biotech analyst at Piper Sandler. Before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and our next presenting company, Syros, which are located at the back of the room and also down at the registration desk. Syros is developing tamibarotene for acute myelogenous leukemia and also myelodysplastic syndrome. Here with us today from Syros is outgoing President and CEO, Nancy Simonian, as well as incoming CEO, Conley Chee. Nancy, I just have to say, it has been an absolute pleasure-
Thank you.
working with you, getting to know you over the next several years, and you will be missed, but I know that you will still be busy and still be involved in biotech. And I just want to ask, why is now the time that, you know, what went into you making this decision, and why is now the time, and Conley the right guy to turn over the helm to?
Thanks, Ted. I'll first just start by saying it's been a wonderful partnership and collaboration with you and your firm over the years, and you've been a big part of kind of helping us to get to where we are today. For me, you know, I started the company 11 years ago, all with an idea of sort of translating so new science and gene regulation into helping patients and making new medicines, and I couldn't be more proud of where we are today. We are on the cusp of phase III data next year from SELECT-MDS-1 for tamibarotene on the path towards commercialization. We have some upcoming data in December in AML, and to me, the time was right for me, as well as making sure that we could hit the ground running for commercialization next year-
Yeah.
With a highly experienced individual sitting next to me, Conley Chee, who has deep expertise in launching targeted oncology therapies, and that's what's most important as the next phase of the company to make sure that patients benefit as much as possible.
Yeah.
So I couldn't be more thrilled to have Conley be transitioning as the CEO at the end of this week. Conley came to Syros two years ago as our Chief Commercial Officer. He's been a wonderful contributor and addition to the company, and I think he's going to be great to lead the company to the next phase.
Yeah. Well, Conley, I look forward to working with you, and it's already been a pleasure getting to know you, and I know you know the company well as both Chief Commercial and Chief Business Officer, so looking for a nice, smooth transition. So-
Thanks so much for that question, by the way.
I'm going to be remaining on the board, so I'll continue my-
Yeah
M y service with the company in the next phase.
Great. So tamibarotene is a retinoic acid receptor alpha or RARα agonist. You studied tamibarotene extensively in RARA-positive AML. Over the last few years, standard of care here has changed with the introduction and addition of venetoclax to HMAs, and you're now conducting a phase II SELECT- AML study of really triplet therapy, tamibarotene plus venetoclax in newly diagnosed unfit AML. Nancy, maybe you can start off by describing these patients. Like, what's the current standard of care? What are they achieving? What's the unmet medical need?
Yep. So let's just first start with AML. So when you think about AML, about half the patients, when they present with AML, are what's termed as unfit, meaning they're unfit for intensive chemotherapy. That's typically because of their age or other underlying comorbidities. So really the goal for those individuals, those 50% of AML patients, is to be able to put them into remission and to be able to keep with a good quality of life, because curative intent really isn't on the-
Yeah
O n the table. Over the last couple of years, venetoclax plus azacitidine has become the standard of care in the treatment of newly diagnosed unfit AML patients. And it's really made a big change for patients in the field. But just think about this, the composite CR rate with venetoclax from azacitidine in that patient population is about 66%.
Mm-hmm.
So about a third of the patients don't respond at all, and the overall survival of those patients in the frontline setting with that standard of care is just 14.7 months. When you think about these blood cancers and how much advancements we've made in so many different cancers, we're still-
Mm
T alking about the frontline treatment giving a median OS of 14.7 months. So I think there's so much room to do better-
Mm
W ith those patients. A third of the patients don't respond, and what happens when AML patients don't respond or, or even when they relapse, their prognosis is really bad, a couple months. So we really need to do better in terms of how we treat patients in the upfront setting.
Yep, makes a lot of sense. Now, you guys reported some safety lead-in data at ASH last year. Remind us what you saw. I think it was maybe six patients or so. Remind us what you saw there, and what should we be expecting, you know, at the next update this year for SELECT-AML?
Yeah. So the SELECT-AML-1 study, the goal is to test the triplet tami, Ven/Aza versus venaza in RARA-positive patients. The trial started with a safety lead-in, where we gave the triplet-
Yeah
T o a group of patients, and really the question there was: Can we safely put all three drugs together at their standard doses? And we presented on the sixth, response available patients in December of last year. So first of all, on the tolerability side-
Right
T he three drugs together were tolerated. The safety profile, adding tamibarotene, didn't look any different than the venetoclax profile on its own.
Mm-hmm.
So it looked like we could safely and tolerably put the three drugs together. And also, very excitingly, you know, this is obviously preliminary data, we saw an 83%. So five out of the six patients had a CR or CRi-
Sure
A t that initial data. So that's 83%. Venetoclax, you know, in all-comer population, has a composite CR rate of about 66%.
Mm-hmm.
So we were very pleased with that initial data to see the triplets up higher. But really the important place where we are right now is we initiated the randomized portion of the SELECT-AML-1 trial.
Mm-hmm
I n the first quarter of this year... and we're expecting to report out in early December on approximately 20 patients from the randomized portion. So that's the triplet versus the doublet in RARA-positive patients. So that's what to expect. And, we are expecting to have about 2 cycles, a minimum of 2 cycles of data on, on the patients. But because we started enrollment in the first quarter of this year, I think the primary focus for this data is gonna be on the composite CR rate and on tolerability. And so that's kind of the expectation. We're gonna be presenting, in a company-sponsored conference call in the early part of December.
Great. Excellent. Well, we're looking forward to that data not too far from now. Now, as we look to the fuller enrollment for SELECT-AML, the phase II study, I believe that's a larger patient set that you randomized. Would there be any changes that could be made from this first data set that would impact enrollment or impact the trial design of the rest of SELECT-AML? And when could we get that full SELECT-AML of that full phase II SELECT-AML data?
Yeah. So the trial is designed as, 80 patients randomized 1:1, so 40 in each arm.
Yep.
We're gonna be presenting on this initial 20.
Mm-hmm.
We're continuing to enroll patients, and I think that probably to answer your question of what's next and what to expect, I think probably it's best when we present the data.
Perfect.
I think we've been guiding to having additional data from the trial in 2024, which would include, you know, more patients and will obviously have longer follow-up on the patients that they enrolled in the trial.
And again, understanding that this is gonna be data dependent, and, you know, let's not put the cart before the horse, or in this case, we're gonna get two data readouts before we have to make this decision. What would ultimately be the registrational course? Would you anticipate having to do phase III trials of the triplet versus the doublet? How do you think that plays out?
Yeah, so I think, you know, when we designed this study, as a, you know, randomized study, we did design it as a phase II study.
Yeah.
I think ultimately, you know, it's likely that we will need a registration study-
Sure.
After that.
Yep.
But I think, you know, everything is always data dependent.
Yep.
I think I'll just-
Yep
Sort of stay tuned in terms of the next.
Yep, perfect. Now, you are already conducting a phase III study with tamibarotene called SELECT-MDS, and this is with tamibarotene plus azacitidine, where I think maybe other HMAs, or really just azacitidine?
Yeah, just azacitidine.
Just azacitidine.
I'm gonna have Conley kind of answer these specific questions.
Yeah.
Yes.
This is in myelodysplastic syndrome.
Uh-huh.
So here, we really haven't seen venetoclax move into MDS. Are there other agents that are moving that could cause a similar MDS or a similar change in standard of care to MDS as what we have seen with AML?
Yeah, it's a great question. So, in terms of MDS, currently, there are roughly 21,000 patients with high-risk MDS, both in the U.S. and in Europe. As you mentioned, the standard of care is hypomethylating agents or azacitidine, and they've been around for over 20 years, and there's been nothing new since. When I first joined the company with Nancy, I think there was 4 or 5 phase IIIs in this category, and now we're down to potentially venetoclax, azacitidine, and ourselves. So there's a tremendous unmet need because the azacitidine hasn't set a high bar.
Yeah.
That's not the reason why there hasn't been new inventions in this category. In fact, their trial showed a 17% CR rate, and these patients typically live only a year and a half, and so there's just tremendous unmet need here. What we don't see in the horizon is more phase IIIs, and so for us, it presents a tremendous opportunity with this unmet need. And for tamibarotene, I think it provides a very unique opportunity because we're a targeted therapy, and we go after this disease in a very unique way in terms of looking at RARA overexpression. And what we've seen is that with RARA overexpression, it causes some dysregulation in these patients.
Yeah.
And so the blood cells do not mature, they don't differentiate, and they remain blast cells, and that's the hallmark of both AML and MDS. And so what we found with tamibarotene is that it could potentially re-regulate this, increase blood counts, forcing them to become mature and differentiate and lowering blast counts. And so we're very excited by the new mechanisms of action.
Yep, absolutely. Describe the phase III SELECT-MDS trial for us, and when do you expect reporting data?
Yeah. So it's our pivotal phase III trial. It's a double-blind, randomized II-to-I trial, and it's due to read out. The first 190 patients are due to read out in Q4 of next year, mid-Q4 of next year. And it's targeted to the primary endpoint of CR. And if it's positive, and we'll be showing the data again in mid-Q4 of next year, if it's positive, our intent is to file for an NDA because the FDA has confirmed on several occasions in our discussions that CR is an endpoint that's acceptable for both potentially an accelerated approval or a full approval. But the trial will move forward to 550 patients to achieve the secondary endpoint, the key secondary endpoint of OS.
Yep, great. So that'll be really exciting. Now, again, depending on data, and we've got really kind of two shots on goal here, but what are your current plans for launching tamibarotene, initially in MDS, but ultimately maybe in AML as well?
Y eah, so it's a really exciting opportunity for us, and I can share with you, Ted, I've been in this industry for many years, and I've had the opportunity to launch multiple products, probably more than half a dozen, many of which are targeted therapies with companion diagnostics. And the one really exciting and interesting thing about tamibarotene, and really one of the reasons that brought me to this company, is really, again, the unmet need in MDS-
Sure
Which is tremendous. But it's also this unique opportunity to use a targeted therapy in the space. And unlike other commercial opportunities, even though it's targeted therapy, it's the RARA overexpression exists in over 50% of MDS patients, so it's not finding the needle in the haystack, if you will. And so from a commercial opportunity, it represents a sort of a very clear challenge to meet the unmet need. And I fully believe we have the ability to launch commercially ourselves in the U.S., and that's going to be our plan going forward.
That's awesome. Then, what are partnering plans, either for overseas? When is the right time to partner? You know, what might be an ideal type of partner?
Yeah, it's a great question. I, I think right now our focus is, again, mainly commercializing in the U.S.
Sure.
We have a little bit of time before we need to make a decision with, particularly with the EU-
Mm.
Because that will be based on an OS,
Sure
E nd, endpoint. But our plan is to potentially find a partner in Europe and the rest of the world to ensure that our product gets to all the patients that are possible around the world.
Great. And, do you think you would have to do another trial beyond SELECT-MDS-1, or is that enrolled patients in Europe? Do you think that might be able to be something you would file on in Europe as well?
Yeah. So, again, we'll be potentially filing on CR in the U.S.
Sure.
In the OS, there could be the potential to file a CR, but likely we'll want OS at least for pricing, and reimbursement opportunities in Europe, but we don't foresee requiring an additional trial.
That would be-
For you
A secondary endpoint.
Yes, exactly.
So-
It's a secondary endpoint.
Great, excellent. Now, you guys ended the third quarter with cash of somewhere around $112 million, debt, I think, of $41 million. How long does this fund the company, and what does it enable you to achieve?
Yeah, so, fortunately for us, this. We had some restructuring recently, which focused our resources specifically on the tamibarotene program. And so with that focus, our funding will allow us to carry it through to 2025, which passes all of the potential value inflection points that we just talked about, which is the AML data that will be coming out in early December, and then again, the MDS data, which will come out in mid-Q4 next year. And so beyond that, we'll then be setting up for commercialization in the U.S.
Great, excellent. Well, thank you very much. This is a really exciting time for the company. Nancy, we're gonna miss you, but I know that you'll still be involved, and we promise to take good care of your baby here.
Thank you.
I know Conley's gonna be a great successor to you.
Yeah.
Big shoes to fill, of course.
Definitely.
But really-
Not going to believe it.
... exciting time for the company. So thank you.
Thank you. Okay.
Thank you.
Thank you.
Thanks, guys.
Thank you.