Disease Analysis: Type 2 Diabetes

Diabetes mellitus is a group of metabolic disorders which are characterized by hyperglycemia (elevated blood glucose levels) due to insufficient insulin secretion, which in type 2 diabetes occurs in the setting of insulin insensitivity.

Latest key takeaways

• 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. Patent expirations starting in 2025 will also impact the class.
• 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. It should also help to defend against loss of patent protection for Victoza, in 2022–23 in major markets. 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, which will be important for the company, as Trulicity loses patent protection in 2027–29 in major markets. 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 agent 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), and with a second complete response letter, it is unclear whether it will ever be approved. 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 8.6 years from Phase I to approval, compared to 9.2 years in the overall endocrine space.