New data from the SAMARA trial mark the first known demonstration that a blood test can identify semaglutide weight-loss responders before treatment begins and track drug effects over time
FOSTER CITY, Calif.--(BUSINESS WIRE)--GLP-1 medicines are being prescribed for weight loss at a scale the healthcare system has never managed before. Clinicians can measure weight loss. What they still cannot see, in any scalable, non-invasive way, is which patients are biologically positioned to respond before treatment begins, or how therapy is changing disease biology once it starts.
Hepta today announced data at Digestive Disease Week 2026 showing that a blood-based assay analyzing cell-free DNA (cfDNA) methylation speaks to both questions.
In plasma samples from the SAMARA trial, a real-world study of semaglutide in obesity and MASLD, baseline methylation patterns in cfDNA distinguished future semaglutide weight-loss responders from non-responders before a single dose was administered. Additionally, over approximately one year of treatment, patients receiving semaglutide showed epigenetic changes not observed in the placebo arm, demonstrating that drug-associated biological effects can also be tracked directly in blood over time.
The findings represent the first known demonstration that pre-treatment epigenetic signals in circulating cfDNA can distinguish semaglutide responders from non-responders, with direct implications for the future of GLP-1 precision medicine.
"As multiple drugs advance through late-stage trials for obesity and MASH, clinicians will need a tool that can match patients to the therapy most likely to benefit them," said Rohit Loomba, M.D., M.H.Sc., Hepta's Chief Medical & Scientific Advisor and Chief of the Division of Gastroenterology and Hepatology at UC San Diego, who presented the findings at DDW. "What we are observing here aligns with what the field needs. These data show that cfDNA methylation has the resolving power to identify response biology from a blood draw, before committing a patient to a year of treatment. Furthermore, it opens a new path to understanding the pharmacodynamics of therapies and their effect on the patient over the course of treatment."
The study analyzed plasma from overweight and obese MASLD patients, split between treatment arms of semaglutide up to 2.4 mg subcutaneous weekly and placebo, with blood collected at baseline and at approximately one year. Response was defined as 10% or greater annualized weight loss.
Hepta's analysis revealed two distinct findings. In the semaglutide arm, responders and non-responders showed statistically significant differences (p < 0.01) in baseline cfDNA methylation patterns before any drug exposure. Separately, participants receiving semaglutide showed longitudinal methylation shifts absent in the placebo arm, demonstrating that cfDNA captures a treatment-associated biological trajectory distinct from natural variation.
Pathway enrichment of the significant methylation regions surfaced two biologically distinct signatures. For future response prediction, the dominant signal centered on pathways governing hepatic triglyceride export and lipid metabolism, as well as fat cell differentiation. Additionally, characterizing longitudinal treatment effects surfaced methylation shifts across pathways governing de novo lipogenesis, incretin signaling, cholesterol homeostasis, and anti-fibrotic tissue remodeling, indicating that semaglutide's molecular footprint extends well beyond weight loss alone.
“The important signal in this study is baseline biology,” said Soheil Damangir, Ph.D., CTO and co-founder of Hepta. “Future responders were already biologically different before treatment began, including signals tied to how the fat is synthesized and how it is stored. That suggests response is not solely created by the drug, it is partly written into a patient's biology before treatment begins. Some patients may begin treatment in a biological state that makes them more likely to respond, and we can read that state from blood.”
“GLP-1s are being prescribed at a scale the healthcare system has never managed before, but clinicians still cannot tell how patients are biologically positioned to respond before they start treatment, or how these drugs are affecting their physiology once treatment begins,” said Hamed Amini, Ph.D., CEO and co-founder of Hepta. “The ability to identify response-linked signatures from a blood draw, based on the body’s current biological state, before committing a patient to a long course of treatment, is exactly the kind of precision medicine capability this field has so far lacked. What this study shows is that response biology is visible in blood before treatment begins, and that the biological effects of treatment can be tracked the same way. That moves GLP-1 prescribing from trial and error toward biology-guided treatment.”
The analysis was powered by Hepta's LiquidTransformer, an attention-based AI model purpose-built for liquid biopsy that reads hundreds of millions of cfDNA fragments in each sample simultaneously, capturing the distributed biological signals that characterize the disease across the methylome. The LiquidTransformer is the underlying platform Hepta previously used to demonstrate that cfDNA methylation in blood mirrors disease tissue biology at the pathway level, establishing a molecular foundation for non-invasive disease measurement. The semaglutide data extend that foundation into therapeutic stratification.
The implications extend beyond semaglutide. As the use of GLP-1 and other drugs expands across obesity, MASH, and related cardiometabolic conditions, the ability to identify likely responders and track biological effects from blood could shape how future therapies are selected, developed, and monitored. Hepta is actively engaged in discussions with pharmaceutical partners across the metabolic disease landscape and is pursuing expanded clinical programs to validate cfDNA-based response prediction across additional drug classes and mechanisms of action.
The abstract, "A Cell-Free DNA Methylation-Based Liquid Biopsy for Semaglutide Weight-Loss Response in At-Risk MASH," was presented at Digestive Disease Week® 2026 in the session "Weight Loss: Pharmacotherapy & Precision Medicine" on May 5, 2026. Authors include Rohit Loomba, Egbert Madamba, Seema Singh, Leila Bazargan, Chong Lu, Hamed Amini, and Soheil Damangir.
About Hepta
Hepta is building a blood-based epigenetic measurement platform for chronic disease, starting with MASH. Founded by former Illumina, Grail, and Google scientists, the company is backed by Felicis Ventures, Illumina Ventures, SeaX Ventures, Alumni Ventures, and AME Cloud Ventures. Hepta's LiquidTransformer reads cfDNA methylation data from a standard blood draw, enabling non-invasive diagnostics that reduce reliance on invasive biopsies. The same platform is designed to extend across detection, therapy selection, and treatment response monitoring, with applications spanning MASH, obesity, and other metabolic diseases. For more information, visit www.hepta.bio.
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