All right, great. We're live. Thanks, everyone, for continuing to join us here at the Second Annual Guggenheim Healthcare Innovation Conference. My name is Brad Canino. Happy to be sharing the stage now for the next fireside chat with Syndax. We have Michael Metzger, CEO; Nick Botwood, CMO and Head of R&D. Michael, Nick, thank you so much for joining us.
Thanks for having us, Brad. Great to be here with you. I was going to say sunny Boston, but yeah, great to be here. Thank you.
Maybe, Michael, if you just want to spend a minute to introduce Syndax and the state of the business today.
Yeah, so we have two products. We're focused on oncology, of course. I have two products that are now newly commercialized, first year of launch, doing, I think, rather well with both of them. We just reported our quarter for Revuforj, which is now indicated for a second indication, which I'll touch on for KMT2A and NPM1. We had a $32 million quarter. Scripts growing very well, 25% growth since last quarter. Scripts and new patients. The foundation is really set in KMT2A. We have the first drug to be approved there and is really penetrating that market rather well. It's about 2,000 patients in this setting, relapsed refractory disease, of course. We're seeing very strong penetration. We're seeing patients get treated earlier in their treatment course, go to transplant in record numbers, come back from transplant. That's starting to build in the maintenance setting.
This business is foundational to Syndax in the sense that this is a market that we will own. We already do own, and we are going to continue to expand there. We look to get about 50% penetrated by the end of the year on the 2,000 patient incidence, which we will replenish every year, and then really extend that business to NPM1. That is the next driver of growth. Really, establishing this as the foothold for menin inhibition for us is extremely important, and we own this business. Now, NPM1, as we got this approved, we had guidelines in September, approval in October, right on time. That is the next leg of growth for us. We are extremely excited to have a very robust offering for patients for AML, ALL, adult, pediatric indications, and now NPM1.
That's really the start we were looking for, and we'll see extension into next year and beyond. Beyond that, we have a second product called Niktimvo, which is a CSF-1R antibody, which is indicated for third-line cGVHD. This product was launched in February. This quarter grew extensively as well, $46 million net sales compared to last quarter at $36 million. Product's profitable. Can't say that very often. First quarter of sales, this is the second quarter of sales, first quarter of sales turned profitable. So it's very meaningful for Syndax in terms of our contribution.
We have the aspiration, and we feel very strongly that we're going to get to a cash flow break-even and beyond with the cash we have on hand, about $456 million on the balance sheet, and really stable expenses over the next few years as we drive that product, plus what we're doing with Revuforj into newly diagnosed patients as well. We have a robust plan to take these to the next set of patients. In terms of commercial performance, really coming out of the gate very, very well, both products. We're in a good position to succeed from here.
Maybe I can ask on that because, as you've stated, this past year, you guys have executed extraordinarily well on two commercial launches, one in partnership with Incyte, but revumenib was your team fully. You have a stock, though, that this year has underperformed. I think you'd agree with that. Where do you see the disconnect between the stock performance and where you think you've generated real value?
I think, which is not uncommon with smaller companies that are launching products, investors tend to bet that that'll be troublesome and difficult. We've actually outperformed on both launches, as you said, which is not easy to do, but we have fantastic products, and we have a great team that's executing very, very well. I think not one, but two launches that has really set the, I think, the tone for the next stage of growth. In a market that's now starting to appreciate commercial stories like this, I think investors are looking for growth opportunities. This is a significant growth opportunity from here.
Let's talk about that growth potential, especially next year. Can you talk about the levers that you can pull over the next couple of quarters that you'll report for revumenib in particular?
Right. It is very interesting. The paradigm that we have established with revumenib for KMT2A in particular, these are younger patients who have nothing. Standard of care does not work. Most of these patients relapse, sadly, and they are looking for options. What physicians have told us they would do and now are doing is they are treating patients earlier and earlier. About 70% of the patients who receive Revuforj today in the commercial setting are getting it in either second or third line. That is an important driver of potential use and growth. The earlier you get treated, the better you end up doing, the more patients that tend to go to transplant and then have the opportunity to go back on maintenance. That is the paradigm physicians are looking forward to, and that is what they are actually executing.
When you think about more patients going to transplant, we started in our clinical trial about 25% of the patients in KMT2A were getting transplanted. Now it's about a third in the commercial setting. That should grow. Could it go to 50%? It could. We expect that to grow meaningfully over time. The amount of patients that are coming back from transplant, we're just starting to see the impact of what maintenance means to the revenue base. Remember, when you lose a patient to transplant, it's a temporary pause in their treatment. That means about 1/3 of our revenue is coming out on a given quarter because those patients go to transplant and pause treatment temporarily. You have to wait for them to come back. It takes about three to four months to do that.
They reenter and potentially have a long tail of which they're going to stay on maintenance treatment. It could be a year to two years for some of these patients. Most of these patients should get extended treatment. That is an extensive lever of growth. It's both patients getting treated, doing well, getting treated earlier. You're going to get more patients to maintenance and then really bringing them back to maintenance later on, which should really accelerate and compound as you go quarter- to- quarter from here.
Yeah. Maybe just to expand on that, it sounds like you're building up this bolus of patients that have received a transplant but have not yet gone back on revumenib. Is that a dynamic that you think can just flip back on in one quarter where all these patients are now back on maintenance? How does that cadence of that take place?
It takes time. It takes a little bit of time. I think if you think about it, you're losing 1/3 of your revenue, at least in this last quarter, and we've seen about 35%-40% come back. That's not 100%. We think that number, 35%-40%, could grow to 70%-80%. Not every patient will come back for maintenance, but a lot of them will. That takes time to build. As you go and people have been modeling this now more successfully over time, you'll start to see those patients return probably a little bit more in fourth quarter. You'll get more of an impact, certainly next year and the year after, as you go quarter-to-quarter, it should build. It should build meaningfully.
Now, you talked about for KMT2Ar approaching the second line as the treatment option for menin inhibitor and the physicians adopting it there. For NPM1, where you're now expanding into for the next year, where do you see menin in position relative to the other options? Is it going to be the same as KMT2Ar or different?
Yeah, it should be relatively similar. For NPM1, these patients often have co-mutations. For KMT2A, they do not. You'll have options for those patients to get, at least in the front line, they'll get treated maybe for their co-mutations. FLT3 comes to mind. IDH comes to mind as well. There's indications in the front line for these patients. Second line, third line, this is the go-to option for these patients. Revuforj would be a go-to option, just like it is for KMT2A. I'd also add that we've generated just a lot of data in combination with venetoclax and in some cases azacitidine, but we've been able to show that the drug works very well in combination. This is what physicians want to do. They want to treat them with combinations.
They'll do it in the frontline, but more immediately, they're going to do it in the relapsed refractory setting as well in combination with ven/aza. And we're also putting data together, which you'll see at ASH this year for the first time as 7+3. These combinations, this is how physicians want to treat. That will impact what line they're introduced to Revuforj.
Brad, I would maybe just add, this is relapsed refractory AML we're talking about. There's an extraordinary paucity of treatment options for these patients. They don't do well. revumenib is rapidly becoming a well-established standard of care for these subtypes of patients. Physicians want to use it based on the data we generated. Either as a monotherapy in its approved use. Sometimes they want to use it in combination, and we're supporting that with data. There really is a paucity of options for these patients. We're seeing it getting used in earlier lines of therapy because there's an unmet need, and the drug's very effective.
Yeah. I mean, 30%-40% of our utilization is in combination now, which is, as of this quarter, I think that's a big driver and really underscores how physicians are thinking about using the drug.
Got it. Okay. Now, with the NPM1 label update, there was also a change to the QTc from warnings and precautions to black box warning. I guess describe how your conversations have gone with physicians after that update, and do you think it has altered perception of the therapy at all in their minds?
No, I don't. Revumenib is a well-established standard of care, and it's been on the market now for over a year. The physicians are very familiar with managing QT. A lot of drugs in the treatment of AML prolong QT. It was always a warnings and precautions. We have very simple and well-documented management guidelines in the label. The label's extremely transparent about the adverse event profile as we've expanded our safety data sets. The box warning does represent a case of Torsades de Pointes that was non-sustained and non-fatal, but met the criteria for a box warning and appropriate. The physicians are appropriately informed about the potential for QT, and they manage their patients accordingly. With weekly ECGs and optimization of electrolytes, in the context of relapsed refractory AML, the management of QT is not a major consideration. That's the feedback we have heard from them.
What they actually want is a drug that will get a patient into response and give them the potential to get a durable remission and potentially even get them onto a transplant. revumenib across all of the indications that we have, KMT2A, NPM1, including pediatrics and ALL, has a very high probability of achieving that. That is by far the most important consideration in relapsed refractory AML, where the outcomes for these patients are otherwise very poor. We are extremely confident in the profile, the experience we have. We have treated many patients now across commercial settings, clinical trials, expanded access programs with very good benefit and very few clinical sequelae of QT prolongations because they know how to manage it and monitor it appropriately.
Okay.
Yeah. I would just add that this is an efficacy-driven market. Physicians, as Nick said, physicians want a therapy that can get their patients into remission and get them into remission quickly and then keep them there. The ability to give them the drug and get them across the board, get them where they need them, this is the most efficacious drug of the category. I think that's where their head is when they're making their choices.
Yep. Okay. If you have a competitor on the market by the end of this month, how do you see the full profiles of the two drugs for relapsed refractory AML and how you can be competitively positioned for NPM1?
Yeah, I would just say maybe picking up on where I just left off, we have the most efficacious drug in the category from the standpoint of overall response, which is, have you cleared your tumor? We have, I would say, a step change difference in terms of how our drug works in both KMT2A and NPM1. Remember, competitor's drug does not work in KMT2A. When you think about first response, our drug has a meaningful difference there. Other measures such as duration of response as well as time on therapy, overall survival as well. We are thinking about these are key measures for what physicians are looking at. Our drug has best in category efficacy. We are positioned very well from that standpoint. The drug is very well tolerated. A lot of experience, as Nick said, physicians know how to use the drug. It is broadly indicated.
It's the broadest set of indications that you'll see. For adults and pediatrics, KMT2A, AML, ALL, MPAL, and for NPM1, AML. No one will eclipse us from a set of indication standpoint, which really sets us up for success as well. Lastly, I'll say we have a variety of doses, which may go on as a slightly underappreciated part of our story, but I will say having three different doses, the ability to manage a patient of any size or of any complication relative to what they may be on in addition to Revuforj really gives us a great advantage from a tolerability standpoint, safety standpoint. We have excellent flexibility for the physician, and they've been able to do this over the last year and really get a lot of experience and comfort with the drug.
Okay. As you describe maintenance being an important part for the KMT2Ar population, when you speak with physicians, how do they think through the benefit-risk of putting a patient back on maintenance post-transplant when it is not technically a part of the formal label and the published clinical data in that setting are limited?
Yeah, you're right, Brad. It's not part of the label. We're obviously not promoting maintenance. We have allowed for maintenance in our clinical trials, and we're generating data on maintenance because we think it's an important clinical question, and we are seeing patients treated in that post-transplant setting in maintenance. We'll have a couple of important abstracts at ASH, actually, one from MD Anderson in a pediatric cohort, actually, where 10 patients were treated with maintenance with really compelling EFS. At one year, all of the patients were event-free. Another series from Moffitt in Florida where four patients had transplant and three went on to maintenance afterwards. That's what we're seeing in practice.
Physicians think it's a compelling proposition that once you've had a transplant, if you have a mutation to put back onto revumenib, once you've allowed for engraftment, it actually can hold the disease sometimes and can allow for that phenomenon of graft versus disease. I think there's a growing acceptance among the kind of scientific and academic community that maintenance is good for some patients. Again, I think that the flexibility in dosing we're finding is an advantage. These patients are quite fragile after transplant. You need to allow for the engraftment. They can be prone to cytopenias. Whatever you treat them with, you need to treat them carefully. I think the flexibility of dosing we're seeing is helpful.
We've seen some patients started at 160 and then dropped to 110 or even started at 110 just as a function of in a maintenance setting, you need to treat them carefully. We are seeing patients treated in that setting with, from real-world series, seemingly quite promising activity. We have a big book of work working with leading scientists and investigators to add more data to support the science and the use in that setting. There will be more on that to come. It is an important part of the treatment paradigm, I think.
Okay. Now, you mentioned the combo data. A lot of that data is also positioned for frontline development. When you look back at the then aza-revu data that was conducted by the Beat AML Consortium, what about that gives you confidence in the phase III having a strong chance of success?
There are lots of features to it. I mean, firstly, tolerability is important. We were able to show that you can combine safely with very low incidence of QT or differentiation syndrome or discontinuation. You can combine with ven/aza. That's important. We have taken the standard-approved dose forward into the EVOLVE-2 HOVON study. That is the first thing. The second is obviously you want to look for efficacy. We saw a 67% complete response rate. Again, if you compare with the benchmarks for vene alone, that's an order of magnitude better than maybe the 37% you see reported even in a heterogeneous population of unfit patients treated with ven/aza. In those patients that got a complete response rate, we saw very deep responses. Using a quite sensitive flow cytometry test, we saw 100% MRD negativity.
We think all of those things contribute very much to the likelihood of a positive outcome in the EVOLVE-2 study. Those data were relatively immature. I know we've had a lot of discussion about the survival from that study, which was somewhat comparable to what we saw in VIALE-A, but the follow-up is relatively immature. That study has continued to roll and newly diagnosed. We are anticipating the Beat AML group will update it next year and we will have more information. We will, Brad, also have, again, just in terms of our leadership, particularly in combinations, I think, with ven and hypomethylating agents, some data from the SAVE study. We've previously presented data on that in relapsed refractory.
We're now going to present data in newly diagnosed, which again shows it's very tolerable, well-managed at recommended doses, and that you see, again, very, very high rates of complete response rate and MRD negativity. We're creating quite a body of evidence that is supportive of frontline ven/aza combinations. We're excited about that study. The EVOLVE-2 study is enrolling well. It was the first study to start randomizing patients in a frontline setting. We're very much enjoying the collaboration with HOVON. This is a leading academic group with international sites. We're anticipating enrolling in the U.S. as well and really consider that we should be first to read out with a positive study in that setting. I think we're well on track to achieve that.
Okay. Why do you think the decision to run the phase III with the HOVON Consortium will be as competitive as an industry-sponsored study that we're seeing from J&J and Kura, which have both started up?
We talk a lot about speed, and speed's critical. Rightly, we're focused on speed. The thing that sometimes doesn't get talked about so much is the quality. We're equally focused on quality. It's a combination of both speed and quality. The work we're doing with HOVON is quite interesting because you're working with leading academic sites and a leading academic consortium. They're significantly invested in this study and partnering with us. We are benefiting from their expertise, both in terms of the design of the study. There are some design elements within that study that I think are somewhat unique and differentiating. Also, just in terms of the way the study is conducted.
We've opened it at some of the leading sites to ensure the optimal quality and the learnings in terms of the dosing of the ven/aza and ensuring that patients are managed in the most optimal way to give us the best possible chance of demonstrating a benefit both in terms of complete response rate, but also in terms of overall survival. Both of those endpoints are very important. They're dual-prime endpoints. I think working with HOVON and the academic network of sites that that provides is really providing us with a competitive advantage and is really differentiating compared to the competition.
Okay. Maybe a couple of questions on Niktimvo because your partner Incyte has put out some commentary saying that they expect the current third, fourth line GVHD setting to provide maybe a $500 million peak opportunity. If that plays out, how should we think about the value that flows to Syndax?
Yeah, look, I think third and fourth line, I mean, we see it as larger than that. I think what we've discussed is $1 billion+ opportunity in GVHD. I think part of that is getting to frontline. Frontline is a combination potentially with steroids and also a combination with Jakafi. We're doing both of those trials now to make sure that we have the data that we need in order to get the drug approved there. We're talking about 6,500 patients in third line plus GVHD. We're also talking about an indication that, or at least a drug that gets patients to respond very quickly, and they stay on not for months, but potentially for years. That's what the data suggests. With even a smaller patient population, this could be very significant.
I think CML and some of these other indications where patients are staying on for years, not months. I think that even in a third line plus indication really speaks to the breadth of the opportunity. You also have to think about one of the competitors in the space, REZUROCK, which is Sanofi's drug doing $550 million in its third-year sales. We're starting to take share. We're really building where we are today. We're in fourth line. We're starting to penetrate nicely into third line. We're going to continue to take share from them. We think this could be a low watermark for what we can do in third line plus. I think that seems the $500 million estimate seems light to us. I think that's $1 billion+ GVHD opportunity, probably more like closer to $2 billion in total as a TAM.
We should have a new mechanism where we can combine with other standard of care. We should be able to do considerably better than that.
Yeah. In terms of the value that flows to Syndax and those different numbers.
Right. So yeah, thank you. So very simply, we have a co-promotion, or I should say co-development co-promotion deal with Incyte, 50/50 profit and loss split. If you think about it, we split at the contribution level after expenses are taken out, 50/50. The way to think about the contribution to Syndax is about 25%-30% from top line to our line of contribution on our P&L. That is on a stable set of expenses and very focused commercial target audience. We're talking about expanding even potentially beyond 30%. Today, over a foreseeable quarter, we're talking about a contribution of 25%-30%, which is quite meaningful even on the fact that we have a royalty to pay to Royalty Pharma. If you think about $1 billion product, $250 million-$300 million is pretty significant. We think that number could be larger.
Even in the face of a royalty, I think it contributes very meaningfully to what we do and helps us drive to profitability pretty quickly.
Now, you are taking Niktimvo into IPF for the randomized phase II. You're pointing to data in the second half of next year. What is the pitch to investors about why they should believe it has a chance to show clinical activity in that population?
I would just say compelling both preclinical and clinical hypothesis. Actually, CSF-1R antibody was originally conceived as a drug that might have activity in IPF, interestingly. Then we demonstrated extremely compelling data in the AGAVE-201 study in patients that had pulmonary symptoms. This is a very good analog, if you will, for idiopathic pulmonary fibrosis. Patients had significant improvements in FEV1 and symptoms. In a small subset of about 32 patients that had bronchiolitis obliterans syndromes, again, we saw benefits. There is a very good analog to say, well, it works in chronic diseases that are characterized by both fibrosis and inflammation. That is idiopathic pulmonary fibrosis. We have that study. Frankly, the current standards of care are really unsatisfactory. Even recent readouts and recent approvals, you are really just looking at somewhat reducing the deterioration in forced vital capacity.
Our hope is that with our study in IPF, which has a FVC primary endpoint, randomized axatilimab against standard of care on a background of standard of care, we could certainly improve the deterioration in symptoms and FVC and maybe even modify the disease in some way where we could actually see some benefit for patients. We are extremely excited about that study. There was a lot of scientific and clinical interest in enrolling to it. It enrolled really quickly. We are anticipating it being completely enrolled by the end of the year. As you said, Brad, anticipating data into the middle part of next year. If it is positive, we think that could be a very important catalyst to an appropriately powered phase III because phase III in that setting have traditionally been very big.
We would hope to do something more appropriately sized with a more competitive benefit. Potentially also open the door to other diseases because CSF-1R antibodies are such an attractive target and opportunity for other diseases that are characterized by fibrosis and inflammation. It is a really important readout for us, both in IPF, but potentially other settings as well.
Okay. With that, unfortunately, we're out of time. Michael, Nick, thank you so much for joining us. Thank you, everyone, for listening in.
Thanks, Brad.