Treatment of Podocytopathies

Background

In 2003, the authors of this article met in the Nephrology Division at Massachusetts General Hospital. At that time, S. Sever was studying the role of GTPase dynamin in clathrin-mediated endocytosis. While endocytosis in renal polarized tubular cells had been extensively explored in the context of vasopressin receptor trafficking, Sever's research was cell-agnostic until the arrival of J. Reiser. Reiser was one of the physician–scientists who initiated studies of the role of podocytes in glomerular diseases. The first mouse podocyte line was derived from the ImmortoMouse in 1997, and by 2002, a conditionally immortalized human podocyte cell line had been developed.¹ In parallel endeavors, mutations in the NPHS1 gene, which encodes the transmembrane protein nephrin, have been linked to congenital nephrotic syndrome, identifying the crucial role of podocytes in glomerular diseases and allowing for cell type–specific mouse models. Fast forward to the present, the list of mutations implicated in genetic forms of podocyte-based glomerular diseases known as podocytopathies expanded significantly (reviewed in ref. 2). Currently, it encompasses diverse proteins, such as adapters, actin-binding and regulatory proteins, channels, phospholipases, transcription factors, and even mitochondrially encoded tRNA^Leu.

Past Challenges for Developing Novel Therapies

The high expectations generated by podocyte research at the beginning of the 21st century promised the imminent development of novel podocyte-specific therapies and an increasing need for clinical studies funded by the National Institute of Diabetes and Digestive and Kidney Disease. Yet, as of January 2024, there are no US Food and Drug Administration (FDA)-approved podocyte-targeting drugs. It was argued that the lack of novel therapies for podocytopathies is because of (1) a lack of knowledge regarding molecular mechanisms of podocyte injury, (2) a lack of targets, (3) scientific controversies, (4) a lack of entrepreneurship in nephrology, or all of the above. On the basis of our personal experience, the field lacked funds. Specifically, venture capital (VC) funding capable of translating the wealth of knowledge created in academia into investigational novel therapies tested in humans.

We cofounded a first-in-kind podocyte-focused biotech company back in 2011 with a vision to develop podocyte-specific therapies and demonstrate the existence of an entrepreneurial spirit in nephrology. However, as long as the effect of novel therapies was determined on the basis of changes in eGFR, a metric that typically necessitates years of follow-up, no VC funding was available to entrepreneurial nephrologists like us. The landscape transformed dramatically with the FDA’s decision in 2017 to embrace changes in proteinuria as a surrogate end point for budesonide, as a treatment of IgA nephropathy developed by Calliditas Therapeutics. This decision had a profound effect on the dynamics of human trials for kidney diseases (reviewed in ref. 3) and indirectly influenced the availability of VC funding for new biotech startups. Indeed, in 2020, we successfully secured series A funding, marking a significant milestone 9 years after the biotech startup's inception.

Major Successes for Kidney Patients

FDA-approved budesonide in 2021 is a second-generation synthetic glucocorticoid for IgA nephropathy. The same year witnessed the FDA's approval of dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, as a treatment for patients with CKD (reviewed in ref. 4). While budesonide's success drew upon the well-established efficacy of immunomodulators, such as corticosteroids in kidney patients, SGLT2 inhibitors introduced a groundbreaking class of drugs for the CKD population. SGLT2, almost exclusively located in the proximal renal tubule, plays a crucial role in reabsorbing filtered glucose from the nephron. The inhibitors targeting SGLT2 on renal tubular cells slowed down the progression of kidney diseases, reduced the incidence of heart failure, and lowered the risk of kidney failure. Interestingly, the major success in nephrology came from the diabetes field. Similarly, glucagon-like peptide-1 receptor agonists have also demonstrated notable beneficial effects in the CKD population (reviewed in ref. 5). As these agonists target β cells of the pancreas and act on brain neuronal circuits in the hypothalamus, the benefit to kidney health is indirect. Finally, in 2023, Travere Therapeutics announced FDA-accelerated approval of sparsentan as the first nonimmunosuppressive therapy for the reduction of proteinuria in IgA nephropathy. Sparsentan is an orally active small molecule that acts as a selective, simultaneous blocker of endothelin type A receptor and the angiotensin II subtype 1 receptor pathways in numerous cell types, including vascular smooth muscle cells and podocytes.⁶

To date, a singular achievement in translating podocyte biology research into tangible clinical progress is VX-147/inaxaplin. It is an investigational therapy designed for FSGS developed by Vertex Pharmaceuticals. VX-147/inaxaplin is an orally active small-molecule inhibitor of APOL1 function. Vertex Pharmaceuticals completed a single-group, open-label, phase 2a clinical study in 2021 with an enrollment of 16 participants. They reported that targeted inhibition of APOL1 function reduced proteinuria in patients with two APOL1 variants and FSGS.⁷ Because APOL1 variants are also associated with severe arteriosclerosis in renal vessels,⁸ it is possible that VX-147/inaxaplin targets multiple cellular types, in addition to podocytes. Genetic variants in the APOL1 gene,⁹ predominantly found in the Black population, were first described in 2011.

In a parallel endeavor, Walden Biosciences, a kidney-specific biotech company, made strides by completing phase 1 clinical trials for WAL0921—a humanized antibody targeting urokinase plasminogen activator receptor (uPAR) and its soluble uPAR form. Activation of α_vβ₃ integrin signaling pathway(s) by uPAR or soluble uPAR has been implicated as one of the molecular mechanisms that underlie podocyte injury¹⁰ in various types of CKDs, including FSGS, IgA, and diabetic nephropathy. Walden plans to initiate phase 2 trials within the CKD population in 2024. Furthermore, the company is gearing up for phase 1 trials for a small molecule agonist designed to target the GTPase dynamin, a key regulator of the actin cytoskeleton in podocytes. We have suggested that dynamin-specific agonists might exhibit a beneficial effect on preserving and/or re-establishing podocytes' function by influencing actin cytoskeleton dynamics by using dynamin as a proxy.¹¹ Walden's dynamin agonists seem to be one of the first, if not the first, investigational therapies directly targeting podocytes' actin cytoskeleton in patients with kidney diseases. Finally, in 2023, the kidney-focused company Chinook was acquired by Novartis, marking the entry of major pharmaceutical companies onto the kidney treatment stage. Together, these advancements underscore ongoing endeavors to transition innovative therapies from research laboratories to the forefront of clinical applications (Figure 1).

Figure 1.

A brief chronological timeline of inventions, discoveries, and other engagement points in nephrology. FDA, US Food and Drug Administration; GLP-1, glucagon-like peptide-1 receptor; SGLT2, sodium-glucose cotransporter-2; suPAR, soluble urokinase plasminogen activator receptor.

Future Challenges for Entrepreneurial Nephrologists in Academic Settings

At the close of 2023, the National Institute of Standards and Technology issued guidance on government “March-In Rights” under the Bayh-Dole Act. The Bayh-Dole Act, officially known as the Patent and Trademark Law Amendments Act, enacted in 1980, allows universities, small businesses, and nonprofit organizations, such as hospitals, to retain ownership of inventions resulting from federally funded research. It is credited with stimulating innovation and technology transfer of federally funded inventions generated in the research laboratories to the marketplace. March-In Rights refers to the government's authority to intervene and require the owner of a patent arising from federally funded research to grant licenses to third parties under certain circumstances. This provision is intended to ensure that inventions resulting from taxpayer-funded research (such as National Institutes of Health– or National Science Foundation–funded research) are used for the public benefit when the patent owner fails to commercialize the invention or makes it available on unreasonable terms. In lay terms, March-In Rights provide a mechanism for the government to intervene in price negotiations regarding novel therapies that are based on federally funded inventions.

Relaxing the Bayh-Dole Act aims to enhance the benefit to the economy and society overall. However, this action also presents a notable risk to the academic innovation ecosystem. Over the past decade, there has been a noticeable change in patenting trends within the academic setting. Previously, scientists predominantly filed patents for potential targets/proteins and their downstream pathways, but there has been a shift toward prioritizing patents for new chemical compounds or biologics (composition of matter patents). However, even these intellectual property assets may now become more of a burden than an asset for academic institutions.

Forward-looking institutions are establishing dedicated institutes or divisions focused on drug discovery. This strategic approach allows for engagement in philanthropic and industry-funded projects while operating within an academic framework. An example of this shift is the success story of the Therapeutic Discovery division at the University of Texas MD Anderson Cancer Center in Houston.

It is crucial to highlight that scientists in academia are the foundation of both, pharmaceutical and biotech companies. Since March-In Rights is expected to further reinforce the prevailing trend toward philanthropic and industry-funded research in academic settings, nephrologists should ready themselves for the changing discovery landscape. Unlike our counterparts in neurodegeneration and cancer fields, nephrology is facing a unique challenge because it has yet to establish a highly successful track record in securing philanthropic or industry funding.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/E704.

Funding

S. Sever: National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK133364).

Author Contributions

Conceptualization: Jochen Reiser, Sanja Sever.

Visualization: Sanja Sever.

Writing – original draft: Jochen Reiser, Sanja Sever.

Writing – review & editing: Jochen Reiser, Sanja Sever.