Disease Analysis: Diabetic Nephropathy

Latest key takeaways

• Datamonitor Healthcare estimates that in 2018, there were approximately 122.6 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 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 are the mainstay of treatment currently for type 1 and type 2 DN, as they have renal benefits beyond blood pressure lowering. Usage increases at higher renal stages (indicating 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 medications for hypertension, which is present in most patients with DN, or other CV indications, without a specific intention of treating DN.
• In addition to their use for treating diabetes in DN patients, albeit hampered by some side effects, SGLT-2 inhibitors have been found to have benefits in important CV co-morbidities and are also being specifically approved for DN or broader chronic kidney disease (CKD). 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, and Jardiance should have pivotal results in both by 2022. The SGLT-2 inhibitors have a number of benefits in addition to renoprotective and antidiabetic effects, including blood pressure lowering, reducing co-morbid CV risk – especially heart failure (HF), but also in some situations CV death or MACE – weight loss, and a low risk of hypoglycemia. Their antidiabetic effects start to wane in stage 3 renal impairment, however, even though renal and CV benefits may persist further, raising the dilemma for physicians whether to instead then use other antidiabetics with stronger antiglycemic effects, such as the GLP-1 agonists, which also have CV and possibly renal benefits. The SGLT-1/2 inhibitor Zynquista does have some data suggesting more glycemic benefit, including a modest A1C reduction in CKD stage 4 patients, but results are somewhat tentative and the drug is only being submitted for a HF indication, albeit a broad one, including HFpEF patients, where only the HF drug Entresto is approved so far. Jardiance has been the class leader generally in diabetes due to a large reduction in CV death in its CVOT, but curiously in data from a pivotal HFrEF trial, presented in August 2020, it did not show much benefit on CV death, unlike Farxiga, which gained approval in HF in 2019. While Jardiance is likely to still be approved in HF based on its benefit on hospitalization for HF (HHF), physicians could start to think more that there really is not much difference on efficacy between members of the class, just differences in the trials, though that does not appear to have had much impact on Jardiance’s success as yet. Both Farxiga and Jardiance have ongoing trials in HFpEF, with the expectation that they will be as successful as Zynquista, though that is not certain given the latter’s additional inhibition of SGLT-1. Loss of exclusivity for the class starts in 2025.
• Finerenone is a mineralocorticoid receptor antagonist (MRA) that has shown renal and CV benefits in its initial FIDELIO-DKD Phase III study in type 2 DN, though the renal benefit and impact on HHF were not as strong as for the SGLT-2 inhibitors in their renal trials. While this could be due to differences in the trials, and finerenone did have an impact on CV death that was close to what was seen in the SGLT-2 inhibitor renal trials, though numerically not quite as strong, it unfortunately also had a fairly high rate of hyperkalemia. Rates of hyperkalemia as a serious adverse event or reason for discontinuation were not high, but it was unclear if finerenone is really much better on this class side effect than generically available options approved for CV and other indications. Still, while the approved generic MRAs have shown some renal benefits, they have not had a definitive trial in DN, so finerenone could be favored, though physician concern about potential hyperkalemia will likely relegate it to a specialty drug, and the company has said it will not build a primary care sales force. More data on hyperkalemia will come from FIGARO-DKD, which includes patients with less severe DN and has reported a positive CV primary endpoint, though details have not yet been released. Interestingly, in FIDELIO-DKD, finerenone also reduced the incidence of new-onset atrial fibrillation, so it will be interesting to see if this is duplicated in FIGARO-DKD, though there are also data showing a benefit for SGLT-2 inhibitors.
• 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. If positive, Novo Nordisk plans to bridge results to Rybelsus using renal data from the latter’s CVOT. There is some uncertainty, as the evidence for a renal benefit is not as strong as for SGLT-2 inhibitors, and there are still questions about the mechanism by which GLP-1 agonists could have renoprotective effects. Nevertheless, another weekly GLP-1 agonist, Trulicity, showed benefits on a renal composite in DN patients, bolstering confidence, though Trulicity itself is not being further developed in DN. If the results for FLOW are positive, both Ozempic and Rybelsus 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.
• Bardoxolone has had a tortured history in DN, with early termination of the BEACON trial in 2012 due to an excess of HHF or death from HF. Subsequent analyses suggested this was due to fluid retention in at-risk patients, and the drug did indeed have an impact on a renal composite. Following this, development resumed in orphan conditions, with positive results, and in 2021 a Phase II trial was also initiated in CKD patients at risk for rapid progression, including those with DN. In Japan, Kyowa Kirin is also conducting a Phase III study in patients with either type 1 or type 2 DN, stage 3–4, with results expected in 2022. There are some concerns about the drug, though, because it also increases UACR, which typically is a negative sign, though there are possible explanations. In addition, while its trials are excluding those at risk for HF, there is still a possibility it could trigger the condition in unidentified at-risk patients, and even if not, there may be questions on how to avoid this in real-world practice.
• The overall likelihood of approval of a Phase I DN asset is 4.9%, and the average probability a drug advances from Phase III is 42.9%, though the sample for the latter is limited. DN drugs, on average, take 11.8 years from Phase I to approval, compared to 9.7 years in the overall endocrine space.