Pipeline+ Weight Management Front Runners

At Prime/Magellan Rx Management, we are dedicated to providing you with timely and valuable insights surrounding pipeline agents for weight loss. Given the surge in popularity for GLP-1 agents and the obesity epidemic, investigational medicines coming down the pipeline for weight loss are of special interest. Semaglutide (Wegovy®) and liraglutide (Saxenda®) had been the only FDA-approved glucagon-like peptide-1 receptors agonists (GLP-1RAs) for weight management. Recently, Eli Lilly’s tirzepatide, already approved as Mounjaro™ for T2DM, was approved under the brand name Zepbound™ for weight loss.[1] Zepbound, a once-weekly injectable, is a dual-acting agent targeting two incretin hormone receptors – GLP-1 and GIP. A number of companies are developing drugs for chronic weight management offering different options. Dual- and triple-acting mechanisms of action target different obesity-related hormone receptors, potentially resulting in more potent weight loss. Oral formulations that are more patient-friendly are being studied, negating the need for injections. Further, a small molecule non-peptide GLP-1 is under investigation. The most common adverse events with this class of drugs are gastrointestinal (nausea, vomiting, diarrhea, constipation, etc.), which could impact tolerability. Several studies are underway for CV outcomes in patients without diabetes. The published SELECT study, in patients with established CVD who were obese or overweight but did not have diabetes, once weekly SC Wegovy lowered the risk of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke by 20% over approximately 3 years. [2] Outcomes data will be key in determining risks versus benefits of these agents. Lifestyle modification and a holistic approach to weight management are foundational to weight loss. If approved, these new agents for weight loss could offer more options and potential access for patients who cannot achieve weight loss goals with diet and exercise alone. But appropriate patient selection and management should be key considerations.

The Prime/MRx Pipeline+ provides a credible clinical snapshot of weight loss candidates in the U.S. in addition to the recently FDA-approved Zepbound.

Weight Management Candidates

DRUG NAME DEVELOPER	TARGET	FORMULATION & DOSAGE	CLINICAL TRIAL DESIGN (Phase 3)	CLINICAL TRIAL RESULTS Mean % change in body weight	CARDIOMETABOLIC /CVOT DATA	COMMENTS	STATUS & MARKET DYNAMIC
tirzepatide (Zepbound) Eli Lilly	Dual-action GIP/GLP-1	SC Once weekly self-injection	SURMOUNT-1[3] (NCT04184622) n=2,539; nondiabetic; 72 weeks —————————- SURMOUNT-2[4] (NCT04657003) n=938; T2DM; 72 weeks—————————-SURMOUNT-3[5],[6] (NCT04657016) n=579; nondiabetic; 12-week lifestyle weight loss program lead-in; 72-week treatment period —————————- SURMOUNT-4[7] (NCT04660643) n=670; nondiabetic; 36-week tirzepatide lead-in; followed by 52-week treatment/withdrawal period	SURMOUNT-1 5 mg = -15% 10 mg = -19.5% 15 mg = -20.9% placebo = -3.1% —————–placebo = -3.2% —————————-SURMOUNT-3 10 mg & 15 mg = -21.1% (-26.6% total including lead-in)placebo = +3.3% —————————- SURMOUNT-4 10 mg & 15 mg pooled = -6.7% placebo (withdrawal) = +14.8%	SURMOUNT-MMO[8] (NCT05556512) ongoing phase 3 trial of tirzepatide for prevention of CV events in adults with obesity or overweight (nondiabetic); data anticipated in late 2027	Published data are available for SURMOUNT-1 and SURMOUNT-2 trials, for which FDA approval was based SURMOUNT-3 reported some patients may require pharmacological therapy in addition to lifestyle modifications to achieve their weight loss goals SURMOUNT-4 supports chronic pharmacotherapy to maintain treatment benefits —————————- Tirzepatide (Zepbound) is approved for chronic weight management in adults; recommended dosage 5-15 mg once weekly —————————- Tirzepatide (Mounjaro) is approved for adults with T2DM; recommended dosage 5-15 mg once weekly	FDA approved on November 8, 2023; launch expected by end of 2023 in six doses (same strengths as Mounjaro) to be provided in pre-filled, single-dose pens
orforglipron Eli Lilly	Single-action GLP-1 (non-peptide GLP-1)	Oral Once daily	ATTAIN-1[10] (NCT05869903) n=3,000 (estimated); nondiabetic; 72 weeks —————————- ATTAIN-2[11] (NCT05872620) n=1,500 (estimated); T2DM; 77 weeks —————————- ACHIEVE-4[12] (NCT05803421) n=2,620 (estimated); T2DM; insulin glargine comparison CVOT – 2 years	ATTAIN-1 trial data anticipated in 2025—————————- ATTAIN-2 trial data anticipated in mid-2025—————————- ACHIEVE-4 trial data anticipated in 2025	ACHIEVE-4 ongoing phase 3 trial for MACE primary prevention in adults with T2DM & obesity or overweight & increased CVD risks	—	Phase 3 ———————-Annual WAC of $20,516 projected for 2027
retatrutide Eli Lilly	Triple-action GIP/GLP-1/ glucagon	SC Once weekly self-injection	TRIUMPH-1[13] (NCT05929066) n=2,100 (estimated); nondiabetic  ± OSA or knee OA; 89 weeks —————————-TRIUMPH-2[14] (NCT05929079) n=1,000 (estimated); T2DM & OSA; 89 weeks	TRIUMPH-1 trial data anticipated in 2026—————————-TRIUMPH-2 trial data anticipated in 2026	TRIUMPH-3[15] (NCT05882045) ongoing phase 3 trial in adults with severe obesity and established CVD & includes secondary endpoints for cardiometabolic risk factors; duration 113 weeks; data anticipated in 2026	Published data from a phase 2 trial (NCT04881760)[16] suggested retatrutide as most potent weight lowering effect at the highest dose compared to other investigational agents, and may be associated with dose-dependent heart rate increases	Phase 3
semaglutide Novo Nordisk	Single-action GLP-1	Oral Once daily	OASIS-1[17] (NCT05035095) n=667; nondiabetic; 68 weeks —————————-OASIS-4[18] (NCT05564117) n=281; nondiabetic 25 mg dose; 72 weeks	OASIS-1 50 mg = -15.1% (p<0.0001) placebo = -2.4%—————————-OASIS-4 trial data anticipated in 2024	In OASIS-1, oral semaglutide improved cardiometabolic risk factors as secondary endpoints	Published data are available for OASIS-1 —————————- Oral semaglutide (Rybelsus®) is approved for adults with T2DM; recommended dosage 7 mg or 14 mg once daily maintenance —————————- SC semaglutide (Ozempic®) is approved for T2DM and for MACE in adults with T2DM & established CVD —————————- SC semaglutide (Wegovy) is approved for weight management in adults & adolescents	Phase 3; filing anticipated in 2023——————— No shortage for oral Rybelsus; however, ongoing shortages for some strengths of injectable Wegovy & Ozempic
cagrilintide + semaglutide Novo Nordisk	Dual-action Amylin/ GLP-1	SC Once weekly cagrilintide 2.4 mg + semaglutide 2.4 mg	REDEFINE-1[19] (NCT05567796) n=3,400 (estimated); nondiabetic; 68 weeks + 97-week extension phase —————————-REDEFINE-2[20] (NCT05394519) n=1,200 (estimated); T2DM; 68 weeks	REDEFINE-1 trial data anticipated in late 2024—————————-REDEFINE-2 trial data anticipated in late 2024	REDEFINE-3[21] (NCT05669755) phase 3 trial for prevention of MACE in adults (age 55+) with obesity and established CVD ± T2DM; duration up to 242+ weeks; data anticipated in 2027	—	Phase 3 ———————-Annual WAC of $21,700 projected for 2026
survodutide Boehringer-Ingelheim	Dual-action Glucagon/ GLP-1	SC Once weekly self-injection	SYNCHRONIZE-1[22]  (NCT06066515) n=600 (estimated); nondiabetic; 76 weeks —————————-SYNCHRONIZE-2[23] (NCT06066528) n=600 (estimated); T2DM; 76 weeks	SYNCHRONIZE-1 trial data anticipated late 2025—————————- SYNCHRONIZE-2 trial data anticipated late 2025	SYNCHRONIZE-CVOT[24] (NCT06077864) phase 3 trial; data anticipated in 2026	—	Phase 3

Glossary

CV – Cardiovascular
CVD – Cardiovascular Disease
CVOT  – Cardiovascular Outcome Trial
FDA – Food and Drug Administration
GIP – Glucose-Dependent Insulinotropic Polypeptide
GLP-1 Glucagon-Like Peptide-1
MACE – Major Adverse Cardiovascular Events
N/A – Not Available
OA – Osteoarthritis
OSA – Obstructive Sleep Apnea
Q  –  Quarter
SC – Subcutaneous
T2DM – Type 2 Diabetes Mellitus
U.S. – United States
WAC – Wholesale Acquisition Cost

Editorial staff

Maryam Tabatabai, Pharm D, Vice President, Clinical Information and Carole Kerzic, RPh, Drug Information Pharmacist

References

[1] FDA news release. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management. Accessed November 8, 2023.

[2] Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. NEJM. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2307563. Accessed November 13, 2023.

[3] Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. NEJM. Available at: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2206038?articleTools=true. Accessed November 8, 2023.

[4] Garvey WT, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomized, multicentre, placebo-controlled, phase 3 trial. The Lancet. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01200-X/fulltext.

[5] Press release. Available at: https://investor.lilly.com/news-releases/news-release-details/tirzepatide-demonstrated-significant-and-superior-weight-loss. Accessed September 28, 2023.

[6] Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nature Medicine. Available at: https://www.nature.com/articles/s41591-023-02597-w. Accessed October 23, 2023.

[7] Press release. Available at: https://investor.lilly.com/news-releases/news-release-details/tirzepatide-demonstrated-significant-and-superior-weight-loss. Accessed September 28, 2023.

[8] NCT05556512. Available at: https://www.clinicaltrials.gov/study/NCT05556512. Accessed October 23, 2023.

[9] Press release. Available at: https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-zepboundtm-tirzepatide-chronic-weight. Accessed November 8, 2023.

[10] NCT05869903. Available at: https://www.clinicaltrials.gov/study/NCT05869903. Accessed October 23, 2023.

[11] NCT05872620. Available at: https://www.clinicaltrials.gov/study/NCT05872620. Accessed October 23, 2023.

[12] NCT05803421. Available at: https://www.clinicaltrials.gov/study/NCT05803421. Accessed October 23, 2023.

[13] NCT05929066. Available at: https://clinicaltrials.gov/study/NCT05929066. Accessed October 23, 2023.

[14] NCT05929079. https://clinicaltrials.gov/study/NCT05929079. Accessed October 23, 2023.

[15] NCT05882045. Available at: https://www.clinicaltrials.gov/study/NCT05882045. Accessed October 23, 2023.

[16] NCT04881760. https://www.nejm.org/doi/10.1056/NEJMoa2301972. Accessed November 3, 2023.

[17] Knop FK, et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomized, double-blind, placebo-controlled, phase 3 trial. The Lancet. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01185-6/fulltext.

[18] NCT05564117. Available at: https://clinicaltrials.gov/study/NCT05564117. Accessed October 23, 2023.

[19] NCT05567796. Available at: https://www.clinicaltrials.gov/study/NCT05567796. Accessed October 23, 2023.

[20] NCT05394519. Available at: https://www.clinicaltrials.gov/study/NCT05394519. Accessed October 23, 2023.

[21] NCT05669755. Available at: https://www.clinicaltrials.gov/study/NCT05669755. Accessed October 23, 2023.

[22] NCT06066515. Available at: https://clinicaltrials.gov/study/NCT06066515. Accessed October 23, 2023.

[23] NCT06066528. Available at: https://clinicaltrials.gov/study/NCT06066528. Accessed October 23, 2023.

[24] NCT06077864. https://clinicaltrials.gov/study/NCT06077864?term=SYNCHRONIZE-CVOT&rank=1. Accessed November 3, 2023.