Paving the Way to the Clinic
Therapeutic drugs may only be marketed with prior government approval. Government agencies (such as the European Medicines Agency and the US Food and Drug Administration) allow a drug onto the market only if they find that safety and efficacy have been sufficiently demonstrated in clinical trials in humans. Clinical trials are regulated by various directives and guidelines. In fact, entering the clinic with a drug candidate also requires permission. Successful discovery of DUX4-repressing small molecules is our first milestone en route to the clinic, but the way between that milestone and the first-in-human trial must be constructed very carefully in order to once again maximize the chance of success. Therefore, paving the way to the clinic is our second objective. This involves activities on two main levels.
On one level, it must be realized that compounds fit for treating FHSD do not exist; they have to be carefully designed and tested. This means that DUX4-repressing compounds emerging from a screen (known as “hits”) have to pass an extensive battery of tests and experiments before they may evolve into FSHD drug candidates. Tests are necessary because screening results can deceive. For example, a hit compound may show a downward effect on DUX4 but may fail to show that effect when tested again or may prove to be toxic to the muscle cells used in our screening platform. Experiments with “true” hits are necessary to investigate to which extent they are fit for use in treating FSHD. For example, they must have the right chemical properties to enter FSHD-affected muscle cells from the bloodstream, where moreover they must survive long enough to reach those muscle cells in quantities sufficient for the desired effect on DUX4. In addition, it must be established how a DUX4 repressor exerts its effect on DUX4. More likely than not, that effect will be indirect. Having entered an FSHD-affected muscle cell, the DUX4 repressor encounters tens of thousands of proteins and enzymes, and it will probably bind to one or more of those and thereby start a cascade of biochemical events that ultimately result in repression of DUX4. However, that cascade may also result in undesired side effects.
In other words, it’s complicated. Hits coming out of a screen must be confirmed to be “true” DUX4 repressors that have no, or only minimal, side effects in our screening platform. If they aren’t, they must be discarded. If they are, they must survive fit-for-purpose experiments. If they don’t, they must also be discarded. If they do, it is highly likely that their chemical properties must be modified by what is known as “lead optimization” (after all, compounds fit for treating FSHD do not exist). If lead optimization proves to be overly complicated, the compound concerned must be discarded as well. This whole process can be depicted as a funnel. Many compounds (think hundreds) enter the funnel, but only a few of them may make it to the end.
On a second level, it must be realized that clinical trials in FSHD are very challenging because FSHD progresses by leaps and bounds, but overall at a slow pace. This threatens to cause clinical trials to take many years before a clinically meaningful effect might be demonstrated. In addition, symptoms vary widely between patients, which makes it difficult to select a manageable trial population. Consequently, starting clinical trials not only depends on successfully taking a fit-for-purpose DUX4 repressor to the gates of the clinic, but also on resolving these issues.
This is not all. Clinical trials with a DUX4-repressing compound pose a challenge of their own. The theory is that treating people with FSHD with such a compound will give them a better quality of life, for example by stopping the progression of FSHD, but that theory needs to be proven in clinical trials. Reliably quantifying the DUX4 protein in cultured FSHD-affected muscle cells is extraordinarily difficult (though possible, as we have uniquely shown), but has not been achieved in humans. That’s another issue that must be resolved.
And so the need to maximize the chance of success appears yet again. What’s needed is a clinical FSHD biomarker that over time correlates with slowly changing disease severity but changes relatively quickly itself, and that moreover makes it possible to identify fast progressors. What’s also needed is a pharmacological FSHD biomarker that over time links DUX4 repression in humans with improved quality of life (as measured by the clinical biomarker, for example). Neither such biomarker exists.
Importantly, all of the above illustrates that in drug discovery and development there is a constant tension between speed and quality. Being rooted in the FSHD community, we are keen on moving ahead quickly, but not at the expense of quality. Because we are very much aware that progress creates hope in our community, we abide by these two rules: real hope requires real progress; and real progress requires rigorous R&D.
In 2018, we took our first series of potential drug development candidates to the next stage as we announced the selection of our first series of lead candidates. “Lead candidates” are promising compounds ready to go through a process aimed at making them potentially fit for use for treating FSHD. Lead candidates surviving that process are known as “lead compounds”, which must be subjected to pre-clinical testing (government-mandated toxicity studies in laboratory animals) before they may be moved into the clinic.
In 2018, we also made a major step forward by showing that oral treatment with one of our lead candidates results in significant reduction of the DUX4 protein in our platform mouse model. This made us the first in the FSHD field to achieve therapeutically relevant proof of principle in a disease-relevant animal model (“in vivo”). In vivo data represent a key milestone along the way to clinical trials. 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 therefore be seen as a crucial component of a regulatory submission for the initiation of a first-in-human study.
Early 2019, we entered an agreement with the Centre for Human Drug Research (CHDR; Leiden, the Netherlands) on a study aimed at discovering FSHD clinical outcome measures based on real-world patient data. This exploratory study, which is co-financed by Facio and CHDR, represents the very first effort to gather objective, real-world data about the impact of FSHD on daily life, and to evaluate the utility of such data for monitoring disease progression and response to treatment. The study will employ a digital platform developed by CHDR. This platform, dubbed MORE for MOnitoring REmotely, uses a mobile app and a wearable device by which a wide array of physical activity, social activity, and biometric variables can be measured on a (semi-)continuous basis. This will generate an unprecedented wealth of human data, which we believe to have the potential to discover clinical outcome measures that are able to discern small changes in FSHD disease status.