To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

In new evidence-based guidelines, the American Gastroenterological Association recommends noninvasive biomarkers as a first-line strategy for monitoring many patients with ulcerative colitis (UC). These guidelines were published in Gastroenterology.

The AGA guidelines outline use cases for three biomarkers that provide accurate insights into UC disease activity: serum C-reactive protein (CRP) (blood), fecal calprotectin (stool), and fecal lactoferrin (stool). AGA recommends a monitoring strategy that integrates noninvasive biomarkers for patients with UC in remission (no current symptoms) as well as those with current symptoms.
 

Patients with UC in symptomatic remission

• Perform interval biomarker monitoring every 6-12 months.
• AGA recommends stool-based biomarkers over blood testing.
• If biomarkers are normal, AGA suggests continuing biomarker monitoring and avoiding routine endoscopic assessment.
• If biomarkers are elevated, AGA suggests endoscopic assessment by a gastroenterologist.
• Listen to your body! Talk to your doctor about any new symptoms.

Patients with symptomatically active UC

• Biomarker testing should be the first step to determine the need for endoscopic assessment.
• For patients with mild symptoms who have normal or elevated biomarkers, AGA suggests endoscopic assessment by a gastroenterologist.
• For patients with moderate to severe symptoms who have normal biomarkers, AGA suggests endoscopic assessment by a gastroenterologist.
• For patients with moderate to severe symptoms and elevated biomarkers, AGA suggests treatment adjustment and avoiding endoscopic assessment.

With AGA guidelines guiding the use of noninvasive biomarkers, physicians can confidently offer a more convenient and closer monitoring option for their patients.

AGA will advocate for all insurers to cover the cost of biomarker testing in UC.

In new evidence-based guidelines, the American Gastroenterological Association recommends noninvasive biomarkers as a first-line strategy for monitoring many patients with ulcerative colitis (UC). These guidelines were published in Gastroenterology.

The AGA guidelines outline use cases for three biomarkers that provide accurate insights into UC disease activity: serum C-reactive protein (CRP) (blood), fecal calprotectin (stool), and fecal lactoferrin (stool). AGA recommends a monitoring strategy that integrates noninvasive biomarkers for patients with UC in remission (no current symptoms) as well as those with current symptoms.
 

Patients with UC in symptomatic remission

• Perform interval biomarker monitoring every 6-12 months.
• AGA recommends stool-based biomarkers over blood testing.
• If biomarkers are normal, AGA suggests continuing biomarker monitoring and avoiding routine endoscopic assessment.
• If biomarkers are elevated, AGA suggests endoscopic assessment by a gastroenterologist.
• Listen to your body! Talk to your doctor about any new symptoms.

Patients with symptomatically active UC

• Biomarker testing should be the first step to determine the need for endoscopic assessment.
• For patients with mild symptoms who have normal or elevated biomarkers, AGA suggests endoscopic assessment by a gastroenterologist.
• For patients with moderate to severe symptoms who have normal biomarkers, AGA suggests endoscopic assessment by a gastroenterologist.
• For patients with moderate to severe symptoms and elevated biomarkers, AGA suggests treatment adjustment and avoiding endoscopic assessment.

With AGA guidelines guiding the use of noninvasive biomarkers, physicians can confidently offer a more convenient and closer monitoring option for their patients.

AGA will advocate for all insurers to cover the cost of biomarker testing in UC.

In new evidence-based guidelines, the American Gastroenterological Association recommends noninvasive biomarkers as a first-line strategy for monitoring many patients with ulcerative colitis (UC). These guidelines were published in Gastroenterology.

The AGA guidelines outline use cases for three biomarkers that provide accurate insights into UC disease activity: serum C-reactive protein (CRP) (blood), fecal calprotectin (stool), and fecal lactoferrin (stool). AGA recommends a monitoring strategy that integrates noninvasive biomarkers for patients with UC in remission (no current symptoms) as well as those with current symptoms.
 

Patients with UC in symptomatic remission

• Perform interval biomarker monitoring every 6-12 months.
• AGA recommends stool-based biomarkers over blood testing.
• If biomarkers are normal, AGA suggests continuing biomarker monitoring and avoiding routine endoscopic assessment.
• If biomarkers are elevated, AGA suggests endoscopic assessment by a gastroenterologist.
• Listen to your body! Talk to your doctor about any new symptoms.

Patients with symptomatically active UC

• Biomarker testing should be the first step to determine the need for endoscopic assessment.
• For patients with mild symptoms who have normal or elevated biomarkers, AGA suggests endoscopic assessment by a gastroenterologist.
• For patients with moderate to severe symptoms who have normal biomarkers, AGA suggests endoscopic assessment by a gastroenterologist.
• For patients with moderate to severe symptoms and elevated biomarkers, AGA suggests treatment adjustment and avoiding endoscopic assessment.

With AGA guidelines guiding the use of noninvasive biomarkers, physicians can confidently offer a more convenient and closer monitoring option for their patients.

AGA will advocate for all insurers to cover the cost of biomarker testing in UC.

Medicare beneficiary cost sharing will no longer apply to the screening colonoscopy following a positive noninvasive stool-based screening test. To unlock this free benefit, providers must properly apply modifier KX.

What codes does this apply to?

Providers must append modifier KX (“requirements specified in the medical policy have been met”) to HCPCS codes G0105 and G0121 when the screening colonoscopy follows a positive result from one of the following noninvasive stool-based CRC screening tests:

• Screening Guaiac-based Fecal Occult Blood Test (gFOBT) (CPT 82270).
• Screening Immunoassay-based Fecal Occult Blood Test (iFOBT) (HCPCS G0328).
• Cologuard™ – Multi-target Stool DNA (sDNA) Test (CPT 81528).

What happens if I don’t use the KX modifier?

Medicare will return the screening colonoscopy claim as “unprocessable” and you will receive one of following messages:

CARC 16: “Claim/service lacks information or has submission billing error(s)” and RARC N822: “Missing Procedure Modifier(s)”

or

RARC N823: “Incomplete/Invalid Procedure Modifier”

Attach modifier KX and resubmit the claim to Medicare.
 

Should I use modifier KX if I remove polyps?

No. If you remove polyps during a screening colonoscopy following a positive noninvasive stool-based test, report the appropriate CPT code (for example, 45380, 45384, 45385, or 45388) and add modifier PT (colorectal cancer screening test; converted to diagnostic test or other procedure) to each CPT code for Medicare.

Some Medicare beneficiaries are not aware that Medicare has not fully eliminated the coinsurance responsibility yet when polypectomy is needed during a screening colonoscopy. Medicare beneficiary coinsurance responsibility is 15% of the cost of the procedure from 2023 to 2026. The coinsurance responsibility falls to 10% from 2027 to 2029 and by 2030 it will be covered 100% by Medicare.
 

Where can I find more information?

See the MLN Matters notice and the CMS Manual System.

Medicare beneficiary cost sharing will no longer apply to the screening colonoscopy following a positive noninvasive stool-based screening test. To unlock this free benefit, providers must properly apply modifier KX.

What codes does this apply to?

Providers must append modifier KX (“requirements specified in the medical policy have been met”) to HCPCS codes G0105 and G0121 when the screening colonoscopy follows a positive result from one of the following noninvasive stool-based CRC screening tests:

• Screening Guaiac-based Fecal Occult Blood Test (gFOBT) (CPT 82270).
• Screening Immunoassay-based Fecal Occult Blood Test (iFOBT) (HCPCS G0328).
• Cologuard™ – Multi-target Stool DNA (sDNA) Test (CPT 81528).

What happens if I don’t use the KX modifier?

Medicare will return the screening colonoscopy claim as “unprocessable” and you will receive one of following messages:

CARC 16: “Claim/service lacks information or has submission billing error(s)” and RARC N822: “Missing Procedure Modifier(s)”

or

RARC N823: “Incomplete/Invalid Procedure Modifier”

Attach modifier KX and resubmit the claim to Medicare.
 

Should I use modifier KX if I remove polyps?

No. If you remove polyps during a screening colonoscopy following a positive noninvasive stool-based test, report the appropriate CPT code (for example, 45380, 45384, 45385, or 45388) and add modifier PT (colorectal cancer screening test; converted to diagnostic test or other procedure) to each CPT code for Medicare.

Some Medicare beneficiaries are not aware that Medicare has not fully eliminated the coinsurance responsibility yet when polypectomy is needed during a screening colonoscopy. Medicare beneficiary coinsurance responsibility is 15% of the cost of the procedure from 2023 to 2026. The coinsurance responsibility falls to 10% from 2027 to 2029 and by 2030 it will be covered 100% by Medicare.
 

Where can I find more information?

See the MLN Matters notice and the CMS Manual System.

Medicare beneficiary cost sharing will no longer apply to the screening colonoscopy following a positive noninvasive stool-based screening test. To unlock this free benefit, providers must properly apply modifier KX.

What codes does this apply to?

Providers must append modifier KX (“requirements specified in the medical policy have been met”) to HCPCS codes G0105 and G0121 when the screening colonoscopy follows a positive result from one of the following noninvasive stool-based CRC screening tests:

• Screening Guaiac-based Fecal Occult Blood Test (gFOBT) (CPT 82270).
• Screening Immunoassay-based Fecal Occult Blood Test (iFOBT) (HCPCS G0328).
• Cologuard™ – Multi-target Stool DNA (sDNA) Test (CPT 81528).

What happens if I don’t use the KX modifier?

Medicare will return the screening colonoscopy claim as “unprocessable” and you will receive one of following messages:

CARC 16: “Claim/service lacks information or has submission billing error(s)” and RARC N822: “Missing Procedure Modifier(s)”

or

RARC N823: “Incomplete/Invalid Procedure Modifier”

Attach modifier KX and resubmit the claim to Medicare.
 

Should I use modifier KX if I remove polyps?

No. If you remove polyps during a screening colonoscopy following a positive noninvasive stool-based test, report the appropriate CPT code (for example, 45380, 45384, 45385, or 45388) and add modifier PT (colorectal cancer screening test; converted to diagnostic test or other procedure) to each CPT code for Medicare.

Some Medicare beneficiaries are not aware that Medicare has not fully eliminated the coinsurance responsibility yet when polypectomy is needed during a screening colonoscopy. Medicare beneficiary coinsurance responsibility is 15% of the cost of the procedure from 2023 to 2026. The coinsurance responsibility falls to 10% from 2027 to 2029 and by 2030 it will be covered 100% by Medicare.
 

Where can I find more information?

See the MLN Matters notice and the CMS Manual System.

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.

Mitchel L. Zoler/MDedge News

“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.

Mitchel L. Zoler/MDedge News

“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.

Mitchel L. Zoler/MDedge News

“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.

Mitchel L. Zoler/MDedge News

“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.

Mitchel L. Zoler/MDedge News

“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.

Mitchel L. Zoler/MDedge News

“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.