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GRI-0621, an oral retinoic acid receptor beta/gamma (RARβ/γ)-selective agonist, produced a placebo-adjusted increase in forced vital capacity (FVC) and reduced markers of fibrotic remodeling in patients with 

, according to phase 2a data presented at the 

European Respiratory Society (ERS) Congress 2026

 in Barcelona, Spain, held September 5 to 9.

IPF is driven by epithelial injury, immune dysregulation, and excess extracellular matrix, and approved antifibrotics slow disease decline but do not restore lung architecture, according to the study investigators.

 GRI-0621-IPF-02 (NCT06331624) is a phase 2a, randomized, double-blind, placebo-controlled trial evaluating GRI-0621, a molecule from GRI Bio also known generically as tazarotene.

“The breadth of data being presented at ERS marks an important step forward for GRI-0621 and our understanding of its potential in IPF,” said Marc Hertz, PhD, chief executive officer of GRI Bio.

 “We believe these findings provide a compelling foundation for the continued advancement of GRI-0621 and reinforce our conviction in its potential to meaningfully impact the treatment landscape for patients with IPF.”

GRI-0621 improves FVC in the GRI-0621-IPF-02 trial

GRI-0621-IPF-02 randomized 35 patients with IPF in a 2:1 ratio to oral GRI-0621 4.5 mg once daily (n = 23) or placebo (n = 12) for 12 weeks, with 80% of patients receiving background pirfenidone or nintedanib.

 Endpoints included adverse events, RNA sequencing, serum collagen and injury biomarkers, flow cytometry immune phenotyping, and FVC.

 Findings from the trial were presented across a late-breaking oral presentation and 3 posters covering lung function, translational biomarkers, and safety.

Placebo-adjusted FVC change was +99 mL overall and +139 mL among patients also receiving background antifibrotic therapy.

 The proportion of patients with no FVC decline rose to 39% with GRI-0621 versus 20% with placebo, while the proportion with a decline of 10% or more fell to 8% versus 20% with placebo.

 A pre-specified per-protocol analysis showed a similar placebo-adjusted FVC benefit, surpassing the estimated 30 to 40 mL of natural-history decline expected over 12 weeks, according to the poster.

GRI-0621 reduces fibrotic biomarkers with favorable tolerability

GRI-0621, known generically as tazarotene, is an oral retinoic acid receptor beta/gamma (RARβ/γ)-selective agonist from GRI Bio being developed for idiopathic pulmonary fibrosis (IPF).

Did GRI-0621 improve lung function in the phase 2a trial?

Placebo-adjusted FVC change was +99 mL overall and +139 mL with background antifibrotic therapy, and fewer patients on GRI-0621 had a significant FVC decline compared with placebo.

Yes. The most common adverse events were mild dry lips, dry skin, and musculoskeletal symptoms, and patients on GRI-0621 reported less cough, dyspnea, and diarrhea than those on placebo.

Biomarker analyses showed GRI-0621 reduced type III and VI collagen formation while increasing collagen degradation, increased type IV collagen formation, and lowered neutrophil, macrophage, and pro-fibrotic T-helper 2 (Th2) cell activity relative to placebo.

 Whole-blood RNA sequencing identified concordant transcriptional changes across curated anchor genes linked to fibrosis, epithelial injury, and tissue repair pathways, according to the poster.

GRI-0621 was well tolerated; the most common adverse events were mild dry lips (30%), dry skin (22%), and musculoskeletal symptoms (13%).

 Patients treated with GRI-0621 reported less cough (0% versus 25% with placebo), dyspnea (4% versus 17%), and diarrhea (13% versus 33%), with no cases of weight loss compared with 17% among patients receiving placebo.

 Investigators noted these tolerability findings held despite most patients continuing background pirfenidone or nintedanib, both of which carry their own gastrointestinal and dermatologic adverse effects.

Investigators said the convergent molecular, biomarker, immune, and functional signals support larger, adequately powered trials of GRI-0621 in IPF.

 GRI-0621, known generically as tazarotene, received FDA orphan drug designation for IPF in June 2026, potentially providing a pathway to 7 years of US market exclusivity upon approval.

 The oral presentation and posters were delivered by investigators from University College London, University Hospitals Birmingham, Edinburgh, Cambridge, and other UK and international sites collaborating with GRI Bio.

Parfrey H, Porter J, Saunders P, et al. Safety, translational biomarkers and lung function with the oral RARβ/γ-selective agonist GRI-0621 in idiopathic pulmonary fibrosis: a Phase 2a randomised, double-blind, placebo-controlled trial (GRI-0621-IPF-02). Abstract OA2380/63931. Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.

GRI Bio, Inc. GRI Bio to present late-breaking Phase 2a GRI-0621 data highlighting lung function, anti-fibrotic biomarkers and favorable tolerability in IPF at ERS 2026. Published August 24, 2026. Accessed September 6, 2026. 

https://www.globenewswire.com/news-release/2026/08/24/3349779/0/en/gri-bio-to-present-late-breaking-phase-2a-gri-0621-data-highlighting-lung-function-anti-fibrotic-biomarkers-and-favorable-tolerability-in-ipf-at-ers-2026.html

GRI Bio, Inc. GRI Bio secures FDA orphan drug designation for GRI-0621 (tazarotene) in idiopathic pulmonary fibrosis. Published June 18, 2026. Accessed September 6, 2026. 

https://www.globenewswire.com/news-release/2026/06/18/3314182/0/en/gri-bio-secures-fda-orphan-drug-designation-for-gri-0621-tazarotene-in-idiopathic-pulmonary-fibrosis.html

Articles

An oral RARβ/γ-selective agonist (GRI-0621; tazarotene) showed efficacy signals in idiopathic pulmonary fibrosis in a 12‑week randomized phase 2a trial. Among 35 patients, 80% on pirfenidone or nintedanib, placebo-adjusted FVC improved 99 mL overall and 139 mL with background antifibrotics, with fewer ≥10% declines. Biomarkers indicated reduced type III/VI collagen formation, increased degradation, and lower neutrophil/macrophage and Th2 activity with aligned RNA changes. FDA orphan designation (June 2026) supports larger trials. Respiratory symptoms and gastrointestinal AEs occurred less frequently than with placebo. Mild mucocutaneous events predominated.

The oral RARβ/γ agonist improved FVC and reduced fibrotic biomarkers over 12 weeks in a phase 2a trial presented at the ERS Congress 2026.

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GRI-0621 Improves FVC, Reduces Fibrotic Biomarkers in IPF

A polygenic risk score for chronic obstructive pulmonary disease (

) was associated with reduced lung function growth from infancy to age 6, but only among children exposed to high levels of air pollution, according to data presented at the 

Applying adult-derived COPD polygenic risk scores (PRS) in childhood may help elucidate early-life risk factors influencing lung function growth, according to the study investigators.

 Researchers led by Carla da Silva Sena, MD, of University Children's Hospital Basel UKBB and Bern University Hospital, analyzed longitudinal lung function data from 484 children enrolled in the Basel-Bern Infant Lung Development (BILD) cohort, an ongoing Swiss birth cohort study following children born between 1999 and 2020.

“COPD develops through a combination of genetic factors and environmental exposures across the lifespan, leading to an accelerated decline in lung function,” said da Silva Sena, who presented the findings.

 “Studying these trajectories from the earliest stages of life is key to understanding how COPD develops.”

What were lung function trajectories and polygenic risk in the BILD cohort?

Investigators assessed lung function using the infant tidal breathing test (tPTEF/tE) in the first month of life and spirometry (FEV1, FVC) at age 6, converting results to comparable z-scores.

 A COPD PRS derived from adult genome-wide association studies was calculated from blood samples, and outdoor exposure to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) was estimated from birth to age 6. Associations between PRS and lung function trajectories were modeled using linear mixed-effects models with a PRS-by-time interaction term, stratified by the highest versus lower tertiles of PM2.5 and NO2 exposure.

In stratified analysis, a 1-SD increase in COPD PRS was associated with a decrease in tPTEF/tE-FEV1 z-score over time among children in the highest PM2.5 tertile (β = -0.47; 95% CI, -0.80 to -0.14; n = 140) and the highest NO2 tertile (β = -0.61; 95% CI, -0.99 to -0.24; n = 148).

 No significant association was observed among children in the lower exposure tertiles (β = -0.15; 95% CI, -0.37 to 0.07; n = 344).

How does air pollution act as an effect modifier?

A similar pattern was observed for tPTEF/tE-FVC z-score, but only in the highest NO2 tertile (β = -0.66; 95% CI, -1.11 to -0.22; n = 108).

 The high-exposure PM2.5 tertile averaged 15.3 μg/m³, and the high-exposure NO2 tertile averaged 28.3 μg/m³, according to the study investigators.

 The pattern suggests a gene-environment interaction, in which genetic susceptibility to reduced lung growth becomes apparent only under sufficient pollution exposure.

Does genetic risk for COPD affect lung function in children?

A COPD polygenic risk score was associated with reduced lung function growth between infancy and age 6, but only among children exposed to high levels of air pollution.

Which pollutants were linked to the effect?

The association was seen with high exposure to fine particulate matter (PM2.5, averaging 15.3 μg/m³) and nitrogen dioxide (NO2, averaging 28.3 μg/m³) from birth to age 6.

What are the limitations of this research?

Infant and school-age lung function were measured using different tests requiring statistical harmonization, and the polygenic risk score was developed in populations of European ancestry, so findings may not generalize to other populations.

Investigators noted 2 limitations: infant and school-age lung function were assessed using different tests, requiring statistical harmonization for longitudinal comparison, and the PRS was developed using populations of European ancestry, so findings may not directly apply to children from other backgrounds.

 The prospective cohort design allowed researchers to link genetic risk, air pollution exposure, and lung function measured before children displayed respiratory symptoms.

“This shows how genes and environment in the early years can combine to set children on a path to lung disease much later in life,” said Barbara Hoffmann, MD, chair of the ERS Advocacy Council at the University of Dusseldorf, who was not involved in the research.

 “It may help explain why COPD can also occur in non-smokers.”

Hoffmann said the findings align with a 2022 Lancet Commission report describing COPD as shaped by risk pathways across the lifespan rather than by adult smoking alone.

 Researchers plan to follow the BILD cohort into adolescence and adulthood to determine whether the early lung function differences persist or widen over time.

da Silva Sena CR, Gorlanova O, Gwerder M, et al. Early-life lung function trajectories are associated with COPD polygenic risk score only in the presence of high air pollution exposure from infancy to school age. Abstract 6810. Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.

European Respiratory Society. Origins of COPD may lie in how some children's lungs develop, but only when they are exposed to polluted air. Published September 6, 2026. Accessed September 6, 2026. 

https://www.ersnet.org/news-and-features/news/origins-of-copd-may-lie-in-how-some-childrens-lungs-develop-but-only-when-they-are-exposed-to-polluted-air/

Adult-derived COPD polygenic risk scores were linked to impaired lung function growth from infancy to age 6 only under higher early-life air pollution exposure. In the Swiss BILD birth cohort (n=484), lung function was harmonized across infant tidal breathing metrics and age-6 spirometry into z-score trajectories. A 1-SD higher PRS predicted steeper declines in tPTEF/tE-to-FEV1 and, for NO2, tPTEF/tE-to-FVC trajectories among children in the highest PM2.5 or NO2 tertiles, supporting gene–environment interaction.

A COPD genetic risk score was linked to reduced lung function growth from birth to age 6, but only in children with high air pollution exposure.

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Childhood Pollution Exposure May Trigger COPD Polygenic Risk

Kyle Hogarth, MD, professor of medicine and medical director of the Pulmonary Rehabilitation Program and director of the Alpha-1 Antitrypsin Deficiency Clinical Resource Center at University of Chicago Medicine. 

my entire life, I was naturally drawn toward pulmonology as a specialty when I decided to become a doctor.

This fate was sealed during my medical school interviews, when I sat in on one specific lecture. I was enthralled by how the speaker explained the complex physiology of the lungs with such elegant simplicity. Later, when I learned about alpha-1 antitrypsin deficiency (alpha-1), it felt like the ultimate intersection of my fascination with genetics and my personal connection to pulmonary medicine.

Fast forward to when I was out of medical school, and early in my career as a pulmonologist, a colleague challenged me. His question was simple and straightforward: “What do you know about Alpha-1?”

I gave him the standard, technical answer: “Alpha-1 is a genetic condition that increases a person’s risk of obstructive lung disease and sometimes liver disease. Although it is thought to be a relatively common genetic condition, it is frequently underdiagnosed.”

He recognized that I was giving a textbook response and pushed back, asking, “Have you actually read the guidelines?” I had not.

That brief, albeit somewhat humbling, conversation shifted something in me. I went back, read the guidelines, and began changing how I approached my patients.

That experience proved that a good challenge could change the course of a career. Now, my goal is to pass that challenge onto my peers.

The truth is, there are far too many people living with obstructive lung disease, including COPD, emphysema, and chronic obstructive asthma, who have never been tested for Alpha-1. To my fellow physicians, I urge you to start thinking “inside the box”—specifically, by checking a box in your patients’ EMR to include Alpha-1 testing. This simple action can make a world of difference in uncovering this under-recognized disorder.

There is no secret, special clinical gift to diagnosing Alpha-1. It simply requires following the guidelines to ensure your diagnostic workup includes Alpha-1 testing. I continue to be astounded by the number of times this simple box is skipped over.

Guidelines call for Alpha-1 testing in all patients with COPD, emphysema, and chronic obstructive asthma

Common but frequently underdiagnosed genetic condition

Classic profile (< 45 years old, severe emphysema) misses many cases

Documented across all races and ethnicities, not just northern European descent

Lost lung function cannot be recovered, making early testing critical

As physicians, it can sometimes be easy to fall into clinical complacency. We tell ourselves, “Alpha-1 is too rare to warrant a test.” But the guidelines are clear: every patient diagnosed with COPD, emphysema, and chronic obstructed asthma should be tested for Alpha-1.

Consider the steps we already take to come to a diagnosis of an obstructive lung disease. Adding Alpha-1 testing is not a huge lift; it is simply completing the workup we started. And Alpha-1 testing is widely available, including sponsored testing at no charge. We are already drawing blood to check other labs as part of this workup. Why not check 1 more box and include Alpha-1 testing?

One major roadblock to diagnosing Alpha-1 is the archetype of the patient. The classical 

 described in the literature is young, less than 45 years old, with severe emphysema.

While those patients do exist, Alpha-1 can have varied presentations. If you only test patients who fit that narrow profile, you will miss others with the condition.

We also must dispel the notion that we should only test patients we intend to treat. Some physicians may think, “Why test if they aren’t severe enough to treat with augmentation therapy?”

The answer lies in preventative care and lifestyle modifications. When patients learn they carry a genetic risk factor for lung disease, they often make decisions to proactively protect their lungs, such as avoiding environmental pollution or quitting smoking.

Additionally, we must also disregard the old-school myth that Alpha-1 affects mainly people with northern European descent.

 While historically described in those populations, Alpha-1 has been documented across every race and ethnicity. If your patient has obstructive lung disease, they need to be tested, regardless of race or background.

We must find these patients early because of a simple reality: loss of lung function is irreversible.

We all lose lung function as we get older—it’s a natural part of the aging process.

But in Alpha-1 patients, the loss is potentially accelerated.

Let’s look closer at the cellular level. The primary role of the protein alpha-1 antitrypsin (AAT) is to inhibit neutrophil elastase, an enzyme that degrades elastin in the lung’s alveolar walls.

When a patient has Alpha-1, this enzyme goes unchecked. Think of it as a town overrun by fires with not enough firefighters to put out the flames.

When I diagnose patients who have dramatically declined lung function, I can support them, but I cannot give them back what they lost. We need to shift the timeline. We must find these patients 

while they still have most of their lung function intact

so we can step in and prevent more flames from forming for as long as possible.

Our therapeutic goal for Alpha-1 patients with obstructive lung disease is to help protect the lungs.

For decades, weekly augmentation therapy, intended to raise AAT levels in the lungs and bloodstream, has been the standard of care for these patients.

Historically, we have aimed for a putative target of maintaining serum AAT levels above a threshold of 11 µM, a benchmark long thought to be the minimal serum protein level before the risk of lung disease sets in.

 However, this threshold has been increasingly questioned and is potentially due for a reevaluation.

 Other research has shown that risk of potential lung damage may increase when patients’ AAT serum levels fall below the range of approximately 20–53 µM, with the degree of that risk dependent on other factors like genotype or exposure.

I began with a story of being challenged earlier in my career, so it is only fitting to close with a challenge of my own.

I recently gave a talk on Alpha-1, and a fellow physician pushed back on the lack of data regarding therapy in the space, explaining he doesn’t often test patients for Alpha-1 because of this lack of data. My response was straightforward: “We’re never going to get the data you’re looking for if doctors aren’t testing.”

I worried I had been too blunt, but it turns out the message hit its mark. He has started routinely testing his patients for Alpha-1. For me, that is a mission accomplished.

If we want better data, better trials, and better treatments, we have to start by checking the box. Test your patients for Alpha-1.

Hogarth was compensated by Sanofi for his time on this article.

Alpha-1 antitrypsin deficiency. MedlinePlus. 

https://medlineplus.gov/genetics/condition/alpha-1-antitrypsin-deficiency/

Alpha-1 Antitrypsin Deficiency: Answers to 5 Frequently Asked Questions. American Lung Association. Published August 14, 2023. Accessed September 3, 2026. 

https://www.lung.org/blog/alpha-1-deficiency-faqs

American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency, 

American Journal of Respiratory and Critical Care Medicine

, Volume 168, Issue 7, October 2003, Pages 818–900, 

Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. 

http://doi.org/10.15326/jcopdf.3.3.2015.0182

2026 GOLD Report and Pocket Guide. Global Initiative for Chronic Obstructive Lung Disease. Accessed September 3, 2026. 

https://goldcopd.org/2026-gold-report-and-pocket-guide/

Barjaktarevic I, Campos M. Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know. 

. 2021;12_suppl:20406223211010172. Published 2021 Jul 29. 

Frederick J de Serres; Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed.. 

 1 December 2003; 111 (16): 1851–1854. 

Lung Capacity and Aging. American Lung Association. Accessed September 3, 2026. 

https://www.lung.org/lung-health-diseases/how-lungs-work/lung-capacity-and-aging

Stockley RA, Edgar RG, Pillai A, Turner AM. Individualized lung function trends in alpha-1-antitrypsin deficiency: a need for patience in order to provide patient centered management?. 

. 2016;11:1745-1756. Published 2016 Aug 1. 

Xiang S, Yang L, He Y, et al. Alpha-1 Antitrypsin as a Regulatory Protease Inhibitor Modulating Inflammation and Shaping the Tumor Microenvironment in Cancer. 

Treating and Managing Alpha-1 Antitrypsin Deficiency. American Lung Association. Accessed September 3, 2026. 

https://www.lung.org/lung-health-diseases/lung-disease-lookup/alpha-1-antitrypsin-deficiency/treating-and-managing

Wells AD, Woods A, Hilleman DE, Malesker MA. Alpha-1 Antitrypsin Replacement in Patients With COPD. 

Franciosi AN, Fraughen D, Carroll TP, McElvaney NG. Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold. 

. 2022;59(2):2101410. Published 2022 Feb 10. 

Mulkareddy V, Roman J. Pulmonary manifestations of alpha 1 antitrypsin deficiency. 

Alpha-1 antitrypsin deficiency remains underrecognized in obstructive lung disease despite clear guideline recommendations for universal testing in COPD, emphysema, and chronic obstructive asthma. Routine EMR-enabled testing can overcome clinical inertia, broaden detection beyond the “young severe emphysema” stereotype, and address misconceptions about treatment candidacy and ancestry. Early identification matters because alveolar destruction from unopposed neutrophil elastase is irreversible and may be accelerated. Augmentation therapy remains foundational, while the traditional 11 µM protective threshold is increasingly debated.

Kyle Hogarth, MD, urges physicians to complete Alpha-1 testing during every COPD or asthma workup, warning that skipped tests delay diagnosis.

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Why Doctors Need to Complete the COPD or Asthma Workup to Rule Out Alpha-1

Pacibekitug outperformed placebo in reducing hs-CRP, Lp(a), and other inflammatory biomarkers in patients with 

 during the TRANQUILITY trial; however, without being powered for 

, the question of this drug’s efficacy in risk reduction still remains.

Next Steps for Pacibekitug Following Positive TRANQUILITY Results

The data from TRANQUILITY were presented at the 

European Society of Cardiology (ESC) Congress 2026

 in Munich, Germany, by Deepak Bhatt, MD, MPH, MBA, director of Mount Sinai Fuster Heart Hospital and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai. In an exclusive interview, 

 breaks down the results and investigators’ plans for a phase 3 trial of pacibekitug for cardiovascular events.

“This trial was meant to be a proof of principle, that the drug does what it’s supposed to – safely lowering hs-CRP in the context of a modest-size phase 2 trial,” Bhatt told 

. “For the phase 3 trial planning, we were really never considering CKD because that’s a tough population. Things that have worked in other non-CKD populations for cardiovascular risk reduction haven’t always worked in advanced kidney disease.”

TRANQUILITY, a randomized, double-blind, placebo-controlled study evaluating pacibekitug administered quarterly and monthly to patients with CKD and elevated hs-CRP, enrolled patients with a serum hs-CRP level ≥2.0 mg/L and <15 mg/L and a diagnosis of CKD, among other criteria. These patients were randomly assigned in a 1:1:1:1 ratio to either pacibekitug 25 mg or 50 mg every 90 days, 15 mg every 30 days, or placebo.

The primary endpoint was time-averaged percent change from baseline in hs-CRP by day 90. Secondary endpoints included time-averaged percent change in hs-CRP through day 180, the proportion of patients with time-averaged hs-CRP <2 mg/L at 90 days, and the safety and tolerability of pacibekitug.

A total of 143 patients were enrolled, of whom 72% were receiving statins and 59% had diabetes. Bhatt and colleagues noted dose-dependent reductions in hs-CRP by day 30, which were sustained through 180 days. The median time-averaged change was -76% with pacibekitug 25 mg, -85% with 50 mg, and -89% with 15 mg, compared to +7% with placebo. Fibrinogen and Lp(a) also saw sustained reductions in the pacibekitug arms, and no dose-related safety signals were recorded.

However, the trial itself was not powered to detect cardiovascular outcome improvements. Given the additional reductions in Lp(a), coupled with inflammation’s direct influence on cardiovascular disease risk, Bhatt believes that further data from ongoing trials will determine whether these targets are associated with cardiovascular benefit. On the other hand, inflammation is a notoriously narrow window to target – past trials, including CANTOS and ZEUS, have indicated the risk of increased fatal infection if inflammation is too significantly reduced and the lack of cardiovascular benefit if the effect is too small.

“The inflammation story is ongoing,” Bhatt said. “There are a number of trials in different therapeutic areas, and lots of different companies planning trials with various anti-inflammatory agents, phase 2 trials, phase 3 trials, ongoing in the planning stages. We’ll see whether that is also an independent axis of risk reduction. But for now, Lp(a) reduction, hs-CRP reduction, and a broader reduction of arterial inflammation all seem like promising approaches to study.”

Editor’s Note: Bhatt reports disclosures with GSK, Merck, Cereno Scientific, Angiowave, Boehringer Ingelheim, Novo Nordisk, and others.

Bhatt D. TRANQUILITY: Efficacy of monthly and quarterly dosing of pacibekitug (IL-6 ligand mAb) targeting inflammation in CKD with high cardiovascular risk. Presented at the European Society of Cardiology (ESC) Congress 2026, Munich, Germany. August 28-31, 2026.

Tourmaline Bio. A Study to Evaluate TOUR006 in Patients With Chronic Kidney Disease and Elevated Hs-CRP (TRANQUILITY). ClinicalTrials.gov Identifier: NCT06362759. Updated August 11, 2026. Accessed September 4, 2026. 

https://clinicaltrials.gov/study/NCT06362759

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Deepak Bhatt, MD, MPH, MBA, discusses the next steps for pacibekitug in cardiovascular disease following its success in the phase 2 trial.

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The phase 3 Lp(a)HORIZON trial evaluating pelacarsen did not meet its primary endpoint of reducing major adverse 

 events in patients with elevated lipoprotein(a) [Lp(a)] and established cardiovascular disease (CVD), Novartis announced on September 4, 2026.

Pelacarsen, a GalNAc-conjugated antisense oligonucleotide designed to suppress hepatic Lp(a) production at its source, was evaluated in a phase 2, randomized, double-blind, placebo-controlled, dose-ranging trial published in the New England Journal of Medicine in 2020, which enrolled 286 patients with established cardiovascular disease and screening Lp(a) levels of at least 60 mg/dL. The phase 2 trial demonstrated dose-dependent Lp(a) reductions of up to 80% with the 20-mg weekly dose, with injection-site reactions as the most common adverse event, supporting advancement into the phase 3 outcomes trial.

Did pelacarsen meet its primary endpoint in Lp(a)HORIZON?


No. Despite achieving lower Lp(a) levels than placebo, pelacarsen did not significantly reduce the composite cardiovascular endpoint in the overall study population.

What is pelacarsen's mechanism of action?


Pelacarsen is a GalNAc-conjugated antisense oligonucleotide that suppresses hepatic Lp(a) production, previously demonstrating up to 80% Lp(a) reduction in phase 2 dose-finding studies.

“Lp(a)HORIZON was a pioneering cardiovascular outcomes trial designed to answer one of the most important unanswered questions in cardiovascular medicine by evaluating whether lowering Lp(a) can reduce residual cardiovascular risk beyond optimized, guideline-directed care, when other major cardiovascular risk factors are already being managed,” said Shreeram Aradhye, MD, president of development and chief medical officer, Novartis.

Lp(a)HORIZON trial design and topline results

Lp(a)HORIZON (NCT04023552) is a phase 3, randomized, placebo-controlled, double-blind, multicenter global cardiovascular outcomes trial enrolling 8323 patients with elevated Lp(a) and established CVD

. The primary endpoint is a composite 4-point major adverse cardiovascular events (MACE) outcome, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization requiring hospitalization, evaluated in the overall population (Lp[a] ≥70 mg/dL) and a subpopulation (Lp[a] ≥90 mg/dL). Participants received guideline-directed treatments including lipid-lowering and antihypertensive therapies throughout the trial.

According to the company, pelacarsen achieved lower Lp(a) levels compared with placebo, but this reduction did not translate into a significant decrease in the composite cardiovascular endpoint in the overall study population. Full trial data have not yet been released and are planned for presentation at an upcoming medical congress.

Implications for the Lp(a)-lowering treatment landscape

“Although lower Lp(a) levels were observed with pelacarsen, the findings did not demonstrate this translated into reduced cardiovascular risk in the overall study population,” said Aradhye.

 “These are not the results we hoped for, but they provide important evidence that advances scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes and may help inform future approaches to cardiovascular risk management.”

The topline miss arrives as several other Lp(a)-lowering nucleic acid therapies remain in ongoing phase 3 trials. 

Investigators presenting phase 2 ALPACA data on lepodisiran, an extended-duration small interfering RNA (siRNA) targeting Lp(a), at ESC Congress 2026 reported reductions in Lp(a)-bound oxidized phospholipids of up to 94% at the highest studied dose, though they emphasized this biomarker effect does not itself establish clinical benefit.

 Zerlasiran, another siRNA in phase 2 development, has similarly demonstrated substantial Lp(a) reductions sustained through 48 weeks.

Novartis did not indicate whether the Lp(a)HORIZON result will affect the regulatory pathway for pelacarsen or the design of ongoing phase 3 substudies, including trials in Black, African American, and Hispanic populations and in patients with recent acute coronary syndrome.

Novartis reported that the phase 3 Lp(a)HORIZON outcomes trial of pelacarsen failed to significantly reduce 4-point MACE in patients with established CVD and elevated Lp(a), despite achieving lower Lp(a) versus placebo on top of guideline-directed therapy. Earlier phase 2 data had shown dose-dependent Lp(a) lowering up to 80% with weekly 20 mg, with injection-site reactions most common. Full phase 3 results are pending congress presentation, informing the broader uncertainty around Lp(a) lowering translating into clinical benefit.

Novartis announced pelacarsen did not meet its primary endpoint in the phase 3 Lp(a)HORIZON cardiovascular outcomes trial despite Lp(a) lowering.

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