Facio Therapies has announced that oral treatment with one of Facio’s lead candidates results in significant reduction of the human muscle-toxic DUX4 protein in mice engrafted with human FSHD-affected muscle cells. Facio is the first in the FSHD field to achieve proof of principle in an animal model (“in vivo”).
The key event in the progressive muscle wasting disease FSHD is the undue production of the DUX4 protein in skeletal muscle. 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 therapies that restore this repression as much as possible.
Together with its drug discovery partner, Evotec, Facio successfully developed a stable mouse model based on engrafting human FSHD-affected muscle precursor cells (called “myoblasts”) onto a mouse thigh muscle. These human FSHD myoblasts then fuse and develop into mature muscle cells (called “myotubes”), which produce DUX4. Facio’s mouse model represents an important improvement over similar models, which either rely on engrafting human myotubes with low throughput, or on engrafting so-called “immortalized” FSHD cells that deviate from natural FSHD biology because they have been altered to remain alive indefinitely. Facio, however, approximates natural FSHD biology as much as possible by using unadulterated (or “primary”) FSHD-affected muscle cells in its mouse model. Primary FSHD muscle cells are also the basis of Facio’s unique high-throughput DUX4 screening platform.
“Achieving stability was the main challenge”, said Facio’s Managing Director, David Dasberg, “but after about six months we were able to stably engraft human FSHD myoblasts in one mouse thigh and healthy human myoblasts in the other thigh, so that each mouse serves as its own control. DUX4 expression does occur in FSHD myotubes but not in healthy myotubes, which validates the model. Then, in a single-concentration experiment, we orally treated mice with one of our lead candidates or with a placebo. This resulted in a statistically highly significant reduction of DUX4 and of certain DUX4 target genes in human FSHD-affected myotubes. Evidencing that an orally administered compound is able to suppress human DUX4 in a representative animal model is a major leap forward in developing an FSHD therapy. We are extremely pleased with these results, all the more so because chemical optimization of our lead candidates for specific use in FSHD will further improve their efficiency at reducing DUX4.”
Facio has begun expanding its in vivo proof of principle by including other lead candidates, by performing dose-response experiments, and by studying the effect of lead candidates on human muscle cell formation. Together with lead optimization, this will enable selecting two lead compounds for government-mandated pre-clinical safety studies. The lead compound with the best overall performance in terms of efficacy and safety will be taken into a first-in-human clinical trial. As announced previously, Facio currently plans to start a first-in-human trial in the second half of 2021. In consultation with leading clinical experts, Facio is developing an integrated regulatory and clinical development strategy specific to FSHD. “That strategy is the last barrier on the way to clinical trials,” explained David. “We are confident we will cross that barrier, just as we successfully crossed the barrier of establishing a primary-cell-based DUX4 screening platform and then the barrier of demonstrating in vivo proof of principle.”
David stressed that in vivo data represent a key milestone along the way to clinical trials. “It has been said that an FSHD-relevant animal model is technically impossible. We now show that this assertion is incorrect. This has important consequences for the preparation of clinical studies. It is risky to jump from the relatively simple reality of a dish (“in vitro”) straight into the highly complex reality of people with FSHD. After all, results achieved in a dish say nothing a compound’s ability to enter FSHD-affected muscle, or about the dose required to reach the desired effect in such muscle. High doses increase the risk of side effects, especially because an FSHD therapy will be chronic. These risks are mitigated by in vivo proof-of-principle data. Such data should be seen as a crucial component of a regulatory submission for the initiation of a first-in-human study (known as an IND in the US, and as an IMPD in Europe).”
Kees van der Graaf, Facio’s Chairman, noted: “Only two years ago, we were the first to enable reliable quantification of the DUX4 protein in primary FSHD muscle cells. In fact, we still are the only one in the FSHD field with a fully automated, high-throughput DUX4 screening platform. Now, we are the first in the FSHD field to achieve in vivo proof of principle. This double first demonstrates the power of our single focus on FSHD and our commitment to rigorous R&D. People with FSHD need real progress, and real progress requires rigor. We fully intend to stay the course as we prepare for clinical studies.”
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