Building a Portfolio

Drug discovery and development come with an inevitable risk of technical failure, which needs to be managed. We do that by developing not just one compound, but a portfolio of different series of compounds. Each series has its own mechanism of action to repress DUX4. This portfolio strategy also plays into the notion that likely more than one drug will be needed to treat all people with FSHD because the symptoms and rate of progression vary so widely.

Our compounds not only repress DUX4 but also leave muscle cell formation intact in our screening platform. This is essential because muscle cell formation is involved in muscle repair and regeneration. The loss of muscle function seen in FSHD might be exacerbated if people with FSHD would be exposed to compounds that (while appearing to lower DUX4 levels) interfere with muscle cell formation. We are able to study the effects of compounds on muscle cell formation because our cell culture system is dynamic. Basically, the system starts with precursor muscle cells called “myoblasts”, which have one nucleus (the cell nucleus is where almost all DNA, including the DUX4 gene, resides). Over a few days, myoblasts fuse to form mature muscle cells, or “myotubes”, which have multiple nuclei.

In 2018, we selected our first series of potential FSHD drug development candidates comprising several small-molecule families that are associated with a narrowly defined target class (a “target” is the protein or enzyme with which an FSHD drug interacts when it enters an affected muscle cell so as to ultimately exert its pharmacological effect). Neither the compound families nor the target class have ever been linked to FSHD in the scientific literature. We confirmed that members of these families consistently repress DUX4 and leave myotube formation intact, while noting that their chemical properties should enable them to enter FSHD-affected muscle cells from the bloodstream and reach their target inside those cells, for example following oral intake.

In 2018, we also selected our second series of potential candidates for FSHD drug development. Both compound series repress DUX4 expression in a concentration-dependent, drug-like fashion without impairing the mechanism underlying muscle repair and regeneration in FSHD. Importantly, the compounds in our second series do so by engaging a different target. This illustrates the power of our strategy identify compounds that do repress DUX4, rather than compounds that may or may not repress DUX4 by fitting one of the many possible hypotheses about how DUX4 expression is regulated.

Early in 2019, we significantly expanded our portfolio of DUX4 repressors by selecting over 100 novel, chemically diverse compounds that repress production of the human DUX4 protein in cultured FSHD-affected muscle cells. This makes us the only company known to have a pipeline of proprietary, chemically diverse small molecules that target the cause of FSHD. In addition to our first two compound series, all of the 100+ novel compounds have proven to satisfy essential criteria as they concentration-dependently repress DUX4 production while leaving muscle cell formation intact.

The novelty of these compounds is also relevant because of the growing interest in the potential of so-called drug repurposing in FSHD. This means that an approved drug or a drug candidate in clinical development for a condition other than FSHD is evaluated for its use in FSHD. Drug repurposing is attractive because certain available human clinical data may be incorporated in the clinical dossier, which shortens clinical development for FSHD. However, having applied our extensive set of screening and validation platforms to thousands of known drugs and drug candidates, we have not retained any drug repurposing candidates for further development in FSHD, either because at their clinical exposure levels they have no meaningful effect on DUX4; or because they impair the formation of muscle cells; or because they have an otherwise undesirable safety profile. This is why we focus on building a pipeline of proprietary products specifically discovered for targeting the cause of FSHD.