Gene

FDA Halts Sarepta Therapeutics’ AAVrh74 based Gene Therapy Trials after Third Death from Liver Failure

by with No Comment Clinical Trails

19 July 2025

Category: Drug Safety Alert / Gene Therapy Safety Update

Written by: Pharmacally Medical News Desk

Gene

Sarepta Therapeutics has been developing investigational gene therapies based on AAVrh74 vector technology for several forms of muscular dystrophy. One such therapy, SRP-9004, is being tested for limb-girdle muscular dystrophy (LGMD), while another product, Elevidys (SRP-9001), is already approved under an accelerated pathway for certain patients with Duchenne muscular dystrophy (DMD). Both therapies use the same AAVrh74 platform to deliver genetic material to muscle tissue.

On July 18, 2025, Sarepta reported that a third patient died due to acute liver failure, and the first from the ongoing clinical trial for its limb-girdle muscular dystrophy. The patient, a 51-year-old adult with LGMD, was enrolled in a Phase 1 study and received SRP-9004 approximately 80 days before the fatal event. According to Sarepta, the patient was non-ambulatory and had pre-existing comorbidities, but the direct cause of death was liver failure, raising serious concerns about the safety of the gene therapy.

This is the third reported death related to Sarepta’s AAVrh74-based gene therapies in recent months. The first two cases involved non-ambulatory teenage patients with DMD who had received Elevidys. Both patients also died from acute liver failure, one in March and the second in June this year, prompting Sarepta earlier to pause dosing in non-ambulatory patients and apply additional monitoring strategies for liver function.

Sarepta stated it had been monitoring all patients closely and was working with experts to investigate the cause of liver injury. They disclosed the third death only after it occurred, and this comes shortly after announcing internal changes, including restructuring and reduced investment in their LGMD program. While Sarepta claimed the patient had pre-existing conditions, the repeated nature of liver injury across different studies using the same AAVrh74 vector raised red flags.

FDA’s Actions and Instructions

In immediate response to the third fatality, the U.S. FDA has taken decisive action, effective July 18, 2025. The agency has

  • Placed all Sarepta AAVrh74 therapeutic clinical trials, including the LGMD study, on full clinical hold.
  • Requested (informally) that Sarepta voluntarily suspend all shipments of Elevidys, even though the latest death was not in an Elevidys‑treated patient
  • Revoked the company’s AAVrh74 platform technology designation, citing insufficient evidence to ensure safe, multi‑indication use of the platform

FDA Commissioner Dr. Marty Makary emphasized quick action to protect patient safety, stating the risks now outweigh the benefits, particularly for non‑ambulatory patients.

Dr. Vinay Prasad, head of CBER, confirmed the trials were halted due to “unreasonable and significant risk of illness or injury.”

Now Where Sarepta Stands:

Sarepta has paused use of Elevidys in non-ambulatory patients earlier after the second death only, but they resisted full suspension of Elevidys shipments and continue to make it available for ambulatory patients under existing approvals. The company is in discussions with the FDA to update safety labels and may introduce a black‑box warning for liver toxicity and new liver monitoring protocols, such as the use of immunosuppressive agents like sirolimus. Further patient enrollment across AAVrh74 studies is currently halted.

Summary and Implications

Three patients have now died of acute liver failure linked to Sarepta’s AAVrh74 gene therapies: two Elevidys DMD patients (teenagers, non-ambulatory) and one SRP‑9004 LGMD patient (adult).

FDA actions (July 18, 2025): clinical holds on LGMD trials, platform designation revoked, and shipment suspension request for Elevidys.

Sarepta’s stance: continues Elevidys for ambulatory DMD patients, pauses non-ambulatory shipments, and plans updated label and mitigation measures.

Implications

Safety of therapies based on AAVrh74 vector technology in nonambulatory patients is now clearly established.

Ongoing risk investigations may extend to ambulatory DMD patients.

Regulatory approval prospects for future AAVrh74-based therapies are critically impaired.

Closing Remark

This third death due to acute liver failure following use of Sarepta’s AAVrh74-based gene therapies signals a serious safety concern. While gene therapies hold promise, repeated adverse events with fatal outcomes call for extreme caution, especially in vulnerable populations like non-ambulatory patients. Regulatory agencies and companies must prioritize transparent reporting, patient safety, and re-evaluation of risk, particularly when using viral vectors like AAV that may trigger immune-mediated liver injury. Until safety concerns are fully addressed, further clinical use of AAVrh74-based gene therapies remains on hold.

References

FDA Investigating Deaths Due to Acute Liver Failure Following Treatment with Sarepta’s AAVrh74 Gene Therapies, US Food and Drug Administration, 18 July 2025, https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-deaths-due-acute-liver-failure-following-treatment-sareptas-aavrh74-gene-therapies/

FDA Suspends Sarepta’s Gene Therapy Trials after Deaths; But Company Declines ELEVIDYS Shipment Halt, Nasdaq, July 19 2025, https://www.nasdaq.com/articles/fda-suspends-sareptas-gene-therapy-trials-after-deaths-company-declines-elevidys-shipment/

 Elvidys Update: Parent Project Muscular Dystrophy, 18 July 2025, https://www.parentprojectmd.org/elevidys-update/

FDA Shuts Down Sarepta’s Distribution of Gene Therapy Elevidys Following Patient Deaths, Neurology Live, 18 July 2025, https://www.neurologylive.com/view/third-patient-death-leads-significant-concerns-sarepta-gene-therapy-program?utm_source=chatgpt.com

18924

“FDA raises Ocular Toxicity Concerns over GSK’s Blenrep (Belantamab Mafodotin): A Setback for Multiple Myeloma Hope”

by with No Comment Clinical Trails

17 July 2025

Article updated on 17 July 2025 after ODAC meeting

Category: Drug Safety & Regulatory Affairs I Adverse Events & Warnings I

Oncology Drug Safety

Written by: Pharmacally Medical News Desk

18924

The U.S. Food and Drug Administration (FDA) has raised concerns over the safety profile of GlaxoSmithKline’s (GSK) Blenrep (belantamab mafodotin), presenting in a briefing document to the Oncologic Drugs Advisory Committee (ODAC) ahead of the July 17, 2025, meeting. In a briefing document, the FDA has stressed persistent and severe ocular toxicities in patients treated with the drug for relapsed or refractory multiple myeloma (RRMM). This disclosure creates doubt on the long-term practicability of Blenrep’s proposed dosages despite encouraging efficacy results in DREAMM clinical trials.

History of Blenrep

Blenrep was originally granted accelerated approval in 2020, and it was positioned as a breakthrough antibody-drug conjugate (ADC) targeting the B-cell maturation antigen (BCMA). Its approval was based on early efficacy signals in heavily pretreated multiple myeloma patients. However, it was withdrawn from the U.S. market in 2023 following the failure of its confirmatory DREAMM-3 trial to meet the primary progression-free survival (PFS) endpoint. The monotherapy dosage of belantamab mafodotin was 2.5 mg/kg IV once every 3 weeks.

Despite this setback, GSK returned with new data from two pivotal Phase 3 trials, DREAMM-7 and DREAMM-8, evaluating Blenrep in combination with standard multiple myeloma therapies, including:

In combination with bortezomib and dexamethasone in patients who have received at least one prior line of therapy. Dosage was 2.5 mg/kg of actual body weight IV once every 3 weeks, and

In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy, including lenalidomide, dosage was 2.5 mg/kg of body weight IV once on Cycle 1, followed by 1.9 mg/kg IV once every 4 weeks starting on Cycle 2

Both trials have demonstrated prominent efficacy. In DREAMM-7, the median PFS was 37 months in the Blenrep arm compared to 13 months in the control group. Similarly, in DREAMM-8, the PFS hazard ratio favored Blenrep combinations. Even though achieving these significant results, the toxicities and safety concerns overshadowed the efficacy performance.

Mechanism of Belantamab Mafodotin

Belantamab mafodotin is an antibody-drug conjugate (ADC) that specifically targets B-cell maturation antigen (BCMA), a cell surface protein highly expressed on malignant plasma cells in multiple myeloma.

The FDA’s concern over ocular toxicity is as follows:

During the DREAMM-7 and DREAMM-8 trials, higher rates of Grade 3-4 treatment-emergent adverse events (TEAEs) on the belantamab mafodotin-containing arm of each study have been observed. (95% and 92% patients experienced TEAE in DREAMM-7 and DREAMM-8 trial arms, respectively.)

The most common eye-related TEAEs with the DREAMM-7 Belantamab arm (≥20%) were blurred vision, peripheral neuropathy, dry eye, photophobia, foreign body sensation in the eye, eye irritation, and eye pain.

The most common eye-related TEAEs with the DREAMM-8 Belantamab arm were blurred vision, dry eye, foreign body sensation, eye irritation, photophobia, eye pain, cataracts, and reduced visual acuity.

Based on the Sponsor’s Keratopathy and Visual Acuity (KVA), 77% of patients treated in DREAMM-7 Belantamab arm and 78% of patients treated in DREAMM-8 Belantamab arm experienced Grade 3-4 KVA events

High rates of treatment interruptions due to KVA events (DREAMM-7 Belantamab arm 74%; DREAMM-8 Belantamab arm 75%).

The FDA noted that Ocular toxicity is a key safety concern with belantamab mafodotin as described above, and it may lead to irreversible vision loss. The FDA believed the ocular toxicity is related to nonspecific uptake of the MMAF payload into corneal epithelial cells; other factors, such as a systemic inflammatory response, may also contribute to the toxicity.

Potential Mechanism of Ocular Toxicity

Even if the BCMA (The target of belantamab) is not found in the eye, belantamab mafodotin can still enter corneal cells by a nonspecific process called macropinocytosis, leading to cell damage. Lab studies have shown that the drug’s toxic payload can harm corneal cells even at low concentrations. In animal studies, signs of eye damage included cell death, cloudiness, blood vessel growth, and retinal changes. Additionally, inflammation caused by the drug may also play a role in these eye problems.

FDA concern over dosage optimization

Apart from safety concerns, the FDA also raised questions on GSK for limited dose exploration. FDA has already warned GSK to evaluate lower or less frequent dosing schedules during initial withdrawal in 2023. Still, GSK proceeded with a dosing regimen similar to the previously withdrawn monotherapy dose of 2.5 mg/kg every three weeks in DREAMM-7 and a slightly lower frequency (1.9 mg/kg) in the DREAMM-8 trial.

However, in favor of GSK a supporting data from M Protein modelling studies and post-marketing research (DREAMM-14) suggested that efficacy might be preserved with lower doses and longer intervals, potentially reducing the toxicity burden. Nevertheless, the current submissions lacked robust evidence to confirm these lower-dose benefits.

Waiting for Regulatory Decision

The FDA’s core concern remains whether the dosages used in DREAMM-7 and DREAMM-8 are justified because of substantial and sometimes irreversible ocular toxicities.

However, the efficacy data are fulfilling the requirements for regulatory consideration, but the safety profile challenges the overall benefit-risk balance.

The agency has convened the ODAC not just to review the efficacy of Blenrep but on purpose came in to highlight the point of whether a truly optimized and tolerable dosing regimen has been established.

Update from ODAC meeting

The ODAC meeting that concluded on July 17, 2025, voted against the benefit–risk profile of GSK’s Blenrep (belantamab mafodotin) in its current combination regimens for relapsed/refractory multiple myeloma.

For the Blenrep + bortezomib/dexamethasone (BVd) combination, the vote was 5 against and 3 in favor.

For the Blenrep + pomalidomide/dexamethasone (BPd) regimen, the vote was 7 against, 1 in favor

ODAC’s recommendation is non-binding, but historically, the FDA tends to align with its advisory committee.

FDA reviewers and ODAC stressed the need for lower-dose studies and better strategies to mitigate eye toxicity before any approval can be considered.

The final FDA decision, previously expected around the PDUFA date of July 23, 2025, may be delayed or denied, depending on GSK’s ability to address these concerns

Conclusion

GSK’s molecule shows therapeutic promise for a challenging disease like multiple myeloma, but the ocular toxicity risks, especially in the absence of well-defined, lower-risk dosing protocols, may significantly hinder its path to full approval.

Update: The ODAC has rejected the current dosing regimens of Blenrep combinations, citing eye safety issues and insufficient dose optimization. GSK will likely need to conduct further studies—particularly on reduced dosing or enhanced risk management—before FDA approval can move forward.

References

FDA Briefing Document, BLA 761440 Drug name: Blenrep (belantamab mafodotin), Oncologic Drugs Advisory Committee Meeting July 17, 2025 https://www.fda.gov/media/187578/download

FDA’s ODAC Votes against Risk: Benefit Profiles of Belantamab Mafodotin Combos in R/R Myeloma, OncLive, 17 July 2025, https://www.onclive.com/view/fda-s-odac-votes-against-risk-benefit-profiles-of-belantamab-mafodotin-combos-in-r-r-myeloma

GSK provides update on US FDA advisory committee review of Blenrep (belantamab mafodotin-blmf) combinations for patients with relapsed/refractory multiple myeloma, GSK, https://www.gsk.com/en-gb/media/press-releases/gsk-provides-update-on-us-fda-advisory-committee-review-of-blenrep-belantamab-mafodotin-blmf-combinations-for-patients-with-relapsedrefractory-multiple-myeloma/

amgen

Amgen’s Once-Monthly Maridebart cafraglutide (MariTide) Demonstrates Strong Efficacy in Obesity: Positive Phase 2 Maritime 1 Trial Results

by with No Comment Clinical Trails

26 June 2025

Category: Clinical Trial I Obesity & Metabolic Disorders I

Diabetes and Weight loss

Written and Reviewed By:

Vikas Londhe, MPharm

Amgen logo

In recent times, the focus has been shifted to next-generation metabolic therapies and innovative molecules that target the body’s hormonal cascades that are involved in hunger, energy burning, and fat storage. Among them, GLP-1 receptor agonists and GIP-based therapies have improved metabolic health. In this space, Amgen made a bold move into weight loss and diabetes treatments with the development of the maridebart-cafraglutide combination branded as MariTide. Amgen released positive Phase 2 results from their Maritime‑1 trial, and the results are published in the New England Journal of Medicine.

MariTide represents first-in-class dual-action molecules, combining glucagon-like peptide-1 (GLP-1) receptor agonism with glucose-dependent insulinotropic polypeptide (GIP) receptor antagonism potential with a synergistic mechanism that modulates insulin sensitivity and lipid metabolism. MariTide is designed to be administered as a once-monthly subcutaneous dose, which will increase patient compliance and convenience. The trial’s results showing up to 20% body weight reduction position MariTide as a major breakthrough in the near future.

Phase 2 Maritime‑1 Trial

The Phase 2 MARITIME-1 trial was a randomized, double-blind, placebo-controlled, dose-ranging study evaluating maridebart cafraglutide (MariTide) in adults with obesity or overweight who had at least one weight-related comorbidity. A total of 592 participants were enrolled into two cohorts: 465 in the obesity cohort (BMI ≥30 or ≥27 with complications, HbA1c <6.5%) and 127 in the obesity–diabetes cohort (BMI ≥27, HbA1c 7–<10%). Participants received subcutaneous MariTide every 4 or 8 weeks for 52 weeks across varying doses (140, 280, or 420 mg), with or without dose escalation, or placebo. The study assessed weight loss efficacy, metabolic improvements, and safety outcomes.

Endpoints

The primary endpoint was the percentage change in body weight from baseline to week 52. Secondary endpoints included proportions achieving ≥5% to ≥20% weight loss and changes in waist circumference, HbA1c, lipid profiles, CRP, and blood pressure. Safety outcomes focused on gastrointestinal adverse events and treatment discontinuation. The study aimed to evaluate both the weight loss efficacy and broader metabolic benefits of maridebart cafraglutide (MariTide).

Results

In the obesity cohort, maridebart cafraglutide led to a mean body weight reduction of −16.3% to −19.9% (efficacy estimand) compared to 2.6% with placebo. In the obesity–diabetes cohort, reductions ranged from −12.1% to −17.0% compared to 1.4% with placebo. More participants achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss with maridebart cafraglutide. Additionally, significant HbA1c reduction and improvements in waist circumference, blood pressure, hs-CRP, and lipid profiles were observed.

Side Effects

In the phase 2 trial, 90–99% (obesity) and 91–97% (obesity–diabetes) of participants on maridebart cafraglutide reported at least one adverse event, versus 68% and 81% with placebo, respectively. Gastrointestinal events (nausea, vomiting, retching and diarrhea) were most common and mostly mild to moderate, with higher rates in no-dose-escalation groups. Discontinuation due to GI events occurred in up to 27% of participants. There were 35 serious adverse events and 2 deaths, both deemed unrelated to treatment.

In the phase 2 trial, maridebart cafraglutide was associated with mild-to-moderate hypersensitivity (5%), increased gallbladder events, and a few cases of level 2 hypoglycemia. Minor mood events, slight increases in heart rate, amylase, lipase, and calcitonin (within normal range), and decreased liver aminotransferase levels were noted. No cases of pancreatitis, diabetic retinopathy, or C-cell hyperplasia occurred.

Mechanism of Action

Maridebart cafraglutide works through a unique combination of actions. It blocks the GIP receptor and activates the GLP-1 receptor using two attached GLP-1 agonist peptides (cafraglutide), which together regulate body weight. This combination helps people feel full for longer, slows the emptying of food from the stomach, and reduces hunger, leading to lower calorie intake. It also improves how the body responds to insulin and controls blood sugar levels, making it useful for people with obesity.

Strategic Phase 3 Maritime Design

Amgen’s MARITIME Phase 3 program is currently in progress, consisting of 72-week chronic weight management studies evaluating maridebart cafraglutide (MariTide). The program includes two parallel trials: Maritime 1, enrolling participants with obesity or overweight with at least one weight-related comorbidity, and Maritime 2, targeting individuals with type 2 diabetes. Additional Phase 3 trials evaluating MariTide in patients with atherosclerotic cardiovascular disease, heart failure, and obstructive sleep apnea are expected to launch in 2025. Initial readouts from the ongoing Phase 3 studies are anticipated in 2027, positioning MariTide as a major therapeutic option in obesity and diabetic care.

Bottom Line

Susan Sweeney, executive vice president of Obesity and Related Conditions at Amgen, said, “Obesity affects all parts of the world and people of all different populations, and the challenge is significant.”

We have witnessed a lot of patients in our surroundings, including society, friends, or family; for them, Maridebart Cafraglutide (MariTide) represents a promising new candidate in the competitive market of obesity and metabolic disease treatment. This is backed by robust Phase 2 results showing significant weight loss, metabolic improvements, and a manageable safety profile. MariTide showed the potential to offer meaningful clinical benefits with a once-monthly dosing regimen. At the bottom line, Amgen’s MariTide could redefine long-acting obesity treatment with its potent efficacy, broad metabolic impact, and patient-friendly dosing.

Reference

Jastreboff AM, Ryan DH, Bays HE et al, Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial, The New England Journal of Medicine, Published June 23, 2025, DOI: 10.1056/NEJMoa2504214

Results from Amgen’s phase 2 obesity study of monthly Maritide presented at the American diabetes association 85th scientific sessions, Amgen, https://www.amgen.com/newsroom/press-releases/2025/06/results-from-amgens-phase-2-obesity-study-of-monthly-maritide-presented-at-the-american-diabetes-association-85th-scientific-sessions

Inside Amgen’s Phase 3 MARITIME Program: Advancing the Future of Obesity Care, Amgen, https://www.amgen.com/stories/2025/06/inside-amgens-phase-3-maritime-program—advancing-the-future-of-obesity-care

Maridebart Cafraglutide for Chronic Weight Management, iClinique, https://www.icliniq.com/articles/drug-and-supplements/maridebart-cafraglutide#how-does-maridebart-cafraglutide-work-in-obesity-management

Efficacy and Safety of Maridebart Cafraglutide in Adult Participants with Type 2 Diabetes Mellitus Who Have Obesity or Are Overweight (MARITIME-2), ClinicalTrials.gov ID NCT06858878, https://clinicaltrials.gov/study/NCT06858878

ChatGPT Image Jun 24, 2025, 11_56_23 AM

“CagriSema: A Powerful New Weight Loss and Diabetes Combination Therapy Emerges from REDEFINE-2 Trial”

by with No Comment Clinical Trails

24 June 2025

Category: Clinical Trial I Obesity & Metabolic Disorders I

Diabetes and Weight loss

Medically Written and Reviewed By:

Vikas Londhe MPharm

ChatGPT Image Jun 24, 2025, 01_04_16 PM
Generative AI

The race to develop new treatments for obesity and type 2 diabetes is getting more and more competitive. To this race, the results of the REDEFINE 2 trial (NCT05394519), published recently in The New England Journal of Medicine (NEJM). The study highlights the powerful potential of a novel combination therapy, CagriSema. This once-weekly subcutaneous treatment, combining cagrilintide (an amylin analogue) and semaglutide (a GLP‑1 receptor agonist), has shown impressive results for weight loss and glycemic control, especially in individuals with both obesity and type 2 diabetes.

Study at a Glance

The REDEFINE 2 trial (Trial No. NCT05394519) is a Phase 3a, multicenter, randomized, double-blind, placebo-controlled study sponsored by Novo Nordisk, conducted across 12 countries in Europe, North America, and Asia. The study was designed to evaluate the efficacy and safety of CagriSema. CagriSema was administered once weekly in dose dose-escalated manner starting from a 0.25 mg dose and increasing stepwise till it reached 2.4 mg for each drug in 16 weeks. The trial enrolled non-insulin-dependent participants aged 18 years or older with a body mass index of 27 kg/m² or more, HbA1c between 7% and 10%, and at least one self-reported unsuccessful dietary effort to lose weight. The lifestyle modifications were also suggested to study participants. Participants were randomly assigned to receive CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) or placebo over a 68-week treatment period, followed by a 7-week follow-up. The primary endpoint was percentage change in body weight and percentage of patients achieving ≥5% weight loss from baseline to week 68; however, additional secondary endpoints included changes in waist circumference, glycated hemoglobin level, systolic blood pressure, and other physical function measures from baseline to 68 weeks. Results from this trial, published in The New England Journal of Medicine, have shown the potential of CagriSema to offer a new standard of care in obesity and diabetes management.

Key Findings

The REDEFINE 2 trial showed that CagriSema led to significantly greater weight loss and better blood sugar control compared to placebo in people with obesity and Type 2 diabetes. After 68 weeks of treatment, patients receiving CagriSema lost an average of 15.7% of their body weight, which was much higher than the placebo group’s 3.1%. In addition, almost 83.6% of patients in the CagriSema group achieved at least 5% weight loss, a clinically significant benchmark, compared to 30.8% in the placebo group. Additionally, a weight reduction of 10% or more occurred in 65.6% of the patients in the cagrilintide–semaglutide group and in 10.3% of in the placebo group; a weight reduction of 15% or more occurred in 43.8% and 2.4%, respectively, and a weight reduction of 20% or more occurred in 22.9% and 0.5%, respectively. CagriSema also showed greater improvement in blood sugar control, reducing average HbA1c levels by 1.8 percentage points, while the placebo reduced them by only 0.4 percentage only.

On average, systolic pressure went down by 4.1 mm Hg more than the placebo group, a statistically significant difference. Additionally, the combination treatment also showed improvements in diastolic blood pressure, C-reactive protein (a marker of inflammation), and cholesterol levels compared to placebo. On average, waist size reduced by 8.3 cm more than the placebo group.

 These results confirmed that the combination therapy offers stronger benefits for both weight and glucose management, especially in patients with diabetes.

Mechanism of Action

Cagrilintide is an amylin analogue, which mimics the action of the natural hormone amylin. It helps to reduce appetite, increase feelings of fullness, and slow down the emptying of the stomach, which leads to reduced food intake and promotes weight loss. It binds to amylin receptors in the brain, specifically in the hypothalamus and other brain regions, to promote feelings of fullness and reduce food intake. On the other hand, semaglutide is a GLP-1 receptor agonist, a class of drugs that stimulates insulin release in response to high blood sugar levels, suppresses glucagon (a hormone that raises blood sugar), and also delays gastric emptying. It plays a dual role in improving glycemic control and enhancing satiety, contributing further to weight reduction. Together, cagrilintide and semaglutide produce synergistic effects.

Safety Profile

CagriSema was generally well tolerated, with a safety profile consistent with what is typically seen with GLP‑1 receptor agonists like semaglutide. The most common side effects reported were gastrointestinal symptoms, including nausea, vomiting, diarrhea, and constipation. These side effects were mostly mild to moderate in severity. A slightly higher number of participants in the CagriSema group discontinued treatment due to side effects compared to the semaglutide and placebo groups. Importantly, no new safety concerns emerged during the trial.

Future Plan

Following the strong results from REDEFINE 2, Novo Nordisk is expected to seek regulatory approval for CagriSema in 2026, supported by earlier data from the REDEFINE 1 trial, which showed an even greater weight loss of 22.7% in people without diabetes. The company is also developing a pre-filled pen for convenient once-weekly dosing, aiming to simplify treatment and enhance patient adherence.

Conclusion and Pharmacally’s Take

CagriSema may emerge as a landmark treatment after approval for diabetes management and obesity care. It combines the benefits of two powerful drugs from their class, offering patients a more effective and synergistic approach to weight and glucose control. This trial proves that individuals with type 2 diabetes, who typically lose less weight than those without, can achieve meaningful and substantial weight loss.

With semaglutide already a blockbuster and tirzepatide on the rise, CagriSema could be the next market capturer in metabolic health and weight loss, especially for patients with complex comorbidities.

References

Davies MJ, Bajaj HS, Broholm C, et al, Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes, The New England Journal of Medicine, Published June 22, 2025, DOI: 10.1056/NEJMoa2502082

A Research Study to See How Well CagriSema Helps People with Type 2 Diabetes and Excess Body Weight Lose Weight (REDEFINE 2), ClinicalTrials.gov ID NCT05394519, https://clinicaltrials.gov/study/NCT05394519

Garvey WT, Blüher M, Contreras CKO, et al, Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity, The New England Journal of Medicine, Published June 22, 2025, DOI: 10.1056/NEJMoa2502081

 

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Ibezapolstat: AcurX Pharmaceuticals First-in-Class Mechanism Antibiotic for Clostridioides difficile Infection Shows Promising Results in Phase 2b Trial

by with No Comment Clinical Trails

Published On: 20 June 2025

Category: Clinical Trial I Infectious Disease I

Gut and Gastrointestinal Infections

Written By: Pharmacally Medical News Desk

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freepik__artistic-representation-of-clostridioides-difficil__32689
Source: Freepik.com

Clostridioides difficile infection (CDI) is among the most challenging hospital-acquired infections globally. C.Difficile, known for its high recurrence rates and significant impact on the gut microbiome. To date, vancomycin has long been a standard treatment; however, it lacks selectivity and often disrupts beneficial gut bacteria, which contributes to relapses.

Ibezapolstat, a first-in-class antibiotic being developed by AcurX Pharmaceuticals, aims to decipher these issues. Unlike traditional broad-spectrum agents, Ibezapolstat specifically targets DNA polymerase IIIC, an enzyme essential for the replication of Gram-positive bacteria like C. difficile, which is absent in beneficial anaerobic flora.

The recently published Phase 2b clinical trial results in The Lancet Microbe mark a crucial step forward in this drug’s journey, offering new hope in reducing recurrence and treating serious hospital-acquired infections like Clostridioides difficile.

The Phase 2b Trial: Design & Goals

AcurX Pharmaceutical recently concluded its phase 2b trial, and the results are published in Lancet Microbes. The trial was conducted across 15 U.S. centers between March 2021 and October 2023. The randomized, double-blind, active-controlled trial enrolled adults aged 18 to 90 with confirmed C. difficile infection. Patients were randomly assigned to receive

  • Ibezapolstat 450 mg orally every 12 hours (n = 18 total; 16 included in the efficacy analysis)
  • Vancomycin 125 mg orally every 6 hours (n = 14)

The primary objective was clinical cure at the end of treatment (EOT), defined as the resolution of diarrhea and no need for further CDI therapy 48 hours post-treatment.

Efficacy: A Match for Vancomycin

In the Phase 2b clinical trial, ibezapolstat demonstrated clinical efficacy that was analogous to vancomycin, which is the current standard of care for Clostridioides difficile infection. Among the patients evaluated in the trial, 94% of patients treated with ibezapolstat achieved complete clinical cure at the end of treatment, while 100% of patients receiving vancomycin met the same endpoint. This slight numerical difference was not statistically significant and met the criteria for non-inferiority, establishing Ibezapolstat as an equally effective treatment option. More compelling, however, were the findings from a pooled analysis of data from both the Phase 2a and 2b trials. In pooled analysis, done from the combined dataset of Phases 2a and 2b, ibezapolstat achieved a clinical cure rate of 96%. Surprisingly, ibezapolstat sustained a cure rate of 100%, meaning no recurrences were observed one month after treatment. This is in contrast to historical data for vancomycin, where recurrence rates range from 26% to as high as 58%. These results position ibezapolstat not only as an equally effective treatment as vancomycin for acute CDI but also as a promising candidate for reducing the risk of relapse, a critical issue in current CDI management.

Microbiome and Bile Acid Profiles

Even if ibezapolstat showed comparable clinical efficacy to vancomycin, ibezapolstat shows significant advantages over vancomycin in terms of protecting gut health, which is an essential factor in preventing recurrent infections. One of the prominent findings from the study was the rapid microbiological clearance of C. difficile, with 94% of patients treated with ibezapolstat showing eradication of the organism by Day 3, compared to 71% in the vancomycin group. But the main differentiation lies in ibezapolstat’s ability to save the beneficial gut microbiota. Unlike vancomycin, which broadly disrupts the intestinal flora, ibezapolstat preserved vital bacterial groups such as the Firmicutes and Actinobacteria phyla known for supporting immune function and maintaining colonization resistance. This preservation of the microbiome might play a role behind why Ibezapolstat showed zero recurrence rates.

Additionally, stool analysis revealed that ibezapolstat favorably altered bile acid profiles, reducing primary bile acids (which promote C. difficile germination) and increasing secondary bile acids (which inhibit it). This bile acid shift further enhances the gut’s natural defense against reinfection.

These microbiome and metabolomic findings highlight ibezapolstat’s potential not just to treat CDI effectively, but to do so in a way that supports long-term gut health and prevents recurrence, something current therapies generally fail to achieve.

Safety & Pharmacokinetics

Ibezapolstat demonstrated a favorable safety profile in the Phase 2b trial. No drug-related serious adverse events, treatment discontinuations, or deaths were reported in either the ibezapolstat or vancomycin treatment groups.

Pharmacokinetic analysis further supported its targeted mechanism of action, with ibezapolstat achieving high concentrations in stool exceeding 1,000 μg/g by days 8 to 10 while showing minimal systemic absorption. This gut-localized exposure is particularly advantageous in treating C. difficile infections, as it maximizes local antimicrobial activity while minimizing the risk of systemic side effects or toxicity.

The Unique Mechanism of Action

Unlike vancomycin, which largely disrupts bacterial cell wall synthesis and also affects a wide range of gut bacteria due to its common mechanism pathway through inhibiting cell wall synthesis, ibezapolstat offers a more targeted line of attack. It selectively inhibits DNA polymerase IIIC (PolC), an enzyme essential for the replication of Gram-positive pathogens like C. difficile but absent in human cells and many beneficial gut bacteria. This precision targeting enables ibezapolstat to kill C. difficile effectively while showing mercy on much of the gut’s healthy microbiota. As a result, it minimizes disruption to colonization resistance, the gut’s natural defense against reinfection. This selective mechanism is increasingly being recognized as the gold standard in modern antimicrobial development, aligning efficacy with microbiome preservation.

The Road to Approval

Ibezapolstat has already received the U.S. FDA Qualified Infectious Disease Product (QIDP) and Fast Track designations, accelerating its development and review timeline. At the same time, the European Medicines Agency (EMA) has recognized AcurX Pharmaceuticals with Small and Medium-sized Enterprise (SME) status, offering additional guidance and regulatory incentives. A global Phase 3 trial is currently in development and is expected to enroll over 600 patients. This pivotal study will compare ibezapolstat directly with vancomycin in a larger and more diverse population to confirm its efficacy and safety on a broader scale. A crucial regulatory meeting with the FDA is scheduled for mid-2025 to finalize the Phase 3 development plan and determine the path toward potential market approval.

Conclusion & Pharmacally Take

Current treatments for CDI have improved outcomes, but eradicating C. Difficile, preventing recurrence, and protecting other gut microbiomes continue to be major hurdles, “but ibezapolstat offers a new hope in this direction. With its narrow-spectrum precision, gut microbiome-sparing effects, and potential to prevent relapse, it addresses the shortcomings of traditional CDI therapies like vancomycin.

If Phase 3 results confirm these findings, ibezapolstat could emerge not just as an alternative but as a preferred first-line therapy for initial and recurrent CDI.

At Pharmacally, we’re closely watching ibezapolstat’s development as a milestone in microbiome-conscious antibiotic therapy. Its success could pave the way for a new era of targeted antimicrobials that treat without extra damage.

References

Taryn A Eubank, Jinhee Jo, M Jahangir Alam, et al, Efficacy, safety, pharmacokinetics, and associated microbiome changes of Ibezapolstat compared with vancomycin in adults with Clostridioides difficile infection: a phase 2b, randomised, double-blind, active-controlled, multicentre study, Lancet Microbe 2025, https://doi.org/10.1016/ j.lanmic.2025.101126

Acurx Announces Publication in Lancet Microbe of Phase 2b Clinical Trial Data for Ibezapolstat in CDI, AcurX pharmaceuticals, 17 June 2025, https://www.acurxpharma.com/news-media/press-releases/detail/111/acurx-announces-publication-in-lancet-microbe-of-phase-2b

Acurx Announces Publication in Lancet Microbe of Phase 2b Clinical Trial Data for Ibezapolstat in CDI, PRNewswire, 17 June 2025, https://www.prnewswire.com/news-releases/acurx-announces-publication-in-lancet-microbe-of-phase-2b-clinical-trial-data-for-ibezapolstat-in-cdi-302483504.html

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Beyond Weight Loss: First-Generation GLP-1 Drugs Like Liraglutide and Exenatide Show Promising Anti-Cancer Effects

by with No Comment Clinical Trails

Written By: Smaiksha Benke, M.Pharm Pharmacology

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Obesity is a major global health concern and a known risk factor for at least 13 different types of cancer. The increasing prevalence of obesity-related cancers highlights the urgent need for effective and widely accessible prevention strategies. Conventional weight loss approaches often provide only transitory benefits, while bariatric surgery though effective is invasive and not appropriate for everyone. However, first-generation GLP-1 receptor agonists (GLP-1 RAs) such as liraglutide and exenatide, initially designed to manage type 2 diabetes and obesity, are now showing encouraging anti-cancer potential, according to a recent study published in eClinicalMedicine, part of The Lancet Discovery Science series. This discovery indicates that the benefits of these medications may go beyond weight control. They appear to exert anti-cancer effects through mechanisms such as reducing inflammation, inhibiting the growth of cancer cells, and promoting programmed cell death (apoptosis).

Study Design

The study was a retrospective, observational cohort study using electronic medical records from Clalit Health Services in Israel. Researchers compared adults aged ≥24 years with obesity and type 2 diabetes who received either bariatric metabolic surgery (BMS) or first-generation glucagon-like peptide-1 receptor agonists (GLP-1RAs), primarily liraglutide, between 2010 and 2018. A total of 3178 matched pairs (N=6356) were followed for a median of 7.5 years (up to 12.9 years). Matching was based on age, sex, BMI, treatment initiation year, and smoking status. The primary endpoint was the incidence of obesity-related cancers (ORCs), including colorectal, postmenopausal breast, pancreatic, and other specified malignancies. Secondary analysis assessed mediation effects through changes in BMI and HbA1c.

Results

The final study cohort consisted of 6356 individuals (3178 pairs), matched on sex, age, baseline BMI, year of treatment initiation, and smoking status. At baseline, the mean age was 52.3 years, and the average BMI was 41.5 kg/m². The median follow-up time was 7.5 years, with some individuals followed for up to 12.9 years.

During the follow-up period, obesity-related cancers (ORCs) were diagnosed in 298 individuals:

150 cases occurred among those who underwent bariatric metabolic surgery (BMS), with an incidence rate of 5.76 cases per 1000 person-years.

148 cases occurred among those treated with GLP-1 receptor agonists (GLP-1RAs), with an incidence rate of 5.64 per 1000 person-years.

The adjusted hazard ratio (HR) for developing ORC in the GLP-1RA group compared to the BMS group was 1.03, indicating no statistically significant difference in overall cancer risk between the two treatment modalities.

Mediation Analysis

To explore potential mechanisms beyond weight loss, a mediation analysis was conducted:

Patients in the BMS group experienced a mean BMI reduction of 31.1%, whereas those in the GLP-1RA group had a mean decrease of 12.9%.

When the change in BMI was included in the adjusted model, the hazard ratio for GLP-1RA vs. BMS shifted to 0.59, indicating a direct effect of GLP-1RA therapy beyond weight loss, equivalent to a 41% relative risk reduction.

In contrast, when the change in HbA1c levels was tested as a mediator, it did not alter the main association. The adjusted HR remained non-significant, suggesting glycemic control alone does not explain the protective effect of GLP-1RAs.

Subgroup Observations

Among all diagnosed ORC cases:

Breast cancer (postmenopausal) was the most common (26%),

Followed by colorectal (16%) and uterine cancer (15%)

These distributions are aligning with known obesity-related cancer patterns.

Broader Implications

These findings are important in view of the current rising use of newer GLP-1 RAs like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro). While most attention has focused on weight loss and diabetes control, these early-generation drugs may offer additional therapeutic value as cancer-preventive agents.

Conclusions

The study’s findings suggest that treatment with first-generation GLP-1 receptor agonists (GLP-1RAs) like Liraglutide and exenatide may be doing more than helping patients lose weight or manage blood sugar they could also be reducing cancer risk. Also they are not associated with an increased risk of obesity-related cancers when compared to bariatric metabolic surgery (BMS) in patients with obesity and type 2 diabetes. Despite the greater weight loss achieved through BMS, the incidence of obesity-related cancers was statistically similar between the two groups over a long-term follow-up. Importantly, mediation analysis revealed that GLP-1RAs may exert a protective effect against these cancers independent of weight loss, potentially through other mechanisms such as anti-inflammatory pathways. These results position GLP-1RA therapy as a viable, non-surgical alternative for reducing obesity-associated cancer risk in this population. However, confirmation through larger prospective studies and randomized controlled trials is warranted to strengthen causal inference and explore the underlying biological mechanisms.

Reference

Wolff Sagy, Y., Ramot, N., Battat, E., Arbel, R., Reges, O., Dicker, D., & Lavie, G. (2025). Glucagon-like peptide-1 receptor agonists compared with bariatric metabolic surgery and the risk of obesity-related cancer: An observational, retrospective cohort study. eClinicalMedicine, 83, 103213. https://doi.org/10.1016/j.eclinm.2025.103213

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com

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Novel Oncolytic Virus Therapy Uses Transplant Rejection Pathway to Kill Cancer

by with No Comment Clinical Trails

Medically Reviewed By Vikas Londhe M.Pharm (Pharmacology)

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Newcastle Disease Virus selectively infecting human ovarian cancer cells, visualized with fluorescent markers, highlighting the specificity of the viral targeting, dark background (Source: Freepik.com)

Introduction

In a breakthrough that bring together virology, immunology, and genetic engineering, researcher from State Key laboratory of Targeting Oncology, China have developed a novel oncolytic therapy using a genetically modified Newcastle Disease Virus (NDV) that tricks the immune system into treating cancer cells as if they were foreign organ transplants. This approach, which uses the body’s natural “hyperacute rejection” mechanism typically seen in organ xenotransplants, showed notable results in early clinical trials for patients with advanced, treatment-resistant cancers.

Hyperacute rejection is a type of organ transport rejection that happens within minutes to hours after the transplant. It occurs when the recipient’s immune system already has antibodies that quickly recognize the new organ as foreign and attack it. This rapid immune response causes severe damage to the transplanted organ, often leading to its failure almost immediately.

Xenotransplant is a medical procedure where cells, tissues, or organs are transplanted from one species to another for example, transplanting a pig’s heart into a human.

The Innovation: NDV-GT and the aGal Trigger

The therapy uses a recombinant NDV that expresses the porcaine α1, 3-galactosyltransferase (a1, 3GT) gene, resulting in the presentation of αGal antigens on infected tumor cells. In humans, the αGal antigen is recognized as foreign due to the evolutionary loss of the α1, 3GT gene. Our immune systems naturally produce large amounts of anti-αGal antibodies, primarily from exposure to gut microbiota. This makes the immune system especially reactive to any cell displaying αGal.

By engineering NDV to express this foreign antigen on tumor cells, scientists effectively turned cancer cells into targets of a powerful immune cascade similar to organ rejection. This results in rapid tumor destruction through complement activation, thrombosis, and immune cell infiltration.

Preclinical Success in Monkeys

Using CRISPR-Cas9 technology, the researcher created a realistic liver cancer model in cynomolgus monkeys. The intravenous administration of NDV-GT in these monkeys led to remarkable tumor regression with many tumors disappearing entirely. The therapy not only lysed the cancer cells but also caused thrombotic blockage of tumor blood vessels mimicking hyperacute rejection seen in xenograft failures.

Immune profiling revealed activation of both innate and adaptive immune responses, including CD4+ and CD8+ T cell infiltration, increased expression of granzyme B and perforin, and reduced tumor angiogenesis markers. Importantly, no significant toxicity or organ damage was observed.

Clinical Trial Results

In a phase I interventional clinical trial (ChiCTR2000031980), 20 patients with various advanced, treatment-resistant cancers, including liver, lung, rectal, esophageal, breast, and cervical cancer and melanoma, were treated with intravenous NDV-GT. The results were prominent:

90% Disease Control Rate (DCR): 1 complete response, 6 partial responses, and 11 cases of stable disease.

No severe adverse events: Mild side effects, no cytokine release syndrome, and no detectable viral shedding.

Durable response: Severe patients experienced long-term stabilization o remission lasting up to 36 months.

One standout case involved a patient with advanced hepatocellular carcinoma and lung metastases. After 1.5 months of NDV-GT treatment, most tumors had disappeared, and serum tumor markers dropped significantly. Another patient with metastatic ovarian cancer achieved a partial remission for over a year.

Mechanism of Action

NDV-GT’s effectiveness lies in its dual mechanism :

Direct Oncolysis: NDV naturally prefers and destroys tumor cells while sparing healthy ones.

Immune Amplification: The engineered Gal expression triggers complement-mediated cytotoxicity and T-cell driven immune cascade, simulating a rapid rejection response that targets the tumor as a foreign organ.

This dual action also alleviated the immunosuppressive tumor microenvironment, making tumors more susceptible to further immune attack.

Safety and Implications

Despite the robust immune activation, NDV-GT treatment was well tolerated. No significant increase in neutralizing antibodies or adverse immunogenic effects was observed. The lack of toxicity and the specific targeting of tumor tissue underscore its promise for broader clinical use.

Conclusion

NDV-GT represents a groundbreaking shift in oncolytic virotherapy. Bby mimicking a hyperacute rejection response. This therapy turns the body’s natural defense mechanism against tumors in a way that is both powerful and safe. As phase II-III trials are being prepared, this immune- tricking virus could redefine treatment paradigms for refractory and metastatic cancers.

Reference

1. Liping Zhong, Lu Gan, Bing Wang et al, Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients, Cell, Volume 188, Issue 4P1119-1136.E23February 20, 2025.

2. Tricking the Immune System: A New Approach to Targeting Cancer Cells by Mimicking Pig Organs, Insight, 22 Jan 2025, available from https://oncodaily.com/insight/immune-system-229351

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Semaglutide Continues to Impress: Phase 3 Trial Shows Reversal of MASH (Metabolic Dysfunction-Associated Steatohepatitis)

by with No Comment Clinical Trails

Medically Reviewed By Vikas Londhe, M.Pharm, Pharmacology

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Source: Freepik.Com

A new large phase 3 clinical study has shown encouraging results for a medicine called semaglutide in treating people with a serious liver disease known as MASH (metabolic dysfunction-associated steatohepatitis). MASH is a more severe form of fatty liver disease that can lead to serious health problems like liver scarring (cirrhosis) and even liver cancer if not treated. Semaglutide is a drug that works by mimicking a natural hormone in the body called GLP-1 that helps control blood sugar and appetite. These new findings, which were published in a medical journal The New England Journal of Medicine, represent an important breakthrough, especially since there are currently very few effective treatments available for this condition.

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Metabolic Dysfunction-Associated Steatohepatitis, or MASH, is a serious liver disease that happens in people who have health problems like obesity, type 2 diabetes, or high cholesterol. It used to be called non-alcoholic steatohepatitis (NASH), but the name was changed to highlight its link to metabolic health issues.

In MASH, fat builds up in the liver, which causes swelling and damage to liver cells. Over time, this can lead to scarring of the liver (called fibrosis), and if it gets worse, it can turn into cirrhosis, which is severe and lasting liver damage. In the most serious cases, it can even lead to liver failure or liver cancer.

MASH is becoming more common all over the world because more people are living with obesity and diabetes. It usually doesn’t cause any symptoms at first, so many people don’t know they have it until their liver is already damaged.

As of now, resmetirom is the only FDA-approved treatment specifically for MASH with liver fibrosis. Hence, there is an emerging need for alternate options for treating MASH.

Key findings from the ESSENCE Trial

The ESSENCE trial was a major research study that included 1,197 people who had MASH (a serious liver condition) confirmed through a liver biopsy. These patients also had moderate to severe liver scarring (stage 2 or 3 fibrosis). The study was designed as a “double-blind, placebo-controlled” trial. Participants were randomly divided so that for every two people receiving semaglutide, one person received a placebo. They were given either 2.4 mg of semaglutide or the placebo once a week for a total planned duration of 240 weeks (over 4.5 years). The current findings are from an early look at the data after 72 weeks (about 1.5 years) of treatment, involving the first 800 people in the study.

How Well Semaglutide Worked in the Study

Semaglutide showed strong benefits for people with MASH across several key health measures:

Liver inflammation reduced without getting worsening of scar:

About 63% of patients who took semaglutide had declined their liver inflammation (steatohepatitis) without worsening to fibrosis. In comparison, only about 34% of those who took the placebo saw the same result. That’s a nearly 29% better outcome with semaglutide, and the result was statistically significant.

Improved liver scarring without more inflammation:

Nearly 37% of patients taking semaglutide had improvement in liver fibrosis without their liver inflammation worsening. For the placebo group, only 22% saw this kind of improvement a difference of over 14% is also statistically significant.

Both inflammation and scarring improved:

Around 33% of those on semaglutide saw improvements in both liver inflammation and scarring, which was more than double the 16% who experienced the same benefits in the placebo group.

These findings suggest semaglutide could become a highly effective treatment for people with MASH, addressing both inflammation and damage in the liver.

Beyond the improvements seen in liver tissue, semaglutide also helped patients in other important ways. People who took semaglutide lost a significant amount of weight, on average; they lost about 10.5% of their body weight, compared to just 2% in the placebo group. This is a major benefit, especially since excess weight is a key factor in MASH.

Semaglutide also improved several markers related to overall metabolism and health. It helped reduce insulin resistance, lowered levels of triglycerides and cholesterol, and decreased markers of inflammation. These improvements are important because they not only support liver health but also reduce the risk of heart disease and diabetes, which are common in people with MASH.

Safety and Side Effects

Semaglutide was generally safe and well tolerated by patients in the study. The side effects reported were mostly in line with what has been seen in earlier research. The most common issues were stomach-related problems like nausea and diarrhea, which happened more often in people taking semaglutide compared to those on the placebo.

However, serious side effects occurred at about the same rate in both groups, around 13.4% showing that semaglutide did lead to more serious health problems overall. Importantly, no new safety issues were found during the trial, including any liver-related complications, which is reassuring for people with liver disease.

Clinical Implications

The findings from this study show that semaglutide has the potential to not only reduce liver inflammation and scarring in people with MASH, but also improve overall metabolic health. This is especially important because MASH is often linked to other serious conditions like type 2 diabetes and obesity. Since semaglutide helps with both liver disease and these related metabolic issues, it could become a powerful option integrated treatment strategy.

Currently, another drug called resmetirom has received fast-track approval from the FDA for treating MASH with fibrosis. However, based on semaglutide performance in this early analysis, it may soon be approved as well and possibly offer even broader benefits than existing treatments.

What’s Next: Long-Term Outlook

The ESSENCE trial is still in progress, and researchers will continue to follow patients for a total of 240 weeks (about 4.5 years) to understand the long-term effects of semaglutide. One of the key outcomes they’re watching for is whether the drug can help patients avoid serious complications like cirrhosis over time.

If the final results confirm the benefits seen so far such as improved liver health, weight loss, and better metabolic control semaglutide could become a game-changing treatment for MASH. This would be especially important for a disease that has had very few effective options until now.

References

1.Arun J. Sanyal, Philip N. Newsome, Iris Kliers et al, Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis, April 30, 2025, at NEJM, DOI: 10.1056/NEJMoa2413258

2. Metabolic Dysfunction-Associated Steatohepatitis (MASH), Cleveland Clinic, available from https://my.clevelandclinic.org/health/diseases/22988-nonalcoholic-steatohepatitis

3. Keam SJ. Resmetirom: First Approval. Drugs. 2024 Jun; 84(6):729-735. Doi: 10.1007/s40265-024-02045-0. Epub 2024 May 21. PMID: 38771485.

4. Bandyopadhyay S, Das S, Samajdar SS, Joshi SR. Role of semaglutide in the treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Diabetes Metab Syndr. 2023 Oct;17(10):102849. Doi: 10.1016/j.dsx.2023.102849. Epub 2023 Sep 13. PMID: 37717295.

5. Zhu K, Kakkar R, Chahal D, Yoshida EM, Hussaini T. Efficacy and safety of semaglutide in non-alcoholic fatty liver disease. World J Gastroenterology. 2023 Oct 7;29(37):5327-5338. Doi: 10.3748/wjg.v29.i37.5327. PMID: 37899788; PMCID: PMC10600803.

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Is Cytisinicline the Next Big Thing in Quitting Smoking?

by with No Comment Clinical Trails

Medically Reviewed By Vikas Londhe M.Pharm (Pharmacology)

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Source: Freepik.Com

Smoking is the leading cause of preventable death worldwide. Smoke from cigarette contains mixture of toxic chemicals, nearly 5000 chemicals produced during combustion of tobacco and its additives and many of these have harmful effect on every organ of the body. Out of these 5000 chemicals 70 chemicals are the known carcinogens like, formaldehyde, vinyl chloride etc.

But if these chemicals are all harmful and can leads to serious health condition like cancer then why people find it difficult to quit smoking? Nicotine is the chemical present in cigarette, which is highly addictive but it is non carcinogen. Nicotine makes people habitual to smoking.

Health effects of smoking

Smoking is the leading cause of many life-threatening health conditions. Smoking is the main contributor to lung cancer worldwide. Apart from this, smoking is the leading cause of heart disease, stroke, chronic obstructive pulmonary disease (COPD), and many other life-threatening conditions. Smoking can significantly increase the risk of other ailments, including type 2 diabetes, infertility, and pregnancy complications. As this is the established link in active smokers, smoking can cause serious health problems in passive non-smokers, or secondhand smokers who are exposed to smoke from primary smokers, especially children. Passive smoking can lead to health conditions like asthma, respiratory infections, or sudden infant death syndrome (SIDS). The other effects of smoking can include an economic burden on patients from healthcare costs and, at the same time, productivity loss at the workplace.

Prevalence worldwide

According to WHO report 2023, there are 1.1 billion active smokers present worldwide—smoking causes more than 8 million deaths per year globally. As per the CDC report 2023, in the USA alone, 11.5% of adults smoke; out of these, 480,000 deaths occur due to smoking annually in the USA. 41000 deaths are associated with passive smoking annually due to smoking. It all increases the economic burden up to 300 billion dollar.

Conventional smoking therapies

Conventional smoking therapies include Nicotine Replacement Therapy (NRT). It is one of the most commonly used methods and comes in several forms, like patches, gums, lozenges, inhalers, and nasal sprays. Prescription medications such as varenicline, a partial agonist at nicotinic receptors, and bupropion, an antidepressant that helps reduce cravings and withdrawal symptoms, are also widely used. Other behavioral therapies are also included in treatment regimens.

However, even if this therapies are beneficial, these therapies come with drawbacks: NRT may not fully cure psychological dependency on smoking, bupropion and varenicline can cause side effects like insomnia, mood changes, and nausea, and behavioural therapy often requires long-term commitment, access to trained professionals, and consistent follow-up, which can be barriers for many smoking quitters.

What is Cytisinicline?

Cytisinicline is a plant-based alkaloid derived from Cytisus laburnum (golden rain tree). It has been used for decades in Eastern Europe as a smoking cessation aid, particularly in Bulgaria and Poland, under the brand name Tabex. Structurally and pharmacologically, it shares similarities with varenicline, a well-known partial agonist of the nicotinic acetylcholine receptor (nAChR).

Unlike nicotine, which fully activates neuronal nicotinic acetylcholine receptors, cytisinicline acts as a partial agonist, stimulating the receptor enough to reduce withdrawal symptoms and cravings while also blocking nicotine’s ability to bind and create the rewarding “high.” This dual action is what makes cytisinicline so promising.

How Does Cytisinicline Work?

Cytisinicline targets the α4β2 subtype of nicotinic acetylcholine receptors in the brain. These receptors play a key role in the addictive properties of nicotine. By binding to them, cytisinicline helps:

Reduce nicotine withdrawal symptoms

Diminish the rewarding effects of smoking

Ease the transition away from tobacco products

Its mechanism is very similar to that of varenicline, but cytisinicline may have a better safety and tolerability profile, which is a major advantage.

Clinical Evidence and Recent Trials

While cytisinicline has a long history of use in Eastern Europe, it has only recently undergone rigorous clinical trials in the U.S. and other Western countries.

ORCA-1 Trial (2020): This Phase 2b trial showed that cytisinicline significantly improved quit rates compared to placebo. Importantly, the drug was well-tolerated, with fewer reported side effects than varenicline.

ORCA-2 Trial (2022): A pivotal Phase 3 study that met its primary endpoint. The trial demonstrated that a 12-week course of cytisinicline significantly increased smoking abstinence compared to placebo. The quit rates were approximately 2.6 to 6.3 times higher than placebo, depending on the dosing regimen.

ORCA-3 Trial (2024): The most recent Phase 3 trial confirmed the results of ORCA-2, showing sustained abstinence at 6 and 12 weeks, with very few adverse events. The most common side effects were mild gastrointestinal discomfort and sleep disturbances.

Safety Profile

Across multiple studies, cytisinicline has been well tolerated. The most frequently reported side effects Nausea, Abnormal dreams, Insomnia, Headache, Fatigue and Anxiety. Cytisinicline appears to have a more favourable side effect profile compared to varenicline. Cytisinicline is associated with lower rates of nausea and sleep disturbances.

Conclusion

Cytisinicline is emerging as a serious contender in the smoking cessation space. With a strong safety profile, promising efficacy, and a natural origin, it could offer a much-needed alternative to current therapies. If FDA approved, cytisinicline may become a first-line option for smokers trying to quit and possibly the next big thing in the fight against nicotine addiction.

References

1.Varghese J, Muntode Gharde P. A Comprehensive Review on the Impacts of Smoking on the Health of an Individual. Cureus. 2023 Oct 5;15(10):e46532. doi: 10.7759/cureus.46532. PMID: 37927763; PMCID: PMC10625450.

2. Edward D. Gometz, Health Effects of Smoking and the Benefits of Quitting, AMA journal of ethics, Jan 2011, available from https://journalofethics.ama-assn.org/article/health-effects-smoking-and-benefits-quitting/2011-01

3. WHO report on the global tobacco epidemic, 2023: protect people from tobacco smoke, 31 July 2023, World Health Organization, available from https://www.who.int/publications/i/item/9789240077164

4. Notes from the Field: Tobacco Product Use Among Adults — United States, 2017–2023, Morbidity and Mortality Weekly Report, March 6, 2025 / 74(7);118–121

5. Nides M, Rigotti NA, Benowitz N, Clarke A, Jacobs C. A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial). Nicotine Tob Res. 2021 Aug 29;23(10):1656-1663. doi: 10.1093/ntr/ntab073. PMID: 33847362; PMCID: PMC8403245.

6. Rigotti NA, Benowitz NL, Prochaska J, et al. Cytisinicline for Smoking Cessation: A Randomized Clinical Trial. JAMA.2023; 330(2):152–160. doi:10.1001/jama.2023.10042

7. Rigotti NA, Benowitz NL, Prochaska JJ, et al. Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial. JAMA Intern Med.Published online April 21, 2025. doi:10.1001/jamainternmed.2025.0628

8. Current Cigarette Smoking among Adults in the United States, 17 Sep 2024, Smoking and Tobacco Use available from https://www.cdc.gov/tobacco/php/data-statistics/adult-data-cigarettes/index.html

9. Centers for Disease Control and Prevention (US); National Center for Chronic Disease Prevention and Health Promotion (US); Office on Smoking and Health (US). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2010. 3, Chemistry and Toxicology of Cigarette Smoke and Biomarkers of Exposure and Harm. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53014/

10. What’s in a cigarette? Cancer research UK, available from https://www.cancerresearchuk.org/about-cancer/causes-of-cancer/smoking-and-cancer/whats-in-a-cigarette-0