Shots: 

• Conventional therapeutic models for Duchenne Muscular Dystrophy (DMD) primarily focus on the role of dystrophin in maintaining muscle cell integrity. However, Satellos’ SAT-3247 takes a novel approach, targeting the lack of dystrophin in muscle stem cells to restore muscle fiber regeneration and repair 

• Today at PharmaShots, we are joined by Phil Lambert, Chief Scientific Officer at Satellos, to discuss the ongoing Phase I clinical study evaluating SAT-3247 as a treatment for patients with DMD 

• In addition to its promising preclinical and toxicology results, Phil highlights that SAT-3247 has already been granted Rare Pediatric Disease Designation (RPDD) and Orphan Drug Designation (ODD).  

Saurabh: Considering the promising results you've seen in the canine model, how confident are you about SAT-3247's potential performance in the upcoming human trials?  

Phil: We have been very happy with the SAT-3247 results we have seen in all animal models but are particularly impressed with our canine model studies. As we presented at the recent World Muscle Society meeting, beyond the initial improvements in muscle fiber regeneration and muscle force that we saw in hind and forelimbs, we’ve also seen regenerative improvement in the diaphragm, which impacts breathing. And when compared to benchmark studies, muscle function in animals treated with SAT-3247 compares favorably to that of healthy dogs and those receiving μDystrophin gene therapy. 

As to human trials, I believe that the early success of SAT-3247 in animal models has the potential to translate into human trials for a number of reasons. First, SAT-3247 works by inhibiting AAK1, a kinase that is conserved in the murine and canine models as well as in humans; in-vitro experiments across each of these species show the compound is quite effective in mouse, dog, and human tissues. 

Secondly, although neither the mouse nor dog models perfectly replicate the human condition, the stem cell driven deficit in muscle regeneration that we identified to be at the heart of Duchenne muscular dystrophy (DMD) are clearly evident in all three. And, in terms of replicating human disease, the canine model best recapitulates the disease progression, histopathology, clinical outcomes, and reduced lifespan seen in human DMD patients. Thus, we believe very strongly that we have the potential to see the promising results we’ve demonstrated in dogs reflected in patients. 

Saurabh: Could you walk me through how SAT-3247 works and how its mechanism of action stands out vs other DMD treatments currently in development?  

Phil: Most of the effort in DMD treatment has focused on the role of dystrophin in maintaining muscle cell integrity, where its absence was believed to be the sole explanation for the muscle weakness characteristic of DMD. Several years ago, however, Satellos Co-founder Dr. Michael Rudnicki realized that dystrophin also plays a role as a signaling molecule, triggering muscle stem cells to form both new stem cells as well as muscle progenitor (satellite) cells. It is these progenitor cells that are critical for regenerating and repairing muscle fibers. In the absence of dystrophin, too few progenitor cells are produced, meaning tissues cannot recover from damage to maintain their strength thus weakening and eventually disappearing over time. 

SAT-3247 has been designed by Satellos to work around the lack of dystrophin in muscle stem cells to restore muscle fiber regeneration and repair. SAT-3247 inhibits AAK1, a kinase protein involved in a dystrophin-independent pathway that, we discovered, has the potential to reset a process known as asymmetric stem cell division. This process produces a progenitor muscle cell each time a muscle stem cell divides in response to muscle damage. In vitro and animal experiments show that treatment with SAT-3247 results in progenitor cell production, thereby improving muscle regeneration and repair. 

Recognizing DMD as a stem cell disease opens the door to a host of new approaches to treatment, of which SAT-3247 is at the forefront. Our small molecule redefines stem cell disease treatment. 

Saurabh: Can you share more about the design of the upcoming Phase 1 clinical trial for SAT-3247, especially regarding how you'll select healthy volunteers?  

Phil: The Phase 1 clinical trial for SAT-3247 will occur in two stages. In September, we initiated the randomized, placebo-controlled single- and multiple-ascending dose study in 72 healthy volunteers to assess the safety and pharmacokinetics (PK) of SAT-3247. In the second stage of the Phase 1 trial we will treat 10 adult volunteers with genetically confirmed DMD. This part of the Phase 1a trial will be a 28-day, open-label study that will tell us if the safety and PK properties of treatment in patients differs in any way from what we saw in the healthy volunteers. It will also help us identify potential PK markers that might be useful in future clinical trials or in later treatment should the drug receive regulatory approval. 

The Phase 1 studies are being conducted in Australia. We plan to incorporate any initial information coming from the Australian trials into our investigational new drug (IND) application with the FDA to facilitate our regulatory path in the U.S. This strategy is designed to help us get into patients sooner, and the faster we can get to patients in need of treatment, the better. 
Saurabh: How do your preclinical and toxicology study results measure up to the standards set by global regulatory bodies, and what impact do you think this might have on future trials in other jurisdictions?  

Phil: Our initial toxicology and safety data covers up to 28 days of dosing, and based on what we've seen in our preclinical studies, I'm hopeful that we will see the therapy translate safely into people. To date in our animal studies, there have been no adverse events and no significant changes in blood or clinical chemistry at doses 20-fold higher than our expected efficacious dose level. The proof, however, is always in the Phase 1 study results.  

The human safety of AAK1 inhibitors already has support as another company has taken their own AAK1 inhibitor all the way through to Phase 2 and Phase 3 clinical studies. This was a different molecule from SAT-3247 and was developed for a different indication. But as far as on-target safety is concerned, patients have been dosed for many months with an AAK1 inhibitor without any serious adverse events being reported. 

Two things are going to be important for us. One is extending that toxicity profile to tell us if there are any chronic issues; that is, does the safety still hold up as we go to longer periods of dosing? The second piece is that we're also doing juvenile tox work, because this patient population extends all the way from children to adults. We have an obligation to make sure that the compound is equally as safe in children, as it is in adults. 

Saurabh: What potential milestones do you foresee for Satellos in the next year as you move into clinical-stage development?  

Phil: Our initial Phase 1 in healthy volunteers should be fully enrolled by the end of 2024, allowing us to initiate recruitment in the Phase 1a study in adult volunteers with genetically confirmed DMD late in Q4 2024 with data available in the first half of 2025. If all proceeds as we expect with the Phase 1 clinical trials, we plan to initiate a proof-of-concept study in DMD patients in the middle of 2025. 

Saurabh: What impact does the Rare Pediatric Disease Designation from the FDA have on the development and potential approval timeline of SAT-3247, and how does this designation influence your strategy moving forward?  

Phil: The Rare Pediatric Disease Designation we received in August 2024 and the Orphan Disease Designation we received earlier are important milestones for Satellos and our DMD program for a few reasons. At the core, they are a recognition of the significant need for new disease-modifying treatment options for pediatric patients, which we feel can be addressed by SAT-3247. From a drug development perspective, the designations are critical because they expedite the review and approval processes. 

Another benefit is that a sponsor who receives an approval for a drug or biologic for a “rare pediatric disease” may be eligible for a voucher that can be redeemed to receive priority review of a subsequent marketing application for a different product or sold to another sponsor for priority review of their marketing application. 

Furthermore, the Orphan Drug Designation affords us certain tax credits on qualified clinical trials, and upon regulatory approval, the potential for a seven-year market exclusivity. These benefits greatly incentivize our efforts to develop SAT-3247 and will hopefully allow us to get this potentially life-changing therapy more quickly to patients waiting to have their needs met. 

Saurabh: How does SAT-3247 fit into the broader landscape of treatments for degenerative muscle diseases, and what sets it apart from other therapies?  

Phil: Unlike genetic medicine approaches, such as exon-skipping, SAT-3247 is an orally available small-molecule, which gives us a lot of flexibility in terms of dosing. We expect SAT-3247, due to its unique mechanism of action focused on regeneration, will allow us to go to patients across the age range, helping patients at different stages of the disease. Oral dosing with SAT-3247 also provides other benefits from a safety and tolerability point of view, in terms of making it convenient and straightforward for patients to take.  

Another interesting possibility we see from our preclinical data is that we might observe clinical effects sooner with SAT-3247 than with traditional DMD treatments. Other treatments tend to slow progression but don’t facilitate recovery, and it may take a prolonged period for this difference to be observed. In contrast, our treatment promotes regeneration and repair, which have translated preclinically to rapid improvement in muscle function. Thus, we may see efficacy in a shorter-term study. We'll likely start with three months of dosing in patients to look for efficacy and then extend that with approval from the FDA. 
Saurabh: How do you envision SAT-3247 contributing to the long-term management of Duchenne Muscular Dystrophy, and are there any plans to investigate its use for other muscle degenerative conditions?  

Phil: We believe there are two issues to disease progression in Duchenne muscular dystrophy. There's the loss of dystrophin in the muscle fiber, which makes the muscle more susceptible to damage, but there's also the loss of dystrophin in the muscle stem cell, which means that there's reduced muscle regeneration and repair once damage occurs. In a healthy individual, every time the muscle is damaged, there’s regeneration, and the muscle is repaired. In DMD, that doesn’t happen and damage accumulates and eventually destroys muscle. 

For that reason, we believe that our drug could go along with any of the other treatments, such as gene therapy with exon skipping. However, we also believe that the main crux of DMD is the loss of regeneration, and therefore we can develop our molecule to work as a monotherapy, believing that even without the other treatments, our compound has the potential to have a significant, disease modifying impact for patients. 

And because we're going through a dystrophin-independent pathway, our therapy is mutation-agnostic and can work across the various mutations that trigger DMD. We also have data that this therapeutic approach can work across other muscular dystrophies where regeneration is the issue. Regeneration isn’t an issue for all muscle diseases, but we have looked preclinically at some of the other muscular dystrophies, such as facioscapulohumeral muscular dystrophy (FSHD), where the data suggests it is an issue, and SAT-3247 works there, too. So, we’re laser-focused initially on DMD, but we certainly have other disease areas where we can also make a therapeutic impact. 

Image Source: Canva 

About the Author:

Phil Lambert, Ph.D. 

With more than 25 years of drug discovery and development expertise, Dr. Lambert has supported the advancement of more than 20 small- and large-molecule therapeutics through clinical development. Co-founder of contract research organization VivoPath (now part of Charles River Laboratories), he also held positions with Centogene, Life Biosciences, Sirtis Pharmaceuticals, Forum Pharmaceuticals, ALS Therapy Development Institute, Regeneron Pharmaceuticals, GSK, and Parke Davis, and served on the faculty of Emory University School of Medicine. 

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