As you can tell by the title, I really don't know where this post is going. I've had a lot of thoughts crossing paths and not quite sure where the final destination is. The paths touch on Reata, Bardoxolone, NRF2, CKD, Mitochondria, Inflammation, Redox Balance, Reactive Oxygen Species, etc. I figured this brain dump would be appropriate during ERA-EDTA time.

Reata's Bardoxolone CKD programs have come up before. I recently commented on a thread that TopCoin started about Reata's various CKD programs.

"Reata has completed or ongoing trials in autosomal dominant polycystic kidney disease, Alport syndrome, IgA nephropathy, focal segmental glomerulosclerosis, type 1 diabetes CKD and type 2 diabetes CKD. It seems that they may have run into some adverse events in the type 2 diabetes CKD program."

This adverse event issue in the bardoxolone diabetic CKD program caught my attention. I did some cursory research on this bardoxolone adverse event issue that Reata ran into in their BEACON trial. I found this article from 2013 co-authored by Dr. Kamyar Kalantar-Zadeh (head of the Resverlogix CKD steering committee). I also glanced at the published BEACON trial publication.

The Extinguished Beacon of Bardoxolone: Not a Monday Morning Quarterback Story

Bardoxolone Methyl Improves Kidney Function in Patients with Chronic Kidney Disease Stage 4 and Type 2 Diabetes: Post-Hoc Analyses from Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Study

What I learned is that BEACON was halted early because there were warning signs of increased risk of death due to increased fluid retention and heart failure. There were also concerns that the increased eGFR observed was an artifact of loss of muscle tissue/lean body weight. Without doing further due diligence, I concluded that because of these issues the Reata diabetic CKD program must be dead and that they were only focusing on the clinical development of non-diabetic rare forms of CKD. This conclusion was partially based on only seeing active CKD trials on Reata's website for ADPKD and Alport Syndrome.

But after doing some further research (more like not living in the past but catching up to publications and news releases of the past 2 years), I realized I was wrong. The follow up TSUBAKI study looked at changes in eGFR in diabetic kidney disease patients. It disproved this alleged artifactual eGFR issue due to weight loss, and validated that the eGFR change was real by using an inulin clearance method that the beneficial increase .

Bardoxolone Methyl Improved GFR Measured by Standard Inulin Clearance: The TSUBAKI Study

It also turns out that after the halt of the BEACON trial, risk factors for the heart failure in diabetic kidney disease patients treated with bardoxolone were identified, such that patients with these risk factors could be excluded from future bardoxolone trials. 

Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl.

So though Bardoxolone took some early hits, it has made big strides to prove itself again. As the publication titled below implies, Bardoxolone rose again like the Phoenix.

Bardoxolone—the Phoenix?

Of relevance to Resverlogix and Apabetalone, Reata's licensee Kyowa Hakko Kirin last June initiated AYAME, a Phase 3 trial of Bardoxolone Methyl for the treatment of diabetic kidney disease patients with CKD stage G3 or G4. BETonMACE CKD sub-study is looking at diabetic patients with stage 3 CKD.

Reata Announces That Kyowa Hakko Kirin Initiated AYAME, a Phase 3 Trial of Bardoxolone Methyl for the Treatment of Diabetic Kidney Disease

OK. So Reata's Bardoxolone is a legit competitor in the diabetic CKD space for Resverlogix's Apabetalone. But what does Bardoxolone do and how does it compare to the Apabetalone mechanism of action. From Reata's webpage: "Bardoxolone methyl and omaveloxolone activate the Keap1/Nrf2 pathway. The Keap1/Nrf2 pathway plays a key role in the resolution of inflammation by normalizing mitochondrial function, restoring redox balance, and suppressing cytokine production. Bardoxolone methyl and omaveloxolone—exhibit broad anti-inflammatory, antifibrotic, and promitochondrial activity in vitro and in preclinical disease models." 

Also, from this publication:

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

"The synthetic triterpenoid bardoxolone methyl and its analogues (e.g., CDDO-Im) are the most potent known activators of the Nrf2 pathway.26–28 They mimic the cyclopentenone prostaglandins (such as 15-deoxy-Δ12, 14 prostaglandin J2), which are produced during the resolution phase of inflammation and are the most potent endogenous activators of Nrf2 and inhibitors of NFκB.29"

So the main players are activation of the Keap1/Nrf2 pathway and inhibition of NFkB, and through these actions bardoxolone elicits beneficial effects on inflammation, mitochondrial function, redox balance, cytokine production and fibrosis. 

OK. Quick tangent back to apabetalone and BET proteins. There may be cross talk between BET proteins and Nrf2. A nice figure in the story in the first link that summarized the review in the second link. So there is evidence that BET proteins control Nrf2 activity, and that BET inhibition may increase Nrf2 activity.

BET Proteins and Nrf2: Studying their Interplay May Offer New Therapeutic Opportunities

BET-ting on Nrf2: How Nrf2 Signaling can Influence the Therapeutic Activities of BET Protein Inhibitors.

Biochemical processes in the cell that use oxygen result in the production of reactive oxygen species (ROS) mainly due to the production of superoxide. This is a normal part of oxidative metabolism and the mitochondria of the cell is integral superoxide/ROS production. However, if the production of superoxide and other ROS exceeds the cellular pathways to catabolize/inactivate the superoxide/ROS this can lead to deleterious effects. One key enzyme in this process is superoxide dismutase (SOD), which converts superoxide into oxygen (O2) and hydrogen peroxide (H2O2). The H2O2 can then be further metabolized and inactivated by catalase and glutathione peroxidase enzymes. One particular version of the SOD enzyme family is SOD2, which is a mitochondrial targeted version of SOD.  

I'm going to stop here and give some props to Pomponius Capital who previously brought up the mitochondrial electron transport chain and BET inhibition in this post that brought up this paper:

Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations

Pomp quoted the following from that paper:

“In summary, these results indicate that I-BET 525762A-induced mitochondrial respiration is necessary to rescue the bioenergetic defects and maintain survival in human cybrids with mitochondrial CI mutations.”

“A metabolic hallmark of CI malfunction is NADH accumulation caused by reduction in CI-dependent NADH reductase activity… We show that NADH levels are partially restored after bromodomain inhibition and may contribute to the bioenergetic rescue in CI deficient cells.”

Another key takeaway from the abstract of that paper is "We show that I-BET525762A or loss-of-Brd4 remodeled the mitochondrial proteome to increase the levels and activity of OXPHOS protein complexes leading to rescue of the bioenergetic defects and cell death caused by mutations or chemical inhibition of CI. These studies show that Brd4 inhibition may have therapeutic implications for the treatment of mitochondrial diseases."

I'd also like to acknowledge the authors of the Hedge Knight Capital (HKC) report "RESVERLOGIX: A LONG OVERDUE PARADIGM SHIFT IN HEART DISEASE AND OTHER INFLAMMATORY DISEASES." There is a good write up on mitochondria metabolism in that HKC report. For more background and details on mitochondria, the electron transport chain, oxidative phosphorylation, and redox balance/potential etc. I recommend you take a look at that HKC report. The HKC report also brings up the paper that Pomp cited above and discusses it in great detail in the context of beneficial effects of BET inhibition on mitochondrial function.

I admit, I was rather critical of the apabetalone/BET inhibition connection to mitochondria function before. For this, I am extending an apology to Pomponius Capital and the authors of the HKC report. I am starting to appreciate the potential here. Thank you for your insight on this and my apologies for hastily reacting with negativity and skepticism when I first evaluated your proposed connection.

Here are a couple more references that I quickly pulled up on cellular redox balance, ROS and SOD2 if anyone is interested.

Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases

Redox-optimized ROS balance: a unifying hypothesis

This ties in to a prior post of mine from June 5th, which briefly discussed a paper that found the pan-BET inhibitor JQ1 to activate Nrf2 via increased transcription of Nrf2 and restore redox balance and lower ROS, partially due to increased SOD2 expression, under conditions that typically promoted increased ROS production. This does not necessarily mean that apabetalone has these same effects; there are several examples of the bromodomain-2 selective BET inhibitor apabetalone not eliciting the same changes at the pan-BET inhibitor JQ1. But this could potentially represent a partial overlap in mechanisms of action for CKD between Reata's bardoxolone and Resverlogix's apabetalone.

Bromodomain and Extraterminal (BET) Protein Inhibition Restores Redox Balance and Inhibits Myofibroblast Activation" 

OK. I think that completes my brain dump. Hopefully some of these ideas connect with one another.

BearDownAZ