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Lanolin gets nod for Allergen of the Year
Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.
Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.
“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.
“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”
And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.
“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.
Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.
Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
Consider high-risk groups
Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.
Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.
Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”
Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.
Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.
Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.
“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.
“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”
And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.
“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.
Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.
Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
Consider high-risk groups
Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.
Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.
Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”
Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.
Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.
Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.
“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.
“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”
And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.
“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.
Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.
Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
Consider high-risk groups
Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.
Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.
Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”
Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.
FROM ACDS 2023
Study finds quality of topical steroid withdrawal videos on YouTube subpar
NEW ORLEANS –
“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”
Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.
Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”
The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.
“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.
Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.
Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”
One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”
Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.
NEW ORLEANS –
“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”
Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.
Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”
The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.
“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.
Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.
Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”
One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”
Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.
NEW ORLEANS –
“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”
Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.
Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”
The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.
“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.
Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.
Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”
One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”
Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.
AT AAD 2023
Upadacitinib shows positive endoscopic outcomes in Crohn’s disease at 1 year
The findings of this subanalysis come from two phase 3 induction trials (U-EXCEL and U-EXCEED) and one maintenance study (U-ENDURE) of upadacitinib in this patient population.
“Upadacitinib shows large differences relative to placebo in endoscopic response and remission ... in a difficult-to-treat population of patients, the majority of whom had failed an advanced therapy,” lead investigator Brian Feagan, MD, senior scientific director of the GI contract research firm Alimentiv in London, Ontario, said in an interview.
“The absolute magnitude of the finding was unanticipated – a greater treatment effect than might be anticipated for these outcomes compared with other advanced treatments for Crohn’s disease in these higher-risk patients,” he said.
Dr. Feagan presented the research at the annual congress of the European Crohn’s and Colitis Organisation.
Research methodology
At baseline, participants had an average daily stool frequency of 4 or more and/or an abdominal pain score of 2 or greater. They also had a Simple Endoscopic Score for Crohn’s disease of 6 or more, excluding a narrowing component, or a score of 4 or more for isolated ileal Crohn’s disease.
In the treatment induction phase, patients were randomly assigned 2:1, with 674 people receiving 45 mg upadacitinib and 347 taking a placebo once daily for 12 weeks.
Participants who experienced at least a 30% decrease in stool frequency and/or daily abdominal pain scores were enrolled in the maintenance phase of the study. For this phase, patients were randomly assigned again, with 168 receiving 30 mg upadacitinib, 169 receiving 15 mg upadacitinib, and 165 taking a placebo once daily for 52 weeks.
In each induction and maintenance cohort, more than 70% of patients had failed one prior biologic therapy, with failure defined as inadequate response or intolerance. Among those who failed a previous biologic in induction, 96% had also failed prior treatment with an anti–tumor necrosis factor (anti-TNF) inhibitor.
Participants’ mean age was 38-40 years, and 52%-55% were men. Patients who had not failed previous therapy had Crohn’s disease for a median of 6-7 years. In contrast, the prior-failure group had Crohn’s disease for a median of 9-10 years.
Key outcomes
At 12 weeks, endoscopic response among patients who had not failed a prior biologic was 52% in the treatment group versus 16% of the placebo group. In the prior-failure group, endoscopic response was observed in 36% and 5%, respectively.
Endoscopic remission at 12 weeks among patients who had not failed a prior biologic was 36% in the treatment group versus 10% in the placebo group. In the prior-failure group, endoscopic remission was 20% in the treatment group versus 3% in those who took placebo.
Participants in the treatment groups of the 52-week maintenance phase of the study experienced higher endoscopic response and endoscopic remission rates compared with those who received placebo.
Endoscopic response in the group without prior biologic failure was 44% in the 30-mg upadacitinib group, 40% in the 15-mg group, and 18% in the placebo group. Among those with prior biologic failure, endoscopic response was seen in 39% of the 30-mg upadacitinib group, 23% of the 15-mg group, and 4% of the placebo group.
There is a “very striking difference in endoscopic response rates between the high dose and placebo,” Dr. Feagan said. “That difference here is in the response rate. You see dose separation.”
Endoscopic remission among those without prior biologic failure was observed in 34% of the 30-mg upadacitinib group, 27% of the 15-mg group, and 16% of the placebo group. Among those with prior biologic failure, endoscopic remission was seen in 27% of the 30-mg upadacitinib group, 16% of the 15-mg group, and 2% of the placebo group.
The results show “a clear advantage for the 30-mg dose versus the 15-mg in the maintenance component, especially in patients who had failed an advanced therapy,” Dr. Feagan said.
Safety signals
Upadacitinib was well tolerated in the induction and maintenance phases, and no new safety risks were observed compared with the known safety profile of the drug, the researchers noted.
For example, during the induction studies, the rate of any adverse event among patients without prior biologic failure was 60% in the 45-mg upadacitinib group and 53% in the placebo group. Among those who failed a prior biologic, the rates were 67% in the 45-mg upadacitinib group and 66% in the placebo group.
The adverse events were “issues that have already been identified with JAK inhibitors, the biochemical abnormalities with CPK [creatine phosphokinase] elevations and transaminase elevations,” Dr. Feagan said.
There were no cases of herpes zoster among patients who received placebo compared with five cases in the 45-mg upadacitinib group without prior biologic failure and 10 cases in the prior biologic failure group.
“The zoster signal is there even at induction with the 45-mg dose versus placebo,” Dr. Feagan said.
‘Encouraging’ results
The study indicates that upadacitinib is effective in improving endoscopic outcomes for patients with Crohn’s disease, regardless of their prior biologic treatments, Robin L. Dalal, MD, assistant professor of medicine at Vanderbilt University in Nashville, Tenn., said when asked to comment on the study.
“This is important because, as the treatment landscape for Crohn’s disease has expanded, sequencing of therapies has become more complex,” added Dr. Dalal, who was not involved in the research. “For upadacitinib in Crohn’s disease, prior biologic use may not be a factor in endoscopic response rates.”
The findings are “very encouraging for physicians and practitioners who treat IBD [inflammatory bowel disease] patients,” Maithili Chitnavis, MD, of the inflammatory bowel disease section at Atrium Health Gastroenterology in Charlotte, N.C., said when asked for comment.
“We clearly care about how patients feel overall, but endoscopic and histologic outcomes are important to investigate because we want to ensure there is internal healing to prevent a lot of the longstanding complications of Crohn’s disease, such as malignancy, strictures, fistulizing/penetrating disease, and need for surgery,” said Dr. Chitnavis, who was not involved with the study.
Upadacitinib is an oral agent, which distinguishes it from the injectable or infusion-based biologic therapies for Crohn’s disease, Dr. Chitnavis noted.
The finding that the medication works in patients with or without prior biologic failure is important, she said.
“With its anticipated ... approval for Crohn’s disease [by the Food and Drug Administration], it is expected that patients will have had to have demonstrated a lack of or loss of response to another biologic, specifically in the anti-TNF category (for example, infliximab, adalimumab, certolizumab) prior to starting upadacitinib due to concerns of potential side effects associated with the class of medications to which it belongs,” Dr. Chitnavis said. “Therefore, it makes it even more relevant to know how patients who have failed a prior biologic respond to this therapy.”
Dr. Feagan has reported serving as a consultant and speaker for AbbVie. Dr. Dalal has reported being a consultant for AbbVie in 2021. Dr. Chitnavis has reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The findings of this subanalysis come from two phase 3 induction trials (U-EXCEL and U-EXCEED) and one maintenance study (U-ENDURE) of upadacitinib in this patient population.
“Upadacitinib shows large differences relative to placebo in endoscopic response and remission ... in a difficult-to-treat population of patients, the majority of whom had failed an advanced therapy,” lead investigator Brian Feagan, MD, senior scientific director of the GI contract research firm Alimentiv in London, Ontario, said in an interview.
“The absolute magnitude of the finding was unanticipated – a greater treatment effect than might be anticipated for these outcomes compared with other advanced treatments for Crohn’s disease in these higher-risk patients,” he said.
Dr. Feagan presented the research at the annual congress of the European Crohn’s and Colitis Organisation.
Research methodology
At baseline, participants had an average daily stool frequency of 4 or more and/or an abdominal pain score of 2 or greater. They also had a Simple Endoscopic Score for Crohn’s disease of 6 or more, excluding a narrowing component, or a score of 4 or more for isolated ileal Crohn’s disease.
In the treatment induction phase, patients were randomly assigned 2:1, with 674 people receiving 45 mg upadacitinib and 347 taking a placebo once daily for 12 weeks.
Participants who experienced at least a 30% decrease in stool frequency and/or daily abdominal pain scores were enrolled in the maintenance phase of the study. For this phase, patients were randomly assigned again, with 168 receiving 30 mg upadacitinib, 169 receiving 15 mg upadacitinib, and 165 taking a placebo once daily for 52 weeks.
In each induction and maintenance cohort, more than 70% of patients had failed one prior biologic therapy, with failure defined as inadequate response or intolerance. Among those who failed a previous biologic in induction, 96% had also failed prior treatment with an anti–tumor necrosis factor (anti-TNF) inhibitor.
Participants’ mean age was 38-40 years, and 52%-55% were men. Patients who had not failed previous therapy had Crohn’s disease for a median of 6-7 years. In contrast, the prior-failure group had Crohn’s disease for a median of 9-10 years.
Key outcomes
At 12 weeks, endoscopic response among patients who had not failed a prior biologic was 52% in the treatment group versus 16% of the placebo group. In the prior-failure group, endoscopic response was observed in 36% and 5%, respectively.
Endoscopic remission at 12 weeks among patients who had not failed a prior biologic was 36% in the treatment group versus 10% in the placebo group. In the prior-failure group, endoscopic remission was 20% in the treatment group versus 3% in those who took placebo.
Participants in the treatment groups of the 52-week maintenance phase of the study experienced higher endoscopic response and endoscopic remission rates compared with those who received placebo.
Endoscopic response in the group without prior biologic failure was 44% in the 30-mg upadacitinib group, 40% in the 15-mg group, and 18% in the placebo group. Among those with prior biologic failure, endoscopic response was seen in 39% of the 30-mg upadacitinib group, 23% of the 15-mg group, and 4% of the placebo group.
There is a “very striking difference in endoscopic response rates between the high dose and placebo,” Dr. Feagan said. “That difference here is in the response rate. You see dose separation.”
Endoscopic remission among those without prior biologic failure was observed in 34% of the 30-mg upadacitinib group, 27% of the 15-mg group, and 16% of the placebo group. Among those with prior biologic failure, endoscopic remission was seen in 27% of the 30-mg upadacitinib group, 16% of the 15-mg group, and 2% of the placebo group.
The results show “a clear advantage for the 30-mg dose versus the 15-mg in the maintenance component, especially in patients who had failed an advanced therapy,” Dr. Feagan said.
Safety signals
Upadacitinib was well tolerated in the induction and maintenance phases, and no new safety risks were observed compared with the known safety profile of the drug, the researchers noted.
For example, during the induction studies, the rate of any adverse event among patients without prior biologic failure was 60% in the 45-mg upadacitinib group and 53% in the placebo group. Among those who failed a prior biologic, the rates were 67% in the 45-mg upadacitinib group and 66% in the placebo group.
The adverse events were “issues that have already been identified with JAK inhibitors, the biochemical abnormalities with CPK [creatine phosphokinase] elevations and transaminase elevations,” Dr. Feagan said.
There were no cases of herpes zoster among patients who received placebo compared with five cases in the 45-mg upadacitinib group without prior biologic failure and 10 cases in the prior biologic failure group.
“The zoster signal is there even at induction with the 45-mg dose versus placebo,” Dr. Feagan said.
‘Encouraging’ results
The study indicates that upadacitinib is effective in improving endoscopic outcomes for patients with Crohn’s disease, regardless of their prior biologic treatments, Robin L. Dalal, MD, assistant professor of medicine at Vanderbilt University in Nashville, Tenn., said when asked to comment on the study.
“This is important because, as the treatment landscape for Crohn’s disease has expanded, sequencing of therapies has become more complex,” added Dr. Dalal, who was not involved in the research. “For upadacitinib in Crohn’s disease, prior biologic use may not be a factor in endoscopic response rates.”
The findings are “very encouraging for physicians and practitioners who treat IBD [inflammatory bowel disease] patients,” Maithili Chitnavis, MD, of the inflammatory bowel disease section at Atrium Health Gastroenterology in Charlotte, N.C., said when asked for comment.
“We clearly care about how patients feel overall, but endoscopic and histologic outcomes are important to investigate because we want to ensure there is internal healing to prevent a lot of the longstanding complications of Crohn’s disease, such as malignancy, strictures, fistulizing/penetrating disease, and need for surgery,” said Dr. Chitnavis, who was not involved with the study.
Upadacitinib is an oral agent, which distinguishes it from the injectable or infusion-based biologic therapies for Crohn’s disease, Dr. Chitnavis noted.
The finding that the medication works in patients with or without prior biologic failure is important, she said.
“With its anticipated ... approval for Crohn’s disease [by the Food and Drug Administration], it is expected that patients will have had to have demonstrated a lack of or loss of response to another biologic, specifically in the anti-TNF category (for example, infliximab, adalimumab, certolizumab) prior to starting upadacitinib due to concerns of potential side effects associated with the class of medications to which it belongs,” Dr. Chitnavis said. “Therefore, it makes it even more relevant to know how patients who have failed a prior biologic respond to this therapy.”
Dr. Feagan has reported serving as a consultant and speaker for AbbVie. Dr. Dalal has reported being a consultant for AbbVie in 2021. Dr. Chitnavis has reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The findings of this subanalysis come from two phase 3 induction trials (U-EXCEL and U-EXCEED) and one maintenance study (U-ENDURE) of upadacitinib in this patient population.
“Upadacitinib shows large differences relative to placebo in endoscopic response and remission ... in a difficult-to-treat population of patients, the majority of whom had failed an advanced therapy,” lead investigator Brian Feagan, MD, senior scientific director of the GI contract research firm Alimentiv in London, Ontario, said in an interview.
“The absolute magnitude of the finding was unanticipated – a greater treatment effect than might be anticipated for these outcomes compared with other advanced treatments for Crohn’s disease in these higher-risk patients,” he said.
Dr. Feagan presented the research at the annual congress of the European Crohn’s and Colitis Organisation.
Research methodology
At baseline, participants had an average daily stool frequency of 4 or more and/or an abdominal pain score of 2 or greater. They also had a Simple Endoscopic Score for Crohn’s disease of 6 or more, excluding a narrowing component, or a score of 4 or more for isolated ileal Crohn’s disease.
In the treatment induction phase, patients were randomly assigned 2:1, with 674 people receiving 45 mg upadacitinib and 347 taking a placebo once daily for 12 weeks.
Participants who experienced at least a 30% decrease in stool frequency and/or daily abdominal pain scores were enrolled in the maintenance phase of the study. For this phase, patients were randomly assigned again, with 168 receiving 30 mg upadacitinib, 169 receiving 15 mg upadacitinib, and 165 taking a placebo once daily for 52 weeks.
In each induction and maintenance cohort, more than 70% of patients had failed one prior biologic therapy, with failure defined as inadequate response or intolerance. Among those who failed a previous biologic in induction, 96% had also failed prior treatment with an anti–tumor necrosis factor (anti-TNF) inhibitor.
Participants’ mean age was 38-40 years, and 52%-55% were men. Patients who had not failed previous therapy had Crohn’s disease for a median of 6-7 years. In contrast, the prior-failure group had Crohn’s disease for a median of 9-10 years.
Key outcomes
At 12 weeks, endoscopic response among patients who had not failed a prior biologic was 52% in the treatment group versus 16% of the placebo group. In the prior-failure group, endoscopic response was observed in 36% and 5%, respectively.
Endoscopic remission at 12 weeks among patients who had not failed a prior biologic was 36% in the treatment group versus 10% in the placebo group. In the prior-failure group, endoscopic remission was 20% in the treatment group versus 3% in those who took placebo.
Participants in the treatment groups of the 52-week maintenance phase of the study experienced higher endoscopic response and endoscopic remission rates compared with those who received placebo.
Endoscopic response in the group without prior biologic failure was 44% in the 30-mg upadacitinib group, 40% in the 15-mg group, and 18% in the placebo group. Among those with prior biologic failure, endoscopic response was seen in 39% of the 30-mg upadacitinib group, 23% of the 15-mg group, and 4% of the placebo group.
There is a “very striking difference in endoscopic response rates between the high dose and placebo,” Dr. Feagan said. “That difference here is in the response rate. You see dose separation.”
Endoscopic remission among those without prior biologic failure was observed in 34% of the 30-mg upadacitinib group, 27% of the 15-mg group, and 16% of the placebo group. Among those with prior biologic failure, endoscopic remission was seen in 27% of the 30-mg upadacitinib group, 16% of the 15-mg group, and 2% of the placebo group.
The results show “a clear advantage for the 30-mg dose versus the 15-mg in the maintenance component, especially in patients who had failed an advanced therapy,” Dr. Feagan said.
Safety signals
Upadacitinib was well tolerated in the induction and maintenance phases, and no new safety risks were observed compared with the known safety profile of the drug, the researchers noted.
For example, during the induction studies, the rate of any adverse event among patients without prior biologic failure was 60% in the 45-mg upadacitinib group and 53% in the placebo group. Among those who failed a prior biologic, the rates were 67% in the 45-mg upadacitinib group and 66% in the placebo group.
The adverse events were “issues that have already been identified with JAK inhibitors, the biochemical abnormalities with CPK [creatine phosphokinase] elevations and transaminase elevations,” Dr. Feagan said.
There were no cases of herpes zoster among patients who received placebo compared with five cases in the 45-mg upadacitinib group without prior biologic failure and 10 cases in the prior biologic failure group.
“The zoster signal is there even at induction with the 45-mg dose versus placebo,” Dr. Feagan said.
‘Encouraging’ results
The study indicates that upadacitinib is effective in improving endoscopic outcomes for patients with Crohn’s disease, regardless of their prior biologic treatments, Robin L. Dalal, MD, assistant professor of medicine at Vanderbilt University in Nashville, Tenn., said when asked to comment on the study.
“This is important because, as the treatment landscape for Crohn’s disease has expanded, sequencing of therapies has become more complex,” added Dr. Dalal, who was not involved in the research. “For upadacitinib in Crohn’s disease, prior biologic use may not be a factor in endoscopic response rates.”
The findings are “very encouraging for physicians and practitioners who treat IBD [inflammatory bowel disease] patients,” Maithili Chitnavis, MD, of the inflammatory bowel disease section at Atrium Health Gastroenterology in Charlotte, N.C., said when asked for comment.
“We clearly care about how patients feel overall, but endoscopic and histologic outcomes are important to investigate because we want to ensure there is internal healing to prevent a lot of the longstanding complications of Crohn’s disease, such as malignancy, strictures, fistulizing/penetrating disease, and need for surgery,” said Dr. Chitnavis, who was not involved with the study.
Upadacitinib is an oral agent, which distinguishes it from the injectable or infusion-based biologic therapies for Crohn’s disease, Dr. Chitnavis noted.
The finding that the medication works in patients with or without prior biologic failure is important, she said.
“With its anticipated ... approval for Crohn’s disease [by the Food and Drug Administration], it is expected that patients will have had to have demonstrated a lack of or loss of response to another biologic, specifically in the anti-TNF category (for example, infliximab, adalimumab, certolizumab) prior to starting upadacitinib due to concerns of potential side effects associated with the class of medications to which it belongs,” Dr. Chitnavis said. “Therefore, it makes it even more relevant to know how patients who have failed a prior biologic respond to this therapy.”
Dr. Feagan has reported serving as a consultant and speaker for AbbVie. Dr. Dalal has reported being a consultant for AbbVie in 2021. Dr. Chitnavis has reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM ECCO 2023
Oral PCSK9 inhibitor shows encouraging LDL lowering
A new oral formulation of a PCSK9-inhibiting, cholesterol-lowering drug in development by Merck has shown encouraging results in a phase 2 study.
The study was presented by Christie Ballantyne, MD, Baylor College of Medicine, Houston, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“In this diverse population of hypercholesterolemic patients, all doses of MK-0616 showed superior reduction of LDL vs. placebo up to a 60.9% placebo-adjusted reduction from baseline to week 8, which was consistent across subgroups,” Dr. Ballantyne reported.
“Reduction in ApoB and non-HDL cholesterol were consistent with that of LDL cholesterol, with up to a 51.8% reduction in ApoB and a 55.8% reduction in non-HDL,” he noted.
He added that the drug was well tolerated with no difference in adverse events across the treatment groups, compared with placebo.
“These data support the further development of MK-0616, an oral PCSK9 inhibitor that may improve access to effective LDL-cholesterol lowering therapies and improve attainment of guideline-recommended LDL goals aimed at reducing cardiovascular risk,” Dr. Ballantyne concluded. “The results are encouraging for a phase 3 program that is now being designed.”
He explained that elevated LDL is a primary causative factor for atherosclerotic cardiovascular disease (ASCVD), and despite effective treatments (statins), a large proportion of patients fail to achieve guideline-recommended LDL levels. Injectable treatments targeting PCSK9 have demonstrated large reductions in LDL and decreased risk of ASCVD events, but access barriers and need for repeat injections have led to poor adoption. An oral PCSK9 inhibitor may widen access and improve attainment of guideline-recommended treatment goals.
Dr. Ballantyne described the new drug, MK-0616, as a “macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight.”
The current phase 2 study included 381 adult patients (49% female; median age 62 years) with a wide range of ASCVD risk. Average LDL-C level was 119.5 mg/dL at baseline. Around 40% of patients were not taking statins, 35% were on low- to moderate-intensity statin therapy, and 26% were on high-intensity statin therapy.
They were randomly assigned to four different doses of MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo.
Results showed that all doses of MK-0616 demonstrated statistically significant differences in percentage change in LDL-C from baseline to week 8 vs. placebo: –41.2% (6 mg), –55.7% (12 mg), –59.1% (18 mg), and –60.9% (30 mg).
The mean percentage changes in ApoB from baseline vs. placebo were –32.8%, –45.8%, –48.7%, and 51.8% for the four escalating doses of the drug. And non-HDL cholesterol changes were –35.9%, –50.5%, –53.2%, and –55.8% respectively.
The proportion of participants at protocol-defined goals for LDL reduction was 80.5%, 85.5%, 90.8%, and 90.8% with MK-0616 at the 6-mg, 12-mg, 18-mg, and 30-mg doses, compared with 9.3% with placebo.
Dr. Ballantyne reported that the efficacy looked similar in all subgroups, and regardless of baseline therapy.
“This was a dose-finding study, which will help select a dose to be taken forward in larger studies, and it looks from these results as though you get most of the efficacy by 12 mg,” he added.
Adverse events occurred in a proportion of participants in the MK-0616 groups (39.5% to 43.4%) similar to that of placebo (44.0%), and discontinuations as a result of adverse events occurred in two or fewer participants in any treatment group.
‘Super exciting’
Putting the results of his study into perspective at an ACC press conference, Rhonda Cooper-DeHoff, PharmD, associate professor in the department of pharmacotherapy and translational research at the University of Florida in Gainesville, commented.
“For the last quarter of a century we have had statins available to treat elevated LDL and atherosclerosis and despite that we have many patients who refuse to take statins or are afraid to take statins,” she said. “This is not about cost as the statins are all available generically now. But many patients claim to be intolerant or unresponsive.”
She noted that in 2015/2016 the first injectable PCSK9 inhibitors became available “which really were very exciting molecules, but they have a high cost and access issues, and patients often do not like injections so there are still a lot of issues.”
Dr. Cooper-DeHoff pointed out that this oral PCSK9 inhibitor seems to be as effective at lowering LDL as the injectable products regardless of whether statins are on board or not, which she said was “super exciting.”
She added: “We are all going to be waiting excitedly for the outcome data with this oral PCSK9 inhibitor.”
She also noted that another study (CLEAR Outcomes) presented at the ACC meeting showed good lipid-lowering results and a reduction in cardiovascular outcomes in statin-intolerant patients with another oral lipid lowering drug, bempedoic acid (Nexletol).
She said the two oral drugs promised a “very bright for the future for LDL lowering and the treatment of atherosclerosis in our patients,” adding that “we are now really chipping away at the barriers to achieving the holy grail of guideline-directed LDL lowering to prevent hard outcomes.”
The results were published online in the Journal of the American College of Cardiology at the time of presentation.
This study was funded by Merck. Dr. Ballantyne has received grant/research support through his institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostics and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
A new oral formulation of a PCSK9-inhibiting, cholesterol-lowering drug in development by Merck has shown encouraging results in a phase 2 study.
The study was presented by Christie Ballantyne, MD, Baylor College of Medicine, Houston, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“In this diverse population of hypercholesterolemic patients, all doses of MK-0616 showed superior reduction of LDL vs. placebo up to a 60.9% placebo-adjusted reduction from baseline to week 8, which was consistent across subgroups,” Dr. Ballantyne reported.
“Reduction in ApoB and non-HDL cholesterol were consistent with that of LDL cholesterol, with up to a 51.8% reduction in ApoB and a 55.8% reduction in non-HDL,” he noted.
He added that the drug was well tolerated with no difference in adverse events across the treatment groups, compared with placebo.
“These data support the further development of MK-0616, an oral PCSK9 inhibitor that may improve access to effective LDL-cholesterol lowering therapies and improve attainment of guideline-recommended LDL goals aimed at reducing cardiovascular risk,” Dr. Ballantyne concluded. “The results are encouraging for a phase 3 program that is now being designed.”
He explained that elevated LDL is a primary causative factor for atherosclerotic cardiovascular disease (ASCVD), and despite effective treatments (statins), a large proportion of patients fail to achieve guideline-recommended LDL levels. Injectable treatments targeting PCSK9 have demonstrated large reductions in LDL and decreased risk of ASCVD events, but access barriers and need for repeat injections have led to poor adoption. An oral PCSK9 inhibitor may widen access and improve attainment of guideline-recommended treatment goals.
Dr. Ballantyne described the new drug, MK-0616, as a “macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight.”
The current phase 2 study included 381 adult patients (49% female; median age 62 years) with a wide range of ASCVD risk. Average LDL-C level was 119.5 mg/dL at baseline. Around 40% of patients were not taking statins, 35% were on low- to moderate-intensity statin therapy, and 26% were on high-intensity statin therapy.
They were randomly assigned to four different doses of MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo.
Results showed that all doses of MK-0616 demonstrated statistically significant differences in percentage change in LDL-C from baseline to week 8 vs. placebo: –41.2% (6 mg), –55.7% (12 mg), –59.1% (18 mg), and –60.9% (30 mg).
The mean percentage changes in ApoB from baseline vs. placebo were –32.8%, –45.8%, –48.7%, and 51.8% for the four escalating doses of the drug. And non-HDL cholesterol changes were –35.9%, –50.5%, –53.2%, and –55.8% respectively.
The proportion of participants at protocol-defined goals for LDL reduction was 80.5%, 85.5%, 90.8%, and 90.8% with MK-0616 at the 6-mg, 12-mg, 18-mg, and 30-mg doses, compared with 9.3% with placebo.
Dr. Ballantyne reported that the efficacy looked similar in all subgroups, and regardless of baseline therapy.
“This was a dose-finding study, which will help select a dose to be taken forward in larger studies, and it looks from these results as though you get most of the efficacy by 12 mg,” he added.
Adverse events occurred in a proportion of participants in the MK-0616 groups (39.5% to 43.4%) similar to that of placebo (44.0%), and discontinuations as a result of adverse events occurred in two or fewer participants in any treatment group.
‘Super exciting’
Putting the results of his study into perspective at an ACC press conference, Rhonda Cooper-DeHoff, PharmD, associate professor in the department of pharmacotherapy and translational research at the University of Florida in Gainesville, commented.
“For the last quarter of a century we have had statins available to treat elevated LDL and atherosclerosis and despite that we have many patients who refuse to take statins or are afraid to take statins,” she said. “This is not about cost as the statins are all available generically now. But many patients claim to be intolerant or unresponsive.”
She noted that in 2015/2016 the first injectable PCSK9 inhibitors became available “which really were very exciting molecules, but they have a high cost and access issues, and patients often do not like injections so there are still a lot of issues.”
Dr. Cooper-DeHoff pointed out that this oral PCSK9 inhibitor seems to be as effective at lowering LDL as the injectable products regardless of whether statins are on board or not, which she said was “super exciting.”
She added: “We are all going to be waiting excitedly for the outcome data with this oral PCSK9 inhibitor.”
She also noted that another study (CLEAR Outcomes) presented at the ACC meeting showed good lipid-lowering results and a reduction in cardiovascular outcomes in statin-intolerant patients with another oral lipid lowering drug, bempedoic acid (Nexletol).
She said the two oral drugs promised a “very bright for the future for LDL lowering and the treatment of atherosclerosis in our patients,” adding that “we are now really chipping away at the barriers to achieving the holy grail of guideline-directed LDL lowering to prevent hard outcomes.”
The results were published online in the Journal of the American College of Cardiology at the time of presentation.
This study was funded by Merck. Dr. Ballantyne has received grant/research support through his institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostics and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
A new oral formulation of a PCSK9-inhibiting, cholesterol-lowering drug in development by Merck has shown encouraging results in a phase 2 study.
The study was presented by Christie Ballantyne, MD, Baylor College of Medicine, Houston, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“In this diverse population of hypercholesterolemic patients, all doses of MK-0616 showed superior reduction of LDL vs. placebo up to a 60.9% placebo-adjusted reduction from baseline to week 8, which was consistent across subgroups,” Dr. Ballantyne reported.
“Reduction in ApoB and non-HDL cholesterol were consistent with that of LDL cholesterol, with up to a 51.8% reduction in ApoB and a 55.8% reduction in non-HDL,” he noted.
He added that the drug was well tolerated with no difference in adverse events across the treatment groups, compared with placebo.
“These data support the further development of MK-0616, an oral PCSK9 inhibitor that may improve access to effective LDL-cholesterol lowering therapies and improve attainment of guideline-recommended LDL goals aimed at reducing cardiovascular risk,” Dr. Ballantyne concluded. “The results are encouraging for a phase 3 program that is now being designed.”
He explained that elevated LDL is a primary causative factor for atherosclerotic cardiovascular disease (ASCVD), and despite effective treatments (statins), a large proportion of patients fail to achieve guideline-recommended LDL levels. Injectable treatments targeting PCSK9 have demonstrated large reductions in LDL and decreased risk of ASCVD events, but access barriers and need for repeat injections have led to poor adoption. An oral PCSK9 inhibitor may widen access and improve attainment of guideline-recommended treatment goals.
Dr. Ballantyne described the new drug, MK-0616, as a “macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight.”
The current phase 2 study included 381 adult patients (49% female; median age 62 years) with a wide range of ASCVD risk. Average LDL-C level was 119.5 mg/dL at baseline. Around 40% of patients were not taking statins, 35% were on low- to moderate-intensity statin therapy, and 26% were on high-intensity statin therapy.
They were randomly assigned to four different doses of MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo.
Results showed that all doses of MK-0616 demonstrated statistically significant differences in percentage change in LDL-C from baseline to week 8 vs. placebo: –41.2% (6 mg), –55.7% (12 mg), –59.1% (18 mg), and –60.9% (30 mg).
The mean percentage changes in ApoB from baseline vs. placebo were –32.8%, –45.8%, –48.7%, and 51.8% for the four escalating doses of the drug. And non-HDL cholesterol changes were –35.9%, –50.5%, –53.2%, and –55.8% respectively.
The proportion of participants at protocol-defined goals for LDL reduction was 80.5%, 85.5%, 90.8%, and 90.8% with MK-0616 at the 6-mg, 12-mg, 18-mg, and 30-mg doses, compared with 9.3% with placebo.
Dr. Ballantyne reported that the efficacy looked similar in all subgroups, and regardless of baseline therapy.
“This was a dose-finding study, which will help select a dose to be taken forward in larger studies, and it looks from these results as though you get most of the efficacy by 12 mg,” he added.
Adverse events occurred in a proportion of participants in the MK-0616 groups (39.5% to 43.4%) similar to that of placebo (44.0%), and discontinuations as a result of adverse events occurred in two or fewer participants in any treatment group.
‘Super exciting’
Putting the results of his study into perspective at an ACC press conference, Rhonda Cooper-DeHoff, PharmD, associate professor in the department of pharmacotherapy and translational research at the University of Florida in Gainesville, commented.
“For the last quarter of a century we have had statins available to treat elevated LDL and atherosclerosis and despite that we have many patients who refuse to take statins or are afraid to take statins,” she said. “This is not about cost as the statins are all available generically now. But many patients claim to be intolerant or unresponsive.”
She noted that in 2015/2016 the first injectable PCSK9 inhibitors became available “which really were very exciting molecules, but they have a high cost and access issues, and patients often do not like injections so there are still a lot of issues.”
Dr. Cooper-DeHoff pointed out that this oral PCSK9 inhibitor seems to be as effective at lowering LDL as the injectable products regardless of whether statins are on board or not, which she said was “super exciting.”
She added: “We are all going to be waiting excitedly for the outcome data with this oral PCSK9 inhibitor.”
She also noted that another study (CLEAR Outcomes) presented at the ACC meeting showed good lipid-lowering results and a reduction in cardiovascular outcomes in statin-intolerant patients with another oral lipid lowering drug, bempedoic acid (Nexletol).
She said the two oral drugs promised a “very bright for the future for LDL lowering and the treatment of atherosclerosis in our patients,” adding that “we are now really chipping away at the barriers to achieving the holy grail of guideline-directed LDL lowering to prevent hard outcomes.”
The results were published online in the Journal of the American College of Cardiology at the time of presentation.
This study was funded by Merck. Dr. Ballantyne has received grant/research support through his institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostics and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
FROM ACC 2023
Spironolactone: an ‘inexpensive, effective’ option for acne in women
HONOLULU – In the clinical experience of Julie C. Harper, MD, an increasing number of women with acne are turning to off-label, long-term treatment with spironolactone.
“Spironolactone is fairly accessible, inexpensive, and effective for our patients,” Dr. Harper, a dermatologist who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE!
An aldosterone receptor antagonist commonly used to treat high blood pressure and heart failure, spironolactone also has antiandrogenic properties with a proven track record for treating acne and hirsutism. It reduces androgen production, inhibits 5-alpha reductase, and increases sex hormone binding globulin. The dosing range for treating acne is 25 mg to 200 mg per day, but Dr. Harper prefers a maximum dose of 100 mg per day.
According to a systematic review of its use for acne in adult women, the most common side effect is menstrual irregularity, while other common side effects include breast tenderness/swelling, fatigue, and headaches.
“The higher the dose, the higher the rate of side effects,” she said. Concomitant use of an oral contraceptive lessens menstrual irregularities and prevents pregnancies, to avoid exposure during pregnancy and the hypothetical risk of feminization of the male fetus with exposure late in the first trimester. “Early in my career, I used to say if you’re going to be on spironolactone you’re also going to be on an oral contraceptive. But the longer I’ve practiced, I’ve learned that women who have a contraindication to birth control pills or who don’t want to take it can still benefit from an oral antiandrogen by being on spironolactone.”
A large retrospective analysis of 14-year data concluded that routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne. “If you’re between the ages of 18 and 45, healthy, and not taking other medications where I’m worried about potassium levels, I’m not checking those levels at all,” Dr. Harper said.
Spironolactone labeling includes a boxed warning regarding the potential for tumorigenicity based on rat studies, but the dosages used in those studies were 25-250 times higher than the exposure dose in humans, Dr. Harper said.
Results from a systematic review and meta-analysis of seven studies in the medical literature found no evidence of an increased risk of breast cancer in women with exposure to spironolactone. “However, the certainty of the evidence was low and future studies are needed, including among diverse populations such as younger individuals and those with acne or hirsutism,” the study authors wrote.
In a separate study, researchers drew from patients in the Humana Insurance database from 2005 to 2017 to address whether spironolactone is associated with an increased risk of recurrence of breast cancer. Recurrent breast cancer was examined in 29,146 women with continuous health insurance for 2 years after a diagnosis of breast cancer. Of these, 746 were prescribed spironolactone, and the remainder were not. The researchers found that 123 women (16.5%) who were prescribed spironolactone had a breast cancer recurrence, compared with 3,649 women (12.8%) with a breast cancer recurrence who had not been prescribed spironolactone (P = .004). Adjusted Cox regression analysis following propensity matching showed no association between spironolactone and increased breast cancer recurrence (adjusted hazard ratio, 0.966; P = .953).
According to Dr. Harper, spironolactone may take about 3 months to kick in. “Likely this is a long-term treatment, and most of the time we’re going to be using it in combination with other acne treatments such as topical retinoids or topical benzoyl peroxide, oral antibiotics, or even isotretinoin.”
A study of long-term spironolactone use in 403 women found that the most common dose prescribed was 100 mg/day, and 68% of the women were concurrently prescribed a topical retinoid, 2.2% an oral antibiotic, and 40.7% an oral contraceptive.
The study population included 32 patients with a history of polycystic ovarian syndrome, 1 with a history of breast cancer, and 5 were hypercoagulable. Patients took the drug for a mean of 471 days. “As opposed to our antibiotics, where the course for patients is generally 3-4 months, when you start someone on spironolactone, they may end up staying on it,” Dr. Harper said.
Dr. Harper disclosed that she serves as an advisor or consultant for Almirall, Cassiopeia, Cutera, EPI, Galderma, L’Oreal, Ortho Dermatologics, Sol Gel, and Vyne. She also serves as a speaker or member of a speaker’s bureau for Almirall, Cassiopeia, Cutera, EPI, Galderma, Journey Almirall, L’Oreal, Ortho Dermatologics, Sun Pharmaceutical Industries, and Vyne.
Medscape and this news organization are owned by the same parent company.
HONOLULU – In the clinical experience of Julie C. Harper, MD, an increasing number of women with acne are turning to off-label, long-term treatment with spironolactone.
“Spironolactone is fairly accessible, inexpensive, and effective for our patients,” Dr. Harper, a dermatologist who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE!
An aldosterone receptor antagonist commonly used to treat high blood pressure and heart failure, spironolactone also has antiandrogenic properties with a proven track record for treating acne and hirsutism. It reduces androgen production, inhibits 5-alpha reductase, and increases sex hormone binding globulin. The dosing range for treating acne is 25 mg to 200 mg per day, but Dr. Harper prefers a maximum dose of 100 mg per day.
According to a systematic review of its use for acne in adult women, the most common side effect is menstrual irregularity, while other common side effects include breast tenderness/swelling, fatigue, and headaches.
“The higher the dose, the higher the rate of side effects,” she said. Concomitant use of an oral contraceptive lessens menstrual irregularities and prevents pregnancies, to avoid exposure during pregnancy and the hypothetical risk of feminization of the male fetus with exposure late in the first trimester. “Early in my career, I used to say if you’re going to be on spironolactone you’re also going to be on an oral contraceptive. But the longer I’ve practiced, I’ve learned that women who have a contraindication to birth control pills or who don’t want to take it can still benefit from an oral antiandrogen by being on spironolactone.”
A large retrospective analysis of 14-year data concluded that routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne. “If you’re between the ages of 18 and 45, healthy, and not taking other medications where I’m worried about potassium levels, I’m not checking those levels at all,” Dr. Harper said.
Spironolactone labeling includes a boxed warning regarding the potential for tumorigenicity based on rat studies, but the dosages used in those studies were 25-250 times higher than the exposure dose in humans, Dr. Harper said.
Results from a systematic review and meta-analysis of seven studies in the medical literature found no evidence of an increased risk of breast cancer in women with exposure to spironolactone. “However, the certainty of the evidence was low and future studies are needed, including among diverse populations such as younger individuals and those with acne or hirsutism,” the study authors wrote.
In a separate study, researchers drew from patients in the Humana Insurance database from 2005 to 2017 to address whether spironolactone is associated with an increased risk of recurrence of breast cancer. Recurrent breast cancer was examined in 29,146 women with continuous health insurance for 2 years after a diagnosis of breast cancer. Of these, 746 were prescribed spironolactone, and the remainder were not. The researchers found that 123 women (16.5%) who were prescribed spironolactone had a breast cancer recurrence, compared with 3,649 women (12.8%) with a breast cancer recurrence who had not been prescribed spironolactone (P = .004). Adjusted Cox regression analysis following propensity matching showed no association between spironolactone and increased breast cancer recurrence (adjusted hazard ratio, 0.966; P = .953).
According to Dr. Harper, spironolactone may take about 3 months to kick in. “Likely this is a long-term treatment, and most of the time we’re going to be using it in combination with other acne treatments such as topical retinoids or topical benzoyl peroxide, oral antibiotics, or even isotretinoin.”
A study of long-term spironolactone use in 403 women found that the most common dose prescribed was 100 mg/day, and 68% of the women were concurrently prescribed a topical retinoid, 2.2% an oral antibiotic, and 40.7% an oral contraceptive.
The study population included 32 patients with a history of polycystic ovarian syndrome, 1 with a history of breast cancer, and 5 were hypercoagulable. Patients took the drug for a mean of 471 days. “As opposed to our antibiotics, where the course for patients is generally 3-4 months, when you start someone on spironolactone, they may end up staying on it,” Dr. Harper said.
Dr. Harper disclosed that she serves as an advisor or consultant for Almirall, Cassiopeia, Cutera, EPI, Galderma, L’Oreal, Ortho Dermatologics, Sol Gel, and Vyne. She also serves as a speaker or member of a speaker’s bureau for Almirall, Cassiopeia, Cutera, EPI, Galderma, Journey Almirall, L’Oreal, Ortho Dermatologics, Sun Pharmaceutical Industries, and Vyne.
Medscape and this news organization are owned by the same parent company.
HONOLULU – In the clinical experience of Julie C. Harper, MD, an increasing number of women with acne are turning to off-label, long-term treatment with spironolactone.
“Spironolactone is fairly accessible, inexpensive, and effective for our patients,” Dr. Harper, a dermatologist who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE!
An aldosterone receptor antagonist commonly used to treat high blood pressure and heart failure, spironolactone also has antiandrogenic properties with a proven track record for treating acne and hirsutism. It reduces androgen production, inhibits 5-alpha reductase, and increases sex hormone binding globulin. The dosing range for treating acne is 25 mg to 200 mg per day, but Dr. Harper prefers a maximum dose of 100 mg per day.
According to a systematic review of its use for acne in adult women, the most common side effect is menstrual irregularity, while other common side effects include breast tenderness/swelling, fatigue, and headaches.
“The higher the dose, the higher the rate of side effects,” she said. Concomitant use of an oral contraceptive lessens menstrual irregularities and prevents pregnancies, to avoid exposure during pregnancy and the hypothetical risk of feminization of the male fetus with exposure late in the first trimester. “Early in my career, I used to say if you’re going to be on spironolactone you’re also going to be on an oral contraceptive. But the longer I’ve practiced, I’ve learned that women who have a contraindication to birth control pills or who don’t want to take it can still benefit from an oral antiandrogen by being on spironolactone.”
A large retrospective analysis of 14-year data concluded that routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne. “If you’re between the ages of 18 and 45, healthy, and not taking other medications where I’m worried about potassium levels, I’m not checking those levels at all,” Dr. Harper said.
Spironolactone labeling includes a boxed warning regarding the potential for tumorigenicity based on rat studies, but the dosages used in those studies were 25-250 times higher than the exposure dose in humans, Dr. Harper said.
Results from a systematic review and meta-analysis of seven studies in the medical literature found no evidence of an increased risk of breast cancer in women with exposure to spironolactone. “However, the certainty of the evidence was low and future studies are needed, including among diverse populations such as younger individuals and those with acne or hirsutism,” the study authors wrote.
In a separate study, researchers drew from patients in the Humana Insurance database from 2005 to 2017 to address whether spironolactone is associated with an increased risk of recurrence of breast cancer. Recurrent breast cancer was examined in 29,146 women with continuous health insurance for 2 years after a diagnosis of breast cancer. Of these, 746 were prescribed spironolactone, and the remainder were not. The researchers found that 123 women (16.5%) who were prescribed spironolactone had a breast cancer recurrence, compared with 3,649 women (12.8%) with a breast cancer recurrence who had not been prescribed spironolactone (P = .004). Adjusted Cox regression analysis following propensity matching showed no association between spironolactone and increased breast cancer recurrence (adjusted hazard ratio, 0.966; P = .953).
According to Dr. Harper, spironolactone may take about 3 months to kick in. “Likely this is a long-term treatment, and most of the time we’re going to be using it in combination with other acne treatments such as topical retinoids or topical benzoyl peroxide, oral antibiotics, or even isotretinoin.”
A study of long-term spironolactone use in 403 women found that the most common dose prescribed was 100 mg/day, and 68% of the women were concurrently prescribed a topical retinoid, 2.2% an oral antibiotic, and 40.7% an oral contraceptive.
The study population included 32 patients with a history of polycystic ovarian syndrome, 1 with a history of breast cancer, and 5 were hypercoagulable. Patients took the drug for a mean of 471 days. “As opposed to our antibiotics, where the course for patients is generally 3-4 months, when you start someone on spironolactone, they may end up staying on it,” Dr. Harper said.
Dr. Harper disclosed that she serves as an advisor or consultant for Almirall, Cassiopeia, Cutera, EPI, Galderma, L’Oreal, Ortho Dermatologics, Sol Gel, and Vyne. She also serves as a speaker or member of a speaker’s bureau for Almirall, Cassiopeia, Cutera, EPI, Galderma, Journey Almirall, L’Oreal, Ortho Dermatologics, Sun Pharmaceutical Industries, and Vyne.
Medscape and this news organization are owned by the same parent company.
AT THE MEDSCAPELIVE! HAWAII DERMATOLOGY SEMINAR
Lebrikizumab monotherapy for AD found safe, effective during induction
, researchers reported in the New England Journal of Medicine.
The identically designed, 52-week, randomized, double-blind, placebo-controlled trials enrolled 851 adolescents and adults with moderate to severe AD and included a 16-week induction period followed by a 36-week maintenance period. At week 16, the results “show a rapid onset of action in multiple domains of the disease, such as skin clearance and itch,” wrote lead author Jonathan Silverberg, MD, PhD, director of clinical research and contact dermatitis, at George Washington University, Washington, and colleagues. “Although 16 weeks of treatment with lebrikizumab is not sufficient to assess its long-term safety, the results from the induction period of these two trials suggest a safety profile that is consistent with findings in previous trials,” they added.
Results presented at the European Academy of Dermatology and Venereology 2022 annual meeting, but not yet published, showed similar efficacy maintained through the end of the trial.
Eligible patients were randomly assigned to receive either lebrikizumab 250 mg (with a 500-mg loading dose given at baseline and at week 2) or placebo, administered subcutaneously every 2 weeks, with concomitant topical or systemic treatments prohibited through week 16 except when deemed appropriate as rescue therapy. In such cases, moderate-potency topical glucocorticoids were preferred as first-line rescue therapy, while the study drug was discontinued if systemic therapy was needed.
In both trials, the primary efficacy outcome – a score of 0 or 1 on the Investigator’s Global Assessment (IGA) – and a reduction of at least 2 points from baseline at week 16, was met by more patients treated with lebrikizumab than with placebo: 43.1% vs. 12.7% respectively in trial 1 (P < .001); and 33.2% vs. 10.8% in trial 2 (P < .001).
Similarly, in both trials, a higher percentage of the lebrikizumab than placebo patients had an EASI-75 response (75% improvement in the Eczema Area and Severity Index score): 58.8% vs. 16.2% (P < .001) in trial 1 and 52.1% vs. 18.1% (P < .001) in trial 2.
Improvement in itch was also significantly better in patients treated with lebrikizumab, compared with placebo. This was measured by a reduction of at least 4 points in the Pruritus NRS from baseline to week 16 and a reduction in the Sleep-Loss Scale score of at least 2 points from baseline to week 16 (P < .001 for both measures in both trials).
A higher percentage of placebo vs. lebrikizumab patients discontinued the trials during the induction phases (14.9% vs. 7.1% in trial 1 and 11.0% vs. 7.8% in trial 2), and the use of rescue medication was approximately three times and two times higher in both placebo groups respectively.
Conjunctivitis was the most common adverse event, occurring consistently more frequently in patients treated with lebrikizumab, compared with placebo (7.4% vs. 2.8% in trial 1 and 7.5% vs. 2.1% in trial 2).
“Although several theories have been proposed for the pathogenesis of conjunctivitis in patients with atopic dermatitis treated with this class of biologic agents, the mechanism remains unclear and warrants further study,” the investigators wrote.
Asked to comment on the new results, Zelma Chiesa Fuxench, MD, who was not involved in the research, said they “continue to demonstrate the superior efficacy and favorable safety profile” of lebrikizumab in adolescents and adults and support the results of earlier phase 2 studies. “The results of these studies thus far continue to offer more hope and the possibility of a better future for our patients with atopic dermatitis who are still struggling to achieve control of their disease.”
Dr. Chiesa Fuxench from the department of dermatology at the University of Pennsylvania, Philadelphia, said she looks forward to reviewing the full study results in which patients who achieved the primary outcomes of interest were then rerandomized to either placebo, or lebrikizumab every 2 weeks or every 4 weeks for the 36-week maintenance period “because we know that there is data for other biologics in atopic dermatitis (such as tralokinumab) that demonstrate that a decrease in the frequency of injections may be possible for patients who achieve disease control after an initial 16 weeks of therapy every 2 weeks.”
The research was supported by Dermira, a wholly owned subsidiary of Eli Lilly. Dr. Silverberg disclosed he is a consultant for Dermira and Eli Lilly, as are other coauthors on the paper who additionally disclosed grants from Dermira and other relationships with Eli Lilly such as advisory board membership and having received lecture fees. Three authors are Eli Lilly employees. Dr. Chiesa Fuxench disclosed that she is a consultant for the Asthma and Allergy Foundation of America, National Eczema Association, Pfizer, Abbvie, and Incyte for which she has received honoraria for work related to AD. Dr. Chiesa Fuxench has also been a recipient of research grants from Regeneron, Sanofi, Tioga, Vanda, Menlo Therapeutics, Leo Pharma, and Eli Lilly for work related to AD as well as honoraria for continuing medical education work related to AD sponsored through educational grants from Regeneron/Sanofi and Pfizer.
, researchers reported in the New England Journal of Medicine.
The identically designed, 52-week, randomized, double-blind, placebo-controlled trials enrolled 851 adolescents and adults with moderate to severe AD and included a 16-week induction period followed by a 36-week maintenance period. At week 16, the results “show a rapid onset of action in multiple domains of the disease, such as skin clearance and itch,” wrote lead author Jonathan Silverberg, MD, PhD, director of clinical research and contact dermatitis, at George Washington University, Washington, and colleagues. “Although 16 weeks of treatment with lebrikizumab is not sufficient to assess its long-term safety, the results from the induction period of these two trials suggest a safety profile that is consistent with findings in previous trials,” they added.
Results presented at the European Academy of Dermatology and Venereology 2022 annual meeting, but not yet published, showed similar efficacy maintained through the end of the trial.
Eligible patients were randomly assigned to receive either lebrikizumab 250 mg (with a 500-mg loading dose given at baseline and at week 2) or placebo, administered subcutaneously every 2 weeks, with concomitant topical or systemic treatments prohibited through week 16 except when deemed appropriate as rescue therapy. In such cases, moderate-potency topical glucocorticoids were preferred as first-line rescue therapy, while the study drug was discontinued if systemic therapy was needed.
In both trials, the primary efficacy outcome – a score of 0 or 1 on the Investigator’s Global Assessment (IGA) – and a reduction of at least 2 points from baseline at week 16, was met by more patients treated with lebrikizumab than with placebo: 43.1% vs. 12.7% respectively in trial 1 (P < .001); and 33.2% vs. 10.8% in trial 2 (P < .001).
Similarly, in both trials, a higher percentage of the lebrikizumab than placebo patients had an EASI-75 response (75% improvement in the Eczema Area and Severity Index score): 58.8% vs. 16.2% (P < .001) in trial 1 and 52.1% vs. 18.1% (P < .001) in trial 2.
Improvement in itch was also significantly better in patients treated with lebrikizumab, compared with placebo. This was measured by a reduction of at least 4 points in the Pruritus NRS from baseline to week 16 and a reduction in the Sleep-Loss Scale score of at least 2 points from baseline to week 16 (P < .001 for both measures in both trials).
A higher percentage of placebo vs. lebrikizumab patients discontinued the trials during the induction phases (14.9% vs. 7.1% in trial 1 and 11.0% vs. 7.8% in trial 2), and the use of rescue medication was approximately three times and two times higher in both placebo groups respectively.
Conjunctivitis was the most common adverse event, occurring consistently more frequently in patients treated with lebrikizumab, compared with placebo (7.4% vs. 2.8% in trial 1 and 7.5% vs. 2.1% in trial 2).
“Although several theories have been proposed for the pathogenesis of conjunctivitis in patients with atopic dermatitis treated with this class of biologic agents, the mechanism remains unclear and warrants further study,” the investigators wrote.
Asked to comment on the new results, Zelma Chiesa Fuxench, MD, who was not involved in the research, said they “continue to demonstrate the superior efficacy and favorable safety profile” of lebrikizumab in adolescents and adults and support the results of earlier phase 2 studies. “The results of these studies thus far continue to offer more hope and the possibility of a better future for our patients with atopic dermatitis who are still struggling to achieve control of their disease.”
Dr. Chiesa Fuxench from the department of dermatology at the University of Pennsylvania, Philadelphia, said she looks forward to reviewing the full study results in which patients who achieved the primary outcomes of interest were then rerandomized to either placebo, or lebrikizumab every 2 weeks or every 4 weeks for the 36-week maintenance period “because we know that there is data for other biologics in atopic dermatitis (such as tralokinumab) that demonstrate that a decrease in the frequency of injections may be possible for patients who achieve disease control after an initial 16 weeks of therapy every 2 weeks.”
The research was supported by Dermira, a wholly owned subsidiary of Eli Lilly. Dr. Silverberg disclosed he is a consultant for Dermira and Eli Lilly, as are other coauthors on the paper who additionally disclosed grants from Dermira and other relationships with Eli Lilly such as advisory board membership and having received lecture fees. Three authors are Eli Lilly employees. Dr. Chiesa Fuxench disclosed that she is a consultant for the Asthma and Allergy Foundation of America, National Eczema Association, Pfizer, Abbvie, and Incyte for which she has received honoraria for work related to AD. Dr. Chiesa Fuxench has also been a recipient of research grants from Regeneron, Sanofi, Tioga, Vanda, Menlo Therapeutics, Leo Pharma, and Eli Lilly for work related to AD as well as honoraria for continuing medical education work related to AD sponsored through educational grants from Regeneron/Sanofi and Pfizer.
, researchers reported in the New England Journal of Medicine.
The identically designed, 52-week, randomized, double-blind, placebo-controlled trials enrolled 851 adolescents and adults with moderate to severe AD and included a 16-week induction period followed by a 36-week maintenance period. At week 16, the results “show a rapid onset of action in multiple domains of the disease, such as skin clearance and itch,” wrote lead author Jonathan Silverberg, MD, PhD, director of clinical research and contact dermatitis, at George Washington University, Washington, and colleagues. “Although 16 weeks of treatment with lebrikizumab is not sufficient to assess its long-term safety, the results from the induction period of these two trials suggest a safety profile that is consistent with findings in previous trials,” they added.
Results presented at the European Academy of Dermatology and Venereology 2022 annual meeting, but not yet published, showed similar efficacy maintained through the end of the trial.
Eligible patients were randomly assigned to receive either lebrikizumab 250 mg (with a 500-mg loading dose given at baseline and at week 2) or placebo, administered subcutaneously every 2 weeks, with concomitant topical or systemic treatments prohibited through week 16 except when deemed appropriate as rescue therapy. In such cases, moderate-potency topical glucocorticoids were preferred as first-line rescue therapy, while the study drug was discontinued if systemic therapy was needed.
In both trials, the primary efficacy outcome – a score of 0 or 1 on the Investigator’s Global Assessment (IGA) – and a reduction of at least 2 points from baseline at week 16, was met by more patients treated with lebrikizumab than with placebo: 43.1% vs. 12.7% respectively in trial 1 (P < .001); and 33.2% vs. 10.8% in trial 2 (P < .001).
Similarly, in both trials, a higher percentage of the lebrikizumab than placebo patients had an EASI-75 response (75% improvement in the Eczema Area and Severity Index score): 58.8% vs. 16.2% (P < .001) in trial 1 and 52.1% vs. 18.1% (P < .001) in trial 2.
Improvement in itch was also significantly better in patients treated with lebrikizumab, compared with placebo. This was measured by a reduction of at least 4 points in the Pruritus NRS from baseline to week 16 and a reduction in the Sleep-Loss Scale score of at least 2 points from baseline to week 16 (P < .001 for both measures in both trials).
A higher percentage of placebo vs. lebrikizumab patients discontinued the trials during the induction phases (14.9% vs. 7.1% in trial 1 and 11.0% vs. 7.8% in trial 2), and the use of rescue medication was approximately three times and two times higher in both placebo groups respectively.
Conjunctivitis was the most common adverse event, occurring consistently more frequently in patients treated with lebrikizumab, compared with placebo (7.4% vs. 2.8% in trial 1 and 7.5% vs. 2.1% in trial 2).
“Although several theories have been proposed for the pathogenesis of conjunctivitis in patients with atopic dermatitis treated with this class of biologic agents, the mechanism remains unclear and warrants further study,” the investigators wrote.
Asked to comment on the new results, Zelma Chiesa Fuxench, MD, who was not involved in the research, said they “continue to demonstrate the superior efficacy and favorable safety profile” of lebrikizumab in adolescents and adults and support the results of earlier phase 2 studies. “The results of these studies thus far continue to offer more hope and the possibility of a better future for our patients with atopic dermatitis who are still struggling to achieve control of their disease.”
Dr. Chiesa Fuxench from the department of dermatology at the University of Pennsylvania, Philadelphia, said she looks forward to reviewing the full study results in which patients who achieved the primary outcomes of interest were then rerandomized to either placebo, or lebrikizumab every 2 weeks or every 4 weeks for the 36-week maintenance period “because we know that there is data for other biologics in atopic dermatitis (such as tralokinumab) that demonstrate that a decrease in the frequency of injections may be possible for patients who achieve disease control after an initial 16 weeks of therapy every 2 weeks.”
The research was supported by Dermira, a wholly owned subsidiary of Eli Lilly. Dr. Silverberg disclosed he is a consultant for Dermira and Eli Lilly, as are other coauthors on the paper who additionally disclosed grants from Dermira and other relationships with Eli Lilly such as advisory board membership and having received lecture fees. Three authors are Eli Lilly employees. Dr. Chiesa Fuxench disclosed that she is a consultant for the Asthma and Allergy Foundation of America, National Eczema Association, Pfizer, Abbvie, and Incyte for which she has received honoraria for work related to AD. Dr. Chiesa Fuxench has also been a recipient of research grants from Regeneron, Sanofi, Tioga, Vanda, Menlo Therapeutics, Leo Pharma, and Eli Lilly for work related to AD as well as honoraria for continuing medical education work related to AD sponsored through educational grants from Regeneron/Sanofi and Pfizer.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Spinosad: New kid on the block for treating scabies
HONOLULU – , Anthony J. Mancini, MD, said during a presentation at the Hawaii Dermatology Seminar provided by MedscapeLIVE!
In April 2021, spinosad topical suspension 0.9%, was approved by the Food and Drug Administration for treating scabies infestations in adult and pediatric patients 4 years of age and older – a first-in-class drug and the first new scabicide approved in 31 years. It was also approved for treating head lice in adults and children aged 6 months of age and older.
“Scabies has been described as the worst itch one can experience,” said Dr. Mancini, professor of pediatrics and dermatology at Northwestern University, Chicago. “It’s a hallmark of the disease, it can persist for weeks, it’s most intense at night, and patients report various sensations. It’s believed to be a both type I and type IV hypersensitivity reaction.”
The microscopic scabies mite burrows into the upper layer of the skin where it lives and lays its eggs. Besides intense itching, the classic presentation consists of a skin rash composed of inflammatory papules, linear burrows and crusted papules (especially on the hands, feet, and groin), and at times, larger red nodules. “Scabies nodules can persist for many months,” he said.
The Global Burden of Disease Study 2015 cited scabies as having the greatest burden of disease in tropical regions, especially among children, adolescents, and the elderly. The greatest burden of disability-adjusted life years (DALYs) occurred in East and Southeast Asia, Oceana, and tropical South America, but in North America, there was a 24% increase in the DALY rate between 1990 and 2015.
In addition, the World Health Organization designated scabies as a neglected tropical disease in 2017 and included it in its 10-year road map for neglected tropical diseases 2021-2030 with goals of promoting disease awareness and encouraging research and achieving global control.
“In our country, we typically see scabies treated successfully without complications, but there can be complications, especially in underdeveloped areas, like Staph aureus and Group A beta-hemolytic streptococcal infections,” which can be fatal, said Dr. Mancini, who is also head of pediatric dermatology at Ann & Robert H. Lurie Children’s Hospital of Chicago.
Permethrin 5% cream is typically offered as first-line topical therapy in the United States for the treatment of scabies. However, in vitro studies and small investigator-initiated in vivo studies have reported that efficacy appears to be decreasing. In one of the trials, Italian researchers enrolled 155 patients who were treated with permethrin 5% for 8 hours for 2 consecutive days and repeated the treatment 5 days later . Following the course of permethrin, only 34 responded, 96 failed treatment, and 25 were lost to follow-up.
“The study authors concluded that mite resistance to permethrin 5% seems to be increasing, following a path like other ectoparasite resistance,” said Dr. Mancini, who was not involved with the study. “We may even be seeing more ivermectin resistance in some geographic locations, as well.”
According to new scabicide efficacy criteria established by the FDA in 2016, complete cure is now defined as meeting both clinical and confirmatory criteria. A clinical cure means that all signs and symptoms of scabies have completely resolved, including burrows, inflammatory/noninflammatory lesions, and pruritus. A confirmatory cure means there is an absence of mites, eggs, scybala (feces), and burrows via microscopy or dermoscopy.
Enter spinosad, which is derived from a naturally occurring soil microorganism known as Saccharopolyspora spinosa and is composed of two active molecules: spinosyn A and spinosyn D. According to Dr. Mancini, spinosad’s mechanism of action is unique from other medications used to treat ectoparasites. It activates nicotinic and GABA-gated sodium channels, leads to sodium influx in the insect nerves, hyperexcitation, then paralysis and death. Cross-resistance to other insecticides has not been reported, he added, and there is no known evidence of resistance to its active compound.
Approval of the drug was based on data from two phase 3 randomized clinical trials involving 551 index cases and household contacts. In the intent-to-treat population, with the two trials combined, complete cure was achieved in 78.1% of the spinosad-treated group, compared with 39.6% in the vehicle group (P < .0001), clinical cure was achieved in 79.6% of the spinosad group, compared with 41.2% in the vehicle group (P < .001), and microscopic cure occurred in 85.9% of the spinosad group, compared with 52.6% in the vehicle group (P < .001).
Of the 306 participants in the study, the only adverse events reported by more than one patient each included abdominal pain, back pain, cough, headache, neck pain, and decreased weight in two patients each (0.8%), which investigators believed were not attributable to the study drug. Adverse events that investigators considered to be potentially related to the study drug included burning sensation in two participants (0.7%) and dry skin in another (0.3%). In clinical trials reported in the prescribing information, adverse events occurring in greater than 1% of subjects included application-site irritation (3% spinosad vs. 0% vehicle) and dry skin (2% spinosad vs. 0% vehicle).
“Spinosad met the FDA’s new stringent criteria, with all signs and symptoms of scabies completely resolved and confirmed via microscopy or dermoscopy,” said Dr. Mancini, who was not involved in the trials. “The patented formulation drives the active compound to the stratum corneum, where mites live and breed. It’s a single full-body application, without any resistance observed to date. This is an exciting newer option for treating our scabies patients.”
In an interview at the meeting, John S. Barbieri, MD, MBA, of the department of dermatology, Brigham and Women’s Hospital, Boston, said that, while he has no clinical experience with spinosad for scabies, he welcomes a new option for the condition. “The fact that it has a different mechanism of action than permethrin is a good thing,” he said.
Dr. Mancini disclosed that he is a consultant or an adviser for ParaPRO, the manufacturer of spinosad, and Cassiopea, Castle Creek, Novan, Novartis, and Verrica. He was not involved in clinical trials of spinosad. Dr. Barbieri disclosed that he receives consulting fees from Dexcel.
Medscape and this news organization are owned by the same parent company.
HONOLULU – , Anthony J. Mancini, MD, said during a presentation at the Hawaii Dermatology Seminar provided by MedscapeLIVE!
In April 2021, spinosad topical suspension 0.9%, was approved by the Food and Drug Administration for treating scabies infestations in adult and pediatric patients 4 years of age and older – a first-in-class drug and the first new scabicide approved in 31 years. It was also approved for treating head lice in adults and children aged 6 months of age and older.
“Scabies has been described as the worst itch one can experience,” said Dr. Mancini, professor of pediatrics and dermatology at Northwestern University, Chicago. “It’s a hallmark of the disease, it can persist for weeks, it’s most intense at night, and patients report various sensations. It’s believed to be a both type I and type IV hypersensitivity reaction.”
The microscopic scabies mite burrows into the upper layer of the skin where it lives and lays its eggs. Besides intense itching, the classic presentation consists of a skin rash composed of inflammatory papules, linear burrows and crusted papules (especially on the hands, feet, and groin), and at times, larger red nodules. “Scabies nodules can persist for many months,” he said.
The Global Burden of Disease Study 2015 cited scabies as having the greatest burden of disease in tropical regions, especially among children, adolescents, and the elderly. The greatest burden of disability-adjusted life years (DALYs) occurred in East and Southeast Asia, Oceana, and tropical South America, but in North America, there was a 24% increase in the DALY rate between 1990 and 2015.
In addition, the World Health Organization designated scabies as a neglected tropical disease in 2017 and included it in its 10-year road map for neglected tropical diseases 2021-2030 with goals of promoting disease awareness and encouraging research and achieving global control.
“In our country, we typically see scabies treated successfully without complications, but there can be complications, especially in underdeveloped areas, like Staph aureus and Group A beta-hemolytic streptococcal infections,” which can be fatal, said Dr. Mancini, who is also head of pediatric dermatology at Ann & Robert H. Lurie Children’s Hospital of Chicago.
Permethrin 5% cream is typically offered as first-line topical therapy in the United States for the treatment of scabies. However, in vitro studies and small investigator-initiated in vivo studies have reported that efficacy appears to be decreasing. In one of the trials, Italian researchers enrolled 155 patients who were treated with permethrin 5% for 8 hours for 2 consecutive days and repeated the treatment 5 days later . Following the course of permethrin, only 34 responded, 96 failed treatment, and 25 were lost to follow-up.
“The study authors concluded that mite resistance to permethrin 5% seems to be increasing, following a path like other ectoparasite resistance,” said Dr. Mancini, who was not involved with the study. “We may even be seeing more ivermectin resistance in some geographic locations, as well.”
According to new scabicide efficacy criteria established by the FDA in 2016, complete cure is now defined as meeting both clinical and confirmatory criteria. A clinical cure means that all signs and symptoms of scabies have completely resolved, including burrows, inflammatory/noninflammatory lesions, and pruritus. A confirmatory cure means there is an absence of mites, eggs, scybala (feces), and burrows via microscopy or dermoscopy.
Enter spinosad, which is derived from a naturally occurring soil microorganism known as Saccharopolyspora spinosa and is composed of two active molecules: spinosyn A and spinosyn D. According to Dr. Mancini, spinosad’s mechanism of action is unique from other medications used to treat ectoparasites. It activates nicotinic and GABA-gated sodium channels, leads to sodium influx in the insect nerves, hyperexcitation, then paralysis and death. Cross-resistance to other insecticides has not been reported, he added, and there is no known evidence of resistance to its active compound.
Approval of the drug was based on data from two phase 3 randomized clinical trials involving 551 index cases and household contacts. In the intent-to-treat population, with the two trials combined, complete cure was achieved in 78.1% of the spinosad-treated group, compared with 39.6% in the vehicle group (P < .0001), clinical cure was achieved in 79.6% of the spinosad group, compared with 41.2% in the vehicle group (P < .001), and microscopic cure occurred in 85.9% of the spinosad group, compared with 52.6% in the vehicle group (P < .001).
Of the 306 participants in the study, the only adverse events reported by more than one patient each included abdominal pain, back pain, cough, headache, neck pain, and decreased weight in two patients each (0.8%), which investigators believed were not attributable to the study drug. Adverse events that investigators considered to be potentially related to the study drug included burning sensation in two participants (0.7%) and dry skin in another (0.3%). In clinical trials reported in the prescribing information, adverse events occurring in greater than 1% of subjects included application-site irritation (3% spinosad vs. 0% vehicle) and dry skin (2% spinosad vs. 0% vehicle).
“Spinosad met the FDA’s new stringent criteria, with all signs and symptoms of scabies completely resolved and confirmed via microscopy or dermoscopy,” said Dr. Mancini, who was not involved in the trials. “The patented formulation drives the active compound to the stratum corneum, where mites live and breed. It’s a single full-body application, without any resistance observed to date. This is an exciting newer option for treating our scabies patients.”
In an interview at the meeting, John S. Barbieri, MD, MBA, of the department of dermatology, Brigham and Women’s Hospital, Boston, said that, while he has no clinical experience with spinosad for scabies, he welcomes a new option for the condition. “The fact that it has a different mechanism of action than permethrin is a good thing,” he said.
Dr. Mancini disclosed that he is a consultant or an adviser for ParaPRO, the manufacturer of spinosad, and Cassiopea, Castle Creek, Novan, Novartis, and Verrica. He was not involved in clinical trials of spinosad. Dr. Barbieri disclosed that he receives consulting fees from Dexcel.
Medscape and this news organization are owned by the same parent company.
HONOLULU – , Anthony J. Mancini, MD, said during a presentation at the Hawaii Dermatology Seminar provided by MedscapeLIVE!
In April 2021, spinosad topical suspension 0.9%, was approved by the Food and Drug Administration for treating scabies infestations in adult and pediatric patients 4 years of age and older – a first-in-class drug and the first new scabicide approved in 31 years. It was also approved for treating head lice in adults and children aged 6 months of age and older.
“Scabies has been described as the worst itch one can experience,” said Dr. Mancini, professor of pediatrics and dermatology at Northwestern University, Chicago. “It’s a hallmark of the disease, it can persist for weeks, it’s most intense at night, and patients report various sensations. It’s believed to be a both type I and type IV hypersensitivity reaction.”
The microscopic scabies mite burrows into the upper layer of the skin where it lives and lays its eggs. Besides intense itching, the classic presentation consists of a skin rash composed of inflammatory papules, linear burrows and crusted papules (especially on the hands, feet, and groin), and at times, larger red nodules. “Scabies nodules can persist for many months,” he said.
The Global Burden of Disease Study 2015 cited scabies as having the greatest burden of disease in tropical regions, especially among children, adolescents, and the elderly. The greatest burden of disability-adjusted life years (DALYs) occurred in East and Southeast Asia, Oceana, and tropical South America, but in North America, there was a 24% increase in the DALY rate between 1990 and 2015.
In addition, the World Health Organization designated scabies as a neglected tropical disease in 2017 and included it in its 10-year road map for neglected tropical diseases 2021-2030 with goals of promoting disease awareness and encouraging research and achieving global control.
“In our country, we typically see scabies treated successfully without complications, but there can be complications, especially in underdeveloped areas, like Staph aureus and Group A beta-hemolytic streptococcal infections,” which can be fatal, said Dr. Mancini, who is also head of pediatric dermatology at Ann & Robert H. Lurie Children’s Hospital of Chicago.
Permethrin 5% cream is typically offered as first-line topical therapy in the United States for the treatment of scabies. However, in vitro studies and small investigator-initiated in vivo studies have reported that efficacy appears to be decreasing. In one of the trials, Italian researchers enrolled 155 patients who were treated with permethrin 5% for 8 hours for 2 consecutive days and repeated the treatment 5 days later . Following the course of permethrin, only 34 responded, 96 failed treatment, and 25 were lost to follow-up.
“The study authors concluded that mite resistance to permethrin 5% seems to be increasing, following a path like other ectoparasite resistance,” said Dr. Mancini, who was not involved with the study. “We may even be seeing more ivermectin resistance in some geographic locations, as well.”
According to new scabicide efficacy criteria established by the FDA in 2016, complete cure is now defined as meeting both clinical and confirmatory criteria. A clinical cure means that all signs and symptoms of scabies have completely resolved, including burrows, inflammatory/noninflammatory lesions, and pruritus. A confirmatory cure means there is an absence of mites, eggs, scybala (feces), and burrows via microscopy or dermoscopy.
Enter spinosad, which is derived from a naturally occurring soil microorganism known as Saccharopolyspora spinosa and is composed of two active molecules: spinosyn A and spinosyn D. According to Dr. Mancini, spinosad’s mechanism of action is unique from other medications used to treat ectoparasites. It activates nicotinic and GABA-gated sodium channels, leads to sodium influx in the insect nerves, hyperexcitation, then paralysis and death. Cross-resistance to other insecticides has not been reported, he added, and there is no known evidence of resistance to its active compound.
Approval of the drug was based on data from two phase 3 randomized clinical trials involving 551 index cases and household contacts. In the intent-to-treat population, with the two trials combined, complete cure was achieved in 78.1% of the spinosad-treated group, compared with 39.6% in the vehicle group (P < .0001), clinical cure was achieved in 79.6% of the spinosad group, compared with 41.2% in the vehicle group (P < .001), and microscopic cure occurred in 85.9% of the spinosad group, compared with 52.6% in the vehicle group (P < .001).
Of the 306 participants in the study, the only adverse events reported by more than one patient each included abdominal pain, back pain, cough, headache, neck pain, and decreased weight in two patients each (0.8%), which investigators believed were not attributable to the study drug. Adverse events that investigators considered to be potentially related to the study drug included burning sensation in two participants (0.7%) and dry skin in another (0.3%). In clinical trials reported in the prescribing information, adverse events occurring in greater than 1% of subjects included application-site irritation (3% spinosad vs. 0% vehicle) and dry skin (2% spinosad vs. 0% vehicle).
“Spinosad met the FDA’s new stringent criteria, with all signs and symptoms of scabies completely resolved and confirmed via microscopy or dermoscopy,” said Dr. Mancini, who was not involved in the trials. “The patented formulation drives the active compound to the stratum corneum, where mites live and breed. It’s a single full-body application, without any resistance observed to date. This is an exciting newer option for treating our scabies patients.”
In an interview at the meeting, John S. Barbieri, MD, MBA, of the department of dermatology, Brigham and Women’s Hospital, Boston, said that, while he has no clinical experience with spinosad for scabies, he welcomes a new option for the condition. “The fact that it has a different mechanism of action than permethrin is a good thing,” he said.
Dr. Mancini disclosed that he is a consultant or an adviser for ParaPRO, the manufacturer of spinosad, and Cassiopea, Castle Creek, Novan, Novartis, and Verrica. He was not involved in clinical trials of spinosad. Dr. Barbieri disclosed that he receives consulting fees from Dexcel.
Medscape and this news organization are owned by the same parent company.
AT THE MEDSCAPELIVE! HAWAII DERMATOLOGY SEMINAR
FDA OKs first drug for Rett syndrome
Rett syndrome is a rare, genetic neurodevelopmental disorder that affects about 6,000-9,000 people in the United States, mostly females.
Symptoms typically present between 6 and 18 months of age, with patients experiencing a rapid decline with loss of fine motor and communication skills.
Trofinetide is a synthetic analogue of the amino-terminal tripeptide of insulinlike growth factor-1 (IGF-1), which occurs naturally in the brain. The drug is designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function.
The approval of trofinetide was supported by results from the pivotal phase 3 LAVENDER study that tested the efficacy and safety of trofinetide vs. placebo in 187 female patients with Rett syndrome, aged 5-20 years.
A total of 93 participants were randomly assigned to twice-daily oral trofinetide, and 94 received placebo for 12 weeks.
After 12 weeks, trofinetide showed a statistically significant improvement from baseline, compared with placebo, on both the caregiver-assessed Rett Syndrome Behavior Questionnaire (RSBQ) and 7-point Clinical Global Impression-Improvement (CGI-I) scale.
The drug also outperformed placebo at 12 weeks in a key secondary endpoint: the composite score on the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist-Social (CSBS-DP-IT Social), a scale on which caregivers assess nonverbal communication.
The most common adverse events with trofinetide treatment were diarrhea and vomiting. Almost all these events were considered mild or moderate.
‘Historic day’
“This is a historic day for the Rett syndrome community and a meaningful moment for the patients and caregivers who have eagerly awaited the arrival of an approved treatment for this condition,” Melissa Kennedy, MHA, chief executive officer of the International Rett Syndrome Foundation, said in a news release issued by Acadia.
“Rett syndrome is a complicated, devastating disease that affects not only the individual patient, but whole families. With today’s FDA decision, those impacted by Rett have a promising new treatment option that has demonstrated benefit across a variety of Rett symptoms, including those that impact the daily lives of those living with Rett and their loved ones,” Ms. Kennedy said.
Trofinetide is expected to be available in the United States by the end of April.
A version of this article first appeared on Medscape.com.
Rett syndrome is a rare, genetic neurodevelopmental disorder that affects about 6,000-9,000 people in the United States, mostly females.
Symptoms typically present between 6 and 18 months of age, with patients experiencing a rapid decline with loss of fine motor and communication skills.
Trofinetide is a synthetic analogue of the amino-terminal tripeptide of insulinlike growth factor-1 (IGF-1), which occurs naturally in the brain. The drug is designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function.
The approval of trofinetide was supported by results from the pivotal phase 3 LAVENDER study that tested the efficacy and safety of trofinetide vs. placebo in 187 female patients with Rett syndrome, aged 5-20 years.
A total of 93 participants were randomly assigned to twice-daily oral trofinetide, and 94 received placebo for 12 weeks.
After 12 weeks, trofinetide showed a statistically significant improvement from baseline, compared with placebo, on both the caregiver-assessed Rett Syndrome Behavior Questionnaire (RSBQ) and 7-point Clinical Global Impression-Improvement (CGI-I) scale.
The drug also outperformed placebo at 12 weeks in a key secondary endpoint: the composite score on the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist-Social (CSBS-DP-IT Social), a scale on which caregivers assess nonverbal communication.
The most common adverse events with trofinetide treatment were diarrhea and vomiting. Almost all these events were considered mild or moderate.
‘Historic day’
“This is a historic day for the Rett syndrome community and a meaningful moment for the patients and caregivers who have eagerly awaited the arrival of an approved treatment for this condition,” Melissa Kennedy, MHA, chief executive officer of the International Rett Syndrome Foundation, said in a news release issued by Acadia.
“Rett syndrome is a complicated, devastating disease that affects not only the individual patient, but whole families. With today’s FDA decision, those impacted by Rett have a promising new treatment option that has demonstrated benefit across a variety of Rett symptoms, including those that impact the daily lives of those living with Rett and their loved ones,” Ms. Kennedy said.
Trofinetide is expected to be available in the United States by the end of April.
A version of this article first appeared on Medscape.com.
Rett syndrome is a rare, genetic neurodevelopmental disorder that affects about 6,000-9,000 people in the United States, mostly females.
Symptoms typically present between 6 and 18 months of age, with patients experiencing a rapid decline with loss of fine motor and communication skills.
Trofinetide is a synthetic analogue of the amino-terminal tripeptide of insulinlike growth factor-1 (IGF-1), which occurs naturally in the brain. The drug is designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function.
The approval of trofinetide was supported by results from the pivotal phase 3 LAVENDER study that tested the efficacy and safety of trofinetide vs. placebo in 187 female patients with Rett syndrome, aged 5-20 years.
A total of 93 participants were randomly assigned to twice-daily oral trofinetide, and 94 received placebo for 12 weeks.
After 12 weeks, trofinetide showed a statistically significant improvement from baseline, compared with placebo, on both the caregiver-assessed Rett Syndrome Behavior Questionnaire (RSBQ) and 7-point Clinical Global Impression-Improvement (CGI-I) scale.
The drug also outperformed placebo at 12 weeks in a key secondary endpoint: the composite score on the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist-Social (CSBS-DP-IT Social), a scale on which caregivers assess nonverbal communication.
The most common adverse events with trofinetide treatment were diarrhea and vomiting. Almost all these events were considered mild or moderate.
‘Historic day’
“This is a historic day for the Rett syndrome community and a meaningful moment for the patients and caregivers who have eagerly awaited the arrival of an approved treatment for this condition,” Melissa Kennedy, MHA, chief executive officer of the International Rett Syndrome Foundation, said in a news release issued by Acadia.
“Rett syndrome is a complicated, devastating disease that affects not only the individual patient, but whole families. With today’s FDA decision, those impacted by Rett have a promising new treatment option that has demonstrated benefit across a variety of Rett symptoms, including those that impact the daily lives of those living with Rett and their loved ones,” Ms. Kennedy said.
Trofinetide is expected to be available in the United States by the end of April.
A version of this article first appeared on Medscape.com.
Add-on antipsychotic beats switching meds in older adults with resistant depression
NEW ORLEANS –
“We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being – which means how positive and satisfied patients felt – and this is good news,” study investigator Eric J. Lenze, MD, of the department of psychiatry, Washington University, St. Louis, said in a press statement.
“However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people,” he added.
The findings were presented here as part of the American Association for Geriatric Psychiatry annual meeting, and published concurrently in the New England Journal of Medicine.
Need for safe treatment options
Treatment-resistant depression is common in older patients, but switching medications or adding other agents can be challenging. With higher rates of comorbidity and polypharmacy, treatment decisions in this patient population are more complex compared with those involving younger patients.
To compare the benefits of augmentation vs. drug-switching strategies, the researchers conducted a multicenter, two-step trial involving 619 patients with an average baseline age of 69 who had failed to respond to two courses of selective serotonin reuptake inhibitors (SSRIs).
Patients were randomly assigned to one of three groups. These included augmentation of existing antidepressant medication with either aripiprazole (n = 211) or the dopamine and norepinephrine–reuptake inhibitor bupropion (Wellbutrin, Zyban) (n = 206), or to taper off of their current antidepressant and switch to bupropion (n = 202).
After 10 weeks, patients’ psychological well-being was assessed via the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales. The researchers found patients in the aripiprazole and bupropion add-on groups improved by 4.83 points and 4.33 points, respectively. The bupropion switch group had a change of 2.04 points.
The difference between the aripiprazole augmentation group and the switch to bupropion group was significant (difference 2.79 points; P = .014). Other between-group differences were not significantly different.
Remission rates were similar in the aripiprazole and bupropion groups at 28.9% and 28.2%, respectively. The remission rate in the bupropion switch group was 19.3%.
The study results showed patients who received adjunctive bupropion had the highest fall rate at 0.55 falls per patient, vs. 0.33 falls per patient in the aripiprazole group, suggesting that among the three treatment options, adjunctive aripiprazole may be the best choice because of its superior efficacy and lower fall risk.
A total of 248 patients enrolled in the study showed no improvement and were further randomly assigned to receive adjunctive lithium (n = 127) or switch from current therapy to nortriptyline (n = 121).
Well-being scores in the lithium group improved by 3.17 points and 2.18 points in the nortriptyline group. Remission occurred in 18.9% of patients in the lithium group and 21.5% in the nortriptyline group. Fall rates were similar among the two groups.
Overall, “this large, randomized study demonstrated that adding aripiprazole was a superior option for older adults with treatment-resistant depression,” Dr. Lenze told this news organization.
“Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases,” he added.
Practice changing?
In an accompanying editorial, Gemma Lewis, PhD, and Glyn Lewis, PhD, division of psychiatry, University of College London, noted the findings “support aripiprazole augmentation as a strategy for treatment-resistant depression in older persons, largely because of the lower risk of falls than with bupropion augmentation.”
However, “in clinical practice, [it] would be important to tailor treatment in light of potential adverse effects and the preferences of the patient,” they added.
Akathisia, for instance, is a common side effect of aripiprazole, shown in one recent trial to affect 11% of the patients. In addition, weight gain, though typically lower than seen with other antipsychotics, is a consideration with aripiprazole.
With respect to fall risk, they noted that bupropion was largely used in relatively high doses of 300 mg and 450 mg, despite some recent research showing little clinical benefit from increasing antidepressant doses above minimum recommendations.
“It is possible that smaller doses of bupropion than those used in the current trial would retain effectiveness while minimizing adverse effects such as falls,” the editorialists noted.
Commenting on the study, Jennifer R. Gatchel, MD, PhD, assistant psychiatrist at Massachusetts General Hospital/McLean Hospital and assistant professor of psychiatry at Harvard Medical School, Boston, said the findings have high clinical significance in the treatment of geriatric depression.
“These results are of great impact for clinicians managing older adults with treatment-resistant depression. They provide some of the first evidence of safety and efficacy of augmentation with aripiprazole as a strategy in clinical management of older adults who fail to initially respond to treatment,” said Dr. Gatchel, who was not associated with this research.
“Of particular significance, efficacy here is based on patient-centered outcomes and psychological well-being as a primary effectiveness outcome, which could translate into strengthened physician-patient alliance.”
While adjunctive aripiprazole is not necessarily a first-line strategy when older adults fail to respond to antidepressants, there is a lack of data on the risks and benefits of any other antipsychotic medications, she noted.
“Thus, this is evidence that will impact clinical practice and hopefully contribute to reduced societal burden of depression in older adults and the morbidity and mortality associated with it,” Dr. Gatchel said.
The study received support from a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Gatchel reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being – which means how positive and satisfied patients felt – and this is good news,” study investigator Eric J. Lenze, MD, of the department of psychiatry, Washington University, St. Louis, said in a press statement.
“However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people,” he added.
The findings were presented here as part of the American Association for Geriatric Psychiatry annual meeting, and published concurrently in the New England Journal of Medicine.
Need for safe treatment options
Treatment-resistant depression is common in older patients, but switching medications or adding other agents can be challenging. With higher rates of comorbidity and polypharmacy, treatment decisions in this patient population are more complex compared with those involving younger patients.
To compare the benefits of augmentation vs. drug-switching strategies, the researchers conducted a multicenter, two-step trial involving 619 patients with an average baseline age of 69 who had failed to respond to two courses of selective serotonin reuptake inhibitors (SSRIs).
Patients were randomly assigned to one of three groups. These included augmentation of existing antidepressant medication with either aripiprazole (n = 211) or the dopamine and norepinephrine–reuptake inhibitor bupropion (Wellbutrin, Zyban) (n = 206), or to taper off of their current antidepressant and switch to bupropion (n = 202).
After 10 weeks, patients’ psychological well-being was assessed via the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales. The researchers found patients in the aripiprazole and bupropion add-on groups improved by 4.83 points and 4.33 points, respectively. The bupropion switch group had a change of 2.04 points.
The difference between the aripiprazole augmentation group and the switch to bupropion group was significant (difference 2.79 points; P = .014). Other between-group differences were not significantly different.
Remission rates were similar in the aripiprazole and bupropion groups at 28.9% and 28.2%, respectively. The remission rate in the bupropion switch group was 19.3%.
The study results showed patients who received adjunctive bupropion had the highest fall rate at 0.55 falls per patient, vs. 0.33 falls per patient in the aripiprazole group, suggesting that among the three treatment options, adjunctive aripiprazole may be the best choice because of its superior efficacy and lower fall risk.
A total of 248 patients enrolled in the study showed no improvement and were further randomly assigned to receive adjunctive lithium (n = 127) or switch from current therapy to nortriptyline (n = 121).
Well-being scores in the lithium group improved by 3.17 points and 2.18 points in the nortriptyline group. Remission occurred in 18.9% of patients in the lithium group and 21.5% in the nortriptyline group. Fall rates were similar among the two groups.
Overall, “this large, randomized study demonstrated that adding aripiprazole was a superior option for older adults with treatment-resistant depression,” Dr. Lenze told this news organization.
“Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases,” he added.
Practice changing?
In an accompanying editorial, Gemma Lewis, PhD, and Glyn Lewis, PhD, division of psychiatry, University of College London, noted the findings “support aripiprazole augmentation as a strategy for treatment-resistant depression in older persons, largely because of the lower risk of falls than with bupropion augmentation.”
However, “in clinical practice, [it] would be important to tailor treatment in light of potential adverse effects and the preferences of the patient,” they added.
Akathisia, for instance, is a common side effect of aripiprazole, shown in one recent trial to affect 11% of the patients. In addition, weight gain, though typically lower than seen with other antipsychotics, is a consideration with aripiprazole.
With respect to fall risk, they noted that bupropion was largely used in relatively high doses of 300 mg and 450 mg, despite some recent research showing little clinical benefit from increasing antidepressant doses above minimum recommendations.
“It is possible that smaller doses of bupropion than those used in the current trial would retain effectiveness while minimizing adverse effects such as falls,” the editorialists noted.
Commenting on the study, Jennifer R. Gatchel, MD, PhD, assistant psychiatrist at Massachusetts General Hospital/McLean Hospital and assistant professor of psychiatry at Harvard Medical School, Boston, said the findings have high clinical significance in the treatment of geriatric depression.
“These results are of great impact for clinicians managing older adults with treatment-resistant depression. They provide some of the first evidence of safety and efficacy of augmentation with aripiprazole as a strategy in clinical management of older adults who fail to initially respond to treatment,” said Dr. Gatchel, who was not associated with this research.
“Of particular significance, efficacy here is based on patient-centered outcomes and psychological well-being as a primary effectiveness outcome, which could translate into strengthened physician-patient alliance.”
While adjunctive aripiprazole is not necessarily a first-line strategy when older adults fail to respond to antidepressants, there is a lack of data on the risks and benefits of any other antipsychotic medications, she noted.
“Thus, this is evidence that will impact clinical practice and hopefully contribute to reduced societal burden of depression in older adults and the morbidity and mortality associated with it,” Dr. Gatchel said.
The study received support from a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Gatchel reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being – which means how positive and satisfied patients felt – and this is good news,” study investigator Eric J. Lenze, MD, of the department of psychiatry, Washington University, St. Louis, said in a press statement.
“However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people,” he added.
The findings were presented here as part of the American Association for Geriatric Psychiatry annual meeting, and published concurrently in the New England Journal of Medicine.
Need for safe treatment options
Treatment-resistant depression is common in older patients, but switching medications or adding other agents can be challenging. With higher rates of comorbidity and polypharmacy, treatment decisions in this patient population are more complex compared with those involving younger patients.
To compare the benefits of augmentation vs. drug-switching strategies, the researchers conducted a multicenter, two-step trial involving 619 patients with an average baseline age of 69 who had failed to respond to two courses of selective serotonin reuptake inhibitors (SSRIs).
Patients were randomly assigned to one of three groups. These included augmentation of existing antidepressant medication with either aripiprazole (n = 211) or the dopamine and norepinephrine–reuptake inhibitor bupropion (Wellbutrin, Zyban) (n = 206), or to taper off of their current antidepressant and switch to bupropion (n = 202).
After 10 weeks, patients’ psychological well-being was assessed via the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales. The researchers found patients in the aripiprazole and bupropion add-on groups improved by 4.83 points and 4.33 points, respectively. The bupropion switch group had a change of 2.04 points.
The difference between the aripiprazole augmentation group and the switch to bupropion group was significant (difference 2.79 points; P = .014). Other between-group differences were not significantly different.
Remission rates were similar in the aripiprazole and bupropion groups at 28.9% and 28.2%, respectively. The remission rate in the bupropion switch group was 19.3%.
The study results showed patients who received adjunctive bupropion had the highest fall rate at 0.55 falls per patient, vs. 0.33 falls per patient in the aripiprazole group, suggesting that among the three treatment options, adjunctive aripiprazole may be the best choice because of its superior efficacy and lower fall risk.
A total of 248 patients enrolled in the study showed no improvement and were further randomly assigned to receive adjunctive lithium (n = 127) or switch from current therapy to nortriptyline (n = 121).
Well-being scores in the lithium group improved by 3.17 points and 2.18 points in the nortriptyline group. Remission occurred in 18.9% of patients in the lithium group and 21.5% in the nortriptyline group. Fall rates were similar among the two groups.
Overall, “this large, randomized study demonstrated that adding aripiprazole was a superior option for older adults with treatment-resistant depression,” Dr. Lenze told this news organization.
“Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases,” he added.
Practice changing?
In an accompanying editorial, Gemma Lewis, PhD, and Glyn Lewis, PhD, division of psychiatry, University of College London, noted the findings “support aripiprazole augmentation as a strategy for treatment-resistant depression in older persons, largely because of the lower risk of falls than with bupropion augmentation.”
However, “in clinical practice, [it] would be important to tailor treatment in light of potential adverse effects and the preferences of the patient,” they added.
Akathisia, for instance, is a common side effect of aripiprazole, shown in one recent trial to affect 11% of the patients. In addition, weight gain, though typically lower than seen with other antipsychotics, is a consideration with aripiprazole.
With respect to fall risk, they noted that bupropion was largely used in relatively high doses of 300 mg and 450 mg, despite some recent research showing little clinical benefit from increasing antidepressant doses above minimum recommendations.
“It is possible that smaller doses of bupropion than those used in the current trial would retain effectiveness while minimizing adverse effects such as falls,” the editorialists noted.
Commenting on the study, Jennifer R. Gatchel, MD, PhD, assistant psychiatrist at Massachusetts General Hospital/McLean Hospital and assistant professor of psychiatry at Harvard Medical School, Boston, said the findings have high clinical significance in the treatment of geriatric depression.
“These results are of great impact for clinicians managing older adults with treatment-resistant depression. They provide some of the first evidence of safety and efficacy of augmentation with aripiprazole as a strategy in clinical management of older adults who fail to initially respond to treatment,” said Dr. Gatchel, who was not associated with this research.
“Of particular significance, efficacy here is based on patient-centered outcomes and psychological well-being as a primary effectiveness outcome, which could translate into strengthened physician-patient alliance.”
While adjunctive aripiprazole is not necessarily a first-line strategy when older adults fail to respond to antidepressants, there is a lack of data on the risks and benefits of any other antipsychotic medications, she noted.
“Thus, this is evidence that will impact clinical practice and hopefully contribute to reduced societal burden of depression in older adults and the morbidity and mortality associated with it,” Dr. Gatchel said.
The study received support from a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Gatchel reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT AAGP 2023
‘Unheard of’ PAH improvement with novel drug: STELLAR
NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.
Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,
“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm−5 reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.
“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.
Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
‘A new hope’ for patients with PAH
Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.
“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.
“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.
But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.
The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
Death or clinical worsening cut by 84%
STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.
In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.
The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.
The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.
The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.
“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.
Drug binds activin, a pathologic driver of PAH
Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.
“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”
Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.
Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.
STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.
NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.
Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,
“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm−5 reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.
“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.
Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
‘A new hope’ for patients with PAH
Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.
“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.
“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.
But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.
The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
Death or clinical worsening cut by 84%
STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.
In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.
The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.
The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.
The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.
“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.
Drug binds activin, a pathologic driver of PAH
Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.
“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”
Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.
Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.
STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.
NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.
Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,
“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm−5 reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.
“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.
Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
‘A new hope’ for patients with PAH
Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.
“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.
“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.
But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.
The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
Death or clinical worsening cut by 84%
STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.
In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.
The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.
The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.
The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.
“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.
Drug binds activin, a pathologic driver of PAH
Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.
“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”
Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.
Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.
STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.
At ACC 2023