Kevin Kunzmann

Selective PPAR-delta agonist seladelpar (Livdelzi) was associated with significantly improved measures of cholestasis and liver injury among patients with 

 compensated cirrhosis, according to interim, long-term data from the phase 3 ASSURE trial.

American College of Gastroenterology (ACG) 2024 Scientific Sessions

 in Philadelphia, PA, this week, a team of US investigators supported by Gilead reported that seladelpar may be an effective, safe, and tolerable treatment for patients with PBC and compensated cirrhosis.

The US Food and Drug Adminsitration (FDA) approved seladelpar for the treatment of patients with PBC on an accelerated regulatory pathway this August; the approval was supported by topline findings from the RESPONSE trial that which showed about two-thirds (62%) of patients treated with the agent achieved composite biochemical response at 12 months—a tripled rate versus the placebo arm (20%). At the time of the indication, Gilead stated seladelpar was the only marketed US treatment for PBC that has shown statically significantly improved measures in key biomarkers, alkaline phosphatase (ALP) normalization and pruritus symptoms versus placebo.

In the phase 3, international, open-label ASSURE data presented at ACG, investigators led by Stuart C. Gordon, MD, of the Creighton University School of Medicine, presented interim efficacy and safety results in patients with both PBC and compensated cirrhosis receiving the newly regulated therapy.

Eligible patients in the trial had been selected from prior seladelpar clinical research if they had an inadequate response or intolerance to ursodeoxycholic acid (UDCA) and had no history of hepatic decompensation. The participants in RESPONSE received daily oral 10 mg seladelpar for open-label assessment.

At the time of data cutoff on June 29, 2023, the team had enrolled 174 patients from 4 prior seladelpar studies, including the ENHANCE trial. Among them, 33 (18.9%) had compensated cirrhosis at the time of study entry.

Gordon and colleagues sought efficacy endpoints including composite response to ALP <1.67 times the upper limit of normal (ULN); ALP decreases of ≥15%; total bilirubin ≤ULN; ALP normalization; and change from baseline in ALP, total bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and asparate aminotransferase (AST) at 12 months.

Among the patients with PBC and compensated cirrhosis, 30 (91%) were female; mean age was 60.4 years old. Another 8 (24.2%) patients had portal hypertension, 93.9% were Child-Pugh (CP) class A, and 6.1% were CP-B. At baseline, mean liver stiffness was 19.3 kPa, mean ALP was 241.9 U/L, total bilirubin was 0.92 mg/dL—27.3% greater than ULN.

Through the data cutoff date, 23 patients with compensated cirrhosis had completed 12 months of treatment. More than half (n = 12 [52.2%]) met the composite biochemical endpoint at 12 months. Another 9 (39.1%) patients achieved ALP normalization, and mean percent change in ALP was -38.1% from baseline.

The team additionally reported reductions in GGT and ALT (-35.1% and -19.6%, respectively) from baseline to 12 months. However, no significant changes in AST nor total bilirubin were observed.

Overall, the treatment was safe and tolerable, with no liver- nor drug-related serious adverse events nor discontinuations reported in patients. The team concluded their findings are supportive of perhaps expanded indications for seladelpar in the spectrum of cholestatic liver disease patients.

“In this interim analysis, PBC patients with compensated cirrhosis treated with seladelpar 10 mg for 12 months achieved meaningful improvements in cholestasis and markers of liver injury; seladelpar was safe and well tolerated,” investigators wrote. “These findings suggest that seladelpar may offer a safe and effective therapy for PBC patients with compensated cirrhosis.”

Gordon SC, Jacobsen I, Younes ZH, Silveira M, et al. Efficacy and Safety of Seladelpar in Patients With Primary Biliary Cholangitis and Compensated Liver Cirrhosis in the Open-Label, Long-Term ASSURE Safety Study: Interim Results. Abstract presented at: American College of Gastroenterology (ACG) 2024 Scientific Sessions. Philadelphia, PA. October 25 – 30, 2024.

Brooks A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. 

 Published August 14, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis

Articles

Seladelpar, a selective PPAR-delta agonist, has shown significant improvements in cholestasis and liver injury markers in patients with primary biliary cholangitis (PBC) and compensated cirrhosis, according to interim data from the phase 3 ASSURE trial. Approved by the FDA for PBC treatment, seladelpar demonstrated a tripled composite biochemical response rate compared to placebo. The ASSURE trial reported that seladelpar was safe and well-tolerated, with no serious adverse events, suggesting potential expanded indications for cholestatic liver disease treatment.

Open-label, interim data from ASSURE shows positive effect and tolerability with once-daily seladelpar in patients with primary biliary cholangitis and compensated cirrhosis.

Seladelpar Efficacious for Patients with PBC and Compensated Cirrhosis

Available alcohol use disorder pharmacotherapy is rarely utilized in patients with high-risk clinical history including 

, according to an analysis of commercially insured patient data in the US.

 in Philadelphia, PA, this week showed that key pharmaceutical options to treat the severity and risk of mortality in patients with alcohol use disorder are disproportionately not reaching patients with ALD or hepatic decompensation. The findings additionally found patients with high-index comorbidities, psychiatric conditions, or those at older age are significantly more likely to receive alcohol use disorder pharmacotherapy.

Investigators led by Alex R. Jones, MD, of UT Southwestern Medical Center, sought to characterize pharmacologic treatment for alcohol use disorder among US adults with commercial insurance; they additionally wanted to identify factors linked to a receipt for such therapy and discern any apparent patterns in prescribing.

The current pharmacologic armamentarium for alcohol use disorder include options like naltrexone, acamprosate, disulfiram, gabapentin, baclofen, and topiramate. These agents have been commonly associated with reduced risk of mortality and hepatic decompensation in clinical trials—necessary treatment options given the increasing rate of ALD, and therefore cirrhosis in the US.

Jones and colleagues assessed commercial insurance data from the PharMetrics Plus for Academics to identify adult patients with alcohol use disorder—defined as ≥2 outpatient or ≥1 inpatient diagnostic codes—in the time period of 2006 – 2021. The team sought a primary outcome of receipt of pharmacotherapy for the disorder any time following diagnosis; multivariable logistic regression analyses were conducted to identify any factors inked to receipt of therapy.

The analysis identified 28,625 adult patients with alcohol use disorder. Among them, 1201 (4.2%) were diagnosed with ALD cirrhosis and 439 (1.5%) were diagnosed with acute alcohol-associated hepatitis. The remaining 26,985 (94.3%) had no ALDs.

Patients who received alcohol use disorder pharmacotherapy were generally older per median age (45 years vs 42 years; 

 <.001). They were primarily male (64.5%) and were diagnosed with a psychiatric condition other than substance disorder (45.9%). Another one-third (35.7%) did have a non-alcoholic substance use disorder as well.

Investigators found that 15% of all patients with non-ALD alcohol use disorder received a pharmacotherapy during the observed time period. Comparatively, only 2.0% of patients with ALD cirrhosis and 10.0% of patients with alcohol-associated hepatitis from the same cohort received such a prescription. Even one-time prescription rates were higher for patients without ALD (28.4%) than those with ALD cirrhosis (10.7%)

Median time to alcohol use disorder treatment prescription for patients without ALD was 301 days (IQR, 45 – 879). The median wait time was even greater for patients with ALD cirrhosis (334.5; IQR, 36.25 – 441.5) and alcohol-associated hepatitis (367; IQR, 66.5 – 852.5; 

The most commonly prescribed medications to all patients with alcohol use disorder were gabapentin (n = 2695 [9.4%]), combination therapy (n = 866 [3.0%]), oral naltrexone (n = 756 [2.6%]), and topiramate (n = 579 [2.0%]).

Investigators noted that each of psychiatric comorbidity (adjusted odds ratio [aOR], 2.76; 95% CI, 2.56 – 2.98) and Charlson Comorbidity Index scores of ≥3 (aOR, 2.21; 95% CI, 1.80 – 2.71) were linked to a more than 2-fold increased odds of patients receiving alcohol use disorder pharmacotherapy. Patients being ≥50 years old was associated with a 33% increased likelihood of receiving pharmacotherapy (aOR, 1.33; 95% CI, 1.23 – 1.43), and female sex was associated with a 31% increased likelihood (aOR, 1.31; 95% CI, 1.22 – 1.41).

Adversely, ALD cirrhosis (aOR, 0.24; 95% CI, 0.16 – 0.35) and hepatic decompensation (aOR, 0.08; 95% CI, 0.03 – 0.17) were associated with significantly decreased likelihood of pharmacotherapy.

Though the trial was limited due to the utility of commercial insurance data and a lack of demographic details in the patient population, investigators concluded the findings show alcohol use disorder pharmacotherapy is provided to few patients with ALD—and the wait for those who do receive it is significantly delayed.

“In a large nationally representative cohort of commercially insured patients, AUD pharmacotherapy was underutilized in at risk populations, especially patients with ALD, among whom just 1 in 50 received AUD therapy,” investigators wrote. “Providers caring for patients with ALD should consider this underutilized therapy, or refer for psychiatric consultation when appropriate.”

Jones AR, Jiang Y, Tadros MM, Bardhi O, et al. Pharmacologic Therapy for Alcohol Use Disorder Is Under-Utilized in Alcohol-Associated Liver Disease Among Commercially Insured U.S. Adults. Abstract presented at: American College of Gastroenterology (ACG) 2024 Scientific Sessions. Philadelphia, PA. October 25 – 30, 2024.

Kunzmann K. Relentless: The Concurrent Alcohol Abuse, Liver Disease Epidemics in the US. 

. Published October 3, 2023. https://www.hcplive.com/view/concurrent-alcohol-abuse-liver-disease-epidemics-us

Pharmacotherapy for alcohol use disorder (AUD) is underutilized in patients with alcohol-associated liver disease (ALD), despite its potential to reduce mortality and hepatic decompensation. A study analyzing US commercial insurance data revealed that patients with ALD are less likely to receive AUD pharmacotherapy compared to those without ALD. Factors such as older age, psychiatric comorbidities, and higher Charlson Comorbidity Index scores increase the likelihood of receiving treatment. The study highlights the need for increased consideration of pharmacotherapy in high-risk populations, particularly those with ALD.

Only about 2% of eligible patients with ALD have received a pharmacotherapy for alcohol use disorder—and the prescription takes more than a year to receive.

Patients with Liver Disease Rarely Get Alcohol Use Disorder Pharmacotherapy

A trio of stakeholders join Lungcast to discuss the ongoing, long-term assessment into the patterns and drivers of chronic lung disease in a real-world cohort.

Checking in on the Lung Health Cohort Trial

 Introducing the Lung Health Cohort Research Study


 Seeking “the cholesterol of lung disease”


 Imaging strategies for long-term lung assessment

The American Lung Association (ALA) Lung Health Cohort Research Study is aiming to provide pulmonary specialists what is available in spades across specialties like cardiovascular medicine: a robust data pool defining the progression of chronic disease in young adults.

The ongoing cohort trial aims to discern patterns in 

 progression as they relate to lifestyle choices and patient demographics; it could potentially highlight new biomarkers for COPD and lung cancer, or refine understanding of the impact of environmental or socioeconomic factors on how asthma worsens over time. As is often the case with ongoing, longterm analyses, the potential for impact on the field is high.

, a trio of expert stakeholders in the Lung Health Cohort Research Study join the show to discuss its design, progress and potential. The featured guests include:

Ravi Kalhan, MD, Louis A. Simpson Professor of Pulmonary Medicine at Northwestern University’s Feinberg School of Medicine

George Washko, MD, professor at Harvard Medical School and physician at Brigham and Women’s Hospital

Amy Olson, MD, MSPH, executive director of medical affairs for Boehringer Ingelheim (BI) Pharmaceuticals

Lungcast is a monthly respiratory health podcast series hosted by Albert Rizzo, MD, chief medical officer of the American Lung Association (ALA), and produced by 

Rizzo and the group discuss the parameters of the ongoing, 4000-participant cohort, including its initial observations, hurdles in recruitment and representation, the utility of assessments, and support from industry including BI.

Podcasts

The American Lung Association's Lung Health Cohort trial seeks to establish a comprehensive data pool for understanding chronic respiratory disease progression in young adults, akin to cardiovascular studies. The trial aims to identify patterns related to lifestyle, demographics, and potential biomarkers for COPD and lung cancer, while examining environmental and socioeconomic impacts on asthma. In a recent Lungcast episode, experts discussed the trial's design, progress, and challenges, including recruitment and industry support. The trial's potential impact on respiratory medicine is significant.

Checking in on the Lung Health Cohort Research Study

Obeticholic acid (Ocaliva) is being infrequently used as a second-line therapy in eligible patients with 

, according to new findings—and even among those that it’s being used, a considerable delay to initiating it may result in progression to poor outcomes including cirrhosis.

 in Philadelphia, PA, this week, a team of investigators supported by Intercept Pharmaceuticals found that fewer than 8% of patients with PBC eligible for second-line therapy actually initiated obeticholic acid care; the mean time from initiating said care since becoming eligible for it was more than 1 year. The findings highlight a persistent gap in timely, effective care for patients with worsening state from the cholestatic disease.

The research team led by Sonal Kumar, MD, MPH, of Weill Cornell Medical College in New York, sought to estimate the time from second-line therapy eligibility to the initiation of obeticholic acid in patients with PBC. Obeticholic acid is currently 1 of 3 second-line therapies approved by the US Food and Drug Administration (FDA) to treat PBC, the others being elafibranor (Iqirvo) and seladelpar (Livdelzi). Obeticholic acid was originally indicated for use as a second-line treatment in PBC under an accelerated approval in 2016, but it remains without a full approval as of October 2024.

Investigators identified patients with PBC via Komodo Health database. Eligible patients had 1 inpatient or ≥2 outpatient claims for their condition and were eligible for second-line PBC therapy, defined as an inadequate response to ursodeoxycholic acid, between June 2016 and February 2022.

The team used first date of second-line therapy eligibility as index; patients were enrolled for ≥12 months pre-index and were ≥18 years old at index. Patients were followed until the first to occur between obeticholic acid initiation; end of insurance enrollment; longterm care admission; death; or end of study in May 2023.

The final assessment included 3880 adult patients with PBC who were defined as eligible for second-line therapy between 2016 – 2022. Mean patient age was 61.0 years old; 90.8% were female and approximately half (50.5%) were White.

Among the eligible patients, only 306 (7.9%) initiated obeticholic acid second-line therapy. Mean time to treatment from index was 14.2 months, or a median of 10.2 months (IQR, 2.8 – 18.1). Patients who did initiate obeticholic acid therapy were slightly younger (mean age, 57.2 years vs 61.3 years), and were similar proportions of female (90.7%) and White (42.1%).

In the 12 months prior to and including index date, a greater rate of patients with PBC who initiated obeticholic acid had cirrhosis than those who did not initiate (17.6% vs 12.4%). They were also more likely to have an autoimmune disease (29.3% vs 26.3%). The proportion of patients with cirrhosis was nearly doubled at the time of second-line therapy initiation versus the index of when they first became eligible for it (31.4% vs 17.6%).

Kumar and colleagues additionally observed that patients initiating obeticholic acid had higher mean baseline alkaline phosphatase (ALP) levels than those who did not, and that two-thirds (65.3%) of patients had ALP levels >1.67 times the upper limit of normal by the time of initiated second-line therapy.

Investigators concluded that, among eligible adult patients with PBC since 2016, approximately 1 in 12 actually initiated second-line obeticholic acid therapy, “with a considerable delay observed.”

“This delay suggests patients may experience disease progression, including cirrhosis, before starting second-therapy therapy,” they wrote. “Timely initiation of obeticholic acid in appropriate patients could enhance its clinical benefit on long-term outcomes.”

Kumar S, MacEwan JP, Levine A, Bessonova L, et al. Time to Initiation of the Second-Line Therapy Obeticholic Acid in Patients With Primary Biliary Cholangitis. Abstract presented at: American College of Gastroenterology (ACG) 2024 Scientific Sessions. Philadelphia, PA. October 25 – 30, 2024.

Brooks A. FDA Extends Review of Obeticholic Acid (Ocaliva) sNDA for Primary Biliary Cholangitis. 

. Published online October 17, 2024. https://www.hcplive.com/view/fda-extends-review-obeticholic-acid-ocaliva-snda-primary-biliary-cholangitis

Obeticholic acid is underutilized as a second-line therapy for primary biliary cholangitis (PBC), with less than 8% of eligible patients initiating treatment. The delay in starting therapy, averaging over a year, may lead to disease progression, including cirrhosis. The study, presented at the ACG 2024 Scientific Sessions, highlights a significant gap in timely care for PBC patients. Despite being the only FDA-approved second-line therapy since 2016, obeticholic acid remains without full approval. Timely initiation could improve long-term outcomes for patients with PBC.

Data from ACG 2024 show only 1 in 12 patients eligible for second-line PBC therapy are actually doing receiving it—and it may take up to a year to initiate.