Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice.

Abstract: "Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models. While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments. At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology. Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure."

My comments: Genentech/Roche shows good data for why JQ1 is not a viable clinical candidate by thoroughly documenting the JQ1-elicited lymphoid and hematopoietic toxicities of this old first-generation pan-BET inhibitor. This paper could have benefited from a discussion about the problems of this first generation diazepine scaffold and how other next-generation BET inhibitor scaffolds could have less adverse effects. A discussion of bromodomain-specific inhibitors (BD1 vs. BD2) would have also been beneficial but is missing.

Paragraph from intro: "While the biology of BET in various preclinical models speaks to the attractiveness of this therapeutic target, the safety consequences of BET inhibition has not been fully explored. The first BET inhibitor to start clinical trials was RVX-208 for atherosclerotic cardiovascular disease (Bailey et al., 2010). In the later phase 2b study, a greater incidence of patients taking RVX-208 reported elevations in hepatic transaminases higher than three times the upper limit of normal compared to the placebo group (Nicholls et al., 2015). The liver enzyme elevations were observed between 4 and 8 weeks of treatment and resolved when drug administration was discontinued. This adverse clinical safety finding calls into question the safety profile of BET inhibitors, especially given that BET is ubiquitously expressed and the currently available small molecules are promiscuous BRD inhibitors."

My comments: Are the authors biased, jealous, or just ignorant? They do not even acknowledge that the elevation in transaminases was transient and resolved itself with continued RVX-208 treatment after this transient spike. The authors seem to be trying to link the transaminase elevations with the JQ1-elicited toxicity observed in this paper. Very weak argument. Furthermore, authors fail to mention that RVX-208 has been shown to be safe out to 6-months of treatment. The authors also fail to mention that unlike pan BET-inhibitors, RVX-208 is a BD2-selective inhibitor. This omission by the authors may lead readers to believe that all BET inhibitors would have the JQ1-like effects documented in this paper.

Paragraph from discussion: "BET has emerged as a promising therapeutic target in oncology and inhibitors are being evaluated in clinical trials (Filippakopoulos and Knapp, 2014). Patient safety data from clinical trials is consistent with the toxicity findings from the nonclinical studies, and these findings are in turn consistent with the pharmacology of the target. Bone marrow toxicity, in particular thrombocytopenia and neutropenia, appeared to be the dose-limiting toxicities observed in a phase 1 trial with OTX015 (Thieblemont et al., 2014). While these adverse effects are not unexpected given the available nonclinical data generated in vitro and in vivo with various BET inhibitors, it does suggest the probable lack of a sufficient therapeutic index for BET inhibitors for non-oncology disease indications. The 30 mg/kg BID oral dose level of JQ1 has been shown to be efficacious in mouse models of anti-inflammation for immunology and atherosclerosis for metabolic disease (internal observations, data not shown). However, although this dose was tolerated, it was also associated with toxic effects on lymphocytes in the thymus and spleen and corresponding hematology changes. Overall our findings reveal that BET inhibition affects the lymphoid and hematopoietic tissue compartments in the mouse, indicating that there are very narrow safety margins. As the medicinal chemistry research for BET inhibitors expands and better selectivity and potency are gained, it will be interesting to determine if a selective inhibitor for BRD2 would have a better safety profile compared to BRD4 or vice-versa for a non-oncology indication."

My comments: Yes, OTX015 is a pan BET inhibitor in clinical trials that has been shown to have a number of toxic side effects. But like JQ1, OTX015 is a first generation BET inhibitor that is based upon a scaffold that has been shown to have a lot of problems. Again, they could have pointed out that RVX-208 is based on a different scaffold, is BD-2 selective, has been shown in clinical trials to be safe out to 6 months (with exception of transient transaminase elevation), and does not seem to elicit these severe effects of JQ1 and other first generation pan BET inhibitors like OTX015.

Not sure if everyone would have access to the full manuscript, so I thought I'd paste the relevant paragraphs above.

Best regards,

BearDownAZ