 29%), and swelling (33% vs. 16%). There were 11 cases of dysphagia, all of which resolved, except for 1 patient who withdrew from the study and was not available for follow-up. There have been no cases of glandular injuries, including salivary or thyroid injuries, according to the company.

In a safety database of almost 2,000 patients, including 1,050 treated with DCA, the rate of marginal mandibular nerve injuries has been 4% in those treated with DCA. The nerve injuries lasted a median of 45 days (1-298 days) and all resolved. The rate of dysphagia was 2% among those on DCA , lasting a median of 3 days, vs. fewer than 1% among those on placebo, according to the FDA reviewers. One patient did not resolve, but the company noted that this patient dropped out of the study and was not followed. There were no cases of anaphylactic reactions; injection site urticaria was rare and resolved.

In addition, the potential risk of marginal mandibular nerve injuries, issues raised during the meeting included the concerns that the treatment would be used by clinicians who were not adequately trained to provide the treatment or not adequately familiar with the anatomy of the treated area. Other concerns include potential use of the product in areas that include the periorbitum, as well as off-label use of large amounts in different parts of the body, such as the abdomen or thighs. The company said that the product will not be provided to clinicians who have not gone through the planned training program and that it was better suited to small areas of the body.

While there are some questions that still need to be answered and concerns about off-label use and the need for proper training, the panel agreed this was safe and effective if used properly with appropriate training and appropriate precautions, said the panel chair, Dr. Lynn A. Drake of the department of dermatology, Massachusetts General Hospital, Boston.

DCA should not be used off label, a concern that could be at least partially addressed in the label, and “without appropriate training, this product could be misused and mishandled and cause damage,” she added. In addition, because of some “very novel” aspects to this treatment, postmarketing data are needed, addressing questions that include whether it causes scarring that could affect surgery and other interventions in the future, she said.

The FDA usually follows the recommendations of its advisory panels. None of the panel members had relevant disclosures.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD – A less-invasive alternative to liposuction and other cosmetic treatments for submental fat will likely become available in the United States in the wake of a Food and Drug Administration advisory panel’s unanimous support for approval of deoxycholic acid as an injection into subcutaneous fat under the chin.

At a meeting on March 9, the FDA’s dermatologic and ophthalmic drugs advisory committee voted 17-0 that the efficacy and safety data on 1% deoxycholic acid (DCA) injection supported approval for the proposed indication, “the improvement in the appearance of moderate to severe convexity or fullness associated with submental fat” in adults.

The product is a synthetic version of naturally occurring DCA, an endogenous secondary bile acid that “serves to emulsify and solubilize dietary fat,” and for cosmetic use, “disrupts cell membranes of adipocytes, causing destruction of fat cells,” according to the manufacturer, Kythera Biopharmaceuticals.

The regimen proposed by Kythera is up to six treatment sessions with 4-week intervals between sessions. Each session would involve up to 50 injections, with 0.2 mL of DCA solution per injection, administered subcutaneously using a grid to control spacing of injections. The product would be the first drug approved for treatment of submental fat.

A pair of phase III studies including about 1,000 adults (median age, 48-49 years) randomized patients to treatment with DCA or placebo saline injections of 6 or fewer treatments, one month apart. The effects were evaluated with validated Clinician-Reported and a Patient-Reported Submental Fat Rating Scales (CR-SMFRS and PR-SMFRS), which Kythera developed in consultation with the FDA. On the CR-SMFRS, a 5-point rating scale ranged from 0 (no localized submental fat evident) to 4 (extreme submental convexity).

Most patients enrolled were rated as 2 (moderate, with prominent localized submental fat) or 3 (severe, with marked localized submental fat); the company is not seeking an indication for extreme submental convexity. On the PR-SMFRS, patients had five options to check off, based on how much fat they thought they had under their chin when looking in a mirror, ranging from “no chin fat at all” to a “very large amount of fat.”

The coprimary efficacy endpoints were those who had at least a 2-grade improvement on both scales, or at least a 1-grade improvement in both scales, 12 weeks after the first treatment.

In the two studies, 70% and 66% of those treated with DCA achieved at least a 1-grade improvement in both scales, vs.19% and 22%, respectively, in the placebo group. The difference was statistically significant. In addition, 13% and 19% of those treated with DCA in the two studies had at least a 2-grade improvement in both scales at that time, vs. 0-3% of those in the placebo group, also statistically significant differences.

One issue raised at the meeting was that the scales were somewhat subjective. A more objective secondary endpoint used MRI volumetric measurements to evaluate results in 449 patients from both studies; this measure determined that 40%-46% of those treated with DCA achieved at least a 10% reduction in MRI volume of submental fat, vs. 5% of those on placebo.

Most patients in the placebo and DCA groups experienced adverse events that were mostly mild and were related to the injections. The rate of moderate adverse events was 17% in the DCA-treated patients and 10% in the placebo group. Injection site reactions more common in the DCA group vs. placebo included pain (70% vs. 31%), numbness (66% vs. 6%), edema (60% vs. 29%), and swelling (33% vs. 16%). There were 11 cases of dysphagia, all of which resolved, except for 1 patient who withdrew from the study and was not available for follow-up. There have been no cases of glandular injuries, including salivary or thyroid injuries, according to the company.

In a safety database of almost 2,000 patients, including 1,050 treated with DCA, the rate of marginal mandibular nerve injuries has been 4% in those treated with DCA. The nerve injuries lasted a median of 45 days (1-298 days) and all resolved. The rate of dysphagia was 2% among those on DCA , lasting a median of 3 days, vs. fewer than 1% among those on placebo, according to the FDA reviewers. One patient did not resolve, but the company noted that this patient dropped out of the study and was not followed. There were no cases of anaphylactic reactions; injection site urticaria was rare and resolved.

In addition, the potential risk of marginal mandibular nerve injuries, issues raised during the meeting included the concerns that the treatment would be used by clinicians who were not adequately trained to provide the treatment or not adequately familiar with the anatomy of the treated area. Other concerns include potential use of the product in areas that include the periorbitum, as well as off-label use of large amounts in different parts of the body, such as the abdomen or thighs. The company said that the product will not be provided to clinicians who have not gone through the planned training program and that it was better suited to small areas of the body.

While there are some questions that still need to be answered and concerns about off-label use and the need for proper training, the panel agreed this was safe and effective if used properly with appropriate training and appropriate precautions, said the panel chair, Dr. Lynn A. Drake of the department of dermatology, Massachusetts General Hospital, Boston.

DCA should not be used off label, a concern that could be at least partially addressed in the label, and “without appropriate training, this product could be misused and mishandled and cause damage,” she added. In addition, because of some “very novel” aspects to this treatment, postmarketing data are needed, addressing questions that include whether it causes scarring that could affect surgery and other interventions in the future, she said.

The FDA usually follows the recommendations of its advisory panels. None of the panel members had relevant disclosures.

emechcatie@frontlinemedcom.com