Syndax Pharmaceuticals Inc (SNDX) 2021 Q3 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Syndax Third Quarter 2021 Conference Call. (Operator Instructions). I would now like to hand the conference over to your first speaker today, Melissa Forst with Argot Partners. Thank you and please go ahead.

Thank you, operator. Welcome, and thank you to those of you joining us on the line and the webcast this afternoon for view of Syndax's third quarter 2021 financial and operating results. With me this afternoon to discuss the results and provide an update on the company's progress are Dr. Briggs Morrison, Chief Executive Officer; and Michael Metzger, President and Chief Operating Officer.

Also joining us on the call today for the question-and-answer session is Dr. Michael Meyers, Chief Medical Officer; Dr. Peter Ordentlich, Chief Scientific Officer; and Dr. Anjali Ganguli, Chief Business Officer. This call is being accompanied by a slide deck that has been posted on the company's website. So I would ask that you please turn to the forward-looking statements on Slide 2.

Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors.

This includes those discussed in the Risk Factors section in the company's most recent quarterly report on Form 10-Q as well as other reports filed with the SEC. Any forward-looking statements represent the company's views as of today, November 15, 2021, only. A replay of this call will be available on the company's website following the call. And with that, I'm pleased to turn the call over to Dr. Briggs Morrison, Chief Executive Officer.

Great. Thank you very much, Melissa, and thank you to everyone who's joining us on today's call and the webcast. Slide 3 provides a high-level summary of our current corporate priorities as we strive to realize a future in which people with cancer live longer and better than ever before. Our prepared comments are a bit more extensive today than some of our prior calls, and that is because this has really been a breakout quarter for us.

We'd like to ensure investors have a full view of our progress. We can really feel the momentum building in our company. We continue to advance both of our clinical programs and both were selected for oral presentations at ASH this year. AUGMENT-101, our Phase I/II trial of SNDX-5613, our selective menin inhibitor has progressed as anticipated. We're pleased to announce today that our 3 pivotal Phase II trials for SNDX-5613, which we call AUGMENT-101 Cohorts 2a, 2b and 2c are now open and enrolling patients after we obtained important agreements from FDA.

Notably, we were the first to demonstrate clinical validation of targeting menin for acute leukemias, and now ours is the first program to advance to registration-oriented trials. For axatilimab, our antibody against CSF-1R, enrollment is ongoing in our pivotal AGAVE-201 trial, and we are immensely gratified that we have insight as a fabulous partner to maximize the value of this important program.

We, therefore, now have 2 registrational programs ongoing for 2 first-in-class potentially best-in-class medicines for 2 areas of important unmet medical need. Thanks to the support of our many committed investors, we are well financed to vigorously pursue both of our existing programs and to aggressively look for additional opportunities to bring targeted oncology drugs into our pipeline.

Let's now turn to Slide 4 and update you on where we are with SNDX-5613. We have completed the Phase I portion of Arm B of AUGMENT-101 and have agreement from FDA on key aspects of our go-forward clinical development plan. First, we have now opened 3 single-arm Phase II trials that FDA has agreed may each serve as a pivotal trial. Each of these single-arm Phase II trials represents an independent path to a separate indication.

AUGMENT-101 cohort 2A will enroll patients with relapsed/refractory MLLr ALL. Cohort 2b will enroll patients with relapsed/refractory MLLr AML and 2C will enroll patients with relapsed/refractory NPM1 AML. Each trial is open to patients aged 1 month or older and each trial will enroll independent of the other 2. We may seek initial regulatory approval for SNDX-5613 based on the results of any one of these trials should one trial enroll faster than the others, or we may seek additional regulatory approval for any 2 or all 3, just depending on when they complete enrollment.

Needless to say, we are thrilled to have advanced the program into these initial pivotal trials. We anticipate being the first company to achieve regulatory approval for menin inhibitor and today's announcement regarding the advancement of the program increases our confidence that we will do so. We have agreement with FDA that for each trial, the primary endpoint will be the percentage of patients achieving CR plus CRh, with secondary endpoints, including durability of CR/CRh responses, transfusion independence, overall survival and tolerability.

Importantly, the trial design allows patients to be treated with SNDX-5613 after bone marrow transplant, a design feature that allows us to start to understand the role of 5613 in the post-transplant setting. We also have agreement with FDA on the statistical design of each trial.

Each trial will enroll 64 adult patients and up to 10 pediatric patients. Finally, we have agreement with FDA that our recommended Phase II dose of 163 milligrams PO every 12 hours, given with any strong CYP3A4 inhibitor is an appropriate Phase II dose and that is the dose we are taking forward in each trial. We know that the majority of eligible patients are on a strong CYP3A4 inhibitor. We will be finalizing our Phase II Arm A dose over the next few months and we anticipate being able to enroll patients who are not on a strong CYP3A4 inhibitor as our pivotal -- our 3 pivotal trials proceed.

I want to again reinforce that we are incredibly excited about what we have seen in our Phase I program. On November 4, ASH released an abstract that summarized our data at June 29 of this year, which we briefly summarize on Slide 5.

Let me first remind everyone that this is a Phase I trial, patients had received on average 3 prior therapies, and about 40% had relapsed after bone marrow transplant, a very negative prognostic sign, and almost 60% had previously received venetoclax. These are very difficult to treat patients, and we were delighted to report in the abstract a 44% overall response rate, a 22% CR/CRh rate, and 70% of the responses were MRD-negative, meaning using the most sensitive assays available.

There was no detectable leukemia after treatment with SNDX-5613. Despite having only a median of 3.2 months of follow-up, the initial estimate of durability of the CR/CRh responses was 5.2 months and that did not include patients who had gone on to transplant. We are finalizing our ASH presentation, which represents an additional approximately 3 months of follow-up, and we remain excited about breaking out the efficacy data by mutational status and to present the updated durability of CRh -- CR/CRh responses with the patients who went on to transplant.

Additional details will present -- be presented by Dr. Eytan Stein in his oral presentation on Monday, December 13. Beyond the AUGMENT pivotal program in relapsed or refractory disease, Slide 6 highlights some of the additional opportunities we are exploring with SNDX-5613, all of which builds on the excellent safety and efficacy profile we have thus far seen with the molecule.

The panel on the left highlights the trial we are planning in collaboration with the Leukemia & Lymphoma Society, otherwise known as LLS. They have selected SNDX-5613 as the first menin inhibitor to be tested as a specific targeted therapy for patients with MLLr and NPM1 AML in their umbrella trial that they call BEAT-AML. The collaboration we have agreed to with them will test 5613 in combination with venetoclax and azacitidine in newly diagnosed AML patients that are unfit for induction chemotherapy and will consist of a Phase I followed by a Phase II/III trial, which could serve as the basis for regulatory filing.

Our scientists have generated preclinical data that supports the benefit of menin inhibition in combination with chemotherapy. And therefore, the middle panel of the slide highlights a trial to explore the use of 5613 in combination with standard salvage chemotherapies used for pediatric patients with ALL or AML, that we are calling AUGMENT-102.

And the panel on the right illustrates a new trial that explores the activity of 5613 in patients with AML who have MRD-positive disease. This trial is being conducted as part of the INTERCEPT master clinical trial being led by the Australian leukemia and lymphoma group. The INTERCEPT trial is focused on investigating novel therapies to target early relapse and clonal evolution as preemptive therapy in AML. The trial will enroll patients with measurable residual disease progression following their initial treatment, a group of patients who are at very high risk of relapse and represents an important unmet medical need.

As I think I have mentioned previously, a general observation in the treatment of cancer is that the earlier in the patient's disease course that you treat, the better patients do and the longer the patients stay on therapy. The INTERCEPT trial is an innovative approach to treating patients early in their disease course. I will also note that SNDX-5613 is the first menin inhibitor to be included in the INTERCEPT of master clinical trial.

We believe the selection of 5613 for inclusion in 2 master clinical trial protocols highlights the enthusiasm that investigators have shown for treating patients with acute leukemias with our compound. We anticipate announcing additional trials over the next 6 to 12 months that will further build out the 5613 franchise.

And as I mentioned earlier, the registration cohorts of AUGMENT-101 will allow for patients to be dosed post-transplant, providing an early look and setting the stage for future trials in the maintenance setting. As I mentioned on our second quarter earnings call this past August, we are excited to expand the clinical opportunities for 5613 beyond the initial approval in relapsed/refractory leukemia.

Slide 7 highlights our goal as a company to be first to market in relapsed/refractory disease, and then to be first to garner additional value-driving indications by expanding the use of 5613 into newly diagnosed patients and into the maintenance setting in patients with both MLLr and NPM1 acute leukemia. We are taking our first steps towards building out the franchise through the collaborations with LLS to explore newly diagnosed patients. And with the Australian Leukemia Group in patients with AML who have MRD-positive disease despite their initial standard of care treatment.

Let me now turn to Slide 8, axatilamab, our potentially best-in-class monoclonal antibody therapy targeting the CSF-1 receptor. We were delighted to announce that Syndax and Incyte have entered into a broad long-term global collaboration that brings together 2 companies with a solid track record of innovation to accelerate and maximize the development of axatilimab.

As you know, we presented our Phase I GVHD data last year at ASH in December. The reaction to our data was extremely positive. And given our belief in the broad clinical potential of axatilimab, we initiated a process to look for a global partner to collaborate with us on further development of this exciting molecule. To briefly recap the agreement, the deal provides $152 million upfront, $117 million in cash and notably $35 million in equity at a 30% premium, which we believe is a strong endorsement of our company and its overall value proposition.

The 50-50 profit split in the U.S. enables us to retain significant upside and actively participate long term in the franchise build-out, the 45%, 55% cost sharing mechanism limits our downside and extends our cash. And the opportunity for co-commercialization in the U.S. will allow us to participate in the launch of an important product alongside a strong commercial partner. Outside the U.S., we will rely on Incyte to develop and launch the product in all the major markets to maximize its full potential as a global brand. The economics to Syndax over the course of the collaboration are enhanced with key regulatory and sales milestones, covering multiple indications throughout the world. The payments total an additional $450 million and Syndax receives double-digit royalties ex U.S.

Also important to highlight is the development plan, which calls for the partners to design novel combinations with axatilimab and Incyte JAK inhibitors with the goal of establishing axatilimab in earlier settings within chronic graft-versus-host disease and expanding its market opportunity. As we previously mentioned, it was our intention that Syndax will initiate a POC trial in interstitial pulmonary fibrosis, the first expansion outside of establishing chronic graft-versus-host disease as a beachhead into other fibrotic diseases where we believe axatilimab could have a significant impact.

Significant successful development in IPF will lead to an additional approval and a very important indication of considerable value and would provide support for axatilimab and other fibrotic chronic diseases that the parties could explore over the course of the collaboration.

As you know, our ASH abstract for axatilimab also recently published and Slide 9 is a brief summary of that data. There were 40 patients enrolled who had received a median of 4 prior therapies at the 1 milligram per kilogram dose given every 2 weeks, which we anticipate will be our label dose, the drug was well tolerated, and we saw an overall response rate of 75%. We believe this is a material data set that significantly derisks our ongoing registration trial. And additional details will be presented by Dr. Stephanie Lee in her oral presentation on Saturday, December 11.

Slide 10 is our pivotal trial for axatilamab in chronic graft-versus-host disease. This is -- this trial is axatilimab for a chronic versus host disease trial called AGAVE-201. The trial is enrolling patients with chronic graft-versus-host disease, whose disease has progressed after 2 prior therapies. Patients must be at least 6 years of age and have met overall entry criteria. This is a pivotal dose-ranging trial in which patients will be randomized to 1 of 3 treatment groups, each investigating a distinct dose of axatilimab given either every 2 weeks or every 4 weeks. The primary endpoint as overall response rate using the 2014 NIH consensus criteria for chronic graft-versus-host disease. Secondary endpoints will include duration of response and validating quality of life assessments using the Lee Symptom Scale. Enrollment to the study is underway, and we are on track to deliver top line data in 2023.

Slide 11 highlights our view of the broad clinical and commercial opportunity for axatilimab. We believe chronic graft-versus-host disease represents a high unmet medical need and an important commercial opportunity with approximately 14,000 patients suffering from chronic graft-versus-host disease in the U.S. today. The recent approvals of Incyte's Jakafi and Kadmon's Belumosudil will begin to delineate the commercial opportunity in this disease. Despite recent advancements in this area, to our knowledge, axatilamab is the only agent in clinical development that specifically targets the monocyte-macrophage lineage.

Both Syndax and Incyte believe the data generated to date with axatilimab suggests it has the potential to play an important role in the treatment of chronic graft-versus-host disease, both as monotherapy and given its safety profile in combination with other mechanisms. As we move axatilimab into additional indications starting with IPF, we really see axatilimab contributing materially to the value of our company going forward.

Finally, Slide 12 summarizes the transactions that led to the acquisition of both the menin and axatilimab programs. We believe these transactions underscore our robust capabilities to evaluate and identify high-value, differentiated assets as well as the clinical development expertise to bring these compounds through key value inflection points.

We anticipate we will be able to continue to expand our pipeline through product acquisitions or in-licensing of quality differentiated assets. We expect to remain among preferred partners of such transactions. I'll now turn the call over to Michael to review our financial results.

Thank you, Briggs. The results of our operations for the third quarter of 2021 and the comparison to the prior year quarter are included in our press release, so I won't repeat these -- them in our remarks. Additional financial details are available in the third quarter report on Form 10-Q, which was filed earlier today. I would like to point out that our net loss for the quarter was $20.6 million or $0.40 a share, compared to $20.4 million or $0.46 per share for the same period last year.

Turning to Slide 13. We ended the third quarter with $229.7 million in cash and cash equivalents and 52.2 million shares and prefunded warrants outstanding. The cash balance does not include any proceeds related to the recently announced collaboration agreement with Incyte. We anticipate those payments would extend our cash runway into 2024 and support our expanded development plans for both the axatilimab and the menin programs during this period.

Looking ahead, I'd like to provide financial guidance for the full year of 2021. Full year 2021 guidance remains unchanged, and we continue to expect R&D expense to be $90 million to $100 million and total operating expense to be $110 million to $120 million. This includes approximately $13 million in noncash stock compensation. And with that, I would like to turn the call back over to Briggs.

Thank you very much, Michael. Let me close the call by again noting that this management team has been focused on obtaining regulatory approval for drugs that extend and improve the lives of people with cancer and other diseases, and we consider having 2 ongoing registration programs as a major achievement. We're also very excited about the broad franchise opportunities for both programs beyond their initial registrational indications.

We believe 5613 could have broad utility across a wide range of clinical settings in acute leukemia. Our goal at the company is to be the first to market in relapsed/refractory disease and then to be first to garner additional value-driving indications by expanding the use of 5613 into newly diagnosed patients and in the maintenance settings, in patients both with MLLr and NPM1 in acute leukemias. And axatilimab also holds the promise of a broad franchise opportunity both in various lines of therapy in GVHD and across a broad range of fibrotic diseases, starting with IPF.

We are comfortable given our cash on hand that we have the financial resources to aggressively advance our programs and achieve upcoming milestones. We remain optimistic that we can continue to identify and bring in novel molecules to deepen our portfolio. We have a proven track record of delivering on this pillar of our corporate strategy, and I believe this is a core strength of our company.

As always, I would like to thank the wonderfully talented team here at Syndax, our collaborators and most importantly, the patients, trial sites and investigators involved with our clinical programs. In addition, I would like to thank our committed long-term investors who are helping us to build this great company. With that, I'd like to open the call for questions.

(Operator Instructions) Our first question comes from the line of Phil Nadeau of Cowen and Co.

Congrats on progress. Just a couple from us. So first, on the pivotal cohorts. Can you go into a little bit more detail why the nonsip dose has not been defined yet. What else do you need to do to define that dose? Is there additional patient experience that you're expecting or feedback from the FDA kind of what's the rate limiting step into nailing down that dose?

Thanks very much for your question. The -- so I want to emphasize that we -- the 163 with any strong CYP3A4 inhibitor is an acceptable recommended Phase II dose that we agreed to with FDA, and that's the dose that's going forward. We have 2 very good doses in Arm A 226 and 276. And what we think we need is a little bit more PK data on a few more patients to pick between those 2 to see which one most closely matches the PK of the 163 with any strong CYP3A4 inhibitor.

Perfect. That's very helpful. And then second, I'm not sure you're going to be willing to answer this question. But we're all curious in the ASH presentation versus the abstract that we've all reviewed. How many more patients will there be? And in particular, I think we're all focused on NPM1 patient population, give us some sense of how many NPM1 patients are likely to be presented at ASH.

I'm not sure I know off the top of my head how many additional patients there are compared to the abstract. I don't know if Michael Meyers, do you know that?

It's about 5 additional patients, Briggs.

And the total number of NPM1 patients, Michael, that will be in the presentation?

That is in the presentation, yes.

No. I think Phil is asking how many total patients -- total NPM1 patients will there be?

I think it's about 13 patients in the presentation itself.

[Does that answer] your question, Phil?

Yes, that's very helpful.

Our next question comes from the line of Yigal Nochomovitz of Citi.

This is Ashiq Mubarack on for Yigal. Congrats on all the progress. I just wanted to ask about the post-transplant durability. Can you kind of help put into context how post-transplant durability might be assessed and interpreted and maybe the dynamics there? Is it -- will it be durability of CR/CRh, or the most recent CR or something else, can you walk me through the dynamics. And I have a follow-up.

Sure. So first, let me just say that for all the durability information that we have in the abstract and that we'll present at the oral presentation it's durability of CR/CRh. So if you look at the labels of targeted agents that have been approved in AML, you will see the CR/CRh rate and the durability of those responses. In the approved labels, the durability is from the time of first obtaining a CR or a CRh until relapse, including the time post bone marrow transplant. So if a patient had a CRh that lasted 3 or 4 months, they were then able to go on to bone marrow transplant, and that complete remission continued post bone marrow transplant that's what's counted as the durability of their response and that's the way the data is, for example, in the gilteritinib label.

If you look at their median duration of response, it includes the time after transplant. So what we have in our ASH abstract does not include time post-transplant for any of the patients. What we will present at the oral presentation is we now have data on those patients post bone marrow transplant. So it will be from the time of their first CR or CRh until relapse if they've relapsed.

Okay. And I guess I just had one other question on your end of Phase I meeting. Were there any other takeaways you might be able to share, especially -- I'm just especially curious about the inclusion of the OS endpoint. Was that something you were expecting? And maybe what do you think the OS bar should be? How should we think about that?

Yes. Again, I'd say that the primary endpoint is the percentage of patients who have either a CR or CRh, the durability of those responses, transfusion independence. OS is an exploratory endpoint in the trial. As you know, the agency finds it difficult to interpret uncontrolled PFS or OS data. So it's descriptive, but it's -- I don't think there's a bar there because there really isn't a control group.

Our next question comes from the line of Justin Walsh of B. Riley Securities.

Based on what you saw in the Phase I portion of AUGMENT-101, do you have any expectations with respect to enrollment rates for those 3 populations?

Yes. I guess the only thing that we would say is the AML cohorts may enroll a bit faster than the ALL cohort simply because of the competition for patients. There's a fair amount of innovation that's being tested in patients with ALL, a little less in the AML space. So I think the AML cohorts may enroll a bit faster. But again, it's -- you just have to see as we open up the trial.

Got it. And then maybe one more for me. Maybe you guys can remind us of the unmet need and opportunity in IPF. And if you have any thoughts on what other fibrotic diseases you think could be a fit for axatilimab, that would be great.

Yes. Maybe I'll let Anjali talk a little bit about the patient numbers, but I would just say that from a clinical point of view, there are 2 agents approved for the treatment of IPF, they've been shown to slow the progression of the disease, but they don't reverse the progression of the disease. And unfortunately, [it] does continually deteriorate. So I think there's lots of -- from a clinical point of view, what we've heard from physicians who treat these patients, a big, big need for additional agents to either further slow the progression of the disease or potentially, at some point, reverse that progression. But Anjali, you may want to speak a little bit about the numbers of patients.

Yes. Thanks, Frank. Happy to. I think in the current estimates for prevalence for the U.S., it's upwards of 150,000 patients. So it's still considered an orphan indication, but it's a few fold larger than what the prevalence of chronic GVHD is today. And it's very similar across EU5, if you will, and then Japan is a little bit smaller. So I guess it's a worldwide -- or 7 major markets, the estimate is closer to 275,000 patients today.

Our next question comes from the line of Joe Beatty of Baird.

Congrats on the progress. My first one is on 5613. In the ASH abstract the -- that is not broken out on CR/CRh or NPM1 and the menin population. But we do have that data in the CRc rates, and it seems like it's trending a little bit more favorable for MLLr compared to NPM1. I'm just curious on your thoughts of what may be behind that, if it could be due to a drug or chance or other considerations?

Yes. Look, Joe, as I said in my prepared remarks, I think we're quite excited to be able to break out more details on the response rate in NPM1 versus MLLr in the oral presentation. As you know, when we entered the clinic based upon all the preclinical data, we thought that the efficacy would be roughly comparable in the 2 populations. We saw very, very good efficacy in preclinical models for both diseases. So we think that as the sample size increases, and we get a better point estimate, we're feeling -- are still excited that potentially the 2 will have fairly similar efficacy performance.

Appreciate that. And then maybe one other question on the AUGMENT-101 registrational trials, what endpoints will be important from a competitive landscape perspective with clinicians. Would it be the same CR/CRh rate that's important to regulators or other focuses?

Well, so it's quite interesting. Obviously, from a regulatory point of view, it's the CR/CRh rate. As we've talked about previously, the -- from a clinical point of view, the other excitement that we've gotten from investigators to participate in the trial is the high MRD-negative rate. So there -- we do have patients in the trial, and this goes to the earlier question about durability, who had a CRp, their platelets hadn't fully recovered yet they were MRD negative and they immediately went to the bone marrow transplant. Those patients won't get counted in the CR/CRh rate. And so in terms of your CR/CRh rate and durability of CR/CRh, those CRps who go to bone marrow transplant don't get counted, that's the regulatory rule, that's okay. But from a clinical point of view, that's a very, very important result for the patients. So the total number of MRD-negative CR patients who can go on to bone marrow transplant is something that we've heard a lot of excitement about from our investigators.

Our next question comes from the line of Peter Lawson of Barclays.

Thanks for the update. Very much appreciate it. On -- just on -- I guess, as patients move on to transplant on SNDX-5613, how quickly do they move on to transplant in your studies?

Yes, it's a good question, Peter. I don't have that data right at the tip of my fingers of how long it takes from when they start treatment to go on to transplant. I think the one other thing to remember, and I mentioned this in my prepared remarks about the design of our pivotal trial and the pivotal trials, once they go on to transplant, they are eligible to go back on 5613 once they engraft. And that, again, has been a frequent request from the treating physicians. They look at their patient and they say, I had nothing to offer this patient. Your drug got them to an MRD-negative CR, great, took them to transplant. I'd love to put them back on your drug and maintain that CR post bone marrow transplant. And in the Phase I trial, the trial wasn't really set up to do that. But in the pivotal trial, we will be able to do that. So I think we'll start to learn a bit about how the drug performs in the post-transplant setting.

And then when do you expect to start the arm where patients don't have the strong CYP3A4 inhibitor?

Yes, we think it will just be a couple of months. As I mentioned in the response to Phil's question, we do want to get a little bit more PK data to decide between the 226 and the 276. So it will be a couple of months to enroll some additional patients and make that final decision.

Got you. And then just finally, is there anything that precludes NPM1 patients, do you think, from reaching CRH?

No.

There are no questions coming in at this time. I'm now turning the call back to Dr. Morrison.

Thank you very much, operator. Thank you, everybody, again for joining us on the call today. As I said, we feel like this was really a very important breakout quarter for us. We now have FDA buy in to take our clinical program into pivotal trials. We've finalized the agreement with Incyte and we really feel a tremendous sense of momentum building in the company. So we look forward to sharing additional updates on both programs at ASH and thank you for your time.

This concludes today's conference call. Thank you for participating. You may now disconnect.