orforglipron (OWL833) / Roche, Eli Lilly - LARVOL DELTA

Novel Oral Small Molecule GLP1 Agonist Reduces Body Weight and Improves Glucose Control in DIO Mice (OBESITY WEEK 2024) - "Six groups, 10 mice per group were (vehicle, 3 dose levels of MLX-7006, Semaglutide and Orforglipron) dosed daily for 4 weeks. The novel, orally available small molecule GLP-1 agonist, MLX-7006, demonstrated significant and robust reductions in body weight and improved glucose homeostasis in DIO mice. These findings highlight the potential of MLX-7006 as a promising treatment for obesity and type 2 diabetes. Further preclinical investigations to characterize MLX-7006 in obesity models and studies on its general toxicology, safety, and tolerability are underway."

Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Improved HRQoL and Functioning in Adults With Obesity Treated With Orforglipron in a Phase 2 Study (OBESITY WEEK 2024) - "In this 36-week Phase 2 study, higher doses of the novel oral OFG treatment significantly improved multiple domains of HRQoL, including functioning, vs. placebo in adults with obesity or overweight, which is comparable to outcomes with injectable GLP-1 RAs."

Clinical • P2 data • Diabetes • Genetic Disorders • Obesity • Type 2 Diabetes Mellitus

ATTAIN-OSA: A Master Protocol for Orforglipron in Participants With Obstructive Sleep Apnea and Obesity or Overweight (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

A Study of Orforglipron for the Maintenance of Body Weight Reduction in Participants Who Have Obesity or Overweight With Weight-Related Comorbidities (ATTAIN-MAINTAIN) (clinicaltrials.gov) - P3 | N=300 | Enrolling by invitation | Sponsor: Eli Lilly and Company | N=480 ➔ 300

Enrollment change • Genetic Disorders • Obesity

ATTAIN-OSA: A Master Protocol for Orforglipron in Participants With Obstructive Sleep Apnea and Obesity or Overweight (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Genetic Disorders • Obesity • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

ACHIEVE-4: A Study of Daily Oral Orforglipron (LY3502970) Compared With Insulin Glargine in Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk (clinicaltrials.gov) - P3 | N=2749 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial primary completion date: Apr 2025 ➔ Sep 2025

Trial primary completion date • Cardiovascular • Chronic Kidney Disease • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

Effects of once-daily oral orforglipron on weight and metabolic markers: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Arch Endocrinol Metab) - "In this meta-analysis, the use of once-daily oral orforglipron by adult patients was associated with a significant decrease in body weight, as compared with placebo, with an increase in non-severe gastrointestinal adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-daily oral orforglipron over the long term."

Biomarker • Clinical • Journal • Retrospective data • Review • Gastrointestinal Disorder • Genetic Disorders • Obesity

GASTROINTESTINAL ADVERSE EVENTS WITH GLP-1 RAS IN NON-DIABETIC OVERWEIGHT AND OBESE INDIVIDUALS: SYSTEMATIC REVIEW AND DOSE-RESPONSE META-ANALYSIS (UEGW 2024) - "Across all evaluated GLP-1 RAs, a notable elevation in nausea risk was noted, with orforglipron exhibiting the highest risk, succeeded by exenatide, tirzepatide, semaglutide, and liraglutide. In conclusion, GLP-1 RAs are associated with an increased risk of GI adverse effects, including nausea, vomiting, diarrhea, constipation, and abdominal pain. Importantly, distinct GLP-1 RAs exhibited varying degrees of risk for these adverse effects, underscoring the importance of tailored risk assessment and management strategies in clinical practice."

Adverse events • Retrospective data • Review • Constipation • Gastrointestinal Disorder • Genetic Disorders • Obesity • Pain

Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials. (PubMed, Metabolism) - "Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists."

Journal • Retrospective data • Review • Diabetes • Genetic Disorders • Hypoglycemia • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Emerging Pharmacotherapies for Obesity: A Systematic Review. (PubMed, Pharmacol Rev) - "Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide, survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate...This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives."

Journal • Review • Developmental Disorders • Genetic Disorders • Obesity

A multicenter, blinded, placebo-controlled, randomised single- and multiple-ascending dose study of orforglipron, an oral GLP-1 receptor agonist, in Japanese patients with type 2 diabetes (EASD 2024) - P1 | "The safety and tolerability profiles of single and multiple doses of OFG were consistent with those of other GLP-1 RAs. Safety, pharmacokinetic, and pharmacodynamic results were similar to those of previous OFG studies. These results establish the appropriate dose range for further study of OFG in Japanese patients with T2D."

Clinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Orforglipron, an oral GLP-1RA, improves CV risk biomarkers in patients with obesity (EASD 2024) - P2 | "The novel, once daily, non-peptide OFG demonstrated clinically meaningful reductions in lipid, leptinand inflammatory biomarkers with simultaneous weight loss. The magnitude of reduction of hsCRP levels following OFG treatment is similar to the effects reported with injectable GLP-1 RAs. These observations suggest that OFG might improve CV risk in patients with obesity, as has been shown in long-term outcome trials with other GLP-1 RAs."

Biomarker • Clinical • Diabetes • Metabolic Disorders • Obesity • APOB • CRP • IL6 • LEP

Effects of Orforglipron, a novel oral GLP-1 receptor agonist, on metabolic dysfunction-associated steatotic liver disease related biomarkers (EASD 2024) - P2 | "These results suggest that once-daily oral non-peptide GLP-1 RA orforglipron may improve MASLD-related liver biomarkers in this patient population. Orforglipron demonstrates a similar effect on these biomarkers as injectable GLP-1 RAs. Further studies are needed to determine if such improvements lead to better outcomes."

Biomarker • Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus • KRT18 • LEP

A Study of Orforglipron for the Maintenance of Body Weight Reduction in Participants Who Have Obesity or Overweight With Weight-Related Comorbidities (ATTAIN-MAINTAIN) (clinicaltrials.gov) - P3 | N=480 | Enrolling by invitation | Sponsor: Eli Lilly and Company

New P3 trial • Genetic Disorders • Obesity

A Study of LY3502970 in Chinese Participants With Obesity or Are Overweight With Weight-related Comorbidities (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

ACHIEVE-4: A Study of Daily Oral Orforglipron (LY3502970) Compared With Insulin Glargine in Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk (clinicaltrials.gov) - P3 | N=2620 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Chronic Kidney Disease • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

A Drug-Drug Interaction (DDI) Study of Orforglipron With Carbamazepine in Healthy Participants (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: Eli Lilly and Company | Recruiting ➔ Completed

Trial completion

A Study of LY3502970 in Participants With Impaired and Normal Liver Function (clinicaltrials.gov) - P1 | N=33 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Jul 2024 ➔ Nov 2024 | Trial primary completion date: Jul 2024 ➔ Nov 2024

Trial completion date • Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

A Drug-Drug Interaction Study of Orforglipron (LY3502970) in Healthy Overweight and Obese Participants (clinicaltrials.gov) - P1 | N=50 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Obesity

ACHIEVE-3: A Study of Orforglipron (LY3502970) Compared With Semaglutide in Participants With Type 2 Diabetes Inadequately Controlled With Metformin (clinicaltrials.gov) - P3 | N=1576 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Discovery of a Potent, Orally Efficacious Small Molecule Agonist of Glucagon-Like Peptide-1 (GLP-1) Receptor (ADA 2024) - "Several small molecule agonists of the GLP-1 receptor have been investigated as potential alternatives to peptide-based GLP-1 agonists like Danuglipron, and Orforglipron... In Conclusion, MLX-7005 is a highly potent, orally available, GLP-1 agonist. pre-clinical in vivo DIO, db/db rodent models studies are underway along with safety, and tolerability to further evaluation as a potential therapy for T2DM and obesity will be presented."

Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Study to Compare Tablets and Capsules of Orforglipron (LY3502970) in Healthy Participants Who Are Obese or Overweight (clinicaltrials.gov) - P1 | N=508 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

Orforglipron Improves Markers of Beta-Cell Function and Insulin Sensitivity in Type 2 Diabetes (ADA 2024) - "Funding By Eli Lilly and Company Orforglipron (OFG), an oral, non-peptide GLP-1 receptor agonist, demonstrated significantly greater glycemic control and weight loss at doses ≥12 mg vs placebo (PBO) or dulaglutide (DU) 1.5 mg in a 26-week phase 2 study of adults with type 2 diabetes (T2D) (Table). These exploratory analyses investigated mechanisms by which OFG improved glycemic control in T2D by analyzing exploratory biomarkers.Participants with T2D (mean age, 58.9 years; baseline HbA1c, 8.1%; weight, 100.3 kg) treated with diet and exercise, with/without metformin, were randomized to PBO, DU 1.5 mg, or once-daily OFG 3, 12, 24, 36, or 45 mg...Fasting glucose-adjusted glucagon significantly decreased with OFG at doses ≥12 mg vs PBO and with OFG 12, 24, and 45 mg vs DU.These analyses suggest improved glycemic control with OFG vs DU may be partly explained by improved β-cell function and insulin sensitivity. Additional studies are ongoing to understand these mechanisms."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

ACHIEVE-1: A Study of Orforglipron (LY3502970) in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Diet and Exercise Alone (clinicaltrials.gov) - P3 | N=520 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

ACHIEVE-J: A Long-term Safety Study of Orforglipron (LY3502970) in Participants With Type 2 Diabetes (clinicaltrials.gov) - P3 | N=399 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus