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Diabetic Nephropathy Disease Analysis Report 2021: Overall Likelihood of Approval of a Phase I DN Asset is 4%, and the Average Probability a Drug Advances from Phase III is 33.3%

Research and Markets
·7-min read

Dublin, March 23, 2021 (GLOBE NEWSWIRE) -- The "Disease Analysis: Diabetic Nephropathy" report has been added to ResearchAndMarkets.com's offering.

Diabetic nephropathy, also known as diabetic kidney disease, is caused by damage to small blood vessels which can cause the kidneys to be less efficient in their blood filtration role or to fail altogether. The disease is a clinical syndrome characterized by albuminuria, decline in glomerular filtration rate, and elevated arterial blood pressure. Up to 50% of diabetics with a disease duration of over 20 years have diabetic nephropathy.

Latest Key Takeaways

  • The publisher 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 among 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.

  • The antidiabetic SGLT-2 inhibitors are already used in some DN patients to treat their diabetes, albeit they are hampered by some side effects, but are poised to expand further, with additional approvals specifically for type 2 DN, as well as in CKD without diabetes and with the co-morbidity of heart failure (HF). They 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. Invokana was the first SGLT-2 inhibitor with a type 2 DN indication, but is unlikely to be able to capitalize much on it due to concerns about a possible increased risk of amputations. Farxiga is likely to be approved 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. 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 yet. Both Farxiga and Jardiance have ongoing trials in HFpEF, for which there currently are no approved treatments, but expectations are muted given how difficult the condition has been to treat. 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 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.

  • Ozempic is a weekly injectable GLP-1 agonist, and Rybelsus is its daily oral formulation. Both drugs are highly effective in treating type 2 diabetes and have shown signals of a CV benefit, though only Ozempic currently 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 outcomes 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 and type 1 DN. It is not clear if Reata will develop it further in the latter, as other indications would allow orphan pricing, but in Japan, Kyowa Kirin is 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. Physicians will also have to be concerned about avoiding it in patients who may be at risk for HF.

  • While bardoxolone is the only drug including type 1 DN in its development, which would give it an advantage in that indication, that is a smaller group of patients, and other drugs could be used off-label by specialists, especially as there are not mechanistic reasons to think they may not also work in type 1.

  • The overall likelihood of approval of a Phase I DN asset is 4%, and the average probability a drug advances from Phase III is 33.3%, though the sample for the latter is limited. DN drugs, on average, take 12.0 years from Phase I to approval, compared to 9.6 years in the overall endocrine space.

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