Okay. I think we'll get started. Good morning. I'm Eric Joseph, Senior Biotech Analyst with JP Morgan. Our next presenting company is Karyopharm Therapeutics, and presenting on the part of the company is CEO, Richard Paulson, and Chief Medical Officer, Reshma Rangwala. There's a Q&A session after the presentation. Just raise your hand. We'll get a mic to you. For those tuning in via the webcast, feel free to submit questions via the digital conference book, and we'll work them in where appropriate. With that, Richard.
Good morning, everyone, thank you, Eric, for hosting us this morning at the JP Morgan conference. It is invigorating to be able to see everyone in person, it's a little bit wet to be running outside. We're really pleased to be able to update everybody on the progress that Karyopharm has made in the last year and our plans moving forward to continue to generate value for patients and shareholders. You know, as Eric mentioned, joining me today is going to be Dr. Reshma Rangwala, who's our Chief Medical Officer, and also for the Q&A portion, we'll have Sohanya Cheng, who is our Chief Commercial Officer, and Mike Mason, who's our Chief Financial Officer. Before we get started, a little housekeeping.
I'd like to remind you that various remarks we do make today will constitute forward-looking statements. Please refer to our most recent 10-Q. Now, Karyopharm was founded in 2008 as an innovation and patient-focused company to deliver on the promise of the selective inhibition of nuclear export as a foundational mechanism to treat cancer. If you fast-forward to today, Karyopharm is approved in multiple myeloma and DLBCL in 40 countries around the world. With our increasing utilization in earlier lines of multiple myeloma, in 2022, we delivered approximately $158 million in total revenue, which is within our range of guidance. We are strongly positioned for our next phase of growth with a focused clinical pipeline and multiple phase III programs.
Phase III programs in multiple myeloma, in endometrial cancer, a soon-to-start phase III program in myelofibrosis. We have a strengthened cash position through being very disciplined and focused in advancing our pipeline and through our recent financing with existing shareholders and new investors. We've strengthened our financial position with a cash runway through to late 2025 to enable us to deliver on the key milestones we have in front of us, advance our pipeline as we work to create value for patients and shareholders. Just wanna touch on some key accomplishments in 2022, as we had a very productive year in 2022. In the U.S., within a very competitive multiple myeloma market, we grew sales 22% to $120.4 million, which is at the lower end of our guidance.
We initiated another phase III trial in multiple myeloma, which is XPd, an all-oral opportunity in the relapsed refractory multiple myeloma setting. In endometrial cancer, we're very excited to be moving forward with our phase III study and leveraging the substantial benefit that we've observed in selinexor in patients whose tumors are TP53 wild-type within endometrial cancer. An exciting partnership with Foundation Medicine that'll enable us to develop a companion diagnostic for these women. In myelofibrosis, we're very encouraged by the preliminary results we've observed from our phase I study across the three relevant domains, including SVR35, TSS50, and hemoglobin stabilization. Finally, in high-risk MDS, we're excited to be advancing our second novel SINE compound, eltanexor.
We're advancing this right now in a population with a very high unmet need, and we're looking forward to seeing the results of our interim analysis in the near future. If I step back and look at multiple myeloma, ixabepilone is a novel class of therapy. It's a convenient oral serving an unmet need in the second to fourth line of multiple myeloma, and it's combinable with a number of different agents. In the first lines of therapy, you have the three big classes being used, IMiDs, PIs, and anti-CD38s. Towards later lines of therapy, in the fifth line plus, you're seeing the emergence of T-cell redirecting therapy. There really is no standard of care in that second to fourth line, and it's in this space where we see selinexor providing the greatest opportunity for patients to benefit from the multiple classes of therapy in multiple myeloma.
In particular, we've been able to generate a strong body of evidence to show the efficacy we have post-anti-CD38, and we're seeing increasing utilization in that second to fourth line. In addition, this year, we're gonna be creating a strong body of evidence to show the benefit that selinexor can bring before T-cell-engaging therapies to ensure patients can get the greatest benefit from novel new therapies coming in the later lines of therapy. We want to ensure we enable patients to benefit from the multiple classes of therapy as we continue to prove outcomes for patients across the multiple myeloma journey.
If we look specifically at our revenue in 2022, we grew ixabepilone 22%, as I mentioned, the lower end of the range of our guidance, despite increased competition in the academic setting, in the late line setting, with new therapies coming to place and specifically the commercial launch of a new BCMA therapy in December and the expanded use of CAR-T therapies in later lines. Our focus remains on expanding the use of ixabepilone in the community setting, which contributed to over 70% of our business in Q4. In addition, we continue to make strong progress on moving ixabepilone into those earlier lines that I mentioned, the second to fourth line, with now approximately 55% of our patients treated in the second to fourth line.
In the second to fourth line, we're seeing patients have longer duration of therapy, which is what we'd expect in earlier lines. We also continue to see a positive shift in the perception of XPOVIO in the second to fourth line through our intent to prescribe metrics, as physicians are gaining confidence in managing patients at the lower dose of selinexor. Looking ahead to this year in 2023, we expect to deliver double-digit growth and will provide specific sales guidance on our Q4 call. Globally, as we look at how do we leverage our approvals in 40 countries around the world with our partners, we're excited to see the launch sequence continue to move forward as our partners work through the reimbursement sequence in a multitude of countries, and we'll see increasing royalty adding to our total revenue globally.
With that, I'd like to turn it to Dr. Reshma Wangwala to take us through our mechanism of action and our exciting and focused pipeline. Reshma?
Thank you, Richard. The nuclear pore is a very complex gate. The influx and efflux of proteins across this nucleus and cytoplasm are regulated by a number of different proteins, including the nuclear export proteins. The best characterized of these nuclear export proteins is known as Exportin 1 or XPO1. We know that inhibition of XPO1 ultimately leads to reduced proliferation and increased apoptosis of cancer cells. That ultimate goal is achieved through three main mechanisms, including increasing nuclear levels of tumor suppressor proteins, enabling their further activation. In addition, it traps oncoprotein mRNA within the nucleus, leading to reduced oncoprotein levels. Third, it retains activated glucocorticoid receptors within the nucleus, leading to altered expression of these genes ultimately involved in the inflammatory pathway. Karyopharm is currently developing two novel SINE compounds. SINE refers to selective inhibitors of nuclear export.
Both of these compounds are oral selective inhibitors of XPO1. As Richard mentioned, selinexor is our first novel XPO1 inhibitor. It's approved in multiple indications, including multiple myeloma as well as diffuse large B-cell, and is currently in active developing in multiple solid as well as hematologic malignancies. eltanexor is our second novel XPO1 inhibitor. It's an investigational compound we're currently developing in myelodysplastic neoplasms. It differentiates from selinexor by two key features. One, it crosses the blood-brain barrier at a lower level. It also has a lower IC50 that facilitates more chronic dosing of this compound. Karyopharm's focused pipeline is evaluating both selinexor and eltanexor in that mid to late stage development stage. We are targeting multiple cancers of high unmet need, including myelofibrosis, myelodysplastic neoplasms, endometrial cancer, and also multiple myeloma. Through these programs, we are also rapidly optimizing the dose of selinexor.
Since XPOVIO was first approved in 2019, we have utilized real-world evidence coupled with our observations from our clinical trials to demonstrate that lower doses of selinexor can optimize the patient benefit by improving its tolerability. By improving tolerability, we allow patients to remain on therapies longer, ultimately improving their overall benefit. As a result, all of our ongoing clinical trials incorporate selinexor doses at 40 mg or 60 mg once weekly, which is a quarter to a less than half of the original approved dose of 80 mg twice weekly. With that said, I'm now gonna transition to endometrial cancer. Richard mentioned, we were very excited to announce in November the initiation of a phase III trial evaluating selinexor as a maintenance therapy in patients who are TP53 wild-type endometrial cancer.
The EC-042 is a global phase III randomized double blind trial that again, is evaluating selinexor as a maintenance therapy in women whose tumors are TP53 wild-type. A total of 220 patients are planned to be enrolled. These patients will be randomized in a 1:1 ratio to either selinexor at the 60-mg weekly dose or placebo. The primary endpoint of this trial will be progression-free survival as assessed by the investigator with the key secondary endpoint of overall survival. We look forward to updating top-line results in the second half of 2024. The rationale for this study is further provided in this updated subgroup analysis that we just released earlier this week.
In this updated exploratory analysis from the SIENDO trial, we now observe a progression-free survival for selinexor-treated patients at 21 months, compared to only 5.2 months observed in the placebo arm. The safety profile has not changed. These data suggest a potential for a significant paradigm shift for treatment of women with advanced or recurrent TP53 wild-type endometrial cancer and represents a large market opportunity given that P53 wild-type is identified in approximately 50% of all endometrial cancer patients. With that, let's now transition to our myelofibrosis program. Selinexor also has the potential to improve patient outcomes with patients who suffer from this devastating disease. Myelofibrosis causes multiple side effects and downstream impacts due to a bone marrow fibrosis that occurs amongst these patients. That fibrosis ultimately leads to cytopenias, enlarged spleen, as well as multiple constitutional symptoms.
The only therapies that have been developed for patients with myelofibrosis are the JAK inhibitors. Jakafi or ruxolitinib is the standard of care for the treatment of treatment-naive myelofibrosis patients. Unfortunately, less than half of these patients will respond to these therapies, and response durations are quite limited. When those patients ultimately become refractory or relapse from Jakafi, unfortunately, median survival is very short at only about 14 months. Selinexor has the potential to improve current standard of care in myelofibrosis by decreasing spleen size, improving constitutional symptoms, and improving hemoglobin and anemia. The mechanism by which selinexor can facilitate improvement across all of these relevant endpoints is because selinexor targets multiple downstream effectors from the JAK pathway, including Akt, as well as the ERK pathways, as well as multiple XPO1 cargo proteins.
This broad multiple mechanisms potentially facilitate selinexor as a monotherapy as well as potential synergistic activity when combined with the JAK inhibitors. We are currently evaluating the safety and efficacy of selinexor in combination with ruxolitinib in our ongoing phase I study, XPORT-MF-034. This phase I study included a phase I-A dose escalation in which we evaluated selinexor at two different doses, the 40 mg and 60 mg, again in combination with ruxolitinib in treatment-naive myelofibrosis. No DLTs were observed. We enrolled an additional 18 patients as part of the phase I-B dose expansion. In total, 24 patients were enrolled as part of this phase I-A. The primary endpoints of this phase I-A are maximum tolerated dose, safety, and tolerability, as well as identification of the recommended phase II dose.
We have multiple secondary endpoints, including efficacy parameters of SVR35, TSS50, overall survival, as well as anemia response and hemoglobin stabilization. We had an opportunity to present updated preliminary week 24 data recently at ASH last month. What we observed in this updated assessment was that spleen volume response or SVR35 was achieved in 92% of evaluable patients or 11 out of 12 assessed at week 24. In fact, 100% all patients achieved that SVR35 at any point. In addition, we observed 67% or four out of six patients achieved a TSS50 response at week 24. I'll note here that the six patients that were included as part of this TSS50 analysis were those patients that completed a symptom evaluation score. The other six patients remain on therapy.
While they did not complete a symptom evaluation score, their symptoms are included as part of the medical chart, and those data will be updated at a future medical congress. Lastly, we also saw very meaningful impacts on hemoglobin levels, with 57% of patients either maintaining their hemoglobin levels or improving relative to baseline. All of these endpoints, SVR, TSS50, and hemoglobin improvements, were observed in the context of a safe and tolerable side effect profile. This waterfall plot here shows the impressive decrease in the patients' spleens relative to baseline. Again, at week 24, all patients' spleens decreased relative to baseline, with 11 out of 12 achieving that 35% or greater threshold. As further support of these phase I combination data, we recently performed a subgroup analysis.
This subgroup included seven patients whose ruxolitinib doses were reduced to 5 mg or lower as early as cycle 1. 5 mg, if you look at the literature, really is a very subtherapeutic dose. There's no meaningful improvement in spleen volume reduction or symptom scores at that dose level. Despite that reduction in that ruxolitinib, again to 5 mg, what we observed is very meaningful improvement in spleen as well as symptom score. In fact, if you look at the five patients who are evaluable for SVR at week 24, all patients achieved a 35% or greater reduction. Similarly, if you look at the total symptom score reduction, again, all patients achieved a very meaningful improvement in their symptoms relative to baseline. We have previously provided an update on the ESSENTIAL study.
These data suggest that selinexor has monotherapy activity, especially in that hard-to-treat, relapsed, or refractory patient population. In this study, we observed a 30% SVR35 at week 24, climbs up to 40% when you look at week 24 and beyond. If you aggregate the data from our combination study of 034, the subgroup analysis, as well as the ESSENTIAL study, it suggests that selinexor and XPO1 inhibition specifically is a potential foundational mechanism within myelofibrosis and suggests that selinexor can be broadly developed in this treatment-naive myelofibrosis using novel add-on approaches as well as novel combinations. With that said, I'll lastly touch upon myelodysplastic neoplasms. Here again, a very high unmet need area. Patients with myelodysplastic neoplasms unfortunately suffer from devastating cytopenias. The standard of care in treatment-naive myelodysplastic neoplasms are the hypomethylating agents or the HMAs.
There is no standard of care, unfortunately, for patients who relapse or become refractory to these HMAs. The median overall survival for high-risk relapsed refractory MDS is very short at only 4-6 months. We've previously presented overall survival data from a phase I cohort evaluating Eltanexor as a monotherapy in this high-risk relapsed refractory MDS. In this cohort, a median overall survival of 10 months was observed. We have an ongoing study. This is a phase II expansion, again, evaluating Eltanexor as a monotherapy in this high-risk relapsed refractory MDS patient population. We've completed enrollment as part of the interim analysis and look forward to updating efficacy as well as safety later this quarter. With that, I'll hand it back to Richard.
Thanks, Reshma. As I mentioned earlier, given our very focused and disciplined approach to advancing our pipeline and with our recent financing, we ended the year in a very strong financial position with cash equivalents of $279 million and a cash runway through to late 2025. That cash runway will enable us to deliver on the key milestones we have in front of us. As everyone at Karyopharm works to deliver on our next phase of growth, we're excited about our upcoming milestones and the opportunity to create value for patients and shareholders. With that, I'll turn it back to you, Eric, for the Q&A portion.
Great. Thanks for that presentation, Richard. Yeah. Start off with questions. For those who have, please just look out for some of the, excuse me, the circulating microphones. Mike, do you wanna come up?
Yeah.
Okay. I thought it might be worth following up on the updated data from the SIENDO study. Look, the PFS update that you're presenting here from the SIENDO study.
Sure.
maybe just kinda put that data set sort of in broader context and maybe just talk a little bit about sort of the utility of TP53 as a prognosis marker currently in endometrial cancer.
Yeah. Absolutely. Great question. If you step back and look at the NCCN guidelines, there are no maintenance options for patients with endometrial cancer, specifically in that recurrent or advanced state. Those patients are treated with a finite number of chemotherapy cycles, usually 4- 6 cycles. At the completion of those 4- 6 cycles, and again, it really is a watch and wait. Progression-free survival for those patients is very short at approximately five months. Overall survival is also very short. There really is a high unmet need opportunity to develop a maintenance option to improve PFS and ultimately overall survival for these patients. When we look at P53, it's a very important marker with patients with endometrial cancer.
No company, no therapy has been able to leverage that p53 status in endometrial cancer, which is why, we are so excited about our data in which patients who are p53 treated with Selinexor now have a median progression-free survival of 21 months. Unprecedented in this patient population of high unmet need. If you look at the prognosis from a prognostic standpoint, patients who are p53 are, you know, mildly negatively prognostic, but we really don't see any kind of meaningful difference between patients who are p53 wild-type or mutant when you look at the overall population.
in terms of Well, any difference in the or evolution in mean dose intensity in this longer term data cut?
Yes. Great question. You know, you'll notice in this ongoing trial, we are evaluating selinexor at the 60 mg dose as compared to the 80 mg dose that was evaluated in SIENDO. You know, we identified that 60 mg dose as one that can optimize the benefit risk. This is an ongoing effort that we are doing across all of our programs. We looked at clinical data as well as pharmacokinetic data. We're confident that that 60 mg dose can again optimize the benefit that we see within this trial.
Okay.
Eric.
All right. Yes.
Sorry, can I just follow up on your question?
Sure.
What is the rationale for why the p53 wild-type works so much better with the XPO1?
Yeah, a great question. XPO1 inhibitors, one of the mechanisms that it enables is the retention of the tumor suppressor within the nucleus. The fact that you see greater efficacy in that subgroup for P53 wild-type enables that P53 wild-type tumor suppressor to exert additional antitumor activity. If you look at the subgroup who are mutant or aberrant, therefore, their P53 doesn't work, we see no benefit with selinexor. In that subgroup, which comprises approximately 50% of the patients, the benefit that we saw with selinexor, again, median PFS, is very similar to the placebo arm. It really does demonstrate and, you know, correlate with that strong mechanistic rationale by which XPO1 exerts its antitumor activity.
If I went back and looked at the original SIENDO data.
Yeah.
This is just mechanistically pulling out the half who are p53 mutant. Is there any other...
Yeah.
adjustments to the ITT?
Great question. In the original SIENDO trial, we enrolled all patients, regardless of p53 status. We then looked just at that subgroup who are p53 wild-type. We looked at the efficacy in the p53 wild-type subgroup and in the p53 mutant or aberrant subgroup. At that original cut, what we observed was a median progression-free survival in the p53-treated patients of 13.7 months. In the mutant aberrant, again, there was no difference in the median PFS across the two arms. In this updated data cut, we now show that the median PFS has increased from 13.7 months to now 21 months.
Yeah, how did the median go up? Like, I can see how the total went up, but there isn't Once the medians hit, how did it re-change?
We still have patients on therapy and who have not achieved or have not had a progression event yet. That study is still very much ongoing, and we're continuing to evaluate the patient's progression-free survival as well as overall survival. Because patients are staying on therapy, they have not seen that progression event. We're seeing a longer median PFS.
Is there a regulatory strategy because it wasn't a predefined endpoint for the p53 wild-type group or can you get a label for p53 wild-type endometrial?
Not from the SIENDO trial, which is why we have initiated this ongoing EC-042 trial. This EC-042 will enable the registration of selinexor in p53 wild-type, and contemporaneous with the drug approval is gonna be that companion diagnostic approval. We do anticipate, again, both selinexor as well as P53 that's gonna be facilitated by Foundation Medicine to come hand in hand.
Right now, though, are endometrial people patients subtyped for TP53 status?
Yeah, great question. They are. In endometrial cancer, actually across multiple different tumors, P53 status is being assessed. NGS is probably the most robust method by which to assess the P53 status, and it's the method that we are using in our ongoing EC-042 study. With that said, there really are not therapies, right, that are actionable against that P53. Again, it's studied, but there are no therapies available for those patients who are P53 wild type.
While you're doing the new phase III, is there a way to get this, published trial on NCCN guidelines?
Hopefully, yeah. We look forward to, you know, updating these data at a future medical congress, and potentially, you know, hopefully it'll be incorporated into the NCCN as well.
Thanks.
Can you just talk a little about the enrollment experience in the EC-042 study to date? Maybe just sort of how that contrasts with the SIENDO experience. I imagine you're using a, you know, similar sites and centers. Yeah, I'll leave the question.
Yeah. No, great question. I think we're able to incorporate, you know, sort of the best learnings from SIENDO into this EC-042. In the SIENDO trial, we had approximately 100 sites enrolling both in the U.S. as well as the European as well as the E.U. We were able to identify, you know, the highest enrolling sites from SIENDO. Those will be participating in our ongoing EC-042 study. In addition, we have added additional sites. In total about 140 sites from 12-15 countries will be participating in this trial.
Any interim analyses that are built into the study design and statistical protocol analysis?
We do. We have an interim analysis, at this time, only the DSMB is gonna be made aware of the unblinded results. We anticipate providing, you know, top-line results from the entire study, in that second half of 2024.
I see. Any expectation around when the study will fully accrue?
Haven't provided guidance on that one yet. Yeah.
Maybe just pivoting to the myelofibrosis program. Can you just talk a little bit about sort of what factors will ultimately inform a dose selection as part of the phase III-program based on the activity and tolerability profile that you're assessing currently.
Yeah, absolutely. You know, we're taking a comprehensive approach to identifying the recommended phase II dose from the phase I. Of course, looking at the clinical data, specifically at the safety as well as the efficacy at week 24, which is the time point, you know, from a regulatory standpoint, that SVR and TSS50 are assessed, but of course, overlaying those clinical data with pharmacokinetic data too. You know, ultimately leveraging safety, efficacy, and PK data to inform on that dose.
Uh, uh, and .
Sure.
Just that obviously the myelofibrosis data is really interesting. Are you thinking that eventually you can get it to where this is a first-line treatment with Rux?
Yeah, absolutely. The phase I data that I presented, maybe we can move to that slide. That 92% SVR, the 67% TSS50, and the 57% who achieved that hemoglobin stabilization, all of those patients were treatment naive. They had never been treated with a prior JAK inhibitor. Again, in this trial, we were evaluating the efficacy and safety from a combination standpoint, selinexor plus ruxolitinib. We plan to expand, you know, our evaluation as part of a phase III trial. We'll be looking at the combination of selinexor plus Rux at the recommended phase II dose, compare the efficacy and safety to Rux alone, which will facilitate, hopefully registration with that combination in that treatment-naive myelofibrosis population.
I mean, Rux has pretty long-term outcomes data in order to kind of change the paradigm. Is it enough just to get these kind of biomarkers and unfair thing, is this like long-term clinical outcomes strong enough to be a combination in front line or?
Yeah, great question. I think so right now. You know, I mean, from the regulatory standpoint, you know, some of the key endpoints still remain SVR and TSS50. To your point, we also will be looking at overall survival too. These patients, similar to SIENDO as well as our EC-042, will follow these patients all the way until that survival endpoint is analyzed.
Do you ultimately see a place for selinexor monotherapy in the treatment landscape for myelofibrosis? I know you had a phase II program, I believe, evaluating monotherapy. Where does that currently stand, and ultimately, how does mono, you know, monotherapy fit into life cycle management within myelofibrosis?
Yeah, great question. You know, we've now got multiple different data sets to ultimately inform on the best development opportunities for Selinexor. Again, we have very intriguing preliminary data from the combination, again, in treatment-naive. We also have this very intriguing subgroup analysis from that same phase I, also evidence of monotherapy activity in that relapsed refractory. Those data suggest that there is potential for monotherapy activity with Selinexor, but also potential synergism in combination with the JAK inhibitors. Given its mechanism, it potentially could synergize with other mechanisms that have been identified in myelofibrosis. We believe that the greatest benefit really is in that treatment-naive myelofibrosis. With these data, I think we have an opportunity to optimize our development plan.
As a result, you know, we have put 035 on pause in order to facilitate that optimized development plan that we hope to, you know, provide an update in the first half of this year.
Okay. All right. Well, if there are no further questions, I think we might leave it there for time. Thanks very much, Richard. Thanks.
Great.
Excuse me. Rich.
Yeah.
Sorry. The Karyopharm team for presenting this morning. Really appreciate your time.
Great. Thank you.