The type 2 diabetes market is dynamic and complex. In the non-insulin segment, while older generic drugs are widely used, especially first-line metformin in the US and EU, the more novel branded drugs are used in a sizable minority of patients, generating over $24bn in sales in 2018.
The DPP-IV inhibitors have been the most commonly used of these, due to their safety and tolerability, albeit with intermediate efficacy, but GLP-1 agonists and SGLT-2 inhibitors are poised to overtake them in the important US market, with recommendations in a 2018 American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus report for patients with relevant co-morbidities due to their benefits on major adverse cardiovascular events (MACE), and for the SGLT-2 inhibitors in particular, heart failure (HF) and renal impairment.
This is expected to continue to grow these classes, though clinical inertia still needs to be overcome among a number of physicians, and intense pricing competition, with increasing rebates in the US, is typical across the indication. However, loss of exclusivity will start to take a toll on all of these classes over the next 10 years, particularly starting with patent expirations for the leading DPP-IV inhibitor, Januvia, in 2022.
The SGLT-2 inhibitors are hoping to bolster growth with data and label additions for pivotal HF and chronic kidney disease (CKD) trials, including in non-diabetics. Jardiance has taken the lead, with a strong reduction in cardiovascular (CV) death, after Invokana faltered due to concerns about an increased risk of amputations. Side effects, including increased risk of genitourinary infections, and safety concerns have generally held the class back somewhat.
Sales of the injectable GLP-1 agonists have grown substantially with the addition of a more convenient weekly formulation, Eli Lilly's Trulicity, which expanded usage of the segment rather than displacing Novo Nordisk's daily Victoza, which was the first in the class to show a CV benefit. However, Novo Nordisk's weekly Ozempic, introduced in 2018, is more effective, and has helped the franchise stay ahead in sales. The battle is continuing with trials of higher doses of both drugs, new CV indications, and development of Eli Lilly's GIP co-agonist, tirzepatide.
Another fairly effective weekly GLP-1 agonist in development, efpeglenatide, was dropped by Sanofi in late 2019 as the company did not have confidence it could be differentiated enough. Pipeline ITCA-650 is implanted under the skin every six months, which could be attractive to a segment of patients, though it did not show a clear CV benefit in its modest-sized cardiovascular outcomes trial (CVOT). While the GLP-1 agonists cause weight loss, their main side effect is nausea, and as injectables they tend to be used after oral drugs have failed. However, an oral formulation of Ozempic, Rybelsus, approved in 2019, appears to be the most effective branded oral drug and is poised to disrupt the segment, as well as expand usage earlier on in competition with other oral classes.
In Japan, DPP-IV inhibitors are used more commonly at first line, and guidelines are somewhat equivocal about the implications of the CV findings of the other classes for Japanese patients.
In the insulin segment, the popular analogs are coming under increasing pricing pressure with the advent of biosimilars. The latter have had only limited sales so far, but are still ramping, and additional biosimilars are poised to soon enter the US market. For basal insulin analogs, Toujeo and Tresiba are Sanofi and Novo Nordisk's longer-acting replacements for segment leader Lantus and for Levemir, respectively. Toujeo has not been able to stem losses for Sanofi's basal analog portfolio in the US, with only a quarter of the sales of Lantus, but has had more success in doing so outside the US. For Novo Nordisk, Levemir's profile was not as strong as Lantus's to start with and lagged in sales, so Tresiba is more of an advance, and has helped to increase usage in the US and stabilize overall sales in other areas.
Weekly basal insulins are in development, and while there are questions about their utility, they could be especially useful in fixed-ratio combinations (FRCs) with weekly GLP-1 agonists. For mealtime insulins, the more recent ultra-rapid-acting formulations have relatively marginal benefits over their predecessors, and Novo Nordisk's Fiasp only has modest sales, though it is still early in its ramp. It is also still early in the ramp of mealtime biosimilars, which in the US face the challenge of more exclusive payer contracts. For the insulins space in general, while companies are looking into glucose-sensitive insulins with a lower risk of hypoglycemia, it is still uncertain how promising these will be.
Improving insulin sensitivity is a mechanistic unmet need, but pipeline candidates so far have not appeared very compelling, though imeglimin has shown intermediate efficacy in Japanese patients.
Given limited budgets for many patients, there could be indirect competition with novel dyslipidemia drugs.
The overall likelihood of approval of a Phase I type 2 diabetes asset is 7.5%, and the average probability a drug advances from Phase III is 68.4%. Type 2 diabetes drugs, on average, take 8.7 years from Phase I to approval, compared to 9.2 years in the overall endocrine space.
Key Topics Covered
- Latest key takeaways
2. DISEASE BACKGROUND
- Patient segmentation
- Major treatment guidelines
- Guideline treatment targets are individualized according to patient characteristics
- Treatment guidelines are shifting their approach based on results from recent clinical outcomes studies
5. MARKETED DRUGS
6. PIPELINE DRUGS
7. KEY REGULATORY EVENTS
- As Sanofi Exits Diabetes R&D, Meaning of Diabetes R&D Blurs
8. PROBABILITY OF SUCCESS
9. LICENSING AND ASSET ACQUISITION DEALS
- Hanmi Says Sanofi Made Optimal' Efpeglenatide Decision, Still Eyes 2021 Approval
- Novo Nordisk Enters Its First Strategic RNAi Pact
10. CLINICAL TRIAL LANDSCAPE
- Sponsors by status
- Sponsors by phase
- Recent events
11. DRUG ASSESSMENT MODEL
- Generically available oral drugs
- Branded non-insulin drugs
- Other pipeline mechanisms
12. SWOT ANALYSIS
13. MARKET DYNAMICS
14. FUTURE TRENDS
15. CONSENSUS FORECASTS
16. RECENT EVENTS AND ANALYST OPINION
- ORMD-0801 for Diabetes Mellitus, Type 2 (November 18, 2019)
- PEX168 for Diabetes Mellitus, Type 2 (September 19, 2019)
- Tresiba for Diabetes Mellitus, Type 2 (September 19, 2019)
- PEX168 for Diabetes Mellitus, Type 2 (September 17, 2019)
- Ozempic for Diabetes Mellitus, Type 2 (September 17, 2019)
- ZGN-1061 for Diabetes Mellitus, Type 2 (September 5, 2019)
- Zynquista for Diabetes Mellitus, Type 2 (July 26, 2019)
- Remogliflozin Etabonate for Diabetes Mellitus, Type 2 (July 11, 2019)
- HM12525A for Diabetes Mellitus, Type 2 (July 3, 2019)
17. KEY UPCOMING EVENTS
18. KEY OPINION LEADER INSIGHTS
- Interviews with physicians at the ADA conference
19. UNMET NEEDS
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