Therapeutics, represented by their President and CEO, Richard Paulson, and their CMO, Reshma Rangwala. Richard and Reshma, thank you guys so much for being here.
Thank you.
Thank you for having us, Brian.
There's a lot of data we're gonna be looking for in the coming months, let's dive right into maybe the next data point we're gonna see, which is the phase III SENTRY data for selinexor and MF coming up at the ASCO conference. It was accepted as a late breaker presentation. What should we be expecting at ASCO beyond the initial top line data that you presented earlier this year?
I know you guys just gave quite a few details, might we see any more details regarding the death events seen across the treatment and placebo arms where you saw a potential benefit for selinexor? How much longer will patients be followed up for? What should we be looking for at the conference?
Maybe I'll, Reshma expand on that, but a little housekeeping.
Sure
certain statements we make may be.
Yeah
forward-looking statements, so please refer to our most recent 10-Q. Reshma.
Yeah. really, really excited about ASCO coming up, right? You know, we obviously were selected to late-break our SENTRY results, which is our phase III trial evaluating selinexor plus ruxolitinib, again, in this frontline population. Think of these patients as newly diagnosed myelofibrosis patients, all of whom have, you know, baseline platelet counts of greater than 100. The top line data, as you alluded to, you know, we went into some detail, right?
I think really highlighting the rapid, deep, and sustained SVR35, that we saw meaningful improvements in terms of TSS, which is symptom measurement, you know, at week 24 relative to baseline. Then I think probably and arguably the most intriguing is this promising overall survival signal, again, as early as the data cutoff with the median follow-up of about 12 months.
We're an approved therapy, you know, the safety profile is well-recognized with selinexor. We didn't identify any new safety signals. Going into ASCO, this is going to be the first time the data are going to be presented publicly, especially at a medical congress. We look to, again, show, you know, the totality of data, both from a clinical endpoint perspective, obviously from a safety disease modification data.
What we really want to highlight, and I think John Mascarenhas is the key KOL who will be presenting the data on behalf of all SENTRY investigators, is to really show how this unique mechanism of XPO1 inhibition really reflects what we see in terms of the SVR35, the VAF improvements, which is just a marker of clonal burden. Then of course this OS.
I personally don't think that this is a profile that you would necessarily see with any drug, but is again very unique to XPO1 inhibition. The OS that you alluded to, absolutely, right? This is one of the first phase III trials that I'm aware of that has shown the signal of overall survival improvement. Again, I don't find it a coincidence that we find it as early as this data cut off.
Yeah.
It's very reflective of the mechanism, the rapidity at which the underlying biology is changing with XPO1 inhibition. What we, you know, put out there was that the hazard ratio was 0.43, nominal P value of 0.0222.
Yeah
OS events, I can say is that it's very consistent with what you would expect for the OS events, right? Progressive disease, toxicity. You would also expect, right, for us to see that kind of signal that your percentage of patients who are progressing and ultimately dying due to PD, AEs has to be greater in your ruxolitinib or control arm as compared to the combination arm. You know, don't wanna go into details right now. I don't wanna get ahead of ASCO, but, you know, just one way to frame the results.
Okay.
In terms of, you know, sort of like further maturity, so the data cutoff was February 20th, so just a couple of months ago. No, we're not gonna have another data cutoff. Again, just looking to present the totality of data.
Okay. Got it. Then, you know, as these data continue to mature, what do you see as the potential for this early survival signal to develop over time, and is there a certain time point where you believe that will resonate most with both KOLs and regulators? Is it, you know, 18 months, 24 months?
I think, what's really important to keep in mind is that this trial was designed to follow OS all the way until maturity.
Okay.
Right? It's a double-blind trial. Patients as well as the physicians, you know, remain blinded to the treatment arm to which they are assigned. We continue to follow SVR, other endpoints, as well as overall survival, and we'll continue to monitor as those data, you know, get to maturity.
Okay
would be. You know, again, we want to follow these endpoints all the way out until maturity so we can get a really good understanding of how the benefit, you know, is with the combination.
Yeah
relative to ruxolitinib alone. Do we have a lot of confidence in the OS? I do, and this really is because we know that SVR35, especially if you looked at the published literature, really is a potential surrogate for long-term outcomes. This has been described in phase III trials and meta-analyses. We've shown this as part of our own SENTRY data that SVR has this potential predict overall survival.
Yeah.
I think, you know, the fact that we see over.
Internally consistent.
Absolutely.
Yeah.
It's internally consistent.
Okay. How are you guys thinking about engaging with regulators, with the FDA on a potential path forward? What's sort of the gating steps and the key next steps? Do the changes in leadership at the FDA impact your expectation for engagement?
Yeah. High confidence in terms of the top-line results. We expect to gain clarity and provide more clarity around, you know, sort of the next steps with the FDA over the course of the next one to two quarters. We don't comment on the individual steps. You know, again, with that said, we should have clarity over the course of the next six months, if not earlier. The division for, you know, that we'll be reviewing this has been remarkably stable, right? We know that it's the division that we're gonna have our day-to-day interactions with. You know, these are the group of people that we agreed to on the design three years ago before we even started the SENTRY.
In some cases, they even know selinexor through our multiple myeloma experience, so they have that historical knowledge of what is the mechanism, why is it important in myelofibrosis. Obviously, they agreed to the phase III trial before we even started it, and we will continue to engage all the way into, hopefully, what is an approval.
Excellent. I know there's also there's the possibility of exploring a path with regards to NCCN and getting on those guidelines. Maybe on that, from that standpoint, have you guys received any feedback at this point regarding the potential inclusion of Selly in MF into the NCCN guidelines?
Yeah, Brian, as you highlight, you know, the importance of already being an approved medicine, is critical here. We have received, you know, a lot of very positive feedback already from opinion leaders, from investigators, et cetera, around their desire to have us in NCCN guidelines. I think as you know, you know, to progress with NCCN guidelines, you know, NCCN has different committees.
They can meet when they wanna meet. They have sometimes planned meetings, other times ad hoc meetings. I think it's important also the level of information. I think moving forward with our ASCO presentation, I think it'll be one key area of input for them. Also, we've been moving forward rapidly to have a publication and a peer-reviewed journal.
That's, you know, very much in progress, and we'll be able to share later, more information on that. I think together that will enable the listing in NCCN and I guess you know, there's also a lot of great analogs where products have already been on the market.
Yeah
You know, new data, new science. There's high unmet need, you know, as we heard from Reshma. In myelofibrosis, still very much a high unmet need, only one class of therapies. So in those kind of situations and other analogs, you know, you do see, with an NCCN listing, products probably reaching about 50% of their peak if you did have a full label, 'cause obviously it's not an area we can actively promote to, but it's an area where physicians can choose to use this, you know, because that's the best interest of the patients, and they're wanting to use kind of the best product for those patients.
What does the process look like post ASCO and potential near-term publication with regards to NCCN guidelines?
Yeah, I mean, it's a process. They can review the data. They get together. It's independent, you know, so it moves forward I think pretty quickly, but the committees really own that process.
Okay. You mentioned 50% of potential peak just, you know, from NCCN guidelines alone.
Can you talk about, I guess, the most penetrable initial population that you would foresee with NCCN guidelines? What could payer coverage look like then?
Yeah. you know, I expect it's gonna be the combination in this frontline population, and I think these are gonna be some of the key data that we'll present at ASCO is, you know, looking across the various multiple subgroups, patient-.
populations that truly benefit.
Okay
you know, with the combination relative to ruxolitinib.
I guess I was thinking more like community-based versus.
Okay
academic centers.
Yeah, I think early on in the adoption phase and in all adoptions with new data, you tend to see more of the academics or institutions.
Yeah
start to adopt earlier, and then, you know, really your key MF specialists that are also community-based, and then you start to see a kind of broader evolution and engagement. You know, across both academics and communities, they use NCCN very much across all different areas of cancer. I think from that perspective, it's not really a community or an academic perspective. It just tends to be what you see in a typical adoption.
Okay
perspective. I think that should move forward well, and then from a payer coverage, for sure, NCCN helps to support, you know, very broad payer coverage. We already have well-established capabilities, you know, patient support programs, payer engagement, et cetera. I think that should move forward really positively and enable patients to have access.
Excellent. Maybe we could shift gears to another key upcoming data event, which is the phase III endometrial maintenance study. What do you think you need to show on PFS to really differentiate from dostarlimab in pMMR patients?
Yeah. great question. You know, as we look at the evolving landscape in endometrial cancer, you know, by and large, the workhorse has always been chemotherapy, right?
Yeah.
These patients who are advanced recurrent endometrial cancer are going to be treated with chemotherapy doublets, platinum taxane. With the introduction of the checkpoint inhibitors, these patients now have an option to be treated with a triplet of-.
you know, a PD-1 therapy in combination with chemotherapy and then continue on with their checkpoint into the maintenance setting. Now, despite the fact that the checkpoint inhibitors, and I'm specifically referring to dostarlimab and pembrolizumab, have been granted broad approvals irrespective of MMR status, we know from the data, and biologically this makes sense, that the efficacy is going to be greatest in that MMR deficient population.
These patients comprise approximately 20% of all endometrial cancer patients. Where you see far grade, far more modest efficacy is gonna be that MMR proficient population. And to put it into context, the RUBY trial, which evaluated.
Yeah
dostarlimab in combination with chemotherapy, they performed a post-hoc analysis, exploratory in nature, that specifically evaluated the efficacy in that p53 wild type pMMR subgroup, call them NSMP. You see that efficacy from a hazard ratio of only 0.77 highlights the very modest efficacy that you can achieve with the checkpoint inhibitor in that important subgroup. Comprises approximately 50% of all endometrial cancer patients.
Our SIENDO data, right, clearly has shown substantially better efficacy. You know, my aim, our aim, you know, from the XPORT-EC-042 trial is to show that statistically significant and clinically meaningful outcomes in terms of PFS.
Selly works best in the patients where there's the biggest unmet need, from what we've seen so far.
Absolutely. Absolutely. It's really capitalizing on. Go back to the mechanism. What it's doing is it's retaining p53 into the nucleus. As an XPO1 inhibitor, we block the efflux of proteins from the nucleus to the cytoplasm. This is very relevant in endometrial cancer, and not surprisingly, it's very relevant in myelofibrosis. It's not coincidental that we see selinexor activity across these two very disparate cancers.
Right.
It's actually relying on the same mechanism that's important across the two.
Will you have overall survival data to share, or will it be too early?
Just like SENTRY data, we'll continue to follow OS. You know, we'll have to see, right, you know, sort of in this patient population. Yes, these patients do tend to live, you know, very long periods of time, so we'll need to see. At this point, I'm really focused on the top-line data, so PFS is our primary endpoint, and then of course, you know, the top-line safety data.
What's your sense as to the awareness either amongst KOLs and/or the community of this, these phase III results, and where does your feedback suggest is where docs are looking to fit Selly into the maintenance EC paradigm?
Yeah, yeah.
Yeah, I think there's a really high level of awareness. You know, fortunately, our SIENDO data has been out and talked about quite a bit over the last, you know, two to three years, especially as we've seen the evolution. I think as Reshma touched on, you know, the checkpoint inhibitors, you really see that differential efficacy based on whether it's pMMR or dMMR, and then looking at the p53 wild type population.
Fortunately, there's been a lot of good opportunity to present SIENDO data, to talk to it. You know, molecular classification is standard, so in understanding patients' p53 or their tumor's p53 status is standard, and physicians want a medication which they can act on that p53 status.
In an interesting way, I think it's been kind of fortunate where we now see a lot of desire. We just got back, just over a month ago at a, at a major, you know, gyn-onc conference. You know, in talking to the top opinion leaders, really a high level of excitement around the data. Pleased that we're gonna be wrapping up enrollment as we just did, couple of weeks ago, and looking forward to the data. I think from that perspective, it has evolved very nicely for us. When you look at where it's gonna fit into treatment, you know, I think Reshma just touched on it, is as we see, the greatest opportunity to improve on outcomes is that p53 wild type pMMR patient, right?
Very clear, have that maintenance setting option, post induction therapy, I think that's something also which the gyn-oncs are very used to using. You know, establish the induction therapy and then move to the maintenance treatment. I think it's a, it's a great opportunity for us to really improve outcomes for patients, specifically p53 wild type driven, and this in that pMMR patient population.
Maybe just from an overall relative opportunity standpoint, like, how would you characterize the opportunity in endometrial as compared to, for Selly, as compared to MF or myeloma?
Yeah. I mean, I think endometrial cancer and myelofibrosis both are very different opportunities than multiple myeloma. You know, in multiple myeloma, as you know, there's a lot of different treatment options and within that space. I think when you look at endometrial cancer and myelofibrosis, both of them are areas with very few treatment options and the opportunity to really improve on treatment versus current treatments.
I think both are actually multi-billion dollar market opportunities from that perspective. If we think about endometrial cancer and myelofibrosis, you know, both of them, we see the majority of patients actually treated in the community. It's an opportunity, again, for us to leverage our capabilities.
Right.
I think when you look at the endometrial cancer side, as we know, you know, endometrial cancer is the most common gynecological cancer. Unfortunately, it's still growing in terms of incidence. You know, there's about 17,000 newly diagnosed patients per year. Again, our opportunity is really gonna focus on, you know, about 50% of patients, that p53 wild type pMMR. Really well-defined, clear, and I think an opportunity to drive, you know, benefit to patients rapidly.
Got it. In the myeloma setting. Just can you talk about the latest patterns of use that you're seeing and how that's evolving? Then maybe elaborate a little bit more. You talked about the leverageability of the existing infrastructure. I guess to what degree can your current field force be leveraged for a potential MF and/or EC launch? How much further expansion would you look to do?
Yeah. I think, you know, in the multi myeloma business right now still we have about 60% of our utilization in the community and about 40% in the academic setting. You know, selinexor is very flexible across the whole treatment paradigm, as you know, and I'd say primarily in the community we tend to be positioned in that second to fourth line post-daratumumab when you wanna get an opportunity to treat with a different class. Obviously being an oral provides a lot of benefit, especially in the community setting where patients may have more challenges with regards to travel or access. In the academic setting, we tend to be positioned kind of peri T-cell engaging therapy. Bispecific CAR T, et cetera.
An opportunity for us really to help, you know, enable different treatment lines, you know, help to preserve the T-cell environment. Within that space, again, we do see the opportunity for continued growth just given the evolution of the T-cell engaging therapies. When you look at our commercialization capabilities, you know, as we talked about broadly, multiple myeloma, MF, and endometrial cancer, in all those areas the majority of patients are treated in the community, and there tends to be a good concentration in terms of prescribers. There are some large community groups. Across those areas we have really good wide coverage, and I think the teams will be able to, you know, drive that with approvals in MF and EC and MM.
As we get into more of the institutions and academics, if we're you know, as we commercialize myelofibrosis and endometrial cancer, we'd probably look for some targeted expansion to make sure we can have appropriate coverage in the academic centers from a gyn-onc perspective. Broadly what's really positive is, you know, the payer capabilities we have, the access to patient support, et cetera, all of those we can, you know, leverage across any one of the different disease areas that we have. Also, you know, as we look at the ability to share new data and new science, you know, we have a very strong and well-established medical and scientific affairs group. They're able to get out and really engage with top opinion leaders and thought leaders on the data, on the science, on the disease areas.
From that perspective, again, I think looking at the opportunity in hematology and then building on that from a solid tumor is what we want to look at doing, especially as we really engage, you know, across the breadth of science and help this move forward rapidly.
Good. Maybe last question just in the last few minutes. You know, now that you've turned over the phase III card in myelofibrosis, I know you have additional assets, particularly eltanexor, t hat have maybe some different properties, slightly different profile, maybe a different IP as well. What's your latest view on how and where you might consider positioning or developing eltanexor? What are the next steps there, and where can this fit in, if not in other solid tumors, certainly in other MPNs?
You want to see Reshma get excited now. Next steps and next futures. Resh?
eltanexor is a really exciting second generation XPO1 inhibitor. The targets are the same between selly and elta. You're absolutely correct. It has slightly different properties, including a lower IC50. That lower IC50 just enables lower doses, more chronic doses, chronic dosing. eltanexor has already been in the clinics.
Yeah.
We've evaluated eltanexor as part of a larger phase I/II trial. We looked at multiple solid tumors, multiple myeloma again, also looked at it in MDS. I think, you know, the future lies just, you know, sort of riding on the backbone of where what we saw in myelofibrosis is to look at other MPNs.
Yeah. PV.
PV, ET, strong data that suggests that it can have, you know, meaningful activity in those two disease types. You know, looking at other solid tumors, this is where I would love to be able to leverage that p53 biomarker. Again, we see something very beautiful in its ability to predict the patients who are gonna benefit from XPO1 inhibition. You know, I'd love to be able to look at what other tumors can you also see that same ability to predict. There's, you know, just leveraging basket trials, in which we look at p53 status across multiple other solid tumors. I think there's that's the tip of the iceberg.
Yeah.
I got to start small, but I think that's really where we take our assets next.
remind us the IP life for that asset is?
I mean, obviously a lot of work to continue doing on it. We have to work the development side, et cetera. If you added a couple different areas together from a base perspective, you know, it kind of starts in middle of 2030s, you know, we could probably extend that out nicely into late 2030s. We better continue to do some work on it, look at what it takes from a development side and as we bring it to market. Definitely will take us to a greater patent perspective than we have.
Right
with selinexor, which right now, as you know, with our polymorph patent takes us into August of 2035.
Good. Well, a lot to look forward to, this year in the coming months. We really appreciate you being here and giving us your perspectives ahead of that. Thank you.
Thank you.
Thanks everyone.
Thanks for having us.