Disease Analysis: Type 1 Diabetes

Disease definition

Diabetes mellitus is a group of chronic endocrine disorders characterized by hyperglycemia due to insufficient levels of insulin, a hormone responsible for regulating blood sugar. Symptoms include excessive excretion of urine (polyuria), thirst (polydipsia), constant hunger, weight loss, vision changes, and fatigue. According to the World Health Organization (WHO), approximately 8.5% of adults had diabetes in 2014. Type 1 diabetes accounts for around 5–10% of the total diabetic population. The majority of cases of type 1 diabetes may be classified as type 1a, an autoimmune disease characterized by the destruction of pancreatic beta cells, with a minority of cases making up type 1b, which is described as idiopathic diabetes mellitus.

Latest key takeaways

• Despite newer products with improved PK/PD profiles, the type 1 diabetes treatment market has been gradually declining in value, driven by declines in the US, and factors contributing to this are expected to continue, including net pricing pressures following the launches of biosimilars, saturation with multiple maturing insulins, and limited or uncertain prospects of non-insulin therapies. That said, if very early-stage transformative technologies succeed, such as glucose-responsive insulins, they could recast the market, but there is a lack of good clinical data on these to date.
• In the basal insulin segment, with the advent of biosimilars/follow-on copies to segment leader Sanofi’s Lantus, Sanofi and Novo Nordisk have introduced next-generation, longer-acting products; however, due to continued price pressures, especially in the US, these have not prevented overall sales declines. Sanofi’s longer-acting Toujeo does have some signals for a hypoglycemia benefit over Lantus, but not as much in type 1 diabetes as in type 2, and does allow some patients who require twice-daily Lantus to inject once daily. However, KOLs interviewed by Datamonitor Healthcare suggest that the advantages are somewhat limited, and with modest sales in the US, in the face of franchise competition with Basaglar, a follow-on copy of Lantus, Toujeo has not prevented a steep drop in combined US sales with Lantus over the past five years, leading to a 40% drop worldwide despite some combined stability ex-US. US sales of Lantus plus Toujeo have stabilized somewhat over the past couple of years, with only a small decline, but the introduction of another follow-on copy, Semglee, in 2020 could introduce further pressures, particularly as it was designated as an interchangeable biosimilar in July 2021, with later adoption as a preferred brand by a major pharmacy benefit manager (PBM). Viatris took a dual-product approach for the interchangeable version, with a higher-priced branded Semglee and a lower-priced unbranded version for broad coverage (eg rebates from the branded product can be important to PBMs in particular). In response to these biosimilars/follow-ons, Sanofi launched its own unbranded biologic of Lantus.
• Novo Nordisk’s basal analog Levemir, which requires twice-daily dosing in many type 1 patients, has generally lost share to its successor product Tresiba due to the company’s promotion of Tresiba’s longer-acting duration of 42+ hours and its flexible dosing window (it can be administered at different times each day), which offer improved convenience for patients. Tresiba also has hypoglycemia benefits over Lantus, with a reduction in severe hypoglycemia in a large outcomes study, albeit in type 2 diabetes, with data appearing on its US label. Nevertheless, while Tresiba appears more differentiated than Toujeo, it has been difficult to discern whether there are substantial differences in other clinical benefits between the two, because each sponsor has conducted head-to-head PK/PD and longer-term hypoglycemia studies, but those studies have either shown equivalence or an advantage for the sponsor’s drug (the larger studies have been in type 2). While Tresiba initially had helped increase combined overall usage of the Novo Nordisk franchises, it has come at the expense of increasing rebates in the US, so in the past five years, despite combined sales growth ex-US, worldwide sales have declined by slightly over 20% – though these declines have not been as large as for the Sanofi basal franchise. Tresiba’s volume share growth in the US also appeared to stall in 2020, so it is somewhat unclear how much more it can capitalize there on its advantageous profile.
• There is substantial net price competition in the US. While list prices have historically increased – though in the face of negative publicity and competition from biosimilars/follow-on copies, major brands appeared to have stopped this practice since 2017–19 – rebates have also risen substantially. Endocrinologist KOLs interviewed by Datamonitor Healthcare emphasized the impact of pricing on prescribing trends, as formulary changes in the US lead to regular switching among patients.
• Dynamics are somewhat different in the fast-acting/bolus segment of the market, due to more exclusive contracting in the US, including bundling of insulin mixes, which has made it more difficult for biosimilar/follow-on copies to gain a foothold, though they still contribute to similar pricing pressure. It has also been more difficult to differentiate next-generation, faster-acting products.
• The segment leaders to date have been Novo Nordisk’s NovoLog and Eli Lilly’s Humalog. Interviewed KOLs believe there are no definitive clinical differentiators between the two in a real-world setting. While NovoLog leads in sales worldwide, there are differences within particular geographic regions (and there can be some impact from exchange rates), so in the US, Humalog has similar usage (and, based on estimates, higher sales). However, largely due to price pressures, Humalog and NovoLog sales have declined in the US over the past five years, and sales gains for both outside the US have not been enough to prevent moderate declines overall. While the introduction of Sanofi’s biosimilar/follow-on copy to Humalog, Admelog, has only led to modest sales, it did prompt the other manufacturers to launch “authorized follow-ons/generics” with 50% lower list prices in 2019/20, in order to increase competitiveness in plans such as US Medicare Part D, where patients can end up having to pay a portion of a drug’s gross cost. Viatris (Mylan) and possibly Sanofi (the status of its candidate is unclear) are pursuing US approval as interchangeable insulins for their biosimilars of NovoLog, so it will be interesting to see whether that makes a difference.
• Novo Nordisk’s faster-acting Fiasp can be injected at the start of a meal or within 20 minutes after, rather than immediately before or soon after for NovoLog. Nevertheless, clinicians have been underwhelmed as its faster onset of action has not provided a substantial therapeutic benefit, so uptake has been limited so far. Eli Lilly’s faster-acting Lyumjev launched in mid-2020 in major markets, and while it can also be injected within 20 minutes after a meal, its data are somewhat weaker than Fiasp’s, and expectations are limited.
• Use of continuous subcutaneous insulin infusion (CSII), or insulin pumps, has been increasing, with penetration in the US in a large minority of type 1 patients. The most advanced currently available systems are still hybrid closed-loop, meaning that while they adjust basal insulin frequently in response to a continuous glucose monitor – or, in some cases, also give an automatic bolus dose – they do not take over glucose control completely, and patients need to still input information for mealtime boluses. The latter may be a difficult issue to overcome given time lags between interstitial fluid continuous glucose monitoring (CGM) measurements and blood glucose measures, though companies are also working on incorporating glucagon and using artificial intelligence to better adapt insulin delivery to each patient’s fluctuating glucose trends.
• Pipeline product teplizumab has shown potential to prevent or delay the onset of type 1 diabetes, as Phase II data have demonstrated that a single course of the drug significantly delayed disease onset in at-risk patients by a median of 2.7 years. However, due to issues with the comparability of the drug product intended for commercialization versus that used in the pivotal trial, it received a complete response letter (CRL) from the FDA, though based on a new PK comparison and model, the FDA may allow a dose adjustment to resolve the issue, so it was resubmitted. In addition, repeat dosing has not been tested. Hence, it will face the challenge of appropriate pricing to reflect the market value of delaying or preventing diabetes while ensuring that a high upfront cost does not prevent reimbursement or lead to overbearing prior authorization. Another challenge is the lack of existing screening programs to detect the broader group of patients who are at risk for type 1 diabetes, which could limit the drug’s target population (at least initially). Teplizumab’s commercial success will therefore require healthcare services, physicians, and industry to collaborate on creating and integrating accessible screening programs into different health services globally. In addition, if it fails an ongoing trial in early type 1 diabetes treatment, questions could be raised whether the prevention findings were accurate. On the positive side, developer Provention Bio did recently enter a co-promotion agreement with Sanofi for the US, though it appears somewhat limited.
• SGLT inhibitors may offer benefits to type 1 diabetes patients beyond improved glycemic control (such as blood pressure reduction, weight loss, and cardiorenal benefits), but the effects are modest, and despite Farxiga’s approval for type 1 in Europe, its use in the segment was quite limited and the indication was withdrawn from the market to avoid a potentially confusing safety label. In the US, the FDA has now rejected all three members of the class that have been filed for regulatory approval, and Farxiga and Jardiance are no longer pursuing US approval. Zynquista has had a couple of appeals denied and, in 2022, the FDA issued a proposed order denying a hearing, though Lexicon can still submit material trying to counter that. However, it appears unlikely that the class will ever gain FDA approval for type 1 diabetes without additional studies to further investigate the risk of diabetic ketoacidosis, the durability of glycemic benefits, and the effectiveness of proposed risk management strategies – studies that at this point appear unlikely.
• Datamonitor Healthcare estimates that in 2021, there were approximately 48.4 million prevalent cases of type 1 diabetes in adults aged 20 years and over worldwide, and forecasts that number to increase to 51.8 million prevalent cases by 2027.
• Datamonitor Healthcare estimates that in children and adolescents aged below 20 years, there were approximately 1.09 million prevalent cases of type 1 diabetes worldwide in 2021, which are expected to increase to 1.12 million prevalent cases by 2027.
• The overall likelihood of approval of a Phase I type 1 diabetes asset is 12.7%, and the average probability a drug advances from Phase III is 71.4%. Type 1 diabetes drugs, on average, take 9.8 years from Phase I to approval, compared to 9.9 years in the overall endocrine space.