Wrapping up 2025:  GLP-1

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US GLP-1 Compounding – Regulatory Framework, Unit Economics & Implications for Branded GLP-1 Market Growth

Key insights 

• C250kg of API was imported in 2024, ramping 20-30% YoY. Tirzepatide API is readily available, but demand is lower due to price delta vs semaglutide
• One vial of semaglutide and tirzepatide costs USD 15-20 and USD 25-30, respectively, at maintenance. Fully loaded cost for semaglutide is USD 45. Semaglutide API pricing to decline to USD 12 in 2026, plateauing at USD 10
• Compounding is here to stay. Doctors retain prescriptive authority for personalised medications, making most litigation unviable. Even if successful, other compounders rapidly replace those shut down
• Injectable GLP-1 pricing will decline to cUSD 100 per month. New sublingual formulations and ODTs could significantly disrupt the market, given monthly pricing of USD 50-60 and USD 80, respectively
• Compounded GLP-1 share will ramp from c30% to c60-70% by 2030 driven by multiple tailwinds, including self-insured employers opting for compounded versions. Compounded oral GLP-1s will capture c80% share within a few years of orforglipron and oral semaglutide launches

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Oral GLP-1s – Orforglipron, Oral Semaglutide & Wider Pipeline Review

Key insights 

• ATTAIN-1 efficacy appears inferior to Wegovy and 25mg oral semaglutide, with tolerability broadly comparable. However, oral semaglutide's fasting requirements are a significant nuisance factor and may drag down real-world efficacy due to non-compliance, such that orforglipron may be the preferred option. Moreover, in practice, most patients with obesity without type 2 diabetes, other than those with very high BMIs, only want and/or need c10% weight loss. This is the threshold for metabolic benefits such as the delaying type 2 diabetes onset. Consequently, orforglipron represents a "game changer" in the primary care setting in particular
• Underwhelming ATTAIN-1 data could be due to a variety of reasons. Firstly, based on ACHIEVE-1 and ATTAIN-2, orforglipron appears to be comparable to injectables, implying that ATTAIN-1 was an anomaly. Should the study be re-run, outcomes may be better – "what we saw in ATTAIN-1 is probably not reflective of what we're going to see in future studies"
• Other potential explanations include patient demographics, with ATTAIN-1 enrolling a greater diversity of ethnicities and younger patients than the phase 2, which was predominantly in older and white patients, who typically lose more weight. Specialist finds that African American and Latino patients lose c20-25% less weight. Does not think there was a dosing issue in ATTAIN-1, ie, 45mg should have been tested. Believes the patient populations used in current phase 3 trials are different to those used in STEP and SURMOUNT. Consequently, phase-2-to-phase-3 efficacy plateaus will become increasingly common
• ATTAIN-MAINTAIN study is a "brilliant idea", given c50% of patients drop off injectable therapy within one year. Specialist believes injectable semaglutide patients will likely regain 15-20% body weight, whereas tirzepatide switch patients would regain 25-30%. Greater weight loss is driven by the tolerability delta between tirzepatide and orforglipron being larger than semaglutide and orforglipron
• For patients with obesity but not type 2 diabetes, specialist expects 33% in speciality practice to be on oral therapies, with a 50/50 split between orforglipron amd 25mg oral semaglutide. In the primary care or community setting, expects 50% of patients to be on oral therapies, with orforglipron capturing 66% share. In patients with type 2 diabetes, believes orals will capture <25% share. Injectables will continue to dominate, given the focus on reducing cardiovascular and renal disease, which only the injectables have on label today

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It's Not the Molecule, It's the Model – LillyDirect, NovoCare, Novo-Hims, Lilly-Ro & Novo-CVS-Caremark – What Does It All Mean for Prescription Share?

Key insights 

• Adoption of GLP-1 therapies will ultimately depend on commercial factors, such as pricing, insurance coverage and patient access. Patients want OOP costs near USD 100 per month. While improved efficacy or formulations of next-generation GLP-1s are appealing, uptake will be limited unless these access barriers are addressed. Currently, only 10-15% of specialist’s patients are on the highest doses of tirzepatide or semaglutide, suggesting limited need for more efficacious drugs or dosing constraints due to side effects
• 10-15% of specialist's non-diabetic patients pay OOP – likely below average due to academic practice and older patient base. C40% are commercially insured, of which 50-60% have obesity coverage. Of those, c50% are fully covered, with remainder having high co-pays that limit access. Insurance coverage has declined since January 2025 – 30-40% of patients previously covered are no longer eligible due to stricter prior authorisations, comorbidity requirements or higher body mass index thresholds
• C60-65 and c30-35% of all patients treated with Wegovy and Zepbound, respectively, but Zepbound captures 55% of new starts. This is largely driven by formularies being updated to include Zepbound and its superior clinical profile. Expects Zepbound to capture 60-65% of new scripts going forwards – all else being equal
• c70-80% of patients using compounded GLP-1s are on semaglutide. Believes patients have likely built up around a three-month supply of inventory, implying a lag before any benefit on Wegovy scripts. Because of the cost delta between brands and compounded semaglutide, expects only c10-20% of patients to switch. Of those that do switch, c80% will stick to the same drug
• 10-15% of patients are using NovoCare and LillyDirect, which is expected to increase to c25%. Expects dosing to be higher via telehealth channels, but average duration of therapy to be lower, given side effects. CVS Caremark partnership unlikely to cause step change in Wegovy prescription share. Only c20% of specialist's patients are covered by CVS Caremark – 8% of his total population – and only 50-60% are on a Caremark formulary that covers GLP-1s. Moreover, it's unclear how many members will enrol for these template formularies. Additionally, physicians can influence via medical exemption. Evernorth's USD 200 copay cap may drive patient volumes, but patients prefer the USD 100 per month target

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