Potential use of BET inhibitors for FSHD

Fran Sverdrup
Fran Sverdrup, Phd - Research Fellow, Center for World Health and Medicine, Saint Louis University

What are BET inhibitors?  BET inhibitors are a class of drugs with anti-inflammatory and anti-cancer properties. Although no BET inhibitors are yet approved for use in the US or internationally, there are many clinical trials ongoing in the areas of cancer and cardiovascular disease. These drugs bind to and inhibit Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT. Since BET proteins generally bind to active or “open” chromatin and turn on nearby genes, BET inhibitors act to suppress (turn off) genes that are over-expressed in disease settings.

Why might BET inhibitors be effective for FSHD?  We identified BET inhibitors through a screening effort to look for drugs that would turn off DUX4 expression in FSHD patient cells in culture. DUX4 is the hallmark gene of FSHD, being virtually absent in normal muscles cells while exhibiting aberrant expression in FSHD muscle that ultimately results in muscle degeneration. The discovery that BET inhibitors turn off DUX4 is an exciting finding since we still do not have a complete picture of the factors resulting in DUX4 being turned on and few drug targets have been identified that turn off DUX4. By turning off DUX4, BET inhibitors would theoretically be able to target the core driver of FSHD disease and thereby decrease disease progression.

What data is missing?  The mechanisms by which DUX4 causes muscle degeneration in FSHD patients are very complex and not fully understood. For example, when and where during FSHD muscle maintenance is DUX4 turned on and how does DUX4 then cause a cascade of events that results in specific muscles rapidly degenerating? Much of this is still unknown, causing some uncertainty as to the stage of muscle development that should be targeted to ensure that inhibition of BET proteins would be likely to protect muscle. We have found that some BET inhibitors are good at turning off DUX4 in myoblasts (muscle precursor cells), but not in mature myotubes (basic component of muscle fibers). Since myotubes express higher levels of DUX4, drugs that are good at turning off DUX4 in myotubes may provide a better chance of protecting muscle in patients. It is extremely important to choose the best drug molecules to bring forward for FSHD. Our data suggests that there are large differences between existing BET inhibitors and therefore we are optimizing novel BET inhibitors to be potent in turning off DUX4 at all stages of muscle development.

What are the possible risks?  Every drug class has a side effect profile. Since several BET inhibitors have passed through Phase I and Phase II clinical trials, we know two things. First, the class as a whole has a reasonably manageable safety profile. Second, there will be a balance between achieving drug concentrations high enough to shut off DUX4, yet low enough not to cause intolerable side-effects. Carefully identifying that therapeutic window, i.e., the level of drug that is effective at turning off DUX4 but that is safe from undesirable side effects, is critical for moving BET inhibitors forward in human trials for FSHD. Defining the therapeutic window is very difficult and the subject of ongoing research.

Where are we now with respect to clinical trials?  As mentioned above, it is critical to make sure we put the best BET inhibitor for FSHD into the clinic. A recent press release by Resverlogix suggested the use of their BET inhibitor RVX-208, also called Apabetalone, in FSHD clinical trials. This is an exciting possibility that could be an initial test of whether BET inhibitors are safe and possibly effective in FSHD. It will also be important to evaluate other currently available BET inhibitors and compare them for turning off DUX4 at all stages of muscle development and choose the best one(s) for clinical studies. At first, this can be done by testing existing BET inhibitors and optimizing novel BET inhibitors based on inhibition of DUX4 in FSHD patient cells. Next, it will be critical to compare the ability of specific inhibitors to turn off DUX4 in animal models of FSHD to determine which have the best chance of turning off DUX4 in future clinical trials. This is ongoing work that we and others are pushing forward with a strong sense of urgency.  It is too early in the process to predict which BET inhibitor might be the best candidate for clinical trials or when a clinical trial might start.

Fran Sverdrup, PhD
Research Fellow
Center for World Health and Medicine
Saint Louis University

**Disclosure: Dr. Sverdrup receives research support from Ultragenyx Pharmaceutical.