Disease Analysis: Diabetic Nephropathy

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were approximately 128.1 million prevalent cases of diabetic nephropathy (DN) in adults aged 20 years and older with type 2 diabetes worldwide, and forecasts that number to increase to 138.2 million prevalent cases by 2027, driven by population demographics. Approximately 30% of diagnosed diabetics are also diagnosed with DN. However, screening practices differ between countries and local health systems, which can impact patients identified for treatment.
• The DN market is complex, because in addition to specific mechanisms that directly impact the disease, blood pressure and glycemic control are additional general targets that affect the condition. Moreover, there is high cardiovascular (CV) risk in DN patients, and many physicians may be more concerned about that than the risk for end-stage renal disease, especially in less advanced patients. Hence, drugs that directly impact DN and also benefit these other targets or have a CV benefit can have a competitive advantage.
• The antihypertensive ACE inhibitors or ARBs have been the mainstay of specific treatment for type 1 and type 2 DN as they have renal benefits beyond blood pressure lowering. Usage increases at first with greater renal impairment, though it may decline in stage 4 due to concerns about complications of hyperkalemia or deterioration of renal function in more advanced patients. Patients may also be receiving these classes for hypertension, which is present in most patients with DN, or for other CV indications, without a specific intention of treating DN.
• The SGLT-2 inhibitors are renewing the genericized market due to their renal and CV benefits in DN patients. Along with mineralocorticoid receptor antagonist (MRA) Kerendia, they are expected to continue to grow the market in the intermediate term, with sales growth slowing in 2026 and then eventually declining as the SGLT-2 inhibitors lose patent protection.
• Even before approvals in DN, SGLT-2 inhibitors were used to treat diabetes in DN patients, albeit hampered by some side effects and waning antiglycemic efficacy with more advanced chronic kidney disease (CKD). Members of the class have also been found to have benefits in important CV co-morbidities – especially heart failure (HF), but also in some situations CV death or MACE – leading to label expansions, which along with specific approvals for DN and/or broader CKD have spurred sales growth in the class as a whole, though in the US this has been somewhat offset by net price declines. Invokana was the first SGLT-2 inhibitor with a type 2 DN indication, but has been unable to capitalize much on it due to concerns about a possible increased risk of amputations. Farxiga was approved for CKD in the US in April 2021 based on stellar results from a CKD trial that included both diabetics and non-diabetics, albeit with fairly high levels of albuminuria. Jardiance also had a good lowering of the primary endpoint, and while results were not all as strong as for Farxiga, that may be due to the inclusion of patients with lower degrees of albuminuria, whose event rates were lower. The SGLT-2 inhibitors have other benefits, as well, including blood pressure lowering, weight loss, and a low risk of hypoglycemia. Still, with their antiglycemic effects starting to wane in stage 3 renal impairment, even though renal and CV benefits may persist further, there is a dilemma for physicians of whether to then instead use other antidiabetics with stronger antiglycemic effects, such as the GLP-1 agonists, which also have CV and possibly renal benefits.
• Jardiance has been the SGLT-2 class leader generally in diabetes due to a large reduction in CV death in its CVOT, but Farxiga is gaining, with explosive growth in 2021 outside the US (particularly in emerging markets), where it has always led as first to market. In addition to the earlier CKD approval, Farxiga was the first with approval in heart failure with reduced ejection fraction (HFrEF), in 2019–20. Curiously, Jardiance’s pivotal HFrEF and HFpEF trials, which led to general approvals in 2021 and 2022 for these important co-morbidities, did not show much benefit on CV death, which could bolster the view that outcomes differences are just due to differences in the studies and not due to the drugs themselves; Farxiga has also shown positive data in HFpEF. SGLT-1/2 inhibitor Zynquista, which has also shown a benefit in diabetic HF across a range of ejection fractions and is being submitted for an HF indication, may have slightly more glycemic control in advanced CKD patients, but will likely struggle as a newcomer and will not have a CKD indication or data in non-diabetics. Loss of patent protection for the class starts in 2025.
• MRA Kerendia has been approved, starting in 2021, for reducing the risk of renal and CV events in DN. It showed renal and CV benefits in its pivotal FIDELIO-DKD Phase III study in type 2 DN, and CV benefits with a numerical renal composite improvement in its FIGARO-DKD study of a broader group of DN patients. However, in the latter, unlike FIDELIO-DKD, the CV benefit was primarily driven by HHF. Moreover, in general, its renal benefit and impact on HHF do not appear as strong as for Farxiga in its renal trial, though this could be due to trial differences. Kerendia also has a trial in non-diabetic CKD, as well as HFpEF, so it will be interesting to see how it fares in those. The company hopes to differentiate Kerendia by its mechanism of action, with effects on inflammation/fibrosis, as well as specialists not having to adjust diabetes medications, as for SGLT-2 inhibitors. It is also planning to build awareness of the importance of earlier testing for DN.
• Kerendia unfortunately also had a fairly high rate of hyperkalemia, which could relegate it to a specialty drug, with primary care favoring the SGLT-2 inhibitors, even though rates of hyperkalemia as a serious adverse event or causing discontinuation were not high, and ADA guidelines do not make much of the issue. The company has said it will not build a primary care sales force, though it will market to primary care physicians who see a large number of DN patients, in addition to specialists. The company touts a Phase II HF study showing less hyperkalemia than spironolactone, but, on the other hand, it did not show a significant improvement over eplerenone. Still, these approved generic MRAs have not had a definitive trial in DN, so Kerendia should be favored. Prescription growth in the US has been positive – initially tracking similarly to the launch of HF drug Entresto, though starting around mid-2022 the rate of growth has slowed somewhat.
• It is possible that Kerendia could be used in combination with SGLT-2 inhibitors, especially since there are signs the latter may reduce hyperkalemia, but on this front it could face competition from a fixed-dose combination (FDC) of Farxiga/AZD9977 (an MRA), though the FDC is so far only being developed in HF with CKD, and Bayer could commercialize its own Kerendia FDC once the SGLT-2 inhibitors become generic. An FDC of Farxiga and the endothelin receptor antagonist (ERA) zibotentan could also provide competition. ERAs can cause fluid retention, and while Farxiga may reduce the risk, concern over the issue could well relegate this to a specialty drug as well.
• Ozempic is a weekly injectable GLP-1 agonist, and Rybelsus is its daily oral formulation. Both are highly effective in treating type 2 diabetes and have shown signals of a CV benefit, though only Ozempic has a CV indication in the US. Ozempic is the first GLP-1 agonist with a dedicated type 2 DN outcomes trial, FLOW, though primary completion is only slated for 2024. There is some uncertainty, as the evidence for a renal benefit is not as strong as for SGLT-2 inhibitors. If positive, Novo Nordisk plans to bridge results to Rybelsus using renal data from the latter’s CVOT. The drugs would have the advantage of better glycemic control than SGLT-2 inhibitors, even at more advanced stages of renal impairment, though they do have more GI side effects. However, they may also face competition from dual GLP-1/GIP agonist Mounjaro, which appears to have stronger glycemic control and weight loss. There is no sign currently that it is being developed for DN specifically, though data on improving albuminuria have been presented from a diabetes trial. Nevertheless, especially since glycemic control can also benefit DN, it could be preferred in some patients, particularly if its CVOT is positive, though a DN approval for Ozempic could help it maintain an edge in this segment. Ozempic’s DN trial will also need to avoid too large a difference in A1C with the control group for the FDA to give it a DN indication, and if it looks instead as if the A1C contributed to the renal benefit, there could be more of an argument for using Mounjaro.
• The overall likelihood of approval of a Phase I asset in diabetic nephropathy is 3.7%, and the average probability a drug advances from Phase III is 37.5%, though the sample size for the latter is limited. Diabetic nephropathy drugs, on average, take 13.3 years from Phase I to approval, compared to 10.0 years in the overall endocrine space.