All right. Good afternoon, everyone. Thanks for being with us for the Baird Global Healthcare Conference. My name is Colleen Kusy. I'm one of the senior analysts here at Baird, covering biotech, and I'm pleased to have with me today Karyopharm Therapeutics, including Richard Paulson, CEO, Reshma Rangwala, Chief Medical Officer, and Mike Mason, CFO. So thanks for being with us, guys.
Thanks for having us.
Thanks.
So I'll kick it over to you for a brief corporate overview for those that are less familiar with Karyopharm.
Super, and thanks, Colleen, and thanks to Baird for having us. You know, just a little housekeeping before we begin, right? Anything we say today is forward-looking statements, so please refer to our latest 10-Q on file. You know, Karyopharm, just to share a little bit of a background, is that we are an innovation, patient-focused commercial stage company, which has our first product is XPOVIO, and our foundation is in multiple myeloma. We're now approved in over 40 countries around the world, and kind of countries with partners going through their launch sequence and reimbursement sequence around the world.
Total revenue for the year, we've guided $145 million-$160 million, and as we'll talk with Colleen about, really excited and confident in our position in multiple myeloma as we continue to grow in earlier lines and across kind of the treatment paradigm of multiple myeloma. We have a very focused Phase III pipeline of three Phase IIIs, so that is really setting us up for the next stage of growth, as we move forward with selinexor in three Phase IIIs, which we want to read out over the next couple of years. And also, you know, we have the financial position and the strength to deliver, with a cash runway through to late 2025.
and as we move forward, you know, we've exited Q2 with $238 million in cash, so the confidence to deliver on our phase IIIs, as we continue to work, and focus on patients and improving outcomes for patients with cancer. And as we look at kinda how that's gonna come together, it really enables us, we think, to have selinexor set up to be about a $2 billion product. Looking at building on our current label of multiple myeloma, adding to that with SPd in, multiple myeloma, an all-oral option, endometrial cancer, which we'll talk to, and myelofibrosis.
And so looking at our key milestones over the next couple of years, you know, see our continued growth in multiple myeloma, you see our top-line results across each one of our, our trials, and excited to be moving forward and looking forward to the, the Q&A today.
Great. Awesome.
Thank you.
Thank you for that overview.
Thanks.
So, let's start with the commercial business of XPOVIO and multiple myeloma. There's been some headwinds in the first half of this year, so kind of walk us through what some of the commercial trends have been in the first half of this year.
Yeah, when you look at the first half of the year, you know, selinexor in the first half of the year has grown about 8% from a demand perspective. And if we look at Q2, you know, we grew 9%. Within the community, we grew 11%, and within the academics, we grew 6%. So across the spectrum of treatments options, we're continuing to grow from a demand perspective. That revenue is being challenged with regards to an increase in our carry-forward program, which is free goods, and our patient assistance program. So our net revenue's been impacted negatively, as we've seen a jump from about 5% utilization of patient assistance programs to 14% in Q2.
So that's had a negative impact, but I think from a demand perspective, you know, we continue to grow and continue to establish ourselves both in the community, you know, and in the institutions and academics.
Makes sense. And then what are your current expectations for some of those third-party foundations in the back half of this year and how that might impact your distribution of free drug?
Yeah, I mean, there's 4 main foundations from a patient assistance perspective in multiple myeloma. And obviously, those foundations are running their programs. What we have seen is one of the major foundations, you know, opened during the middle of Q2 and has continued to remain open. So, you know, we can't predict where they're gonna be in the future, but they've continued to maintain openness, which is critical for patients and has resulted in less demand for our patient assistance support.
Great. The increase in 340B discounts that we've seen, do we expect that to be the new steady state, or will there be some fluctuation there?
Yeah, I think we're gonna see that be relatively consistent. It always kind of depends on your book of business, but, you know, from year-over-year, Q2, it went from 17% to 22%, but I imagine that's gonna remain relatively consistent moving forward.
Great. So we've seen a number of approvals in the later line setting of multiple myeloma over the last, you know, year plus. How has that been... How has that impacted XPOVIO in the later and earlier line settings?
Yeah, I mean, I think all the approvals continues to be great for patients, you know, as we continue to see more options for multiple myeloma patients. And, you know, and as I just talked to, I think, you know, despite all the approvals, we managed to grow in Q2 from a demand perspective, 6% in the institutions and academics, and that's with all the new approvals in place. So I think as we move forward, you know, we definitely have a clear strategy to focus on the community, where about the, you know, the majority of multiple myeloma patients are treated, especially in the earlier lines. You know, two-thirds of our business right now is in the community setting.
So our strategy is working, and at the same time, we've also made really nice progress in moving the majority of our patients now in second to fourth line. So over 60% of patients on selinexor are in that second to fourth line, which again, is kind of on strategy. So I think, I think as we move forward, you know, despite the competition, we're seeing the community really strong uptake. And then if you look at the institutions and academics, we've created some really good data to look at the ability for selinexor to be used kind of pre- and post-T-cell engaging therapy. So I think with all the new therapies coming, and from T-cell engaging, that's critically important.
And I think as we're seeing our growth also from a demand perspective in the institutions and academics, it shows that there's a big need, and will do well. At the same time, in institutions and academics, you know, there's a number of patients that can't take many of these new agents, and I think, again, we're a great alternative, because what's critically important as you move through lines of therapy is having access to novel modalities. So obviously, we're a novel modality, and building on the spectrum of care.
Great! And so on your 2Q call, you recently reaffirmed your guidance-
Mm-hmm.
For your revenue guidance for the year for XPOVIO, $110 million-$125 million this year. Talk to us about some of the pushes and pulls, what you and what you expect the second half of the year to reach guidance.
Yeah, I, I think, you know, we, we reconfirm guidance and have confidence in our guidance moving forward. So I think we'll continue to see, you know, good growth. We built in, you know, conservative assumption with regards to patient assistance programs. So obviously, as that continues to, you know, play out in the marketplace, I think we've taken that into account. And I think as we continue to move forward, we have some really exciting data, in the community setting, which is PI-naive data, and maybe I'll let Reshma talk to that. I think that's gonna continue to help us in the, in the community setting.
Yeah, absolutely right. So these data were first presented at EHA, and it's specifically a subgroup analysis from the BOSTON trial that was comparing SVd versus Vd in the second-line plus patient population. And what we observed in that subgroup analysis is that patients, again, who were PI-naive, achieved really an unprecedented benefit, specifically a 30-month PFS for SVd versus only 10-month median PFS for those patients who were treated with Vd, equating to a hazard ratio of 0.29. So it really continues to demonstrate the benefit that selinexor can provide, in addition to all the other prior subgroups, post-Dara, post-anti-CD38, the elderly patient population, and then also patients who are renally impaired. So it really embeds selinexor, again, across a broad population.
Great. Beyond the $110-$125 that you expect XPOVIO to do this year, your total revenue guidance is $145-$160 for the year. So you have a couple of partnerships as you referenced, but lay out for us what the economics look like for Karyopharm that fill that gap in the remainder of the total revenue.
Yeah, I mean, I think our... We have really strong partners in Asia with Antengene. Antengene has just brought on Hansoh as a commercialization partner, so I think that's very positive for us as they look to expand access in China, and a very large sales organization that can really reach in multiple areas. So as we continue to move forward through the reimbursement sequence and work to get on the national drug list, I think we'll continue to see, you know, positive growth in China and in the rest of Asia as they're going through their launch sequences. In Europe, Africa, Middle East, and Latin America, we have Menarini as our partner, so Germany and Austria currently launched, going through the reimbursement processes across Europe and many markets.
So I think, again, as that continues to move forward, we'll start to see, you know, our royalties pick up through those areas. And then in Canada, I can't forget, of course, as a Canadian. In Canada, our partner Forus, you know, also going through the reimbursement processes and getting reimbursement across, you know, the major, major provinces there, and we'll start to see the royalties. So, you know, together, when we, when we look over the, the, the mid to long term, from a royalty perspective, from a milestone perspective, I think there's significant opportunity for us to grow, and significant opportunity to see that uptake.
Great. So while we're still on multiple myeloma, as you referenced, you have a phase III trial with the all-oral regimen. Maybe just kinda remind us why that should be an attractive combination to go after in a phase III setting.
Yeah, I think it's really, really important for a couple of reasons. First is, we're combining with Pomalyst, which is a $2 billion-plus backbone. Also, POM itself is also seen as being T-cell sparing. So if you take selinexor and POM together, T-cell sparing and an all-oral regimen. So that enable, I think, a lot of flexibility to be used across multiple areas. Secondly, it enables us to actually promote at a much lower dose because that study is at 40. So I think very important, as we're seeing, you know, selinexor can be used, improve tolerability, longer duration of therapy at lower dosages, so to be able to actually go out and proactively promote. And third, that study, we're recruiting patients who are post-anti-CD38.
So as we're seeing, you know, increasingly in the frontline, second line post, you know, CD38 is being used as a foundation to be able to continue to show data, give physicians confidence about the ability to use us much earlier, I think really bodes well for continuing growth, you know, as that study will read out in the second half of 2024.
Great. Talk to us a little bit about the selection of the control arm for that study. I think you're looking at pomalidomide, elotuzumab, and dexamethasone. How did you come to that conclusion?
It was really honestly based upon... You know, we had a few options. You know, from a regulatory perspective, you know, they really wanted to compare a triplet to triplet. And so it was really, you know, sort of a suggestion of: Why don't you incorporate elotuzumab in combination with PD? So it was, you know, a pretty simple decision at the end of the day to just pick elotuzumab. You know, based upon the data that we see, again, we have a lot of confidence that selinexor is gonna be able to provide very meaningful benefit in this trial.
Okay, great. Would you expect this to be a meaningful you know, say, the data are positive and you get this expanded label, would this be a meaningful expansion of the multiple myeloma opportunity, or is this a little bit more of a bolt-on? How to think about... Kinda how much of the market this then opens up with an all-oral?
Yeah, I think it's a meaningful growth opportunity because, again, to have an all-oral to be able to promote to it is critical. We're already included in NCCN, so we can't promote to it, but physicians may choose to use it, and at the lower dose. So I think all three of those components, I think, will be meaningful for us and really enable us to drive greater uptake, not only here in the U.S., but also globally, where once that's in the label, depending on the reimbursement guidelines, really enables physicians, you know, to choose step-down therapy, as you go through the reimbursement sequences that they have to follow in many countries, you know, unlike what we have to do in the U.S.
Got it. So let's switch gears a little bit. You have some late-stage development in endometrial cancer, the solid tumor you're going after. So you had some really encouraging phase III SIENDO data in this subpopulation, P53 wild type. So maybe give us an overview of what you saw in that patient population. I think you've also presented some data since then. So what kinda makes you excited about that opportunity?
So going back to the original SIENDO trial that you alluded to, so this was a maintenance trial, specifically evaluating selinexor as a maintenance therapy in patients who are advanced recurrence. All of the patients received prior carboplatin. Although the benefit in that ITT population was marginal, what we saw was a very profound effect, specifically in P53 wild type. It ties directly with the mechanism of XPO1 inhibition. And what we found at the time of that initial data cut was a median PFS for selinexor of 13 months versus placebo, which was performing at around 4 or 5. So a very meaningful delta of about 8 months median PFS at the time of the initial data cut-off. What we did is recently performed an updated long-term PFS analysis, and in this most recent data cut, that median PFS for selinexor has more than doubled.
So gone from 13.1 months to now 27.4 months. The placebo arm, still same at around 5.2, equates to a hazard ratio of 0.42. Now, when we updated the other half of the population, this mutant aberrant, there's no change. So you see no benefit for selinexor, really highlighting the potential for P53 wild type to be an important predictive biomarker that identifies patients who will respond to selinexor. You know, hearing the discussion, I mean, this is where many of the discussions, including Gini Fleming, really called the data unprecedented-
Mm-hmm.
Because it really highlights the importance, especially in this personalized medicine era, to be able to bring a new companion diagnostic and of course, a novel new mechanism in the treatment landscape for endometrial cancer. The last thing I want to highlight is that we also know that the checkpoint inhibitors are now being integrated into endometrial cancer. But by and large, the checkpoint inhibitors continue to show the benefit in that MSI high patient population. MSI represents approximately 20%-30% of all endometrial patients. Even in that P53 wild type, they're going to represent about 30% of all patients. Unfortunately, you don't see that benefit in that MSS patient population. That's 70%, and so there's a void. What we found in the updated data cut is that MSS patients really have very meaningful benefit.
So the medians were not reached with selinexor among those patients who are wild type in MSS. Hazard ratio was 0.32. So suggests a potentially new standard of care for this patient population that really otherwise is only being treated with carboplatin.
Mm-hmm. Great. Yeah, very, very compelling data there. And so now you, you're running a phase III study just in that, in that.
That's-
P53 wild type.
That's right. That's right. So very similar to SIENDO with a couple of key changes. So the patient population, to your point, are only going to be P53 wild type. And we're working with Foundation Medicine, one of the leaders in testing. They're using their proprietary NGS platform to identify the P53 status amongst these potential patients. If the patients are wild type, they potentially can be randomized to either the selinexor arm, it's the 60 milligram dose, or placebo. A total of 220 patients will be randomized, primary endpoint of PFS, and looking forward to top-line results in about a year, end of 2024, beginning of 2025.
Great. And what is that study powered to show?
We don't talk about our powering assumptions, yet across all of our Phase III, you know, we really do power, you know, above 80%. So, you know, and especially with the strength of the data that we've seen, again, a lot of confidence in the success of that trial.
Great. And so when you—you know, let's fast forward and assume that this is positive data. You already have a commercial infrastructure with XPOVIO in multiple myeloma, but you have a broad, you know, exposure in the community setting. So when you think about potential commercialization of your first solid tumor indication, how much additional investment would you need in your commercial infrastructure?
Yeah, I think, Colleen, it's a great point, and as you referenced, we already have a very strong commercialization capability that goes across our field sales organization, our marketing organization, our access organization, as well as our GMSA, our medical and scientific affairs organization. So from a additional resource perspective, it's very little. Majority of these patients are actually in the community setting, so I think we would have some, you know, nuances around the edges, obviously, as we're going into a new area. But really, there's a lot of synergy with what we've already built.
Great. You know, we've seen some examples of drugs approved in the maintenance setting for different solid tumors, thinking, you know, PARP inhibitors as an example. What can we learn about other launches and uptake in the kind of maintenance setting?
Yeah. Especially from the ovarian experience, you know, 70% of patients who are BRCA mutated are going to get a PARP inhibitor in that maintenance setting. So compelling data is going to lead to strong uptake. By and large, the majority of patients are going to go on that maintenance therapy. So I think we can assume something very similar in that endometrial space as well.
Yeah. And I think what's really important, too, is that time to peak was really quick.
Mm-hmm.
You know, that happened over about three years, and so I think, again, in this space, you would see a time to peak being very quick because just the unmet need is significant.
Mm-hmm. What has been the physician feedback on the safety profile and balancing that with, you know, uptake in the maintenance setting where patients maybe otherwise wouldn't be on any treatment? How do they balance the safety profile of XPOVIO in that setting?
Yeah. This was, this was addressed directly by one of the discussants at the ASCO Plenary. And it was, it was very interesting. Although she did not participate in the SIENDO trial, just based upon her assessment of the AE profile, it looked very tolerable for her. And this is especially important. She works in a very rural setting. You know, patients are unable to come and see the physician, you know, very often. So being able to provide an all-oral regimen, an oral regimen, with the safe profile in her mind, really fit that ideal, you know, profile for her. You know, and I'll go back to the data, right? You know, again, in all P53 wild type, we see a hazard ratio of 0.42, and that MSS is 0.32.
That kind of benefit is only observed if patients are able to tolerate drug and stay on drug. So we're seeing that ability to tolerate selinexor in SIENDO and, you know, hopefully, it's going to be recapitulated in the XPORT-EC-042 trial as well.
Great! And so now, shifting gears a little bit to the myelofibrosis-
Mm-hmm.
- opportunity in your pipeline. So you've recently presented some really interesting-
Yeah.
phase 1 data for selinexor in combination with ruxolitinib, standard of care. You initiated a phase 3, and you recently received Fast Track Designation. So maybe talk to us about, you know, what, what it-- Give us maybe a high-level overview of what, what you've seen in myelofibrosis that gets you excited about that opportunity.
Yeah. So we still believe that it's the treatment-naive or the JAK-naive patient population, which we can substantially provide increasing efficacy. So by and large, the standard of care has been Jakafi or Ruxolitinib. It was approved more than 10 years ago. You know, with that said, though, efficacy is still observed in less than half of all patients. So SVR35's spleen volume reduction of 35%, TSS50, is again seen in less than 50% of all patients. Furthermore, we know that some key subgroups don't benefit as well. So male patients, for whatever reason, unfortunately, do not respond well to Ruxolitinib. We also know patients who, because of low platelet counts, who need to start on lower Ruxolitinib doses, also do not achieve that same benefit.
So based upon this, you know, sort of where we are with myelofibrosis, obviously, there's a need to substantially improve the efficacy for this patient population. Based upon preclinical data, we initiated a phase 1 study that combined selinexor plus ruxolitinib in this JAK-naive patient population. All patients had to have platelet counts above 100. At AACR, earlier this year, we were able to provide the full 24-week data amongst the 24 patients enrolled. And what we found in the 60 milligram dose level that's now incorporated into our phase 3 is, again, really impressive benefit, both for SVR as well as TSS50. So in the intent-to-treat population, 79% SVR35, this is almost more than doubling what you see with Rux alone, and a 58% TSS50. Again, a substantial improvement compared to Rux alone.
Furthermore, I'll just highlight one other area that differentiates this combination from some of the other competitors. We found that there potentially could be single-agent activities. In an important subgroup analysis in which patients were maintained on very low doses of ruxolitinib, again, doses that do not provide benefit, what we found is all patients at week 24 achieved that SVR35, four out of five also achieved that TSS50. Again, you don't see that with Rux. That affords flexibility for physicians when they initiate a patient on that combination. They can discontinue that ruxolitinib but not compromise efficacy.
Great. And yeah, I think one of the things that, that stood out to me about your data as well on the SVR was that between week 12 and 24, you actually had an increase in efficacy. So kind of talk us through that.
Absolutely. So what was really intriguing is that the majority of patients, so 11 out of 12 patients on that 60 milligram dose, achieved that SVR35 as early as week 12, so a very rapid decrease in that spleen shrinkage. But from week 12 to week 24, to your point, that spleen continued to shrink. That's, that's gonna have an overall improvement on their TSS50 too, right? So, And we see that same kind of phenomenon occurring with that TSS50. So it really is this very rapid but sustained improvement across both of these important endpoints.
Great. And yeah, on the TSS50, in the updated ASH, I think you had some missing data...
Mm-hmm.
- from some of those patients. So, you know, I think initially, maybe that TSS50 didn't look quite as compelling, but since then you've been able to recover, I think-
Yeah
... some of that data. Maybe talk us through just the anomaly there.
Mm-hmm. Yeah, it was really, you know, at AACR, that was really sort of the top-line results. It was the, you know, data set that we wanted to present at week 24 that incorporated, you know, sort of the full complement of the symptoms collected, either from the paper or from physicians' charts. That 58% that we observed and we presented at AACR, I think really is, it highlights the benefit that the combination can provide on that symptom assessment.
Great. And then on safety, you know, we've seen an increase in thrombocytopenia, but actually a lower anemia rate than what you'd expect for Rux alone. So what's kind of been the physician feedback on the safety profile you're seeing in myelofibrosis?
Overall, they're telling us this is a very tolerable AE profile. By and large, we see two groups of AEs with the combination. We see the cytopenias, and this is very consistent. You see this with Rux alone; you see this across all of the other agents that are currently in development. So AEs, cytopenias, you also see GI toxicity. The kind of GI toxicity that we see with selinexor is primarily gonna be nausea, a little bit of vomiting. You know, with that said, GI toxicity is also very common across other drugs in development or available in myelofibrosis. So other agents can cause a little bit of diarrhea, some vomiting. So overall, this AE profile is, again, it's not an anomaly. It's very consistent. The key thing is that patients are able to tolerate it and stay on therapy.
That ability to stay on therapy, just like endometrial, is what's driving that TSS50 improvement as well as that SVR35 improvement.
Great. And so the phase 3 study you have underway. There's a co-primary endpoint, I believe, of-
Mm-hmm.
SVR 50 and TSS 50, which is a little different maybe than some of the other drugs in development. So will you talk about why you're going with that co-primary approach?
Two endpoints are required in myelofibrosis. So, you know, from a regulatory perspective, from a physician and patient perspective, honestly, they want to see improvement in that symptom score, right? Unfortunately, myelofibrosis causes a lot of intractable symptoms, either stemming from the spleen enlargement or from the cytokine production. So being able to show that they're feeling better is, again, going to be very clinically meaningful for this patient population. We're very focused on being able to provide meaningful benefit on TSS50. And then, yes, you know, SVR35, it's one of the hallmarks of this disease, is this very large spleen. To be able to show reduction, that again, is a marker of benefit that the combination can achieve.
We're focused on showing both, and again, I think our phase I data meaningfully demonstrate that the combination will show benefit across both endpoints.
Great. And so now commercially then, how would you expect a combination to fit into the treatment paradigm in myelofibrosis?
So myelofibrosis, you know, again, by and large, there's not a lot there for them. You know, so it's ruxolitinib, and, and clearly, I think we can show that our profile is superior to ruxolitinib. The only other, you know, combination that I think is important to comment on is the BET inhibitor. So BET inhibitor in combination with ruxolitinib, you know, those data from MorphoSys, from the Manifest trial, hopefully are going to read out later this year. So obviously, you know, we're going to be able to see that, that data. But again, we're confident in our profile, as well as the unique aspects that differentiate us from that compound.
You know, superior SVR 35, superior TSS 50, and also this monotherapy activity, I think in our minds and in other physicians' mind, really suggests that this combination potentially can be best in class.
Awesome. And just before we touch briefly on eltanexor, I think you had some patent exclusivity changes for XPOVIO to maybe get you a little bit longer. So maybe just remind us, as you're kind of exploring these additional indications for selinexor, what the patent exclusivity looks like.
Yeah, we had some positive adjustments to it, so it takes us out an additional year to the middle of 2033. So obviously, a lot of life ahead of us to really deliver on this for patients and obviously to drive value.
Great. And then so just briefly on eltanexor, you're looking at an MDS. What are the next steps for that program?
Yeah. So, encouraged by the data that we've seen with eltanexor in a very frail, hard-to-treat patient population. So specifically, this is going to be our higher risk, relapsed, refractory MDS patient population. Unfortunately, these patients survive very short periods of time, really only four to six months. So the data that we've presented both in phase I and phase II, again, are encouraging, given the fact that median overall survivals across both of those trials are now in the order of nine to ten months. So a lot of opportunity to further develop, and we'll define those next steps by the end of the year.
Great. And so in your 2Q call, you had announced a downsizing of your workforce by 20%. Where does that leave you with your cash runway?
So our cash runway, so we finished Q2 with $238 million in cash, and that gives us a cash runway through the end of 2025. And with the restructuring we announced on the call, that was both employees and contractors, but we wanted to make sure we had the right size organization to drive, you know, these phase III results, but also, you know, our on our commercial front as well.
Great. So just in this last minute here as we wrap up, you know, there's a lot of different interesting programs going on, commercial, clinical. So just as in summary, kind of why should investors be paying attention to Karyopharm over these next 6-12 months?
Yeah. Thanks, Colleen. So, I mean, I think as you just heard, we have a really solid base of business, which is sustained demand growth in multiple myeloma. And we're a product which is able to be combined with multiple agents, you know, no end organ toxicity, and the ability, I think, to be used across multiple paradigms. We know our profile, and we're only improving on it as we've gone from 160 down to everything we're doing now is at 60/40. I think the increased tolerability and the ability for patients to use selinexor, you know, we're seeing that across multiple areas.
So to build on that foundation, growing revenue globally, growing launches globally, growing in multiple myeloma, so a proven commercialization capability, a proven development capability, and then three phase III trials, and I think, as you just heard, all with high probability of success, with great data and high unmet needs that we want to deliver on, and we can do all of that within our cash runway.
Fantastic. And with that, I think we're out of time, so thank you so much, Karyopharm, for being with us.
Thanks, Colleen.
Thank you.
Thank you.