Frances Lee, MD, is an assistant professor of medicine in the division of liver diseases at Mount Sinai.

A. Sidney Barritt, MD, is a tenured associate professor and the director of hepatology in the UNC liver center at the University of North Carolina.

Closing Gaps in PBC Care With Emerging and Established Second-Line Treatments

 has undergone a meaningful transformation in recent years, offering new optimism for a disease long defined by limited treatment options.

While ursodeoxycholic acid remains the cornerstone of first-line therapy, a substantial proportion of patients fail to achieve an adequate biochemical response, placing them at continued risk for disease progression. In an interview with HCPLive, A. Sidney Barritt, MD, a tenured associate professor and the director of hepatology in the UNC liver center at the University of North Carolina, and Frances Lee, MD, an assistant professor of medicine in the division of liver diseases at Mount Sinai, discuss how the arrival of multiple second-line agents is reshaping PBC management, redefining treatment goals, and prompting clinicians to think more broadly about both outcomes and quality of life.

Barritt emphasized that for decades, the 20% to 30% of patients who did not respond adequately to ursodeoxycholic acid represented a critical unmet need. The availability of second-line therapies has changed that equation, with the introduction of seladelpar (Livdelzi) and elafibranor (Iqirvo) allowing clinicians to help more patients achieve normalization of alkaline phosphatase and meaningful reductions in bilirubin. These biochemical improvements, he noted, are closely linked to reduced risks of cirrhosis, hepatic decompensation, and liver transplantation. With better tools now available, he says there is a real opportunity to slow the pace of disease progression for many patients.

Lee echoed this perspective, underscoring the significance of having multiple second-line options for patients with an incomplete response to first-line therapy. She framed these advances as a source of renewed hope, not only for controlling disease activity but also for improving patients’ day-to-day lives.

Despite this progress, both experts highlighted persistent gaps in PBC care. Barritt pointed to delays in diagnosis as a major issue, noting that abnormal alkaline phosphatase levels are often present for years before PBC is recognized. Earlier identification, followed by prompt initiation and optimization of therapy, remains essential to improving outcomes.

Lee focused on the importance of addressing quality-of-life concerns, such as pruritus and fatigue, which can be profoundly disabling yet are frequently underrecognized. She also noted that careful symptom assessment may uncover concomitant autoimmune conditions that warrant targeted management.

Looking ahead, both experts expressed enthusiasm for ongoing research and emerging therapies, including additional PPAR agonists, FXR-targeting agents, and treatments aimed specifically at symptom relief. Both stressed that clinicians should adopt more ambitious biochemical targets, striving for alkaline phosphatase levels as close to normal as possible and aggressive use of second-line therapies when goals are not met. With an expanding therapeutic arsenal, they say the focus in PBC is shifting toward true disease optimization rather than acceptance of partial control.

Editors’ Note: Barritt reports relevant disclosures with Mirum, Madrigal, Target RWE, Boehringer Ingelheim, Merck, and Mallinckrodt. Lee reports no relevant disclosures.

Brooks A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed January 22, 2026. 

https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc

Brooks A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed January 22, 2026. 

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

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A pair of hepatology experts discuss the shifting therapeutic landscape in PBC, lingering unmet needs, and where the field may be heading next.

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Ahmad Masri, MD, MS, is the director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University. 

To close the discussion, Dr Maron and Dr Masri address how surgical myectomy and alcohol septal ablation fit into a therapeutic ecosystem that now includes potent sarcomere-directed drugs. Masri stresses that clinicians have an obligation to present all reasonable options—medical and invasive—and to individualize decisions through shared decision-making. Although cardiac myosin inhibitors offer a noninvasive, reversible approach that can be maintained long term, patients must understand that therapy is generally chronic, and gradients and symptoms recur when treatment is discontinued. By contrast, septal reduction, particularly surgical myectomy, can offer a more definitive “one-and-done” solution, albeit with higher upfront procedural risk and recovery.

Integrating Myosin Inhibitors With Septal Reduction and Future Directions in Nonobstructive HCM

Maron underscores that a subset of patients with complex LVOT and mitral valve anatomy may have residual obstruction and symptoms despite optimal myosin inhibition. For these individuals, structural intervention remains essential to address anatomic contributors that pharmacologic modulation cannot fully overcome. Younger patients, women planning pregnancy, and individuals strongly averse to lifelong pharmacotherapy and monitoring may also reasonably favor septal reduction, provided they understand and accept procedural risks. The experts agree that myosin inhibitors are unlikely to obviate the need for expert septal reduction centers but will instead complement and refine referral patterns.

Finally, the discussion looks ahead to nonobstructive HCM. Masri cites the neutral ODYSSEY-HCM trial of mavacamten in nonobstructive disease but expresses optimism regarding the ongoing ACACIA-HCM trial evaluating aficamten in this population. Both clinicians regard nonobstructive HCM as a major remaining unmet need, given the lack of targeted therapies that reliably improve exercise capacity and symptoms. Maron concludes that results from trials like ACACIA-HCM will be pivotal in determining whether the benefits of myosin inhibition can extend beyond obstructive physiology, potentially redefining care for an even broader spectrum of patients with HCM.

Maron and Masri define the ongoing role of surgical myectomy and alcohol septal ablation in the myosin inhibitor era and preview emerging trials of aficamten in nonobstructive HCM.

Video Series

In this segment, Dr Maron poses a key practical question: in newly presenting, treatment-naive patients with symptomatic obstructive HCM, should clinicians still begin with traditional beta-blockers or calcium channel blockers, or has the evidence base matured sufficiently to justify first-line use of cardiac myosin inhibitors? Dr Masri responds by highlighting the MAPLE-HCM trial, in which aficamten, used as first-line monotherapy, outperformed metoprolol in terms of LVOT gradient reduction and symptomatic improvement. Notably, metoprolol was associated with worsening exercise capacity, higher N-terminal pro–brain natriuretic peptide levels, and increased left atrial volume index.

Positioning Cardiac Myosin Inhibitors as First-Line Therapy: Evidence Versus Beta-blockers

Both faculty members emphasize that, while formal head-to-head comparisons of beta-blockers with mavacamten are lacking, the limited and largely nonrandomized evidence for beta-blockers contrasts sharply with the robust phase 3 data for myosin inhibitors. Given the magnitude and consistency of gradient reduction and symptom improvement, Masri explains that in his practice, he moves rapidly toward myosin inhibition in highly symptomatic, markedly obstructed patients rather than spending prolonged periods titrating conventional agents to maximal tolerated doses. Maron argues that, based on current data, it is reasonable to consider aficamten as initial monotherapy in suitable patients.

The clinicians also acknowledge real-world constraints, including payer requirements that may still mandate a trial of traditional negative inotropes before authorizing myosin inhibitors. Maron clarifies that this first-line positioning pertains specifically to treatment of obstruction-related symptoms and does not supersede beta-blocker use when indicated for other conditions such as atrial fibrillation or hypertension. Nonetheless, both experts concur that the totality of evidence now supports consideration of aficamten as a legitimate first-line option for symptomatic obstructive HCM, reflecting a substantial evolution in standard of care.

Maron and Masri discuss whether myosin inhibitors, particularly aficamten, should be considered first-line therapy for symptomatic obstructive HCM in treatment-naive patients, in light of data from trials like MAPLE-HCM.

Here, Dr Masri outlines the pivotal phase 3 data for mavacamten, beginning with the EXPLORER-HCM trial, a randomized, placebo-controlled study that demonstrated significant improvements in peak oxygen consumption and New York Heart Association (NYHA) functional class in symptomatic obstructive HCM. 

Phase 3 Evidence and Safety Framework for Myosin Inhibitors: EXPLORER, VALOR, SEQUOIA, and REMS

Here, Dr Masri outlines the pivotal phase 3 data for mavacamten, beginning with the EXPLORER-HCM trial, a randomized, placebo-controlled study that demonstrated significant improvements in peak oxygen consumption and New York Heart Association (NYHA) functional class in symptomatic obstructive HCM. These clinical benefits paralleled substantial reductions in LVOT gradients and favorable changes in biomarkers of wall stress and myocardial injury. The subsequent VALOR-HCM trial enrolled patients already referred for septal reduction therapy and showed that mavacamten could avert or defer invasive intervention in a large proportion of participants by effectively lowering gradients and improving symptoms.

Dr Maron then summarizes phase 3 experience with aficamten, particularly the SEQUOIA-HCM trial, which similarly showed marked gradient reduction, consistent symptom relief, and improvement in health status metrics such as NYHA class and Kansas City Cardiomyopathy Questionnaire scores. Both physicians stress that, across studies, a high percentage of treated patients achieve LVOT gradients below 30 mm Hg, aligning hemodynamic improvements with observed functional gains. These data underpin the positioning of cardiac myosin inhibitors as high-benefit therapies capable of restoring many patients to good or excellent quality of life.

The discussion transitions to safety, especially treatment-emergent systolic dysfunction. Maron notes that both mavacamten and aficamten can, in a minority of patients, reduce left ventricular ejection fraction (LVEF) below the desired range. Consequently, the FDA mandated Risk Evaluation and Mitigation Strategy (REMS) programs for both agents, centered on serial echocardiographic monitoring and algorithmic dose adjustment. Masri highlights that aficamten’s development relied exclusively on echocardiographic guidance (without drug-level monitoring), showed a lower incidence of systolic dysfunction, and was not associated with clinical heart failure events in SEQUOIA-HCM. These features, along with fewer drug–drug interactions and more flexible titration, are reflected in a comparatively streamlined and clinician-friendly REMS structure for aficamten.

Maron and Masri review pivotal phase 3 trials of mavacamten and aficamten and explain how efficacy and systolic function monitoring shaped their respective REMS programs.

In this section, Dr Maron transitions to the emergence of cardiac myosin inhibitors as a novel therapeutic class, and Dr Masri details their mechanistic rationale. Mavacamten received US FDA approval in 2022 for symptomatic obstructive HCM, followed recently by the approval of aficamten. Both agents are indicated for patients with symptomatic obstructive disease, requiring demonstrable LVOT gradient at rest or with provocation. At present, their regulatory approvals are confined to obstructive HCM, with nonobstructive disease remaining an area of active investigation.

Cardiac Myosin Inhibitors in Obstructive HCM: Mechanism, Regulatory Milestones, and Clinical Rationale

Masri explains that cardiac myosin inhibitors act directly at the sarcomere, reducing excessive actin–myosin cross-bridge formation and thereby attenuating pathologic hypercontractility. Although both drugs are negative inotropes by classification, their therapeutic aim is not to produce systolic dysfunction but to normalize an abnormally hyperdynamic ventricle. By modulating sarcomeric power generation, these agents decrease or eliminate mitral–septal contact, leading to marked reductions—or complete resolution—of the LVOT gradient and associated SAM-mediated mitral regurgitation.

Maron emphasizes that this sarcomere-targeted approach represents a paradigm shift compared with traditional negative inotropes, which rely on nonspecific hemodynamic effects rather than correction of the primary pathophysiologic mechanism. Phase 3 data with both mavacamten and aficamten demonstrate that profound gradient reduction translates into clinically meaningful gains in symptoms, functional class, and exercise capacity. The segment underscores that by addressing the root hypercontractile biology of HCM, cardiac myosin inhibitors have opened a “new era” in managing symptomatic obstructive disease.

Maron and Masri introduce cardiac myosin inhibitors—mavacamten and aficamten—explaining their sarcomere-level mechanism and the rationale for targeting hypercontractility in obstructive HCM.

Maron and Masri review decades of experience with beta-blockers, calcium channel blockers, disopyramide, and septal reduction therapies, underscoring persistent under-treatment and the unmet need that set the stage for myosin inhibitors.

Historical Management of Obstructive HCM: Limitations of Medical Therapy and Septal Reduction Access

Albert Rizzo, MD, is the chief medical officer of the American Lung Association.

Lungcast reflects on pulmonology in 2025, looking back at topics ranging from ALA's ‘State of the Air’ report to the lung-gut microbiome.



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Infectious Disease condition center page is a comprehensive resource for clinical news and insights on respiratory health. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for asthma, COPD, interstitial lung disease, COVID-19, and more.

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Join the American Lung Association and HCPLive every month as Dr. Al Rizzo interviews world-leading experts on the great challenges, accomplishments, and stories in respiratory medicine.

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Experts Discuss the REPLENISH Trial for Polymyalgia Rheumatica 

Howa Yeung, MD MSc is an associate professor of Dermatology at the Emory University School of Medicine.

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In this Q&A interview with Yeung, a discussion was conducted regarding newly-released findings on acne in patients identifying as transgender.

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New Findings on Acne Incidence in Transgender Individuals, With Howa Yeung, MD, MSc

The Trial Design and Interim Results From the GCAptAIN Trial 

In this opening segment, Martin (Marty) Maron, MD, and Ahmed Masri, MD, PA-C, introduce the discussion and frame obstructive hypertrophic cardiomyopathy (HCM) as the central focus, emphasizing outflow tract gradients as the key driver of symptoms.

Framing Obstructive Hypertrophic Cardiomyopathy: Epidemiology, Pathophysiology, and Clinical Focus

Nada Elbuluk, MD, MSc, is a dermatologist in California. 

This segment of the latest Skin of Color Savvy episode highlights a conversation between Nada Elbuluk, MD, MSc, and Michelle Rodrigues, MBBS.

Practical Approaches to Hyperpigmentation and Hypopigmentation, With Nada Elbuluk, MD, MSc, and Michelle Rodrigues, MBBS

Carly Maucione, MD, a resident physician at Washington University in St. Louis

Machine models identified 2% of CBCs as possibly contaminated and flagged 6–9% of inpatient transfusions as potentially unnecessary, explains Maucione. 


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Uncovering Hidden IV Fluid Contamination Through Machine Learning, With Carly Maucione, MD

Ozan Unlu, MD, is a fellow in interventional cardiology at Brigham and Women’s Hospital and Harvard University.

Despite being considered superior to in-clinic measurements, a substantial number of patients do not follow the HBPM guideline recommendations of 12 readings per week.

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Cardiology condition center page is a comprehensive resource for clinical news and insights on cardiovascular and cardiometabolic diseases. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for heart disease and cardiovascular events, as well as associated diabetes, renal failure, and more...

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The HCPLive hypertension page is a resource for medical news and expert insights on high blood pressure. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments for hypertension, and more.

Home Blood Pressure Monitoring Engagement Suboptimal Among Most Patients, With Ozan Unlu, MD

Nancy Reau, MD, is Professor of Internal Medicine, Richard B. Capps Chair of Hepatology, Associate Director of Solid Organ Transplantation, and Section Chief of Hepatology at Rush University Medical Center.

This segment of Liver Lineup features an in-depth discussion on hepatocellular carcinoma screening in patients with cirrhosis.

Latest News

Closing Gaps in PBC Care With Emerging and Established Second-Line Treatments

Integrating Myosin Inhibitors With Septal Reduction and Future Directions in Nonobstructive HCM

Positioning Cardiac Myosin Inhibitors as First-Line Therapy: Evidence Versus Beta-blockers

Phase 3 Evidence and Safety Framework for Myosin Inhibitors: EXPLORER, VALOR, SEQUOIA, and REMS

Cardiac Myosin Inhibitors in Obstructive HCM: Mechanism, Regulatory Milestones, and Clinical Rationale