Syndax Pharmaceuticals Inc (SNDX) 2021 Q1 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Syndax First Quarter 2021 Earnings Conference Call. (Operator Instructions) Please be advised that today's conference is being recorded. (Operator Instructions)

I would now like to hand the conference over to your speaker today, Melissa Forst of Argo Partners. Please go ahead.

Thank you. Welcome, and thank you to those of you joining us on the line and the webcast this afternoon for a review of Syndax's first 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; Daphne Karydas, Chief Financial Officer. Also joining us on the call today for the question-and-answer session will be Michael Metzger, President and Chief Operating Officer; Dr. Michael Meyers, Chief Medical Officer; and Dr. Peter Ordentlich, Chief Scientific Officer.

This call is being accompanied by a slide deck that has been posted on the company's website, so I'd ask everyone to please turn to 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 our views as of today, May 11, 2021, only.

A replay of this call will be available on the company's website following the conclusion of the call.

And with that, I'm pleased to turn the call over to Dr. Briggs Morrison, Chief Executive Officer of Syndax.

Great. Thank you so much, Melissa, and thank you to everyone for 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. We have continued to make great progress in both our clinical programs during the first quarter of this year. We reported the initial data from the Phase I trial of SNDX-5613, our selective menin inhibitor, and are on track to begin potential registration cohorts in that program shortly.

In addition, we have completed enrollment of 23 chronic graft versus host disease patients on axatilimab at 1 milligram per kilogram in our Phase II of expansion cohort, and enrollment is ongoing in our pivotal AGAVE-201 trial. We, therefore, remain on track to have 2 registrational programs ongoing this year for 2 first-in-class and 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 our recent data disclosure of our Phase I trial of 5613, our selective menin inhibitor, for the treatment of acute leukemia. As we noted in our recent data disclosure, in our Phase I trial, 5613 has been well tolerated over multiple cycles with no patient discontinuing for a drug-related adverse event. Our pharmacodynamic data confirms the mechanism of action. And perhaps most importantly, we have a candidate recommended Phase II dose that meets all of our prespecified criteria. We are, of course, excited to have also observed clear evidence of monotherapy activity in this population of patients with relapsed or refractory acute leukemia with both MLL-r and NPM1c mutations with most responses being MRD-negative.

I want to reinforce why we are so excited about what we are seeing and provide additional data that further builds our confidence in our program. Let me first remind everyone that this is a Phase I trial: patients have received, on average, 3 prior therapies; about 40% had relapsed after a 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 see a 48% overall response rate and 67% of the response is being MRD-negative. Every physician currently treating acute leukemia who has reviewed this data with us has been excited by the efficacy we are seeing. And the data has only gotten better over the past weeks with 2 patients converting to CR with full count recovery.

We had pointed out that it is not uncommon for patients with complete eradication of leukemia to initially have incomplete recovery of their additional blood counts. Full recovery can take time.

Slide 5 is a reprise of one of the vignettes we have presented at our data disclosure event. You will see here a patient with refractory NPM1c acute leukemia who is treated at our recommended Phase II dose and had a rapid MRD-negative CR. Initially, however, her blood counts had not recovered to normal, and she had a CRi, which is an MRD-negative complete response with incomplete recovery of her blood counts. But you can also see that, over time, her blood counts fully recovered. She had an MRD-negative CR with full count recovery and went on to potentially curative bone marrow transplant.

At the time of our data disclosure, we noted that 5 patients had already achieved either a CR or a CRh and that there were 5 patients still ongoing who had an MRD-negative CR but had not yet achieved a CR or CRh. We anticipated that some of those patients would have full count recovery over time, and that's exactly what we have seen.

Over the ensuing weeks, 2 of the patients who had an MRD-negative CR but had not yet achieved a CR or CRh have now had full count recovery and now have achieved a CR and remain on study.

A third patient of the 5 who had an MRD-negative CR but had not yet achieved a CR or CRh has improved from a CRi to a CRp and also remains on study. Of the 2 remaining patients, 1 remains on study with a responsive CRp, and 1 is off study due to progressive disease.

Slide 6 shows the response data we presented on April 20 as well as the updated data as of last Friday. Let me repeat that these data on Slide 6 are from our ongoing Phase I trial. This data on Slide 6 is a snapshot in time, and the data may further improve. There are still 2 patients on trial who have had an MRD-negative CR but have not yet achieved a CR or CRh. We are looking carefully at the patient characteristics with respect to any potentially appropriate adjustments to our enrollment criteria in our upcoming Phase II study.

We understand the regulatory precedent for the efficacy hurdle for the approval of 5613 in relapsed or refractory acute leukemia. While there are no guidelines on a specific rate that is required for approval, we have pointed out the rates that were reported for recently approved FLT3 and IDH inhibitors that suggest a CR plus CRh rate above 20% has been acceptable to the FDA.

The Phase I data that we've generated from our ongoing AUGMENT-101 trial, and again, I want to emphasize, it is our data that gives us confidence that 5613 will achieve that level of efficacy in our upcoming Phase II trial. I also want to provide a broader context about what we are seeing in the NPM1 population as we believe it's quite informative and supports our confidence that the efficacy in the NPM1 population should mirror that of the MLL-r population.

For the avoidance of doubt, we reported that we had treated 7 relapsed or refractory patients with NPM1c acute leukemia, and there were 2 patients with a CR. Of the remaining 5 patients, 1 progressed quite rapidly on the third day of treatment, and 2 had clear evidence of anti-leukemic activity but unfortunately succumbed to a systemic infection, one of the feared complications of acute leukemia prior to attaining a bone marrow response. So we believe the totality of our clinical data suggests, therefore, that as predicted from the preclinical data, 5613 will have good activity in patients with NPM1c acute leukemia as well.

Slide 7 shows our go-forward plans for 5613. We anticipate initiating Phase 2 at the end of this quarter and holding our end of Phase I meeting with FDA shortly thereafter. We also anticipate a further update of the AUGMENT-101 data at the end of this year and will, of course, also look for additional opportunities to provide meaningful updates as events allow.

The Phase II portion of the trial will enroll 3 distinct expansion cohorts, patients with MLL-r acute lymphoid leukemia, ALL; patients with MLL-r acute myeloid leukemia, AML; and patients with NPM1 mutant AML. The Phase II portion will enroll both pediatric and adult patients, thereby, providing us a potential path to regulatory approval with a broad label, including both adults and pediatrics.

I should note that the results are positive, as Phase II portion of AUGMENT-101 could potentially support a regulatory filing given existing regulatory precedents. We do not yet have a final endorsement of our Phase II sample size nor have we finalized our enrollment rate, and yet it is possible that we could have top line data for one or more of the cohorts sometime next year.

Over the last period, we've also been conducting extensive research into the broad landscape of clinical opportunities for 5613 beyond the initial approval in relapsed/refractory acute leukemias, as illustrated on Slide 8. We are not in a position today to lay out the specific next steps in building out the 5613 franchise. I can say that we are using this ongoing analysis to inform specific combination regimens that we anticipate starting to study later this year. Several investigators and leading companies have already reached out to us with novel exciting ideas for future development of 5613, and we are evaluating those opportunities.

Let me now turn to Slide 9 and axatilimab, our potentially best-in-class monoclonal antibody targeting the CSF-1 receptor. As you know, we presented our Phase I chronic graft versus host disease data at ASH in December of last year. You may recall that we had opened a Phase II expansion cohort at the 1 milligram per kilogram dose, and we are pleased to announce that, that cohort has now been fully enrolled.

We anticipate presenting later this year the full updated data from both 17 patients from the Phase I portion of the trial as well as the 23 patients enrolled in the Phase II expansion cohort at the 1 mg per kg dose. I should emphasize that our base assumption is that this 1 mg per kg dose will be our label dose, and hence, the Phase II expansion cohort is quite relevant as a derisking event To the eventual outcome of our pivotal trial.

Slide 10 outlines our pivotal trial for axatilimab in chronic graft versus host disease. This trial is the axatilimab for graft versus host disease trial called AGAVE-201. This 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 is overall response rate using the 2014 NIH consensus criteria for chronic graft versus host disease. Secondary endpoints will include duration of response and validated 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. We believe that 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. With the recent positive pivotal results from both Incyte's Jakafi and Kadmon's KD025, we may soon see regulatory approvals and commercial launches that will begin to delineate the commercial opportunity in chronic graft versus host disease.

Despite recent advancements in this area, to our knowledge, axatilimab is the only agent in clinical development that specifically targets the monocyte macrophage lineage. We believe the data generated to date with axatilimab suggests that 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, potentially in combination with complementary medicines.

We've also been working extensively with experts in the field of fibrotic disease and have found a strong consensus that the scientific rationale for the efficacy of axatilimab in chronic graft versus host disease firmly supports its potential in a wide variety of fibrotic diseases, such as idiopathic pulmonary fibrosis and scleroderma.

We are actively evaluating options by which to build the axatilimab franchise beyond chronic graft versus host disease and take advantage of what we believe are a significant set of opportunities that could materially enhance shareholder value.

As we have previously communicated, we obtained orphan drug designation from the FDA for the use of axatilimab in IPF.

Finally, Slide 11 summarizes transactions that led to the acquisition of the menin MLL-r program and the axatilimab program. We believe that we will be able to continue to expand our pipeline through the acquisition or in-licensing of quality differentiated assets. We believe that we have the necessary skills to evaluate and identify high-quality assets and the clinical development experience to bring these compounds through valuable inflection points. We expect to remain among preferred partners of such transactions.

I will now turn the call over to Daphne to review our financial results.

Thank you, Briggs. The results of our operations for the first quarter of 2021 and the comparison to the prior year quarter are included in our press release, So I won't repeat them in these remarks. Additional financial details are available in our first 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 $27.7 million or $0.54 per share compared to $19.1 million or $0.56 per share for the same period last year.

Turning to Slide 12. We ended the first quarter with $271.3 million in cash and cash equivalents and 51.6 million shares and prefunded warrants outstanding. This cash balance provides us cash runway into 2023 and importantly, covers the development cost of both the axatilimab and the menin registrational programs to their first approvals as well as provides us the flexibility for continued business development.

Looking ahead, I'd like to provide financial guidance for the second quarter of 2021. For the second quarter, we expect R&D expense to be between $30 million and $35 million and total operating expense to be between $35 million and $40 million, including approximately $2.5 million of noncash stock compensation expense. Full year 2021 guidance remains unchanged, and we continue to expect R&D expense to be between $90 million and $100 million and total operating expense to be between $110 million and $120 million, including approximately $2.5 million of noncash stock comp expense per quarter. We continue to expect first half expenses to be more heavily weighted than the second half due primarily to the ramp-up in CMC activities for both programs in the first half of the year.

With that, I would like to now turn the call back over to Briggs.

Thanks so much, Daphne. Let me close the call by again noting that we have begun the registrational trial for axatilimab in chronic graft versus host disease and are on track to start the registrational program for 5613 shortly. This management team has been focused on obtaining regulatory approval for drugs that extend and improve the lives of people with cancer, and we consider having 2 ongoing registration programs as a major achievement. We are also getting increasingly 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, and axatilimab could represent a broad franchise opportunity in fibrotic diseases.

We are comfortable given our cash on hand that we have the financial resources to aggressively advance our programs and achieve key 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 strategy, and I believe it is a core strength of our company.

As always, I'd like to thank the wonderfully talented team here at Syndax, our collaborators and most importantly, the patients, the trial sites and the investigators involved with our clinical programs. In addition, I'd 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 Phil Nadeau with Cowen and Company.

Congratulations on the progress. First, a clarifying question on the data that you released tonight. In terms of the NPM1 patients and the 29% overall response rate, have you disclosed whether the 2 responders have had complete hematologic recovery?

So 1 of the 2 NPM1 patients is the vignette that I covered today and was 1 of the 3 vignettes that Eytan covered. So that patient clearly had initially a CRi and then had full hematologic recovery, went on to a bone marrow transplant. We have not given any further information on the second patient who had a complete response.

Got it. Okay. And second question is in regards to the Phase II dose. Many people have noted that recently, another cohort was added to the dose escalation study looking at cobicistat boosting. Can you talk about the goals for that cohort and how that plays into your decision on which dose to move into the pivotal study?

Yes. Thanks for the question. So the cobicistat arm is really an exploratory arm to look at the effect of cobicistat on the PK of 5613. It has nothing to do with the doses that we will take into Phase II. We're not waiting for the data from the cobicistat arm to start Phase II. So Phase II are the -- is the data set that we presented at our data disclosure to the 226 in Arm A and the 113 in Arm B. Cobicistat is really, I just said, an exploratory sort of life cycle management study just to look at the PK -- the effect of cobicistat on the PK of 5613.

Perfect. Last question for me. I'm curious if you be willing to address it. I guess the biggest pushback we got after the initial dose was people who were worried that the therapeutic window of 5613 was a bit too narrow. That if you could push the dose just a little bit harder, maybe the efficacy would improve a bit. But maybe perhaps they're somewhat limited by QTC prolongation at higher doses. What's your perspective on that argument? How valid is it? And what gives you confidence that you're maximizing efficacy at the doses that are acceptably safe?

Yes. So as we indicated in the presentation, we had prespecified criteria for our recommended Phase II dose, including exposures that we thought were required for efficacy. We've been able to make those criteria at the recommended Phase II dose. The response rates at the recommended Phase II dose are generally the same as what we see in the overall population, which, again, is not all that surprising since many of the patients, in fact, were treated at the recommended Phase II dose.

Again, the vignette I just presented today is a patient treated at the recommended Phase II dose, had NPM1 disease, a rapid CR high that then progress to full count recovery. So we feel very comfortable that the dose that we are picking for our recommended Phase II dose meets our criteria, and that we're not leaving any efficacy on the table by not going higher.

Our next question comes from Bert Hazlett with BTIG.

Yes. I think you just answered it. Congratulations on the progress. I think you just answered it, but maybe just ask slightly differently. So what then are the specific goals of the interim cohort -- the interim dose cohort? And is that a gating item to moving forward into the potential pivotal start of 5613?

Yes. Thanks for the question, Bert. So as I just said to Phil, we're very comfortable with the dose, the 226 Arm A, 113 Arm B, as a recommended Phase II dose. The investigators and our clinical team wanted to study that intermediate dose to see if, in fact, there was a dose in between the doses we have studied that could also meet our criteria. If those intermediate doses do meet our -- all of our criteria, they could be the doses that we take into Phase II. If they don't, it's not a problem. So those are gating. We do want to wait to get the answer to that question before we start the Phase II trial. And again, we feel like we're on track to have that by the end of the quarter.

Our next question comes from Colleen Kusy with Baird.

Congrats on the progress. For the -- thanks for the clarity on the NPM1 patients. I know you noted the 2 of them to come to infections. Did you see any of those in the MLL-r patients involved in the study?

I don't remember off the top of my head. I think there was 1 MLL-r patient. Maybe Michael Meyers, you can answer that question. I think it was 1 MLL-r patient who didn't make it through because of an early infection. But Michael?

Yes, Briggs, thank you for that. Colleen, yes, we have seen MLL-r patients be -- to have infections. It is an expected complication of AML, especially in patients who have active disease whose counts are not sufficient to protect them from specifically bacterial infections. So as Eytan Stein said in the presentation, infectious complications of AML are expected and not at all unusual.

That's helpful. And what is the protocol for stem cell transplants in this study? And will there be any changes for the Phase II?

Well, there isn't a protocol for stem cell transplant in this study. The standard of care for the treatment of acute leukemia, if you can get a patient into a complete response and particularly, if you can get a patient into an MRD-negative complete response and the patient is otherwise eligible for a transplant, meaning they have identified an adequate donor, their other general medical conditions are stable, then the patient goes to transplant. So it's the investigator and treating physician's decision about whether they want to take them to transplant. What they're hoping for is that they can get the patient into an MRD-negative complete response. And if so, then they will look to take the patient to transplant. It's not formally part of our Phase I study, but it is obviously a very good result for the patients who are able to go to transplant.

That's great. And then for the updated data today, I guess, can you confirm, were those centrally reviewed? Or how were those reviewed?

So they're reported to us by the -- they are scans that you centrally review as you do for solid tumors. So the information is communicate to us by the investigator, and then Michael and his team review the information to confirm it.

Our next question comes from Peter Lawson with Barclays.

Congrats on the progress and the update. So 5613, is there any way of breaking out the CR rate for the, I guess, the 113 milligram go-forward dose?

Yes, Peter, I think there will -- we're looking for opportunities to present the data at scientific congresses. We'll break out everything by dose and arm. So I think you're going to look forward to that at an updated scientific presentation.

But is it -- could you disclose if it's above or below the overall CR, CRh rate?

Yes. So as I said before, if you look at any of the parameters that we've -- we've reported on overall response rate, CR, CRh, the responses in NPM1, the responses in MLL-r, at the recommended Phase II dose, those responses are generally consistent with what we reported for the overall population.

Got you. Got you. And then just on the additional arm that was added, just if I could circle back on that. Would that be something you'd want to file on with the 6384 kind of onboard? Just trying to work through the -- if that's something that gets reported out in 2 years' time or it's something you kind of have to perhaps use as a go-forward strategy.

Right. So as I indicated, I think in Phil's question, it's not a gating item for Phase II. We will proceed with the doses that we've been talking about for Phase II. This is really an exploratory arm as part of our sort of life cycle management. We are thinking down the road to the point where we get patients in remission who then perhaps, in a maintenance point of view, if we can have a greater exposure for any given dose, that obviously decreases the cost of goods. But it's really more of a downstream life cycle that we're thinking about long-term chronic therapy, and it really doesn't play a role in the ongoing Phase I to Phase II transition.

Got you. That's really helpful. So it could be in that maintenance setting where you kind of extend the drug into post therapies.

Exactly.

Our next question comes from Justin Walsh with B. Riley Securities.

A couple of months ago, a competitor announced that it's using MRD-negative CR as a primary endpoint for its drug in newly diagnosed NPM1 mutant AML. First, do you have any comments on how this endpoint is different and may or may not impact your thinking for the regulatory strategy for SNDX-5613? And second, how do you see the targeted NPM1 mutant AML landscape evolving with the potential for multiple therapies available for the population?

Justin, thanks so much for your question. So the first has to do with MRD negativity as an endpoint. We give a lot of credit to our competitor who has brought that forward and apparently got an FDA endorsement to use that as a endpoint for accelerated approval in a randomized trial. To our knowledge that, that as an end point in a single-arm trial in a relapsed/refractory population is not something the agency has been open to, to date. Obviously, something for further regulatory discussions. So I think that, that is a -- it's probably not something we're going to be -- we'll discuss with the FDA, but we're not counting on that being an endpoint for our relapsed/refractory population. But similar to what Dave described, we do think that could be an endpoint in a, let's say, a first-line trial where you use that as your accelerated approval endpoint.

I think your second question about the landscape for NPM1 disease. I think there's -- obviously, we believe that the menin inhibition pathway demand inhibitors are going to be very important agents for those patients, whether there'll be other agents that work for those patients as well. Time will tell.

Got it. And I have 1 more question. You've mentioned the potential approvals in cGVHD. I was wondering if you can provide some additional color on your thoughts on the landscape there. Do you anticipate that most of the GVHD patients end up cycling through all of the available drugs? Or do you think that they'll remain on 1 drug for a long period of time, and there'll be a lot of competition in the first and second line on that front?

Yes. It's a good question. The -- I think the landscape in chronic graft versus host disease is in its infancy and sort of evolving. We haven't really had approved drugs. There's not a defined treatment pathway for patients if you go on this one than that one. We also think that different agents may have, let's say, better efficacy for different manifestations of the disease. So I think it's something that we'll sort of see how that evolves. But I think we're quite excited to have an agent that shows broad activity against many manifestations of the disease. And of course, it's the only one that's targeting macrophages.

I think the other part to your question about how this landscape will evolve is are there rational combinations that perhaps even earlier in the treatment course, you could have a more profound effect on the patient's disease.

(Operator Instructions) Our next question comes from David Lebowitz with Morgan Stanley.

Understanding that the numbers are somewhat limited at this point, is there any qualitative insight you can give us as to the effect of 5613 on ALL patients in the study?

Yes. I think, David, you're right that numbers are on the small side. Most of the patients with MLL-r that have come in have been AML patients. Again, one of the vignettes that Eytan reviewed at the data disclosure was a patient with what we call mixed phenotypic acute leukemia. Many people bucket that in the ALL bucket. But -- so the numbers are small. I guess, I'd say, to your question, qualitatively, it looks the same in ALL as it does in AML, but the numbers are small.

Fair enough. And as far as the NPM1 patients, I guess, how does that 29% response rate look vis-à-vis the response rate for the current standards in the similar treatment population?

Yes. So again, for relapsed/refractory acute leukemia in -- for both NPM1 and MLL-r, there really aren't good therapies for these patients. So today, if they're truly relapsed/refractory with either of those mutations is they're generally being treated with chemotherapy. And there's not a lot of really solid data on the response rate in -- for those specific lesions.

But overall, if you look in the relapsed refractory population, you'll see a response rate, again, at CR rate for chemotherapy, probably no higher than 10%. So we think that what we're seeing both in NPM1 and in MLL-r, again, with a safe oral agent, is probably quite in excess of what you would anticipate with yet another round of toxic chemotherapy.

And I'm not showing any further questions at this time. I would now like to turn the call back over to Dr. Morrison for any further remarks.

Great. Thanks very much, operator. Thanks, everybody, for joining us on the call today. Again, I think we remain really quite excited about what we're seeing both with 5613 and with axatilimab, and we look forward to presenting additional data in the future. Thank you for joining.

Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.