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 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 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 for 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). These developments 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, and Jardiance should have pivotal results in both during 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 of 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.
• 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, where it has always led as first to market. In addition to the earlier CKD approval, Farxiga was the first with approval in HFrEF, in 2019–20. Its growth has been particularly strong in emerging markets, where it was added to China’s national drug reimbursement list. Curiously, in data from Jardiance’s pivotal HFrEF trial, which led to general approvals in 2021 for the important co-morbidity, it did not show much benefit on CV death, unlike Farxiga. Jardiance has shown positive data in a dedicated HFpEF trial, including non-diabetics, gaining approval in the high unmet need indication, though as in HFrEF, this was driven by a reduction in HF hospitalization (HHF) and not CV death, so it will be interesting if Farxiga improves CV death in HFpEF, as it did in HFrEF, which could influence some physicians. Jardiance’s benefit also appeared to diminish with higher EF, and if the same is seen for Farxiga, there could be an argument that SGLT-1/2 inhibitor Zynquista, which is being submitted for an HF indication, has an advantage, as its benefits appeared to be as good or better with higher EF. Zynquista may also have slightly more glycemic control in advanced patients, but will likely struggle as a newcomer. Loss of patent protection for the class starts in 2025 unless a polymorph patent for Farxiga holds up.
• Kerendia is a mineralocorticoid receptor antagonist (MRA) 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 only seen in HHF. Moreover, in general, its renal benefit and impact on HHF do not appear as strong as for the SGLT-2 inhibitors in renal trials, though this could be due to trial differences. The company touts a similar effect as Invokana when adjusted for trial differences, but Invokana’s benefit was not as strong as Farxiga’s in general CKD. 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. Kerendia unfortunately also had a fairly high rate of hyperkalemia, though rates of hyperkalemia as a serious AE or causing discontinuation were not high, so it will be useful to see what guidelines focus on. 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. The drug is also being studied in non-diabetic CKD and HFpEF.
• Physician concern about potential hyperkalemia, however, could relegate Kerendia to a specialty drug, with primary care favoring the SGLT-2 inhibitors, though initially Kerendia could be prescribed more by primary care as specialists with more advanced patients gain experience on hyperkalemia. If fears about hyperkalemia are allayed, the drug could substantially increase its use among primary care prescribers. The company has said it will not build a primary care sales force, though it will market to primary care physicians who see many DN patients, in addition to specialists. The company is also planning to build awareness of the importance of earlier testing for DN. It is possible 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, unless Bayer develops its own Kerendia FDC once the SGLT-2 inhibitors become generic.
• 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. 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, with early termination of the BEACON DN trial in 2012 due to an excess of HF events. 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. Development resumed in orphan conditions, where eGFR results appeared positive, but the FDA thought acute reversible effects could cloud evaluation, and the drug received a complete response letter in Alport syndrome. In 2021, a Phase II trial was 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 during 2022. There are other concerns about the drug, as well, because it also increases UACR, which typically is a negative sign. There are possible explanations, but FDA advisory committee panelists were not convinced. Also, 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.