Novartis has announced positive final results from the phase 3 APPLAUSE-IgAN study of iptacopan (Fabhalta) in adults with IgA nephropathy (IgAN).

As described in an October 16, 2025, press release from the Company, the oral alternative complement pathway inhibitor demonstrated statistically significant, clinically meaningful superiority compared to placebo in slowing IgAN progression measured by annualized total slope of estimated glomerular filtration rate (eGFR) decline over 2 years. Of note, Novartis described plans to use these data to support regulatory submissions for iptacopan in 2026.

“Progressive diseases such as IgAN present an urgent need for interventions that can ultimately improve kidney health. Many people with IgAN commonly experience fear and anxiety of disease progression,” Ruchira Glaser, Development Unit Head, Cardiovascular, Renal & Metabolic, Novartis, said in a statement.

 “We are excited about today’s positive Phase III APPLAUSE-IgAN results showing slowed eGFR decline, which add to the growing evidence of Fabhalta as a targeted therapy to preserve long-term kidney function, giving hope to people living with this condition.”

Iptacopan received US Food and Drug Administration (FDA) approval in December 2023 for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH), later receiving accelerated approval in August 2024 for the reduction of proteinuria in adults with primary IgAN at risk of rapid disease progression. Most recently, in 2025, iptacopan received FDA approval for the treatment of adults with C3 glomerulopathy (C3G), making it the first treatment approved for this ultra-rare kidney disease.

The oral alternative complement pathway inhibitor is also being studied in atypical hemolytic uremic syndrome, immune complex membranoproliferative glomerulonephritis, and lupus nephritis, with ongoing studies evaluating the safety and efficacy profiles in these investigational indications to support potential regulatory submissions.

APPLAUSE-IgAN is a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of twice-daily oral iptacopan 200 mg in 477 adults with primary IgAN. Patients were randomly assigned to iptacopan or placebo, in addition to supportive care, defined as a stable dose of maximally-tolerated renin-angiotensin system inhibitor therapy with or without a stable dose of SGLT2i.

The primary endpoints of the study for the interim and final analysis, respectively, are proteinuria reduction at 9 months as measured by UPCR and the annualized total eGFR slope over 24 months. During the final analysis, the following secondary endpoints were assessed:

Proportion of participants reaching UPCR <1 g/g without receiving corticosteroids/immunosuppressants or other newly approved drugs or initiating new background therapy for treatment of IgAN or initiating kidney replacement therapy

Time from randomization to first occurrence of composite kidney failure endpoint event (reaching either sustained ≥30% decline in eGFR relative to baseline or sustained eGFR <15 mL/min/1.73 m2 or maintenance dialysis or receipt of kidney transplant or death from kidney failure)

Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire

The main study population enrolled patients with an eGFR ≥30 mL/min/1.73 m2 and UPCR ≥1 g/g at baseline. In addition, a smaller cohort of patients with severe renal impairment, defined as eGFR 20–30 mL/min/1.73 m2 at baseline, was also enrolled to provide additional information but not contributing to the main efficacy analyses.

As described by Novartis, in APPLAUSE-IgAN, iptacopan was well tolerated with a favorable safety profile in line with previously reported data. The Company plans to present data from the APPLAUSE-IgAN final analysis at future medical meetings.

Novartis. Novartis Fabhalta® (iptacopan) meets Phase III primary endpoint, slows kidney function decline in patients with IgA nephropathy (IgAN). October 16, 2025. Accessed October 16, 2025. 

https://www.novartis.com/news/media-releases/novartis-fabhalta-iptacopan-meets-phase-iii-primary-endpoint-slows-kidney-function-decline-patients-iga-nephropathy-igan

Campbell P. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. HCPLive. August 8, 2024. Accessed October 16, 2025. 

https://www.hcplive.com/view/iptacopan-receives-accelerated-approval-for-reducing-proteinuria-in-iga-nephropathy

Campbell P. FDA Approves Oral Iptacopan (Fabhalta) as First C3 Glomerulopathy Therapy. HCPLive. March 20, 2025. Accessed October 16, 2025. 

https://www.hcplive.com/view/fda-approves-oral-iptacopan-fabhalta-as-first-c3-glomerulopathy-therapy

Articles

Novartis has reported positive results from the phase 3 APPLAUSE-IgAN study, demonstrating that iptacopan significantly slows the progression of IgA nephropathy (IgAN) compared to placebo. The study's primary endpoint was the annualized total slope of eGFR decline over two years. Iptacopan, an oral alternative complement pathway inhibitor, has previously received FDA approvals for various conditions, including paroxysmal nocturnal hemoglobinuria and C3 glomerulopathy. The drug is also being investigated for other renal and autoimmune conditions, with ongoing studies assessing its safety and efficacy.

Final results from APPLAUSE-IgAN demonstrate iptacopan’s superiority versus placebo for slowing IgAN progression and will be used to support its full approval.

APPLAUSE-IgAN: Iptacopan (Fabhalta) Meets eGFR Decline Primary Endpoint

 experienced meaningful improvements in emotional well-being and daily functioning after 48 weeks of ritlecitinib 50 mg use, according to recent long-term data.

These findings were the result of the ALLEGRO-2b/3 analysis (NCT03732807), the results of which had previously shown that ritlecitinib treatment led to notable hair regrowth and other patient-reported improvements versus placebo.

 During the 24-week placebo-controlled trial phase, improvements in AA Patient Priority Outcomes (AAPPO) emotional symptoms (ES) or activity limitations (AL) were not noted.

In this analysis, authored by investigators such as Ernest H. Law, PharmD, PhD, from Pfizer, Inc., the investigators looked at AAPPO scores in patients from the aforementioned study given a 50-mg ritlecitinib maintenance dose (+/− 4-week loading dose of 200 mg) and those given subtherapeutic ritlecitinib 10 mg through the 48-week mark.

“This post hoc analysis of ALLEGRO-2b/3 data compares improvements in AAPPO ES and AL domain and item scores between the ritlecitinib 50-mg QD maintenance dose…and the subtherapeutic ritlecitinib 10-mg QD dose through Week 48,” Law and colleagues wrote.

The investigative team highlighted that within the ALLEGRO-2b/3 studies, a total of 718 eligible study participants were randomized to be treated with either a placebo or 1 of a possible 5 dosing regimens of ritlecitinib. This 48-week study was double-blinded consisted of an initial 24-week placebo-controlled period. This period was later followed by a 24-week extension, during which those taking part who were previously given a placebo transitioned to active ritlecitinib therapy.

In this exploratory analysis, an assessment of 3 ritlecitinib treatment cohorts was conducted. These arms were as follows: (a) study subjects given 50 mg once-per-day (QD) only; (b) subjects initiating with a 200 mg QD loading dose for a 4-week course followed by a 50 mg QD maintenance dose (200/50 mg); and (c) the pooled population of all study participants who were given any 50-mg dose, combining both a and b groups. The comparison group consisted of individuals who were given a subtherapeutic 10-mg QD dose.

The Alopecia Areata Patient Priority Outcomes (AAPPO) instrument, a validated 11-item self-administered questionnaire, was implemented by Law and coauthors to evaluate the effect of alopecia areata in individuals aged ≥12 years. Changes in least squares mean (LSM) from the point of baseline (CFBs) were calculated by the investigators for domain scores across the full analysis set as well as for those who showed baseline domain scores which were ≥1.

Law and colleagues looked at item-level shifts, analyzing them for participants with baseline item scores ≥2. This was carried out since lower baseline scores (on a 0–4 scale) would suggest less frequent or severe impacts related to hair-loss.

In this post-hoc analysis, 325 participants were included. There were 132 in the 200/50-mg cohort, 130 in the 50-mg cohort, and 63 in the 10-mg cohort. Across all of the 50-mg arms of this analysis, Law and coauthors found that LSM CFBs in the Emotional Symptoms (ES) and Activity Limitations (AL) domain scores generally improved through the 48-week mark. They noted statistically significant differences versus the 10-mg arm, observed starting at the 34-week mark for ES and the 40-week mark for AL.

Responder rates for individual ES and AL items were also shown by the investigators to tend to rise through the 48-week mark in all 50-mg groups. The team added that the greatest improvements relative to the 10-mg group were observed for ES items 5 and 6, which they added had evaluated self-consciousness and embarrassment, and AL item 11, which assesses interactions with others.

“The results of this study suggest that a longer follow-up period may be needed to observe downstream psychosocial improvement following effective treatment,” the investigative team concluded.

EH Law, B Sherif, A Mostaghimi, et al. Improvement in Patient-Reported Emotional Symptoms and Activity Limitations due to Hair Loss in Patients With Alopecia Areata Treated With Ritlecitinib: Additional Analyses From ALLEGRO-2b/3. International Journal of Dermatology (2025): 1–9, 

B King, X Zhang, WG Harcha, et al. Efficacy and Safety of Ritlecitinib in Adults and Adolescents With Alopecia Areata: A Randomised, Double-Blind, Multicentre, Phase 2b-3 Trial. Lancet 401, no. 10387 (2023): 1518–1529, 

https://doi.org/10.1016/s0140-6736(23)00222-2

Long-term data indicates that adults with alopecia areata experienced significant improvements in emotional well-being and daily functioning after 48 weeks of ritlecitinib 50 mg treatment. The ALLEGRO-2b/3 analysis compared the effects of a 50 mg maintenance dose to a subtherapeutic 10 mg dose, revealing notable enhancements in emotional symptoms and activity limitations. Statistically significant improvements were observed from week 34 for emotional symptoms and week 40 for activity limitations. The study suggests that extended follow-up may be necessary to fully capture psychosocial benefits.

These post hoc findings suggest psychosocial burden may improve following hair regrowth with ritlecitinib.


ALLEGRO-2b/3: Post-Hoc Analysis Suggests Alopecia Areata Improves With Ritlecitinib

 delabeling in children is safe and effective in the long term, with 76.4% of children reusing the previously avoided antibiotics without significant adverse events.

“More than three-quarters of delabeled children reused the drug without any significant issues, and no clinical reactions,” wrote study investigator Nikolaos Kitsos, MD, PhD, from the University of Thessaly in Greece, and colleagues.1

Up to 20% of the US population carries an antibiotic allergy label; however, many of these cases reflect reactions from viral rashes or other benign conditions rather than true allergies.

 Mislabeling results in significant consequences, such as avoiding first-line antibiotics, more treatment costs, using broad-spectrum alternatives, longer illness, and contributing to the global problem of antimicrobial resistance.

A negative drug provocation test gives clinicians confidence to safely lift the antibiotic allergy label. Although drug provocation tests are validated for safety and accuracy in clinical trials, little is known about their long-term real-world reliability. Additionally, limited data exists on whether individuals actually reuse the once-avoided antibiotics after delabeling and whether new reactions occur.

Investigators addressed these questions in a 5-year follow-up study of 106 children (mean age, 8.3; range, 3 – 15 years) who had undergone antibiotic allergy evaluation and delabeling at a tertiary pediatric allergy center.1 Antibiotic allergy evaluation was a comprehensive assessment including detailed history, skin testing, and a drug provocation test following EAACI/ENDA protocols.

Clinicians informed families, both verbally and in writing, that their children could safely use the previously suspected antibiotic. About 5 years later, investigators reached out through structured interviews during clinic visits or by telephone, asking whether families had reused the delabeled antibiotic, who prescribed it, for what indication, whether any adverse events occurred, and whether they administered antihistamines. They also asked families to explain any decision not to reuse the antibiotic.

Among the 106 delabeled children, 81 (76.4%) reused the previously suspected antibiotic at least once in the 5-year follow-up, with most prescribed from primary care pediatricians (89%). In 18% of cases, parents took initiative and influenced pediatricians’ decisions.

Most prescriptions were for common childhood infections, such as otitis media and respiratory tract infections. Children most often reused penicillins (57%), followed by macrolides (24%) and cephalosporins (19%). On average, it took 5 years from testing to reuse antibiotics.

It was rare for children to experience adverse events following reuse. Three children reported mild cutaneous reactions, including transient urticaria in 2 children and non-pruritic erythematous rash in 1 child, which appeared within 48 hours of initiating treatment and resolved spontaneously without requiring medication or discontinuation. These reactions resembled or were milder than the initial symptoms that led to the allergy referral.

“Although resensitization cannot be completely excluded because re-testing was not performed, the clinical course and ability to complete the antibiotic course without complications strongly suggest that these were not true allergic reactions, but likely coincidental or related to underlying illness,” investigators wrote.

Investigators noted that 9 families reported giving prophylactic antihistamines during antibiotic administration, though this was mostly due to parental anxiety and not the physician’s recommendation. This showed that parents continue to have persistent concerns about recurrence, despite negative testing and formal delabeling.

Among the sample, 25 children (23.6%) did not reuse the antibiotic and cited reasons included parental anxiety (n = 12), absence of clinical need for that particular drug (n = 11), and physician’s reluctance (n = 2).

“The latter is particularly notable as it indicates that some healthcare providers may still lack confidence in allergy testing results, highlighting a knowledge gap that needs to be confronted,” investigators wrote.

The study ultimately demonstrated that negative drug provocation tests predict long-term tolerance of antibiotics in real-world settings, with more than three-quarters of delabeled children being able to reuse the drug.

“To fully realize the benefits of delabeling, health systems must address behavioral barriers through targeted education and reassurance for families and clinicians,” investigators concluded.

 “By delabeling and reducing unnecessary avoidance of beta-lactams and other first-line drugs, we contribute to antimicrobial stewardship, confronting bacterial infections and subsequently improving the overall healthcare.”

Kitsos N, Mavroudi A, Grivea I, Cassimos D. Once Allergic, Now Not: Do Children Use Delabeled Antibiotics?-A 5-Year Follow-Up Study. 

. Published online October 7, 2025. doi:10.1111/apa.70340

Plager J, Cutrer WB. Not a Benign (Mis)Label: Penicillin Allergy Education for the Nonallergist. MedEdPORTAL. 2024 Sep 27;20:11440. doi: 10.15766/mep_2374-8265.11440. PMID: 39347473; PMCID: PMC11427523.

A 5-year follow-up study confirmed the safety and efficacy of antibiotic allergy delabeling in children, with 76.4% reusing previously avoided antibiotics without significant adverse events. Mislabeling of antibiotic allergies can lead to unnecessary avoidance of first-line treatments, increased costs, and antimicrobial resistance. The study involved 106 children who underwent comprehensive allergy evaluations, including drug provocation tests. Despite successful delabeling, some families and healthcare providers remain hesitant due to persistent concerns and knowledge gaps, highlighting the need for targeted education to enhance confidence in allergy testing results.

A 5-year follow-up showed 76% of delabeled children reused the previously avoided antibiotic without significant adverse reactions.

Most Children Safely Reuse Antibiotics 5 Years After Allergy Delabeling

Over the past decade, the management of asthma and chronic obstructive pulmonary disease (COPD) has undergone a remarkable evolution, moving beyond broad anti-inflammatory and bronchodilator approaches toward targeted biologic therapies that address the root drivers of airway inflammation. Once limited to inhaled corticosteroids and long-acting bronchodilators, the therapeutic arsenal now includes a spectrum of monoclonal antibodies directed at type 2 inflammatory pathways—transforming outcomes for patients once resigned to frequent exacerbations and chronic steroid use. Approvals of agents such as dupilumab (Dupixent), tezepelumab (Tezspire), benralizumab (Fasenra), and mepolizumab (Nucala) have broadened the definition of treatable asthma, offering precision approaches that not only control symptoms but also reduce exacerbation rates and hospitalizations in previously refractory populations.

At the same time, growing evidence for biologics in select COPD populations is reshaping conventional views of airway disease as distinct silos, emphasizing overlapping inflammatory mechanisms and shared therapeutic potential. Clinicians are increasingly focused on early identification of candidate patients, the integration of biomarkers like eosinophil counts and IgE, and real-world strategies for overcoming insurance and logistical barriers to care. 

 in Chicago, Illinois, a group of pulmonologists, led by Joseph Khabbaza, MD, pulmonary and critical care physician at the Cleveland Clinic and a director of the non-cystic fibrosis bronchiectasis program, discussed the changing treatment landscape of severe airway disease, the clinical nuances of biologic selection, and how these advances are redefining what it means to achieve control in severe asthma and COPD.

"I think like wording is very important to patients for them to accept things. So I stopped using the word biologic because some people take that word and it's like I'm messing with their biology because I'm giving them biologic treatment. And I started [saying to] the patients I'm giving you targeted therapy. Like we gave you like the blanket therapy where you're getting the inhaled steroids. We suppressed on all inflammation and that's not enough. You're still having a lot of inflammation and we are going to use more targeted therapy so that we're blocking certain pathways that's [causing] your asthma. And I think the word targeted therapy has been more successful in my patients than using biologic," one participant said, advising on how to talk to patients about initiating biologic therapy.

Khabbaza and colleagues discussed barriers to precision therapy and guiding biomarkers, such as local lab practices, insurance requirements, and timing of tests. They concurred on using dupilumab as the preferred starting biologic due to its strong applicability, ease of home use, and strong efficacy; other biologics are chosen based on phenotype or coverage.

"[With targeted therapy] you're not just targeting their asthma. Most of these people have nasal polyps, they have allergic rhinitis, they have eczema. It's part of this prodrome. And then when you give them inhaled steroids, you're targeting their airways, but they're still suffering. And when they come back after targeted therapy, they come back and say, my eczema's much better. I don't have the itchy eyes and the crusting around my eyes anymore and I can breathe much better with my nose because a lot of these biologics are also been approved for nasal polyposis. It's a systemic disease and with these biologics, you're treating a systemic disease systemically versus locally with asthma inhalers," another participant said, stressing the multifaceted benefits of targeted therapy.

They also emphasized patient treatment goals that focus on reducing exacerbations, minimizing systemic steroid use, and improving daily quality of life. In general, they also praised the long-term safety and efficacy data seen in multiple extension studies. Lastly, they looked forward to a future of potentially ultra-long-acting drugs like depemokimab or combination therapies that can further personalize care.

FDA Approves Tezspire™ (Tezepelumab-ekko) in the U.S. for Severe Asthma. News release. Amgen. December 17, 2021. 

https://www.amgen.com/newsroom/press-releases/2021/12/fda-approves-tezspire-tezepelumabekko-in-the-us-for-severe-asthma

Dupixent® (dupilumab) Approved in the U.S. as the First-ever Biologic Medicine for Patients with COPD. Regeneron Pharmaceuticals, Inc. September 27, 2024. https://www.globenewswire.com/news-release/2024/09/27/2954552/0/en/Dupixent-dupilumab-Approved-in-the-U-S-as-the-First-ever-Biologic-Medicine-for-Patients-with-COPD.html.

Asthma and COPD management has evolved significantly, incorporating targeted biologic therapies that address specific inflammatory pathways. This shift has expanded treatment options beyond traditional inhaled corticosteroids and bronchodilators, improving outcomes for patients with severe airway diseases. Biologics like dupilumab, tezepelumab, benralizumab, and mepolizumab have redefined treatable asthma, reducing exacerbations and hospitalizations. Clinicians are focusing on early patient identification, biomarker integration, and overcoming logistical barriers. The multifaceted benefits of targeted therapies extend beyond asthma, addressing systemic conditions like nasal polyps and eczema, enhancing overall patient quality of life.

Experts explore the evolution of asthma and COPD treatments with targeted biologic therapies.

Redefining Severe Airway Disease Care: Clinicians Weigh In on Biologics and Barriers

The Medical Sisterhood: Leadership and Sisterhood in Dermatology, With Neda Shahriari, MD

, host Mona Shahriari, MD, assistant clinical professor of dermatology at the Yale University School of Medicine and associate director of clinical trials at Central Connecticut Dermatology Research, welcomes her real-life sister, Neda Shahriari, MD, dermatologist and associate physician at Brigham and Women’s Hospital and assistant professor of dermatology at Harvard Medical School. Together, the 2 leaders in the field offered an honest look at their parallel journeys in 

, the realities of balancing professional and personal life, and the importance of mentorship among women physicians.

The sisters begin by reflecting on their paths into medicine. Mona Shahriari knew early on that she wanted to become a doctor, while Neda Shahriari explored other healthcare fields before ultimately finding dermatology to be the ideal combination of visual learning, patient care, and immunologic science. Although she initially resisted following in her sister’s footsteps, Neda Shahriari eventually discovered that the specialty was the right fit on her own terms.

Their conversation moves into the challenges of navigating careers in medicine while raising young children. Both had their first children within days of each other, an experience that allowed them to share the unique physical, emotional, and logistical challenges of pregnancy, maternity leave, and returning to practice. They discuss how that shared experience provided a source of understanding and support, helping them manage demanding clinic schedules while maintaining their well-being and patient care standards.

Mona and Neda Shahriari also delve into the concept of mentorship—particularly the idea of sisterhood-based mentorship that emphasizes mutual support and growth over hierarchy. They highlight the value of building trusted, collaborative relationships where women can learn from one another through shared experiences. Neda Shahriari offers insights into forming these professional “chosen sisterhoods” early in residency or at conferences by connecting with mentors and peers who align with one’s values and goals.

The episode also includes lighter moments, with anecdotes about being mistaken for one another at meetings and the everyday advantages of having a sibling in the same specialty. Through humor and candid reflection, the 2 speakers shed light on the shared realities of women in dermatology while underscoring the value of professional connection, collaboration, and community in medicine.

Want to join The Medical Sisterhood community? Click here to join our LinkedIn Group!

Videos

In this episode, sisters and dermatologists Mona and Neda Shahriari discuss mentorship, motherhood, and the meaning of sisterhood in medicine.

ATTRibute-CM: Acoramidis Reduces Cardiovascular Mortality and Hospitalization with Ahmad Masri, MD

Acoramidis significantly reduced cumulative cardiovascular mortality (CVM) and recurrent cardiovascular-related hospitalization (CVH) over 30 months in patients with 

transthyretin amyloid cardiomyopathy (ATTR-CM)

, based on an exploratory analysis of ATTRibute-CM.

Heart Failure Society of America (HFSA) Annual Scientific Meeting 2025

 by Ahmad Masri, MD, director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University, this analysis also revealed surprisingly rapid changes in both endpoints, reaching significance after the first month.

 sat down with Masri to discuss the exploratory analysis, its findings, and the implications for treating the underserved ATTR-CM patient population.

“One important point that emerged – and these are all exploratory analyses – is the timing when you start to see those events accruing in the acoramidis arm versus placebo,” Masri told 

. “We usually think of this disease as needing some time to confer some benefit to patients on the drug. However, what we’ve seen here is that once you start acoramidis, within a few months, even as early as the first month, you start to accrue fewer events than placebo.”

ATTRibute-CM, a phase 3, double-blind clinical trial, saw investigators randomly assign patients with ATTR-CM in a 2:1 ratio to either acoramidis 800 mg twice daily or matching placebo. The trial lasted 30 months, with a 4-step primary hierarchical analysis endpoint consisting of all-cause mortality, CVH, change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and change from baseline in 6-minute walk distance.

Patients were eligible if they had an established diagnosis of ATTR-CM and clinical 

 with ≥1 previous hospitalization for heart failure, volume overload, or heart failure resulting in diuretic treatment. Patients also had to have a 6-minute walk distance of ≥150 m on ≥2 tests performed between 24 hours and 3 weeks apart, a level of NT-proBNP of ≥300 pg/mL, and a left ventricular wall thickness of ≥12 mm on a previous imaging study.

Ultimately, 632 patients underwent randomization, with 421 assigned to acoramidis and 211 to placebo. Mean age was 77 +/- 6.6 years, 90.2% of participants were men, and 90.3% of patients had wild-type TTR. Most patients also had either New York Heart Association class II (72%) or III (17.2%) symptoms.

Investigators found that acoramidis outperformed placebo by a win rate of 1.8 (95% CI, 1.4-2.2) based on the 4-step hierarchical analysis. CVM and CVH contributed over half of the wins and losses to the win ratio, while NT-proBNP pairwise comparisons showed the highest ratio of wins to losses.

Masri and colleagues’ exploratory analysis found that CVM and CV-related hospitalization occurred in 33.3% (136) of participants in the acoramidis arm versus 98 (48.5%) in the placebo group. Acoramidis also substantially reduced the risk of cumulative CVM or recurrent CVH compared to placebo (hazard ratio [HR], 0.51; 95% CI, 0.43-0.62; 

 <.0001). Masri and colleagues observed treatment effects beginning at Day 16, which continued to improve through month 30. Difference in mean cumulative events reached 53 per 100 participants (95% CI, 29-79; 

“I think this is the most important takeaway of what we have presented,” Masri said of the early cumulative event change. “Usually, there is no urgency on average for getting a diagnosis of transthyretin amyloidosis. People in general think of it as more of a chronic disease, and that 6 months’ delay is not going to make a huge difference for initiating therapy. I think this analysis actually challenges that.”

Editor's Note: Masri reports disclosures with Pfizer, Attralus, Eidos, Ionis, Cytokinetics, BioMarin, and others.

Masri A, Judge D, Ruberg F, et al. Effect of Acoramidis on Recurrent and Cumulative Cardiovascular Outcomes in ATTR-CM: Exploratory Analysis from ATTRibute-CM. Presented at the Heart Failure Society of America Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.

Razvi Y, Judge DP, Martinez-Naharro A, et al. Effect of Acoramidis on Myocardial Structure and Function in Transthyretin Amyloid Cardiomyopathy: Insights From the ATTRibute-CM Cardiac Magnetic Resonance (CMR) Substudy. Circ Heart Fail. 2024;17(12):e012135. 

An exploratory analysis of the ATTRibute-CM trial spotlighted acoramidis’s superior efficacy in lowering CVD-related risks versus placebo.

ATTRibute-CM: Acoramidis Reduces Cardiovascular Mortality and Hospitalization, With Ahmad Masri, MD

Data from the phase 3 APPEAR-C3G trial of iptacopan (Fabhalta) in patients with biopsy-confirmed C3 glomerulopathy (C3G) are providing further support for the oral alternative complement pathway inhibitor’s use in the ultra-rare, progressive kidney disease following its March 2025 US Food and Drug Administration approval for this indication.

 and showed a statistically significant and clinically meaningful proteinuria reduction at 6 months, along with stabilization of estimated glomerular filtration rate (eGFR) and reduction in C3 deposits, following treatment with iptacopan, which showed a rapid onset of action and sustained efficacy through 12 months.

“Current guideline recommendations for C3 glomerulopathy rely on supportive treatments—eg, blockade of the renin–angiotensin–aldosterone system with angiotensin-converting enzyme inhibitors or AT1-receptor blockers, with or without mycophenolic mofetil or corticosteroids,” David Kavanagh, MBChB, PhD, professor of complement therapeutics at the National Renal Complement Therapeutics Centre, and colleagues wrote.

 “However, evidence related to these supportive treatments is limited to small, retrospective observational studies and such treatments often come with considerable side-effects. Therefore, a concerted effort is required to develop a novel, targeted therapy for C3 glomerulopathy, to address the high unmet medical need for patients with this condition.”

Iptacopan’s initial FDA approval came in December 2023 for the treatment of adults with paroxysmal nocturnal hemoglobinuria and was followed by an August 2024 accelerated approval for proteinuria reduction in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression. The agent later received approval for the treatment of C3G on March 20, 2025, based on data from APPEAR-C3G, making it the first FDA-approved agent for the ultra-rare kidney disease.

A multicenter, randomized, double-blind, placebo-controlled, phase 3 study, APPEAR-C3G assessed the efficacy and safety of iptacopan versus placebo, both in addition to supportive care and immunosuppression. It enrolled adult participants 18–60 years of age with biopsy-confirmed C3 glomerulopathy from 35 hospitals or medical centers in 18 countries. For inclusion, patients were required to have reduced serum C3 concentration <77 mg/dL, defined as <0.85 × lower limit of the central laboratory normal range, at screening, urine protein–creatinine ratio (UPCR) of ≥ 1.0 g/g at day –75 and day –15 before randomization, eGFR of ≥ 30 mL/min per 1.73 m2 at screening and day –15, and vaccination against 

All eligible participants were randomly assigned in a 1:1 ratio via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both. In the iptacopan group, participants took 200 mg iptacopan orally twice daily for 6 months followed by open-label iptacopan at 200 mg twice daily for an additional 6 months. In the placebo group, participants took placebo orally twice daily for 6 months followed by open-label iptacopan 200 mg twice daily orally for an additional 6 months.

The primary endpoint was relative reduction in proteinuria measured by log-transformed ratio to baseline in UPCR sampled from a 24-h urine collection at 6 months.

Between July 2021, and February 2023, 132 participants were screened, of whom 74 (64% male; 69% White) were randomized to receive either iptacopan (n = 38) or placebo (n = 36). Investigators noted one participant in the placebo group discontinued treatment during the open-label period.

Results showed the 24-h UPCR percentage change relative to baseline at 6 months was –30.2% (95% CI, –42.8 to –14.8) in the iptacopan group and 7.6% (95% CI, –11.9 to 31.3) in the placebo group. In the iptacopan group, the geometric mean of 24-h UPCR was 3.33 g/g (95% CI, 2.79 to 3.97) at baseline and 2.17 g/g (95% CI, 1.62 to 2.91) at 6 months, whereas in the placebo group, this was 2.58 g/g (95% CI, 2.18 to 3.05) at baseline and 2.80 g/g (95% CI, 2.37 to 3.30) at 6 months.

Investigators noted the primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 35.1% (95% CI, 13.8 to 51.1; 

Regarding safety, 30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events compared with 24 (67%) of 36 participants in the placebo group, with most being mild or moderate severity. Of note, there were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections.

Serious adverse events were reported in 3 (8%) participants in the iptacopan group and 1 (3%) participant in the placebo group.

“The positive results presented here provide evidence that iptacopan targets the underlying cause of C3 glomerulopathy and has the potential to alter the course of this progressive disease and improve patient outcomes,” investigators concluded.

Kavanagh D, Bomback AS, Vivarelli M, et al. Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study. The Lancet. doi:

Campbell P. FDA Approves Oral Iptacopan (Fabhalta) as First C3 Glomerulopathy Therapy. HCPLive. March 20, 2025. Accessed October 15, 2025. 

Iptacopan (Fabhalta) has shown promising results in treating C3 glomerulopathy (C3G), an ultra-rare kidney disease, following its FDA approval in March 2025. The phase 3 APPEAR-C3G trial demonstrated significant proteinuria reduction, stabilization of eGFR, and decreased C3 deposits over 12 months. The trial involved 74 participants and confirmed iptacopan's efficacy and safety compared to placebo. The study highlighted the need for targeted therapies in C3G, as current treatments are limited and often have significant side effects. Iptacopan's approval marks a significant advancement in C3G management.

The phase 3 data reinforce iptacopan’s safety and efficacy in C3G and support its recent US Food and Drug Administration approval for this indication.

APPEAR-C3G: Iptacopan Shows Proteinuria Reduction, eGFR Benefits in C3G

A study showed the effectiveness and safety of CM326, a monoclonal antibody against thymic stromal lymphopoietin, in the treatment of 

chronic rhinosinusitis with nasal polyps (CRSwNP)

The findings also indicated that patients with baseline plasma thymic stromal lymphopoietin (TSLP) levels of 330 fg/mL or higher responded particularly well to treatment.

“To our best knowledge, this study pioneers the establishment of plasma TSLP as a predictor in anti-TSLP treatment, which needs to be further validated in an independent cohort,” wrote investigators from the department of otolaryngology at Beijing TongRen Hospital, Capital Medical University, in China.

The team, co-led by Mu Xian, MD, Feng Lan, PhD, Bing Yan, MD, PhD, and Shen Shen, sought to explore the therapeutic potential of blocking thymic stromal lymphopoietin (TSLP) in patients with CRSwNP. While current biologics target downstream cytokines such as IgE, IL-4, IL-5, and IL-13, inhibiting TSLP offers an upstream strategy that may broadly suppress type 2 inflammation.

 This approach is supported by findings in asthma, where the TSLP inhibitor tezepelumab effectively reduced exacerbations across different inflammatory profiles, suggesting potential benefits for other type 2–driven diseases like CRSwNP.

To assess the safety and efficacy of CM326, investigators conducted a phase 1b/2a randomized, double-blind, placebo-controlled trial involving 84 patients with CRSwNP.

 Primary endpoints included safety over the 64-week study and change from baseline in endoscopic bilateral endoscopic nasal polyp score in week 16 in patients with eosinophilic CRSwNP (ECRSwNP). Secondary endpoints included the change from baseline in nasal polyp score at week 16 in non-eosinophilic CRSwNP (nonECRwNP) and pharmacodynamic markers.

The sample had a median age of 43.5 years (range, 34.0 – 55), and 71.4% males. More than half of the participants had a history of nasal polyp surgery (56%) and a history of SCS use (61.9%).

The team randomized participants to receive CM326 220 mg (n = 40) or placebo (n = 20) every 2 weeks and CM326 220 mg (n = 20) or placebo (n = 4) every 4 weeks for 16 weeks.

 Afterward, all participants continued to receive CM326 220 mg for 36 weeks, followed by a 12-week follow-up. The analysis stratified patients based on baseline tissue eosinophil count.

CM326 displayed a favorable safety profile, with most treatment-emergent adverse events (TEAEs) mild or moderate. The most common TEAEs were COVID-19 and upper respiratory tract infection.

Serious TEAEs occurred in 3 patients during the open-label period: unilateral renal calculus and knee ligament injury (CM326 every 2 weeks), community-acquired pneumonia (CM326 every 4 weeks), and ureterolithiasis (CM326 every 4 weeks); 2 patients discontinued due to TEAEs—one for treatment-related allergic dermatitis and one for treatment-unrelated primary biliary cirrhosis. None of the patients developed detectable anti-drug antibodies during the study, suggesting that CM326 has low immunogenicity.

Participants on CM326 every 2 weeks had significantly improved nasal polyp score at week 16 compared to placebo (mean difference, -1.2; 95% confidence interval [CI], -2.3 to -0.1; 

=.04), with sustained benefits during the open-label and follow-up periods.

Participants also had reduced peripheral blood and tissue eosinophil counts and concentrations of plasma IL-13 and IL-5 by week 16 compared to placebo.

A post hoc analysis showed that all patients treated with CM326 who had baseline thymic stromal lymphopoietin levels above 330 fg/mL experienced a significant reduction in nasal polyp score by week 16 (mean difference, −1.75; 95% CI, −3.06 to −0.44;

 =.01). These findings suggest that a baseline plasma thymic stromal lymphopoietin level of 330 fg/mL may be a potential predictive marker of CM326 treatment efficacy.

Investigators noted several limitations, including a small sample size (84 patients) and no multiplicity adjustments, making all P values nominal.

 They also added that long-term use of mometasone furoate nasal spray during the open-label phase may have contributed to improvements in both groups. Investigators also noted that they recruited most participants from the Han population.

“Further studies with larger sample sizes are in preparation to investigate the safety and efficacy of CM326,” investigators wrote.

Xian M, Lan F, Yan B, et al. An anti-TSLP monoclonal antibody for uncontrolled CRSwNP: the DUBHE randomized clinical trial. 

. 2025;16(1):8607. Published 2025 Sep 29. doi:10.1038/s41467-025-63682-x

Ebina-Shibuya R, Leonard WJ. Role of thymic stromal lymphopoietin in allergy and beyond. 

. 2023;23(1):24-37. doi:10.1038/s41577-022-00735-y

Corren J, Parnes JR, Wang L, et al. Tezepelumab in Adults with Uncontrolled Asthma. 

. 2017;377(10):936-946. doi:10.1056/NEJMoa1704064

. 2022;82(4):461-468. doi:10.1007/s40265-022-01679-2

A study evaluated the efficacy and safety of CM326, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), in treating chronic rhinosinusitis with nasal polyps (CRSwNP). The trial demonstrated that patients with baseline plasma TSLP levels of 330 fg/mL or higher responded particularly well to CM326. The study involved a phase 1b/2a randomized, double-blind, placebo-controlled trial with 84 participants. CM326 showed a favorable safety profile, with most adverse events being mild or moderate. Further research with larger sample sizes is needed to validate these findings.

A phase 1b/2a study showed CM326 significantly improved nasal polyp scores; baseline plasma TSLP levels ≥ 330 fg/mL may predict treatment response.


Anti-TSLP Monoclonal Antibody CM326 Shows Efficacy and Safety in CRSwNP

TTVR Versus T-TEER in Treating Tricuspid Regurgitation With Stephen Little, MD

Tricuspid Transcatheter Edge-to-Edge Repair (T-TEER) and Transcatheter Tricuspid Valve Replacement (TTVR), 2 new therapies for reducing 

, have emerged as safe and effective methods of managing this significant predictor of mortality and morbidity in patients with 

TTVR involves inserting an anchoring mechanism via the transfemoral or transjugular venous access, which attaches the delivery system to the mitral valve. The attached catheter then carries a compressed replacement tricuspid valve into the heart. TTVR is typically reserved for elderly patients with severe tricuspid valve disease who are considered poor candidates for open-heart surgery.

T-TEER is a similar procedure, although the catheter is inserted through the femoral vein. Unlike the plethora of devices applicable in TTVR, T-TEER specifically uses the TriClip, a mechanism with 2 arms to capture and lock valve leaflets. Initially designed as the MitraClip by Abbott, it was adapted to TR treatment, leading the company to develop the TriClip specifically for TR.

 Annual Echocardiography and Structural Heart Symposium in Coral Gables, Florida, Stephen Little, MD, a cardiologist with Houston Methodist DeBakey Heart & Vascular Center and program director of the Cardiovascular Fellowship, discussed the differences between the 2 treatments, when each can be implemented, and how clinicians can manage patients’ – and their own – expectations given the promising nature of these new procedures.

 sat down with Little to discuss the implications presented by T-TEER and TTVR for patients with various cardiovascular impairments and diseases, as well as the practical guidelines and limitations for diagnosing patients with TR and choosing the correct therapy.

Little noted the wide anatomic spectrum which determines how patients with TR can be treated and the risks and limitations included with both procedures.

“At 1 end of the spectrum, a T-TEER makes perfect sense; at the other end of the spectrum, T-TEER is just impossible,” Little told 

. “And then you have therapies like TTVR valve implantation. So the first real discussion point is, does the anatomy allow both procedures? And often it doesn’t.”

Despite successful trials and the effectiveness of the treatment, both T-TEER and TTVR have notable limitations. First, both are approved only for a disease that is notoriously difficult to diagnose, as well as being commonly known as a “forgotten disease” due to a significant lack of treatment innovation. Additionally, patients must have suitable anatomy and sufficient imaging quality via transesophageal echocardiography.

Little explained the struggle of diagnosing TR, given its shared symptoms with a variety of other diseases – and with simply aging.

“What defines a symptom for TR? In some people, it’s a manifestation of liver dysfunction which is their first sign, and in some people it’s just a little bit of fatigue,” Little told 

. “But, as the saying goes, you only grow old once, so you don’t have something to compare it to. So, is your fatigue because you’ve had 70 birthdays, or because you have TR? And these aren’t easy things to resolve.”

Little S. TTVR vs. T-TEER: Balancing Excitement with Practicality for the General Cardiologist. Presented at the 42nd Annual Echocardiography and Structural Heart Symposium. Coral Gables, Florida. September 26-27, 2025.

Hausleiter J, Stolz L, Lurz P, et al. Transcatheter Tricuspid Valve Replacement. J Am Coll Cardiol. 2025;85(3):265-291. 

Hao Q, Horton J; Authors. Transcatheter Edge-To-Edge Valve Repair for Tricuspid Regurgitation: CADTH Health Technology Review [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Aug. Available from: 

https://www.ncbi.nlm.nih.gov/books/NBK596754/

Little discusses 2 recently emerged therapies for TR, spotlighting the benefits and limitations associated with each procedure.

A new study found that soft drinks may contribute to 

 through gut microbiota alterations involving 

“While some studies link artificially sweetened beverages to increased depression risk, our data did not show a specific effect on depressive symptoms, likely due to insufficient detail in data collection, warranting further investigation,” study investigator Sharmili Edwin Thanarajah, MD, from the department of psychiatry at University Hospital Frankfurt–Goethe University in Germany, and colleagues wrote.

Already, research has demonstrated the link between soft drink consumption and negative mental health outcomes. One study reported that women who regularly consume soft drinks are 34% more likely to develop major depressive disorder (MDD) after 4 years.

 However, researchers had yet to fully understand how soft drink consumption relates to MDD or the mechanisms driving this link.

Investigators conducted a multicenter cohort study to examine whether drinking soft drinks was associated with MDD diagnosis and severity.

 The team also sought to assess whether changes in the gut microbiota, particularly 

 abundance, mediated this association. Soft drinks often include additives such as artificial sweeteners (e.g., aspartame, saccharin) and preservatives (e.g., benzoates, sorbates), which may disturb the gut microbiota balance.

This study used cross-sectional data from the Marburg-Münster Affective Cohort, which had recruited patients with MDD (n = 405; 67.9% females; mean age, 36.37 years) and healthy controls (n = 527; 65.5% females, mean age, 35.33 years) aged 18 – 65 years from the general population and primary care settings between September 2014 and September 2018. Data analyses occurred between May and December 2024.

Primary analyses used multivariable regression and analysis of variance models to assess associations between soft drink consumption and MDD diagnosis or symptom severity, adjusting for site and education. Additional models examined the relationship between MDD and 

 abundance, adjusting for site, education, and library size. Mediation analyses evaluated whether microbiota abundance mediated the association between soft drink intake and MDD.

The study found that soft drink consumption predicted MDD diagnosis (odds ratio [OR], 1.081; 95% confidence interval [CI], 1.008 – 1.159; 

 =.03) and symptom severity (partial η2 [ηp2], 0.012; 95% CI, 0.004 – 0.035; 

 <.001). These findings had even stronger effects in women (diagnosis: OR, 1.167; 95% CI, 1.054 – 1.292,

 =.003; severity: ηp2, 0.036; 95% CI, 0.011 – 0.062; 

Among women, soft drink consumption was associated with increased 

 =.007; ηp2, 0.017; 95% CI, 0.0002 – 0.068) but not 

abundance. The mediation analyses further confirmed that Eggerthella significantly mediated the association between soft drinks and MDD (diagnosis: 

Investigators noted that, despite the small effect sizes, the link between soft drink consumption, 

 abundance, and depression may have clinical implications.

“Given the complex interaction between diet and mental health, it is not surprising that the effect of soft drinks on MDD diagnosis and depressive symptoms is rather small,” investigators wrote.

 “However, it is important to highlight that this is a widely distributed but fully avoidable risk factor.”

Investigators added that incorporating dietary assessments and nutritional counseling into depression prevention and management may help address modifiable lifestyle factors, including soft drink consumption.

A recent study explored the link between soft drink consumption and major depressive disorder (MDD), focusing on gut microbiota alterations, particularly Eggerthella. The research found that soft drink intake predicted MDD diagnosis and symptom severity, with stronger effects observed in women. Mediation analyses confirmed Eggerthella's role in this association. Despite small effect sizes, the findings suggest clinical implications and highlight the importance of dietary assessments in depression management. Public health policies, such as beverage taxation and marketing restrictions, are recommended to reduce soft drink consumption and address modifiable lifestyle factors.

New research links soft drink consumption to depression, revealing gut microbiota changes as a potential mediator, particularly in women.

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