Clinical Brief: FDA approves new drug with dual action for weight loss

Eli Lilly recently received United States (U.S.) Food and Drug Administration (FDA) approval for tirzepatide (Zepbound™) for weight loss.

Highlights:

• Indication: An adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of ≥ 30 kg/m² (obesity) or BMI ≥ 27 kg/m² (overweight) in the presence of ≥ 1 weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus [T2DM], obstructive sleep apnea, or cardiovascular [CV] disease [CVD])
• Mechanism: Glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide 1 (GLP-1) receptor agonist (RA); GLP-1 regulates appetite/caloric intake; GIP may further regulate food intake
• Formulation: 0.5 mL of solution in pre-filled, single-dose pens (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg)
• Dosing: 2.5 mg once weekly starting dose, increased to 5 mg once weekly after 4 weeks; further dosage increases can be made in 2.5 mg increments after ≥ 4 weeks on the current dose; maintenance dosages are 5 mg, 10 mg, or 15 mg (maximum dose) once weekly; self-administered subcutaneously (SC)
• Boxed warning: Risk of thyroid C-cell tumors; warnings: severe gastrointestinal (GI) disease, acute kidney injury, acute gallbladder disease, acute pancreatitis, hypersensitivity reactions, hypoglycemia, diabetic retinopathy complications in T2DM patients, suicidal behavior/ideation
• Clinical studies: Approval is based on two published, phase 3, randomized, double-blind, placebo-controlled, 72-week trials (SURMOUNT-1; n=2,539 [patients without T2DM] and SURMOUNT-2; n=938 [patients with T2DM]) conducted in adults with obesity or overweight with ≥ 1 weight-related condition; in conjunction with counseling on reduced-calorie diet and increased physical activity; 20-week titration phase followed by maintenance phase (5 mg [SURMOUNT-1 only], 10 mg, or 15 mg once weekly)
  • SURMOUNT-1: Mean change in weight: -15% (5 mg dose), -19.5% (10 mg dose),
    -20.9% (15 mg dose) versus -3.1% with placebo (p<0.001)
  • SURMOUNT-2: Mean change in weight: -12.8% (10 mg dose) and -14.7% (15 mg dose) versus -3.2% with placebo (p<0.0001)
• Common adverse events (5 mg to 15 mg dose): GI – nausea (25% to 29%), diarrhea (19% to 23%), vomiting (8% to 13%), constipation (11% to 17%), abdominal pain (9% to 10%), dyspepsia (9% to 10%). Other common side effects (incidence <10%): injection site reactions, fatigue, hypersensitivity reactions, eructation (burping), hair loss, gastroesophageal reflux disease

Market Dynamics:

• Availability: Launch expected by end of 2023 in six dosage strengths
• Cost: List price $1,059.87 (about 20% lower than semaglutide 2.4 mg for weight loss)
• Eli Lilly launching commercial savings card:
  • with insurance and plan covers Zepbound, $25 for 1- or 3-month supply or
  • with insurance but no Zepbound coverage, $550 for 1-month supply
• Weight loss drugs are not covered by Centers for Medicare and Medicaid Services (CMS)

Market Impact:

Approximately 70% of adults in the U.S. have obesity or overweight. Furthermore, obesity-related conditions (e.g., CVD, T2DM, cancer) are top causes of preventable early deaths. A 5% to 10% body weight reduction is associated with a decreased risk for CVD in adults with overweight and obesity. In recent years, demand for GLP-1s has soared leading to off-label use, shortages, and access issues for patients with T2DM. The active ingredient in Zepbound, tirzepatide, first received FDA approval in May 2022 under the brand name Mounjaro^® (for adults with T2DM). The dosage strengths of Mounjaro are the same as for Zepbound, and both products are approved as single-dose pens.

Zepbound is the first and only FDA-approved obesity agent with activity at both GIP and GLP-1 receptors. In the SURMOUNT-1 trial (without T2DM), patients randomized to 15 mg once weekly of Zepbound had an average reduction in body weight of over 20%. In the SURMOUNT-2 trial (with T2DM), patients in the Zepbound 15 mg once weekly arm had an average reduction in body weight of over 14%. More patients discontinued Zepbound compared to placebo, with most discontinuations occurring in the first few months of therapy due to GI adverse effects. Zepbound should not be coadministered with other GLP-1s, including other tirzepatide-containing drugs. The safety and efficacy of Zepbound used concurrently with other weight management agents have not been established.

Lifestyle modification remains the cornerstone of weight management. Pharmacotherapy options for weight loss have expanded in recent years with the approval of GLP-1 RAs for weight management in adults – liraglutide (Saxenda^®) and semaglutide (Wegovy^®) also indicated for children and adolescents. In clinical trials, GLP-1s resulted in up to 15-16% weight loss in adults. Notably, a phase 3 study (SURMOUNT-5) is comparing tirzepatide to semaglutide for weight loss in patients without T2DM; results are expected in November 2024. There are several investigational agents for weight loss in the pipeline offering patient-friendly oral formulations and multi-target mechanisms. Moreover, pipeline agents are being studied for CV outcomes. Results of these trials will inform guidance and their long-term health benefits. In the published SELECT study, in patients with established CVD and 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. The SURMOUNT-MMO trial is evaluating tirzepatide for prevention of CV events in adults with obesity or overweight but without diabetes; data are anticipated in late 2027. Visit the Prime/MRx Weight Management Pipeline+ for more insights on investigational GLP-1s.

Prime + Magellan Rx Management Action:

Prime and Magellan Rx Management continue to closely monitor the weight management pipeline and provide clinical updates as appropriate.

References:

• FDA News Release: https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management.
• Eli Lilly Press Release: https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-zepboundtm-tirzepatide-chronic-weight.
• Centers for Disease Control and Prevention Adult Obesity Facts: https://www.cdc.gov/obesity/data/adult.html.
• Zepbound Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217806s000lbl.pdf.
• Mounjaro Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215866Orig1s002s006lbl.pdf.
• SURMOUNT-1 (NCT04184622): https://www.nejm.org/doi/full/10.1056/NEJMoa2206038.
• SURMOUNT-2 (NCT04657003): https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01200-X/fulltext.
• SURMOUNT-5 (NCT05822830): https://clinicaltrials.gov/study/NCT05822830.
• Saxenda Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206321s016lbl.pdf.
• Wegovy Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215256s007lbl.pdf.
• SELECT Trial: https://www.nejm.org/doi/full/10.1056/NEJMoa2307563.
• SURMOUNT-MMO (NCT05556512):  https://classic.clinicaltrials.gov/ct2/show/NCT05556512.