Here we go. All right. Thank you everyone for joining us here at the Sionna Fireside Chat at the TD Cowen Healthcare Conference. I'm covering analyst Ritu Beri. With us today from Sionna, we have from my right, CEO Mike Cloonan, CFO Elena Ridloff, and CMO Charlotte McKee. Thank you guys for joining us today. Sionna, leaders in NBD1 mechanistic medicines for CF, a new class that has really been a focus of investor discussion in the CF field since you guys IPO'd. The original conversations always go back to, you know, with generations of CF modulators, multiple generations of CF modulators available, each one with increased efficacy over the last. What's the rationale for pursuing NBD1 stabilizers as a next gen? What's left on the table?
Yeah, I'll take that one, Ritu. First, thank you, Ritu, and thanks TD Cowen for inviting us today. Always a pleasure. Thanks everybody for joining us today. Let's talk about NBD1, but let me just step back for one second and talk about the market, and then we can dive into this, to NBD1 and the role it plays. Our goal at Sionna is to revolutionize the treatment paradigm in CF. Using NBD1 as the anchor to that revolution, we have an opportunity to do something very, very different in CF. Despite the advancements that have been made, we give Vertex a lot of credit for. Is it not working? The developments. Despite the advancements that have been made in CF over the last few years, the unmet need continues to be high in CF.
Oh, no.
Turn it on. Is that working? Can you hear me now? It's not green.
One, two.
Do you wanna do a quick check?
It's not on.
This is on. It's on? Okay. Thank you. I think that's working. All right, let me go back. I don't know what was heard, we'll start over. Thank you, Ritu. Thank you, TD Cowen, for inviting us today. The goal of Sionna is to revolutionize the treatment paradigm in CF by doing something very, very different, leveraging NBD1, this unique target that we'll get into. We give Vertex a lot of credit for the developments that have been made in CF over the last several years. The advancements have been significant yet even with those advancements, the unmet need continues to be high in CF. We know that because for two-thirds of the patients on the standard of care today, they are not getting to normal CFTR function. To your question, Ritu, that is the goal.
The goal should be to drive as many patients to normal CFTR function as possible. NBD1 really is the key to unlocking additional improvements for patients specifically related to the CFTR function. If we look at the biology of NBD1, what we know, the number one genetic mutation that causes CF is F508del. The deletion of that phenylalanine resides within the NBD1 region of the protein.
One of the four testers.
Right. Exactly. There's different regions or domains of the protein. NBD1 is a very important region because with that F508del mutation, it causes NBD1 to irreversibly unfold at body temperature. It's creating this instability not only in NBD1, but the protein, crippling its folding, its ability to traffic to the cell surface, and then its overall functionality is impaired. The current standard of care, Trikafta and Alyftrek, are correcting around NBD1. They are not directly stabilizing NBD1, and so they're partially correcting the protein, which leaves an opportunity with the stabilization of NBD1, we believe there's an opportunity to unlock additional CFTR function improvement.
What we know from our preclinical data, that when we stabilize NBD1, we are doing something fundamentally different to the protein in terms of its ability to traffic to the cell surface, its functionality, its half-life. All of those are improved when you stabilize NBD1. When we look specifically in our CF HBE assay, which is the gold standard in vitro assay in CF, if we just look at the monotherapy, the single agent NBD1 by itself at Emax, and we compare that to the triple combination of three compounds that make up Trikafta at Emax, we are nearly equivalent. One compound nearly equivalent to the triple combination of the standard of care, which that speaks to the power, right? The power of NBD1 and its potential to correct the protein.
Our goal as our top priority is to develop what we call a dual combination. Two drugs that come together where NBD1 plays the foundational role, and we add one other component that we think gives us the potential to fully normalize, fully correct the CFTR protein because of how differentiated and important NBD1 is.
That is the next question. What is the differentiation? Is it... Oh, goodness, now mine... This was working. I'm good? Okay, great. So how? What is it that NBD1, like physically on the CFTR, how does it change the CFTR such that it normalizes function? There were some posters this year at NACFC that illustrated trafficking versus stability and that whole like grid. How does it, how does it fall?
Yeah. Yeah. Can people hear me? Is it okay?
Yeah.
Thanks. I'm not sure if I need the handheld or not. What we know from the tools available, from the translational tools, which are quite powerful, we know that stabilizing NBD1 does a number of things. You've touched on a number of the things that we can show in these in vitro models. One is that when you stabilize NBD1, that differentially and, you know, that adds substantially versus the current modulator mechanisms to the generation of mature CFTR band, mature CFTR protein. Related to that, the ability to put mature CFTR band on the cell surface. That means it's gotten through the cell machinery. It hasn't been, you know, it hasn't been identified or tagged as defective, and that's a really important proof point.
The other thing that, you know, you've mentioned is we know from our in vitro assays or what we see in our in vitro assays is with NBD1 stabilization, there is a vastly different ability to improve the half-life of mutated F508del CFTR on the cell surface.
At body temperature.
At-
I think that was the other part of it.
Well, that is. Yes. That is part of the whole proof of principle.
The post area.
That also is the thermal stability.
Yes
of the isolated F508del NBD1 domain, that's a more unique assay to us. When you take the isolated F508del NBD1 domain, we can see that our NBD1 stabilizers are the only ones to improve that thermal stability, which really speaks to being able to stabilize that protein at body temperature. Then we have, of course, the HBE assay, which tells us that all of this rolls up as you would expect into improved function. Mechanistically, something at a level that we don't see with any of the approved modulators.
One sentence I've heard more than any other is, "Oh, well, if this was possible, why didn't Vertex do it?
Yeah.
Charlotte?
Well, Charlotte can't answer that one.
I'll turn it over to Mike.
Yeah. Even though Charlotte worked at Vertex. We won't put her on the spot. Well, there are certain things we know about NBD1, the history of NBD1. This is not a new target. It has been studied, it has been known for a long time. The biology has been well understood.
It was considered undruggable.
Considered undruggable, mainly because of the very, very shallow binding pockets. Pfizer did a lot of work on the target back over a decade ago. They published a paper about this, and that was their conclusion. They think this is undruggable because of the shallow binding pockets. Personally, I think once Pfizer issued that paper, it probably scared a lot of people away from that target, right? 'Cause they went after this pretty hard. As you know, the history, our programs originated at Genzyme and continued on at Sanofi, and by the time that paper was written, we were well past the breakthroughs. We had made a lot of breakthroughs across NBD1.
We do know that more recently, Vertex has come out and have said they did try to go after this target in NBD1, and I believe their words they chose, "We could not optimize the target," which we think speaks to the chemistry, how challenging the chemistry is because of the very, very shallow binding pockets, which was why it had that label of being undruggable. Again, it's not that the biology isn't understood and its potential role in the correction of the protein. It is very well understood. It has just proven to be a very, very difficult target. We wouldn't be where we are today without the 15 years of history behind our programs. Again, going back to Genzyme, Sanofi, and now Sionna, we've been fortunate to leverage the perseverance and the effort that took place at Big Pharma.
When we spun out of Sanofi in 2019, we were able to be a hyper-focused CF-only company and advance these programs in the way that we have, that we have multiple programs now of NBD1 stabilizers in the clinic.
Let's move on to your next data readout. This is a phase II PreciSION CF study. I mean, it's kind of first gen SION-719 NBD1 as an add-on to Trikafta, and the trial is versus Trikafta alone. Can you discuss beyond that part, the design, the endpoints of this phase II , including doses, and where do you set the bar for success?
Yeah. maybe I'll talk first about what we're hoping to show with that study.
Mm-hmm
And some of the endpoints and the design. This really is a proof of concept or proof of mechanism study, and we're leveraging the characteristics of sweat chloride. The primary activity readout will be sweat chloride in patients who are F508del homozygous as a homogeneous genotype background. We're really intending to show that NBD1 stabilization does something unique, mechanistically unique and synergistic with the components of the standard of care-
Mm-hmm
... in this study design. Importantly, we're intending to correlate for the first time in patients with CF the predictions that we have from our CF HBE assay.
Assay
... in patients with CF via CFTR function or sweat chloride. Also, if this reads out as we expect and hope, the intention is to really demonstrate with that sweat chloride output that NBD1 is able to drive, as we would expect from the distribution of sweat chloride, that it's able to drive substantially more CFTR function.
Mm-hmm
... in patients who are already stable on Trikafta. We, you know, we think that will give us a lot of mechanistic and important proof points and lines in the sand that they would translate to future, you know, potential predicted benefit in patients.
What is that sweat chloride threshold?
Yes.
What will it mean?
Yeah, maybe I'll start.
Mm-hmm
... where the study is powered for a change of at least 10 millimole per liter change in sweat chloride in the patients who are on 719.
Mm-hmm.
A low dose of SION-719
Mm-hmm
... added to the components of Trikafta-
Mm-hmm
... versus just on Trikafta alone.
Mm-hmm.
That is a threshold that historically has translated, first of all, it has been sort of the clinically meaningful kind of target. We have spoken with thought leaders.
Mm-hmm
... and people in the CF community.
Have you screened for, I guess, screened out for, like, Trikafta super responders that have normalized?
We have eligibility criteria.
Yeah.
Yes. We're really looking to enroll. We're not talking about the specific criteria.
Yep
We do have eligibility criteria to ensure that these patients have had a typical response, but they're not already in the normal range.
Is it fair to say they're sort of in the bottom half of the distribution of response?
The middle.
The middle.
We call them in the middle.
the middle-
You know.
... of Trikafta responses.
Right.
on
You know, so they've had-
... assay, sweat chloride
yeah, they've had an expected response, but not already in normal, and they haven't had.
These are not the Trikafta poor responders.
Correct.
That's correct.
That's not to say those patients would not respond to NBD1.
Right
This study is a small, efficient study.
Mm-hmm
... trying to select the patients that we feel like have had a typical response, right? As we get into-.
Mm-hmm
... bigger, later-stage studies, the enrollment criteria will open up, and we can access many more patients than what we see here. As Charlotte's outlined, we really wanna make sure we understand these patients first, and having that protocol and the enrollment criteria we have today puts us in the best position to do that.
that 10 millimole per liter-
Mm-hmm
sweat chloride bar is really important because that has also generally translated to clinically meaningful FEV1 benefit.
Mm-hmm.
That's not what we're-.
So three percent-
Yes, at least say a three percentage point of FEV1.
Mm-hmm.
That's not what we're really looking for in this study because it's too small and too short.
Mm-hmm.
That's part of why that 10 millimole per liter bar is important, in the, you know, in terms of expectations and down the line.
What is the sample size in powering for that 10 millimoles?
Yeah, 16 patients.
Mm-hmm
... in a two-way crossover, and that's important because in a two-way crossover study design, each patient serves as their own control. The variability is substantially decreased, and so it allows us to be really efficient and to be powered for that threshold with a fairly small number of patients.
That's where the variability. You've basically designed for low variability.
Right
... into the assumptions. Beyond sweat chloride, what secondary endpoints are being measured, and will any of them be included with the top-line data?
Because it's a really early-stage-
Yeah
study, the overall primary endpoint is safety.
Mm-hmm.
Um-
At 28 days, correct?
Pardon me?
28 days.
It is a two-week dosing period.
Two weeks. Oh, so two weeks on-
Two weeks.
Two weeks off.
Two weeks on.
28 days trial.
There's a 14 days of treatment then they wash out for a while before they go on to the second version of whatever they're gonna get.
Yep.
They're randomized. You know, the patients are randomized, and no one on the study knows who starts on what first and who then gets, you know, whatever they're gonna get in the second period.
That 14 days is too short.
Right. Right. Exactly.
Have there been any studies that moved FEV in 14 days?
FEV1, so when you think about maybe either powering or really looking for precision in FEV1, You're thinking about both the duration of the study, but really importantly, the size of the study. While, you know, for all of these endpoints, you might start to see hints of things, but this study, in particular, is both a little too short to really have strong read on FEV1, importantly, it's really too small to really read FEV1 with any precision.
How do you see a linear relationship? Is this that sort of 10 millimoles that correlates on a linear basis with the assay and then further? I mean, what is that relationship? This was a big discussion at the CF conference again, with, I guess, debate on how baseline CFTR function, whether they were talking about sweat chloride levels or whether they were talking about the assay data, how baseline impacts the ability of the next drug, regardless of mechanism, to move the needle, either biomarker or even clinically. How do you view that relationship?
I'll start. You know, what we know to date is, you know, the data we have are the data, you know, that are out there in the public domain. To date, when you look at patients on everything up to Trikafta, you know, taking Trikafta and Alyftrek is very similar, same mechanism of action, you know, really very similar sort of sweat chloride outputs and the same FEV1 output. If you look at the spectrum of responses from nothing up to what is currently, you know, the standard of care, that relationship has been remarkably quite linear.
Mm-hmm.
Even across, you know, with some variability across sort of large mutation groups. That's what we know.
Mm-hmm.
What we don't know is what would happen beyond that point when you really substantially move sweat chloride or improve sweat chloride.
close to normalized levels.
Right
is
We don't really know in the larger populations what might happen. We have some hints when patients who were on Kalydeco were switched to Trikafta the gating patients, that small group of patients had a substantial and still actually remarkably linear improvement in both their sweat chloride and their FEV1, pretty close as a mean.
Mm-hmm
... normal range. We know it's possible, but, we hope to be the ones testing that hypothesis.
Mm-hmm
to see exactly what happens. We believe there's room still to improve FEV1 if you can really substantially improve CFTR function.
It sounds like in your many years of experience in CF, you wouldn't, you wouldn't predict a ceiling effect when you are targeting that average Trikafta response that you have enrolled in PreciSION.
Not based on what we see, not based on the range of, say, lung function numbers that were enrolled, let's say, in the Trikafta program. You know, and we don't think there's anything that proves that if there is a ceiling, that it's been reached.
Just, just two points or two I think Charlotte.
Mm-hmm
... has made just to reiterate this. Every bit of sweat chloride improvement we can deliver is good for the patient. Lower sweat chloride is better. That is absolutely something that I think the CF community believes. Vertex and Sionna are absolutely very much aligned. Lower sweat chloride is better, so that's our goal is to deliver that. We think the gateway to FEV1 is sweat chloride, which is why we're targeting that 10 millimoles. That is the line, that's the sort of minimum bar for clinically meaningful improvement as it relates to sweat chloride and would also give us a higher degree of confidence that we can move FEV1, and that's really the key. You wanna be outside the noise of lower sweat chloride levels that you would be at risk of not moving FEV1.
Our target has been that double digit, 10 or more, which would give us a high degree of confidence we'll see that 3 percentage point improvement in FEV1 if we deliver the sweat chloride.
Another, you know, jumping off point or probably the second or third point that comes up with investors I talk about your company and the program is like, "Where did AbbVie go wrong with the assay?" You have very beautiful assay data, in your deck and in your publications and your posters. And they say, "Well, so did AbbVie, and look what happened." As you look at that triple, and you look at the assets that you guys elected to bring in, what was predictive and what was wrong, run wrong, misinterpreted?
Yeah, probably worth going back on the AbbVie history.
Mm-hmm
... to really peel the onion of what happened there. The history of AbbVie, as many folks may know, they in-licensed these compounds initially from Galapagos. When they were started to work in CF and they licensed those assets in, the standard of care at that time was Orkambi and Symdeko.
Mm-hmm.
The double combinations were the standard of care. Where AbbVie first set out was to get their own dual combination that could be competitive with Orkambi and Symdeko, and they did. They actually had developed two different compounds, galicaftor and navacaftor, which are two of the compounds we licensed in, that when you look at their clinical data, Phase II data, they were competitive and equivalent, very similar to what Orkambi was and Symdeko on both sweat chloride and FEV1. At that time, I think AbbVie was feeling pretty good about themselves.
Mm-hmm. Yeah
... that they had something that could be competitive. Unfortunately, for them, good for the CF community, Trikafta then launched.
Mm-hmm.
It significantly raised the efficacy bar, and the standard of care went from a dual to a triple combination with much higher efficacy. In order to be competitive, AbbVie had to change the strategy and now.
A triple.
... a third compound.
Their triple.
Right, a triple combination that could be successful, and ultimately, they could not get that third compound to get to the level of efficacy of Trikafta. We don't see that as sort of an assay failure. It was really a compound failure.
Mm-hmm.
They tried multiple third compounds to combine with their active dual. They couldn't get there. Because when we did the deal with AbbVie, before we were able to do diligence, we had synthesized the two compounds that we in-licensed, galicaftor and navacaftor, in our HBE assay. We ran it through our HBE assay. The results that we got in our assay showed that those compounds had the potential to be like Symdeko and Orkambi. We didn't find out until we did the diligence that their Phase II data, which had not been published, actually matched that prediction.
Mm-hmm.
It validated our assay having that data from AbbVie.
Were you able to look at the assays that ran their third?
Well, all I'll tell you is we did not select any of those third compounds for a reason, right? We did model compounds that we didn't select.
I'm gonna say yes, you did.
We picked the ones that had the most activity in the assay and the ones that paired the best with NBD1.
In our assay.
In our assay.
In your assay.
Exactly. In our assay, we ran them through. We picked the compounds that were most active-
Mm-hmm
... had clinical data, that would be the best complementary modulators to combine with NBD1, which was why we picked the three. We had our choice of their entire portfolio, we picked the three best.
Is there an independent commercial opportunity for SION-719 as a monotherapy adjunct?
Do you wanna talk about, I would say add-on. Right?
Add-on.
Add-on.
Yeah.
Yeah.
Yeah. Yeah. Just strategically-
Mm-hmm
... our prioritized path is the dual combination.
Yeah, the proprietary dual.
Yeah.
Yeah. Mm-hmm.
However, there is a very attractive commercial opportunity as well for an add-on to standard of care. We've done market research on that. There are, you know, as compelling as an opportunity as the dual is, there's always patients who are happy on their existing therapy but could still benefit from more efficacy. We think there could be an opportunity if we were to pursue both to commercialization, where those could be co-positioned and have a very attractive commercial opportunity for an add-on.
Let's move to the proprietary dual. This is galicaftor, and SION-109. Either galicaftor or SION-109.
SION-451
Sorry, SION-451.
Yep.
Galicaftor, SION-109 with SION-451. How will the optimal combination be selected for further development in...? Like, what are you looking for? What sort of behavior in combination with SION-451 are you looking for with either of those?
Yeah. It's a healthy volunteer study where we're looking at the combination, as you said, Ritu.
Mm-hmm
... where we're looking at 451, our second NBD1 stabilizer that's gonna form the anchor or the foundation of that dual combination, and we're looking at 451 in combination with galicaftor, which is SION-2222, one of the AbbVie assets. There's 451 with 109, our own ICL4 corrector. The goal of this study really is to look at 2 pieces of the dual combinations. One is the safety and tolerability profile of the two different combinations to be able to compare them to each other.
At the same time, we're looking at the PK or the exposure profiles of the dual combination that when we have that exposure profile, we can then take that and implement it back into the HBE assay to see how high up the curve we can get with the PK and exposure that we achieved in the phase I studies. The goal is to select the best dual combination from those studies. We have the two different combinations, but the goal will be leveraging that safety and tolerability data and the PK and exposure profiles and select the combination that we think has the best potential to deliver that clinically meaningful benefit bar that we've talked about, at least 10 millimoles of sweat chloride above the standard of care. That continues to be the goal, whether it's a dual combination or it's the add-on.
That's the bar we've set for both options.
Whichever has better assay activity will be the one chosen. Is that fair?
That'll be a key part of the decision, right? Safety and tolerability, right?
Of course. Always.
It's like, is there any separation as it relates to that? What exposure do we achieve? When we put that into our assay, how high up the assay curve do we get? Then we'll look at just the interplay of the compounds together as well.
Mm-hmm
just how they worked together.
Do you predict any sort of, like, formulation issue or co-administration like ADME issues with them?
we selected, you know, as you know, you know, we selected specifically galicaftor and SION-109.
Mm-hmm
... as the preferred complementary-
Mm-hmm
... you know, partners based on their mechanisms.
Mm-hmm
... obviously. either one of them in vitro really looks to, you know, to be very powerful when paired with 451, but also their metabolic profiles and things like that.
Mm-hmm.
You know, so that was, you know, that was part of the whole selection process. Why.
So you're-
why we elevated those.
... you're aiming for something better than Trikafta, which is, like, these two pills here... 'Cause it's a TID.
Yeah, from a co-formulation-
Yeah
... perspective, since
Yeah
... since we are still evaluating-
Mm-hmm
... two different combinations, we haven't yet invested in that.
Right.
Yes, our goal would be to co-formulate-
Mm-hmm
... SION-451 with whichever dual partner we select.
Mm-hmm
... for commercialization.
Got it. Safety, actually. Coming to that, one of my biggest learnings coming out of the CF conference this year was the fact that, was it 20%? Or it was 10%. 20% of CF patients are actually intolerant to modulators currently 'cause their liver enzymes start spiking, like, literally makes them intolerant. I didn't realize it was such a large percentage in the real world. What is the level of liver enzyme alterations or elevations that would still indicate to you what the threshold for a viable compound?
like every, you know, every...
Mm-hmm
... you know, we're looking across a host of safety outputs. We're, you know, have an extreme vigilance in terms of our the safety parameters. The liver function tests are just.
Mm-hmm
one of those-
Mm-hmm
... sets of parameters, obviously, typically very important in small molecule-
Mm-hmm
... development. Everything also is really a benefit risk, you know, balance. You know, I wouldn't say there is no, like, set, preset line in the sand for any, lab output or safety output. We want these to be as well-tolerated and, you know, to have the best benefit risk profile possible.
Mm-hmm.
I mean, that's the other way of looking at what we're hoping to get out of that phase I.
Yeah.
Would you still put the emphasis on improved efficacy if it means equivalent safety? Is that the election, you would choose in any dose-finding work going forward?
We are very focused on the efficacy, Ritu.
Yeah.
I agree with you. I think we want to try. Based on everything we see with NBD1, we think we have this opportunity to potentially raise the bar from an efficacy perspective. We absolutely want to have a balance, as Charlotte said, with the tolerability profile relative to the efficacy. It's always about benefit risk. I think what your comment is around how patients are, you know, not tolerating Trikafta or wanting different options, that's really what you're hearing from the community is they want new, different options, new mechanisms of actions. They have choices, right? Trikafta and Alyftrek are good drugs. There is no shortage of an opportunity here to deliver something new and meaningfully different that would give them options and give patients and physicians that choice to make of which option would be best for them.
The next study for the dual, is that going to be, like, a factorial sort of dose finding, multi-dose?
The next step either of these paths either the add-on and/or, you know, or the dual and/or, would be dose ranging.
Mm-hmm.
That would be the next kind of stage. For the dual combination, it would be in patients with CF.
Mm-hmm.
For the add-on study, it would be, you know, very relatively straightforward dose ranging of just SION-719 on a background of standard of care.
We are over. However, I have one last question. Any regulatory guidance, recent relevant regulatory guidance on this sort of combination development approach?
Because it's early on, you know, our interactions with the regulators have been very straightforward and very simple. We, as the programs, either or both of these programs mature, you know, we'd be engaging in more, you know, detailed guidance. It's been very much business as usual, you know, from a regulatory perspective.
We are fortunate to have the Cystic Fibrosis Foundation also as a partner of ours. They've been great to work with. They provide counsel. They collaborate with us on trial design and different things we should be thinking about, so it's a good supplementation or add-on to what the FDA will provide to us as well.
Great. With that, we are well over time. Thank you guys so much.
Thanks, Ritu.
Appreciate it.
Thanks, everyone.
Thanks, Ritu.