Joining Guggenheim's 3rd Annual Healthcare Innovation Conference. Our next presenting company is Satellos Bioscience, and joining us from Satellos are Wildon Farwell, its Chief Medical Officer, and Liz Williams, CFO. I am Debjit, one of the Therapeutic Analysts up at Guggenheim. Well, thank you. Good morning. Thanks for your time.
Good morning. Thank you for having us.
When we originally made these questions, that was two weeks ago. The story has changed, especially with the alignment with the FDA. Wildon, maybe I'll ask you to first give a quick intro on the lead asset, because the mechanism is still being sort of or people still haven't grasped the mechanism, and then we can go on to the FDA alignment.
Sure. Happy to, Debjit. Thanks again for inviting us, and it's very nice to be able to talk with you and everyone about Satellos and our approach to people living with serious muscle disease. Forazapadin is a small molecule that is able to inhibit a protein called AAK1. What is known in people living with serious muscle disease, including Duchenne muscular dystrophy, is that the disease not only affects the muscle fibers, but actually also affects the satellite cells, the cells that are responsible for regenerating new muscle. In people living with Duchenne, they're missing a protein called dystrophin, and in the satellite cells, dystrophin has been identified to be involved with stem cell polarity. When it's missing, stem cells are not able to create muscle progenitor cells as effectively as when dystrophin is present.
Forazapadin is able to allow enhanced stem cell polarity to then enhance muscle regeneration. Satellos has now conducted phase I clinical trial. It has two phase II clinical trials ongoing in people living with Duchenne, one called TRAILHEAD, which is in adults living with Duchenne, and one called BASECAMP, which is in kids living with Duchenne. We also are just beginning to start a program in FSHD. Most recently, we had a conversation with the FDA around potential paths to accelerated approval. We believe that our BASECAMP study is designed in a way in which it really could create a dataset that could potentially lend itself to conversations around accelerated approval. When we had the discussions with the FDA, it was around whether fat fraction could serve as an endpoint reasonably likely to predict clinical benefit.
The FDA provided us with feedback that allows us to incorporate fat fraction as our new primary endpoint for BASECAMP, and we've adjusted the protocol to allow for that.
Got it. Let's talk about the fat fraction. What was the underlying data that caused that change in primary endpoint coming from the TRAILHEAD study?
In TRAILHEAD, again, this is a study in adults living with Duchenne. The first four participants in TRAILHEAD were also participants in our phase I clinical trial. These participants were followed for 28 days in that first study, and then followed for five additional months in TRAILHEAD before an evaluation was performed that we reported the results over the summer at ICNMD. What was very compelling in these results is that we saw that each of the four participants had a decline in fat fraction anywhere between 1% and 6%. The natural history for fat fraction in adults in the upper arm, which is the muscle that we evaluated in TRAILHEAD, the biceps brachii, the natural history is an increase of around 6% per year.
The fact that we saw a decline in all participants anywhere from 1%-6% in five months within TRAILHEAD is very different than what's expected in the natural history. It was this data and the totality of other data from TRAILHEAD that we presented to the FDA and had the conversation and led to the feedback that we received.
Got it. BASECAMP is enrolling younger, healthier patients with maybe preserved muscle mass. Do you think the effect is going to be more pronounced in terms of reduction of fat fraction?
The honest answer is we don't know. The honest answer is that this is a study in kids. We've not performed a study in kids with Duchenne, so we don't know what the data will look like. What I can say is the biology should be the same between the adults and the kids. We know that stem cells are present in the adults. The stem cells are even more present in the kids. The muscle injury damage is occurring in the adults and in the kids. These are what's required for forazapadin to have its effect. It needs muscle. The muscle then must be injured. Injury then targets the stem cells to want to divide, and forazapadin can enhance muscle regeneration. This same process is occurring in kids.
We know that in the kids that they develop this fat fraction increase in the same way that the adults do. The trajectory of increase in fat fraction can vary depending upon muscle and depending upon how fast the disease is progressing in that particular person. But all of these factors are still at play in both kids and in adults. And so the fact that we saw this improvement in fat fraction in the adults, I believe, bodes very well that we have a good opportunity to potentially see that in kids as well.
And is the natural history concordant between what happens in adults, the 6% a year, versus the patient's subset that's being enrolled in the BASECAMP study?
In BASECAMP, in the kids, we will be looking at the vastus lateralis, which is a muscle in the thigh. It has been very well characterized in the natural history. Many, many studies have looked, and what is seen consistently is in an age range consistent with BASECAMP, most kids have a fat fraction of between 10% and 20%. What is characterized in the natural history is that once the kids get to about 10%, then their fat fraction increases by about 10% per year. And once they get to about 40%, their risk of loss of ambulation markedly increases. So there is clear correlation between levels of fat fraction and loss of ambulation. So we would expect then within BASECAMP that the kids have elevated fat fraction, so there is an opportunity to be able to show a decline.
Again, the natural history is quite clear that kids really only worsen in fat fraction. There is really very little evidence of any decline in fat fraction among kids living with Duchenne. So, if in BASECAMP we see that there are people stable or declining in fat fraction, that is very different than what would be expected in the natural history, and we think that then will predict changes, improvement in clinical function over time.
Got it. So, does the FDA expect the data to be stat sig, or majority of the patients showing a decrease in fat fraction corroborated with some of the functional measures might support an accelerated approval pathway?
What the FDA said was the larger effect, the better. If one can see a large effect in improved fat fraction, then that makes it easier to be able to have an overall positive result. What they also said was that they do not want to just see one correlation. They want to see multiple correlations, and it is better if one can show durability and show that it is not just one time point, it is multiple time points. That all makes good sense to me.
That is based on clear scientific rationale. If we are truly improving fat fraction, slowing that down, that should translate not just into one clinical assessment, but multiple clinical assessments. That is what the natural history shows. The natural history shows that it is loss of ambulation, it is NSAA, it is time to rise. All of these endpoints are correlated with fat fraction. BASECAMP has been designed to be able to demonstrate this. We have now fat fraction as our primary endpoint. We have several additional efficacy assessments such as stride velocity, such as time to rise, such as four-stair climb, dynamometry. Again, we saw good data on dynamometry in TRAILHEAD. We are not walking away from that endpoint. We still have it as a secondary endpoint. We believe there is an opportunity to look at the correlation between fat fraction and several of these.
Got it. These data are going to be available sometime in the first quarter?
Correct.
Along with the blinded data, at that point, you will have a bunch of patients out in the open label extension?
Absolutely.
How important are those data?
I believe that is a key part of this overall story. Again, there really are no known effective therapies for adults living with Duchenne. There's a sizable population of people who have Duchenne, who are adults, and have very significant unmet medical need. If we continue to be able to demonstrate that in this population, we see a decline in fat fraction, and with time, that's translating into clinical benefit. Again, TRAILHEAD has designed so that we not only evaluating fat fraction, but we're evaluating what's called the total effort, which is a digital assessment of their upper extremities. They're very dependent upon their upper extremities in adulthood for their remaining function. We're looking at the PUL, which is the performance of upper limb, which is a standardized clinical assessment. The FDA and other regulatory agencies are very familiar with this standardized assessment.
We'll have the opportunity to see, can we see continued durable reduction in fat fraction, and with time on drug, can that translate into clinical benefit? If we're able to demonstrate that clearly in the adults and begin to also see that in the kids, to me, that becomes a very compelling data package, not only for the FDA, but for other regulators.
Got it. DMD is also a very heterogeneous disease. You have all these exons. From the randomization perspective, do you think the study has been adequately randomized so you don't land up with, let's say, exon 44 patients in the placebo cohort, and you land up with exon 51s in your treatment arm, and they have very different fat fractions.
Yeah. You're right, Debjit. Duchenne has variability. A lot of that variability can be demonstrated based upon mutation, levels of dystrophin, quality of dystrophin that's produced, how long the person has been living with clinical phenotype. In BASECAMP, we've tried to account for some of this heterogeneity by limiting the population by age. It's limited to boys between seven, eight, nine years of age, and we've also limited by some performance on functional assessments to account for the fact that some boys may have more function than do others. We've not limited by specific genotype. We believe this is a mechanism, a drug that can work in all people living with Duchenne regardless of their phenotype. Because we're looking at fat fraction, we're going to be looking at change over time, and looking at the mean change in people on drug versus the mean change in people on placebo.
We won't stratify based upon genotype, but we will have enough participants in the trial, and how we are accounting for some of the heterogeneity, I think, will minimize some of the variability that does exist.
Got it. What does the givinostat story, or how does that tie in? Because their fat fraction actually, well, there was a delta between placebo and treatment, but both increased over time.
Right. Other sponsors in the field have absolutely looked at fat fraction and provided that data to regulators. It's another reason why we believe fat fraction is a good endpoint to discuss with regulators going forward. We're not the first to work on this endpoint. Many others have used it. In these other programs, as you point out, what is typically seen is a slowing of worsening. The kids continue to increase in fat fraction. It's just that with givinostat or gene therapy, they may not increase in fat fraction as fast as boys who have not received therapy. What that means, though, is that they're still progressing in their disease. They're still having worsening in function or potential loss of milestones over time. What the data from TRAILHEAD suggests is that we may be able to stop or reverse some of this disease progression.
If we are able to do that, then I do think that translates into maintaining benefit or perhaps even regaining benefit over time. That is what we will be looking for in BASECAMP. That is what we are already looking for in TRAILHEAD, and this would be a great result for the community if we were able to show that.
You have two doses, 60 mg and 120 mg. Is there an expectation to show a dose response, or how should we think about those two?
The primary analysis will be looking at all people receiving forazapadin compared to placebo. We will be looking to see, is there evidence of a dose response? Can we see that participants on one dose are having a greater response with the same or better safety profile than folks on the other dose? But the first primary analysis will just be looking at those on treatment compared to placebo.
In DMD, like with any other sort of progressive disease, earlier the intervention, the better, right? If you see a very consistent signal from BASECAMP, how quickly can you move into, let us say, a two or three-year-old newly diagnosed DMD patient?
Yeah, we believe we can move very quickly. The preclinical work is pretty much complete to be able to allow us to continue to advance the program into younger ages. We want to see the data from BASECAMP before we really trigger any of these other clinical studies. So far, we believe we have what we would need to be able to initiate those.
Would you need an alternative formulation, given very young kids may not be able to swallow a pill?
Right now, the protocol does allow for the pills to be crushed, and so that would allow us to move into some younger age. In order for us to move into the infants, we would need to explore some formulary work. But as far as younger kids, I believe we have the data we need to start that study.
Got it. With your introduction, you mentioned the FSHD study is on as well. What does this mean for FSHD?
What we believe is that in many serious muscle diseases, it is not just a disease of the muscle fiber itself, but also of the stem cell. The stem cell is not able to keep up with all of the damage that is occurring, either due to the foundational biology of the disease or the inflammatory component of muscle destruction. We have preclinical data in the FLExDUX4 model, which is the standard model for FSHD, showing that with forazapadin, we are able to increase muscle function, force generation. We are initiating the program in people living with FSHD. We are working very hard to get that protocol active this year. It has already been cleared by the FDA.
We are working with sites to activate them, so that we can enroll that study, hopefully starting this year, completing next year, to then potentially allow data, more likely early 2028.
Got it. Liz, your life could change dramatically if BASECAMP works out.
Yes.
Especially if it is overwhelmingly positive.
How are you prepping for different scenarios here, given where your balance sheet currently is?
Mm-hmm. Yes. We are funded through 2027, so we are funded. The BASECAMP study, the TRAILHEAD study, and FSHD studies are funded well past the BASECAMP readout in Q1, which is great. We will need to raise additional capital to continue to develop the clinical pipeline, which we would do with BASECAMP data in Q1. We are starting to put plans. We are not starting. We are putting plans in place to identify and move forward with the pieces we need to support an NDA filing from CMC, quality, regulatory. So those key long lead items are built into our runway when we say end of 2027. So we are actively working on all those pieces behind the scenes so that when the BASECAMP data is as successful as we believe it has the potential to be, we will be ready to move quickly towards an NDA filing.
From a regulatory strategy perspective, would you share the data with the FDA before disclosing it to the street, or you will have the data out and then ask for a meeting with the FDA and stuff like that?
I think we would be able to provide a high-level visibility into the results. We may want to have some conversation with the FDA before all of the data is presented, but I think there is an opportunity to present high-level overall results to give people awareness of where the program is and the potential next steps with the agency.
If the BASECAMP data are overwhelmingly positive, do you think CMC will be in place for an NDA submission in 2027?
Yes. Yes. We're working towards that. Small molecule, so it's a simpler, more cost-effective CMC program. Yes, it's actively underway now to be ready for that timeframe.
Awesome. Wildon, maybe to close it out, if you get your wish, what kind of data would you like to present in the first quarter?
Well, I look forward to having a dataset that provides us with clear answers to the questions, right? So really, what is the overall safety profile? Again, so far, what we're seeing in TRAILHEAD and to date within BASECAMP has been unremarkable. It's very consistent safety across the age ranges. Do we see an effect on fat fraction in the kids similar to what we've seen so far in TRAILHEAD? If we are seeing that participants in BASECAMP are having improvement in fat fraction, I'm confident based upon the natural history and what other sponsors have shown that that will translate into clinical benefit. The question is, over what period of time and what magnitude? No one in the field thus far has been able to show a reduction in fat fraction, and so we don't know how quickly and in what parameters that will demonstrate benefit.
But the natural history suggests that that could be across multiple parameters, and so we have that built into the study. Stride velocity, time to rise, four-stair climb. Again, lots of others in the field are using stride velocity. We know the agency's familiar with it. We will see how that conversation with regulators evolves. It may be that by the time we are ready to present the data to the agency, they are comfortable with stride velocity as a potential path to approval, and that would be a very nice outcome for us if we are able to show improvement in fat fraction as well as improvement in stride velocity.
Well, first quarter 2027 cannot come sooner. Really looking forward to this because DMD has been a land of disappointment so far.
It has been very challenging for the community for a long time, and I think one of the things that is exciting to me is Satellos is taking a different approach. We are really building upon foundational biology that Michael Rudnicki, one of our Co-Founders, discovered and has really applied. And if this is successful, it has implications for many other people living with serious muscle disease, and I think that is very exciting.
Looking forward to it. Thank you so much. I appreciate the time today.
Great. Thanks, Debjit.
Thanks, Debjit.
Thank you.