Facio plans to select first series of potential drug development candidates early 2018

Leiden, the Netherlands - December 20, 2017

Facio Therapies announced today that early 2018 it plans to select a first series of potential FSHD drug development candidates comprising DUX-4 repressing small-molecule compounds that leave muscle cell formation intact. Facio also announced that BET inhibitors and beta-2 adrenergic receptor (b-2AR) agonists, two compound classes that have been linked to FSHD in the scientific literature, fail to meet Facio’s quality criteria because they both show strong inhibition of muscle cell formation in FSHD-affected muscle cell culture.

Undue production of DUX4 in skeletal muscle is the cause of FSHD. DUX4 sets in motion a cascade of biochemical events that eventually result in the devastating effects of FSHD. In people without FSHD, the production of DUX4 in skeletal muscle is repressed by regulatory mechanisms. Facio’s single goal is to develop a therapy that restores this repression as much as possible.

In November, Facio announced building a portfolio of potential FSHD drug development candidates comprising small-molecule compounds that not only repress production of the DUX4 protein, but also leave muscle cell formation intact. Because muscle cell formation is involved in muscle repair and regeneration, Facio contemplates that the loss of muscle function seen in FSHD might be exacerbated if patients would be exposed to compounds that (while appearing to lower DUX4 levels) interfere with the formation of muscle cells.

Facio selects its potential drug development candidates using an extensive battery of tests performed with Facio’s proprietary screening platform, which is based on cultured skeletal muscle cells derived from FSHD patients. Facio is able to study the effects of compounds on muscle cell formation because its 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. Only a small fraction of the myotube nuclei express DUX4, but this protein is so toxic that even very low overall levels suffice to ultimately kill the myotubes.

Facio has already discovered various compound classes that repress DUX4 production while leaving myotube formation intact. Today, Facio disclosed that BET inhibitors and b-2AR agonists are not among those classes. BET inhibitors (which are in clinical development for certain types of cancer) and b-2AR agonists (which are used predominantly as inhaled therapeutics for certain lung disorders) have been linked to FSHD in the scientific literature. About 15 years ago, various academic groups tested the b-2AR agonist, salbutamol (known in the USA as albuterol), in FSHD patients, but the observed effects were not positive, and salbutamol was never developed for FSHD. More recently, a team of academic scientists reported that BET inhibitors and b-2AR agonists suppress the expression of DUX4 messenger RNA in a small-scale screen of known compounds using an FSHD2 cell line.

Upon adding a range of BET inhibitors or b-2AR agonists when all or almost all cells in culture were still myoblasts, Facio found that myotube formation was strongly inhibited. This phenomenon coincided with an apparent strong reduction of DUX4 levels. Conversely, if BET inhibitors or b-2AR agonists were added when all or almost all cells in culture had become myotubes, the (virtually completed) process of myotube formation was not affected, while DUX4 production was reduced only slightly or not at all. These findings were reproducible and not specific to one type of FSHD genetic background. Facio is planning a detailed publication.

Facio’s managing director, David Dasberg, commented: “Our R&D strategy aims to maximize the probability of successfully developing a safe, effective, and affordable FSHD therapy. Right now this means we are building an innovative portfolio of potential drug development candidates that we have validated in our screening platform to consistently repress DUX4 while leaving myotube formation intact. We plan to select our first series of potential candidates early 2018.”   

On a technical note, David added: “Our proprietary computerized analytical techniques enable measuring DUX4 levels and myotube formation at the same time. That way, we observed that inhibition of myotube formation reduces the number of myotube nuclei that express DUX4. Therefore, if DUX4 suppression coincides with inhibition of myotube formation, it is the latter effect, rather than a true pharmacological effect, that explains why the compound in question is seen to suppress DUX4. This is one of the reasons why we apply the utmost rigor in validating our experimental results. Risk management is what our R&D is all about.”

About FSHD

FSHD (facioscapulohumeral dystrophy) is a skeletal muscle wasting disease that devastates the lives of over 700,000 people worldwide and those close to them. The loss of muscle strength has a huge impact on daily life. Living with FSHD means living with pain, fatigue, and social isolation. Above all, the future becomes uncertain because the course of the disease is unpredictable. About 20% of people with FSHD end up in a wheelchair. Currently, no therapy for FSHD is available other than forms of temporary symptomatic relief.

About Facio Therapies BV

Facio Therapies, established in 2014, is a Netherlands-based company with a single focus: to overcome FSHD by developing a causal therapy that restores the natural repression of the muscle-toxic protein, DUX4. When unduly produced in skeletal muscle, DUX4 sets in motion a cascade of cellular events that eventually result in the muscle wasting seen in FSHD. Facio is the only one in the FSHD field with a fully automated, high-throughput screening platform based on quantifying the DUX4 protein in unadulterated (“primary”) FSHD-affected muscle cells. Facio delivered the first-ever therapeutically relevant proof of principle in FSHD by showing that one of its lead candidates, an orally active small molecule, represses DUX4 levels produced by human FSHD-affected muscle cells in a unique animal model (“in vivo”).

Rooted in, and dedicated to working for the FSHD community, Facio’s business approach is to have a positive impact on lives rather than to maximize financial gain. Since inception, Facio has raised over €16M in equity funding from FSHD-affected families, their friends, FSHD foundations, and Facio’s drug discovery partner, Evotec. Facio’s Board consists of business leaders from the FSHD community – Kees van der Graaf (Chairman; Netherlands), Neil Camarta (Canada), Dave Mackay (USA), Bill Moss (Australia), and Chip Wilson (Canada) – and Evotec’s CSO, Cord Dohrmann (Germany).