Chronic kidney disease (CKD) and other renal indications are currently experiencing a resurgence as targets for drug discovery and development. This revitalization comes after decades of being deprioritized in favor of other organ systems and diseases. For example, the NIH budget for oncology has historically been ten times that of renal diseases (Figure 1).
In addition, clinical trials in nephrology have remained among the lowest for any sub-specialty for the past two decades. At the same time, Medicare spending for CKD and End Stage Renal Disease (ESRD), which surpassed $120B in 2019, is roughly 60% of the estimated $200B cost of cancer in 2020. Given the lack of funding and clinical development, therapeutic options for renal diseases have remained stagnant, with treatment relying on rudimentary options such as control of blood pressure rather than a targeted approach to slow disease progression. As a result, therapies have failed to address the growing health economic burden of kidney diseases.
In recent years, development in CKD and other renal diseases has seen promising growth, with nephrology randomized clinical trials increasing 53% annually from 2015-2019 (Figure 2).
This momentum has also translated to an increase in renal disease pipeline assets in recent years. As Figure 3 shows, growth in the number of renal pipeline assets started to increase in the middle of the last decade and is now accelerating.
Recent growth outpaces historical growth rates largely due to an increase in preclinical assets. Notably, with the current pace set for 2021, the projected growth rate for 2020-2021 in the overall nephrology pipeline is 39% and 28% for preclinical agents, suggesting that we will see continued growth. These metrics indicate that nephrology is experiencing a turning point in clinical development.
Another important metric underscoring this renaissance is a ramp up of publications in CKD and renal diseases. Both areas have seen recent increases, with CKD publications growing 25% annually and renal disease publications 8% annually between 2019 and 2021 (Figure 4).
Increased development activity has begun to bear fruit, as exemplified by FDA’s approval of Farxiga (dapagliflozin), AstraZeneca’s SGLT2 inhibitor, for CKD in April of 2021. As the first drug approved to delay CKD progression due to multiple etiologies, Farxiga marks an important clinical breakthrough with the potential to disrupt the current CKD treatment paradigm. In July 2021, Bayer Pharmaceuticals added to the armamentarium for CKD with a new modality, the non-steroidal mineralocorticoid receptor antagonist, Kerendia (finerenone).
More approvals are likely to follow. In September, Vifor Pharma licensed sparsentan, a dual angiotensin II/endothelin A receptor antagonist in phase III trials for IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). Notably, interim data from the Phase III PROTECT study demonstrated that IgAN patients on sparsentan achieved a mean 49.8% reduction in proteinuria compared to 15.1% seen in control patients treated with the angiotensin II receptor blocker, irbesartan. Based on this data, Vifor Pharma plans to seek accelerated approval for sparsentan in IgAN in early 2022, which would make it the first approved therapy in this indication. These, and other clinical successes, are bound to generate additional investor interest and capital flow into nephrology.
Drivers of the Resurgence?
There are several factors driving the resurgence in nephrology development, including increasing societal burden of disease, scientific advances in methodologies, and discovery of new targets and modalities.
1. Increasing Burden of Renal Diseases
First, the health economic burden of renal diseases on society has been increasing. From 1990-2017, prevalence of CKD increased by 29.3% and mortality by 41.5%, advancing CKD to the 12th leading cause of death. Renal diseases are often not a disease of isolation, as comorbidities such as cardiovascular and cerebrovascular diseases are frequent causes of treatment and hospitalization prior to patients reaching ESRD. The low diagnosis rate of early disease and frequency of comorbidities likely cause underestimation of disease burden. Additionally, in 2019 approximately 34% of the fee-for-service Medicare spend was attributed to CKD or ESRD, up from 23% in 2018. This increased societal burden has generated awareness leading to the 2019 national US initiative aimed at improving diagnosis, treatment, and preventative care of renal diseases. Representatives from FDA, NIH, CMS, academia, and industry gathered in 2019 to strategize on improving treatment options for CKD. Heightened awareness of the unmet need in renal disease most certainly has contributed to the noteworthy growth in nephrology development.
2. Scientific Advances in Methodologies
A significant barrier that has long hindered research and development for renal diseases was the lack of a translatable model of the human kidney and consequently limited understanding of the molecular mechanisms underlying disease. The creation of a glomerulus-on-a-chip model in 2019 revolutionized discovery due to its ability to accurately recapitulate human kidney filtration. This model has facilitated a better understanding of the pathophysiology of kidney disease.
Discerning the molecular mechanisms’ underlying kidney damage has also been aided by advances in multiomics. For example, genomics analysis has enabled identification of mutations associated with disease and facilitated precision medicine approaches, such as the platform behind the founding of Goldfinch Bio. These methodological advances have reduced barriers to research and development in the nephrology space.
3. Discovery of New Targets and Modalities
Both Farxiga and Kerendia, represent new treatment modalities for CKD. Additional new targets are likely to emerge in the coming years as exome sequencing facilitated the identification of 66 monogenic disorders associated with CKD; and efforts towards establishing a kidney genome atlas are underway. By enhancing our understanding of disease drivers and revealing targets for drug development, these discoveries help power the current resurgence in drug development for nephrology.
Revitalization in therapeutic development for kidney disease is evident in the growing number of clinical trials, pipeline assets, and publications. The pace is likely to continue with the recent news from AstraZeneca and Bayer, bolstering predictions of clinical success for early-stage assets. Epidemiological changes, methodological scientific advances, and discovery of new targets and modalities have prompted this renaissance and underpin a new era for renal diseases.
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