Chronic Kidney Disease: Nrf2 Activators - An Emerging Market
Colton Davis - Ph.D. Candidate
Chronic Kidney Diseases, Chronic Inflammation and Fibrosis
Chronic kidney disease (CKD) is a gradual loss of kidney function that in late stages results in the buildup of dangerous levels of fluids that are formed as a byproduct in the body such as electrolytes and waste. Phenotypic symptoms are not visible until a significant amount of damage is done to the kidneys. Diseases and conditions such as type 1 or type 2 diabetes, high blood pressure, polycystic kidney disease, and recurrent kidney infection are the major factors leading to CKD.
Current methods for treatment of CKD and those alike vary depending on severity of the diagnosis. Early stages of CKD are generally treated by lifestyle adaptations or through medications that can regulate blood pressure, reduce swelling, and lower cholesterol levels. However, these patients often progress to severe cases of CKD where loss of kidney function becomes substantial. At this point, patients are typically treated with dialysis. Therefore, an important unmet need for patients with CKD is a therapeutic that can slow down the progression of tissue death and maintain kidney function.
Chronic inflammation, an extended cellular response that persists for months or years when the immune system is unable to relieve the problem, is a main contributor to CKD. As the inflammation persists, the immune system prompts white blood cells to attack nearby healthy tissues and organs; such persistent inflammation plays a central role in additional diseases such as rheumatoid arthritis, cancer, heart disease, diabetes, Friedreich's ataxia, and even Alzheimer's disease.
Chronic Inflammation can also be linked to fibrosis, which results in the thickening, hardening, or scaring of various tissues from excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammation reactions induced by a variety of stimuli. Although many current treatments for fibrosis typically target inflammatory response, it has been suggested that the cellular mechanisms that drive fibrosis are distinct from inflammation regulation.[3-5]
Inflammation and Mitochondrial Metabolism
Inflammation and mitochondrial metabolism are closely related biological processes. Inflammation is a key component in normal immune responses that occurs when cells encounter destructive stimuli, such as irritants, damaged cells, or pathogens. The aim of inflammation is to limit and eliminate the causes of cellular damage, clear and absorb necrotic cells and tissues, and initiate tissue repair. As a result, cells activate inflammatory processes that increase cytokine production to recruit additional immune cells and elicit an immune response. The mitochondria are often referred to as the "powerhouses" of the cell that are necessary to produce energy the cell needs to function. Adenosine triphosphate (ATP) is generated by a process called oxidative phosphorylation, in which mitochondria use pyruvate and fatty acids as the fuel sources. However, during inflammation, mitochondrial metabolism is reprogrammed to suppress generation of ATP, resulting in the accumulation of fatty acids and pyruvate that can be used in the production of pro-inflammatory mediators. Suppression of oxidative phosphorylation also results in mitochondria releasing reactive oxygen species (ROS), that play a critical role in directly attacking foreign stimuli which can further amplify cytokine production to elicit a greater immune response. This suggests that mitochondria play a pivotal role in coordinating pro-inflammatory signaling from the cytosol and other subcellular organelles.
For normal immune cell response, after harmful stimuli have been cleared, the resolution phase of inflammation signals a cessation of pro-inflammatory mediators as ROS species are quenched and mitochondria return to normal metabolic function. In diseases such as CKD, the resolution phase of inflammation is insufficient or does not occur, which leads to pro-inflammatory mediator accumulation, ROS production, and mitochondrial dysfunction.
Targeting the Keap1-Nrf2 pathway is an emerging method to treat chronic kidney diseases.
In inflammation and mitochondrial metabolism, Nrf2 is a transcription factor which plays an integral role in the resolution phase of inflammation by regulating gene expression involved in normalizing mitochondrial metabolism, restoring redox balance, and suppressing cytokine production (Fig. 1).[12,25] Keap1, a repressor protein, binds to Nrf2 and promotes its degradation via the ubiquitin proteasome pathway. Suppression of Nrf2 activity is often related to the cells inability to regulate these processes, which leads to chronic inflammation.[13-16] Therefore, several pharmaceutical companies have taken the approach of resolving inflammation and preventing kidney necrosis by up regulating Nrf2 activity.
Figure 1: Nrf2 inhibits reactive oxygen species and inflammatory pathways that lead to kidney dysfunction.
Global Market for Chronic
Kidney Disease and Chronic Inflammation
Chronic Kidney Disease (CKD) for applications in pharmaceuticals and technologies is one of the largest therapeutic markets in the world. A report from WiseGuy research consultants states the global Chronic Kidney Disease market is valued at 12.4 billion US$ in 2018 and is expected to reach 16.8 billion US$ by the end of 2025, growing at a CAGR of 3.9% during 2019-2025. Allied market research has a similar report about anti-inflammatory therapeutics that estimates this market is expected to generate 106.1 billion US$ by 2020, growing at a CAGR of 5.9% from 2015 to 2020. This market is expected to grow even faster in the Asia-Pacific region at a CAGR of 8.5% during this same time period (Fig. 2). These two markets occupy a large amount of the global therapeutics market, but there is a modern approach that is making its way into both markets. The current market for Nrf2 activators is new and relatively unexplored, but with hopeful therapeutics on the horizon, it is only a matter of time before these begin to make their mark on the global market soon.
Figure 2: World Anti-Inflammatory Therapeutics Forecast.
Major Players in Nrf2
Pathway Activators Market
The physiologic regulation of Nrf2 is through the Keap1-Nrf2 pathway. The "Nrf2 activators" could be more accurately termed "Keap1 inhibitors" due to Keap1 being the molecular target of many of these activators. These compounds can be classified as covalent inhibitors, protein-protein interaction (PPI) inhibitors, and multitarget drugs.
Covalent inhibitors can covalently modify many cysteine residues that lie on the thiol rich Keap1 protein to control activity involving the Keap1-Nrf2 pathway. Tecfidera® (fumaric acid ester dimethyl fumarate, or DMF) from Biogen was approved in 2013 for relapsing-remitting multiple sclerosis but has shown efficacy in other indications. An oral formulation of a monomethyl fumarate (MMF) derivative, VUMERITYTM (ALKS-8700), from Biogen is currently in clinical trials. Reata Pharmaceuticals has gained interest in designing Nrf2 activators that are currently in clinical trials. Bardoxolone methyl (CDDO-Me or RTA 402) is in pivotal trials for treatment of multiple diseases such as CKD caused by Alport Syndrome, Connective Tissue Disease-Associated Pulmonary Arterial Hypertension (CTD-PAH), and Autosomal Dominant Polycystic Kidney Disease (ADPKD). Omaveloxolone (RTA-408) is also in a pivotal trial of a first-in-class treatment for Friedreich's Ataxia. Both small molecules have shown greater potency than any Nrf2 activators to date in cell lines and primary endpoint eGFR measurements during clinical trials.
Many other companies have taken interest in designing Nrf2 Transcription Factor assay kits such as Cayman Chemical and BioVision Inc. for laboratory use.[21-22] KEAP1-Nrf2 inhibitors, agonists and modulators are provided through BOC Sciences for additional laboratory uses. Furthermore, Anti-Nrf2 antibodies have been designed by Abcam.
Challenges and conclusion
Overall, the interest of Nrf2 activators for clinical application will continue to grow, and the huge market potential for disease implications that can be treated via the KEAP1-Nrf2 pathway is appealing. However, pleotropic effects of Nrf2 on cell physiology coupled with potential off-target effects by some Nrf2 activators can help explain the lack of clinical drug development. Off-target effects seen in the BEACON trial with bardoxolone, which was terminated, revealed cardiovascular safety issues. More recently bardoxolone has shown elevated weight loss in patient populations due to activated mitochondria in fat cells. Continuing to find new ways to tackle these issues will be of primary interest to companies in the future who plan to enter into the Nrf2 activator market.
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