Karyopharm Therapeutics Inc. (KPTI) Earnings Call Transcript & Summary

Good afternoon. I'm Eric Joseph, senior biotech analyst with JPMorgan. Our next presenting company is Karyopharm Therapeutics and presenting on behalf of the company to start us out, is CEO, Richard Paulson. There's a Q&A after the presentation. Just raise your hand, we'll bring mics around. And folks tuning in via the webcast, you can also submit questions through the portal. So with that, Richard, thanks for joining us.

Thank you, Eric, and thank you to JPMorgan for hosting us today. I'll be joined in the presentation by our Chief Medical Officer, Reshma Rangwala. And then as we [indiscernible] Q&A, we'll also have our Chief Commercial Officer, Sohanya Cheng join us. Just a little housekeeping before we begin. I'd like to remind you various remarks we make today, will constitute forward-looking statements for purposes of safe harbor provisions under the Private Securities and Litigation Reform Act of 1995 as you can read in detail on this slide. It's an exciting time at Karyopharm today as Karyopharm has had a turning point in its 15-year history with 3 ongoing late-stage trials enabled by a growing body of unprecedented data in solid and hematological malignancies that will read out over the next 2 years. And these trials will potentially create new standards of care for patients and provide significant value creation opportunities in a short period of time as we believe selinexor could create approximately $2 billion of annual peak revenue with these indications alone. To deliver our next stage of growth, our top priority is to drive this late-stage pipeline forward. We are doing this by concentrating our investments into these pivotal programs and leveraging our existing multi-myeloma franchise, which is anchored around our commercial drug, XPOVIO that's now approved in over 40 countries, generating brand profitability and growing experience with physicians. In 2023, we achieved total revenue of approximately $146 million, delivering within our updated range of guidance and through ongoing disciplined expense management and our decision to put our eltanexor development program on hold, we have an expected cash runway into late 2025, to deliver data readouts from each of these Phase III programs. And presented here is an overview of those programs and the timing of the key data readouts, which we expect in 2024 and 2025. Each of our ongoing Phase III clinical trials, if successful, represents an incredibly meaningful opportunity for us to grow our organization and to deliver incremental care to patients. The clinical data that Reshma will review today highlights that and shows the continued strength and confidence we have in each of these programs. Now selinexor is a novel class of therapy and for relapsed/refractory multiple myeloma, we are distinctly positioning it in both the community and academic settings. In the community setting, the majority of physicians tend to treat earlier line patients and are looking for agents that have a novel mechanism of action, are effective, manageable and convenient, which highlights the opportunity we have today but also the importance of the opportunities we have tomorrow with SPd, the ongoing Phase III trial, which is designed to further enhance XPOVIO's [indiscernible] the needs of the community, especially in the second to fourth line, enabling an effective and convenient all oral class switch. For the academic setting, we're building a body of evidence around the effectiveness of XPOVIO pre- and post T-cell engaging therapies to enable future and further uptake in the rapidly evolving and highly competitive academic setting. For 2023, we delivered $112 million of XPOVIO net revenue within our current guidance range. And for the fourth quarter, we delivered $25 million in XPOVIO net revenue. The commercial team continues to drive demand in the community setting, which represents 2/3 of our business, working to offset the decline in the academic setting amidst significantly increased competition and pressure in the late lines. In 2023, Foundation closures resulted in increased patient assistance program utilization, which led to roughly a $6 million impact. IRA-related changes in 2024, will significantly lower the need for Medicare Part D patients to utilize PAP co-pay assistance moving forward. Now as multiple myeloma patients are living longer with the emergence of new classes of therapy, XPOVIO represents an opportunity for these patients to be treated with an effective and novel class of therapy. Our teams are resilient and highly engaged to ensure continued awareness and use of XPOVIO in multiple myeloma for appropriate patients, while preparing for greater growth opportunities and the potential future launches over the next 2 years. Globally, selinexor is now approved in over 40 countries. And in late 2023, reimbursement and pricing was obtained in Mainland China by our partners, and we expect continued further launches through 2024. And now I'd like to turn it to Reshma, who will discuss our unique mechanism of action and our evolving pipeline. Reshma?

Thank you, Richard. The [indiscernible] regulates the export of most large molecules out of the nucleus and into the cytoplasm. Many of these molecules do include large proteins. In humans, the best characterized nuclear export protein is exportin 1 or XPO1. XPO1 inhibitors have a multifactorial mechanism by which they reduce proliferation and increase apoptosis, including by increasing nuclear levels of tumor suppressor proteins as well as their activation, trapping oncoprotein mRNA in the nucleus, leading to reduced oncoprotein levels, and lastly, by retaining activated glucocorticoid receptors in the nucleus, leading to altered expression of genes involved in inflammatory pathways. Currently, we have 2 differentiated but complementary novel XPO1 inhibitors, including selinexor or XPOVIO as well as eltanexor. Our focus is currently on selinexor currently being evaluated across multiple cancers of high unmet need, including myelofibrosis, endometrial cancer as well as multiple myeloma. This promising late-stage pipeline with 3 Phase III studies that are currently ongoing are expected to yield pivotal data readouts later this year as well as in 2025. Our confidence in these pivotal trials has only grown given the positively evolving preclinical as well as clinical data that support each one of these indications. Each of these trials can position selinexor to substantially change the treatment paradigms in each of these populations if ultimately approved. In addition, we have added 2 Phase II trials, one in myelofibrosis and the second in multiple myeloma. The Phase II selinexor monotherapy trial, which is planned to initiate later this year, will be evaluating selinexor as a monotherapy in treatment-naive myelofibrosis patients with moderate thrombocytopenia. We believe that these data in conjunction with the ongoing Phase III trial evaluating selinexor in combination with ruxolitinib has the potential to embed solinexor as a foundational therapy in approximately 90% of treatment-naive myelofibrosis patients. We have also entered into a collaboration with Bristol-Myers Squibb to evaluate selinexor plus mezigdomide, an oral novel [indiscernible] therapy currently in development in triple exposed multiple myeloma patients. This combination has the potential to reverse T cell resistance and builds upon the multiple selinexor combinations that have already demonstrated promising efficacy data in multiple myeloma. Through these programs, we are also rapidly optimizing the dose of selinexor. All of our ongoing clinical trials incorporate selinexor doses at 40 or 60 milligrams dosed weekly, which is a quarter to less than half of the original approved dose of 80 milligrams twice weekly. Now let's turn our attention to endometrial cancer. There's a paradigm shift underway for the treatment of women with advanced or recurrent endometrial cancer. The most common form of gynecologic malignancy in the United States with increasing use of molecular classifications to drive treatment options. TP53 wild type represents a potentially unique but fundamental biomarker in endometrial cancer. Today, MMR deficient patients represent approximately 20% of all advanced recurrent endometrial cancer. There is a new FDA-approved standard for this population with dostarlimab, an anti-PD-1 therapy that is approved in combination with chemotherapy followed by dostarlimab maintenance. For MMR proficient patients, they do not have a new standard of care. They represent approximately 80% of all endometrial cancer patients. Unfortunately, their treatment continues to remain Carbo/Taxol for a fixed number of cycles followed by watch and wait. Importantly, wild-type p53 is found in a majority of advanced recurrent endometrial cancer tumors. Taken together, patients whose tumors are both MMR proficient as well as p53 wild type, represent approximately 40% to 55% of all advanced or recurrent endometrial cancer patients. We had an opportunity to present long-term follow-up data from the SIENDO trial, which evaluated selinexor as a maintenance therapy and thus after completion of chemotherapy in patients with advanced recurrent endometrial cancer. These data demonstrated a median PFS for the selinexor arm of 27.4 months compared to only 5 months in those patients receiving placebo, ultimately translating to a hazard ratio of 0.41. These robust subgroup data demonstrate the substantial benefit in this unique but sizable population defined by their p53 status, which directly ties to selinexor's mechanism of action, given that XPO1 inhibition retains p53 wild type within the nucleus, thus enhancing cell kill. In the pMMR subpopulation, the benefit observed with selinexor is even more impressive with a hazard ratio of 0.32 and a median PFS that still has not been reached. The PFS results observed in those patients who are p53 wild type and MMR deficient are also noteworthy with a median PFS for selinexor 13 months and a hazard ratio of 0.45. The preliminary overall survival data was presented at IGCS meeting last November in Seoul, Korea. In the TP53 wild-type exploratory subgroup in the SIENDO data, we found a hazard ratio of 0.76. In those patients who are both p53 wild-type and MMR proficient, the hazard ratio only decreases to 0.57. In both of these groups, the median overall survival have still not been reached. We are very encouraged about these preliminary overall survival and updated PFS results in the p53 wild-type subpopulation from the SIENDO trial. I believe these efficacy data, coupled with the tolerable side-effect profile suggests that oral selinexor is uniquely positioned as an optimal maintenance therapy where convenience, tolerability and meaningful efficacy are the hallmarks of a maintenance option. In fact, some of our patients are now reaching their fourth year on therapy, and I'm excited to present additional follow-up trial from this trial later this year. The EC-042 pivotal Phase III trial will enroll approximately 220 patients whose tumors are p53 wild-type. Ultimately, this trial will enable the development of a companion diagnostic, and we anticipate the approval of a companion diagnostic would occur at the same time as selinexor, if approved. The study is a collaboration between Karyopharm, ENGOT and the GOG, the latter which are top cooperative groups and include the top KOLs within gynecology oncology. We look forward to presenting top line results in the first half of 2025. Let's now take a closer look at myelofibrosis. Treatment of JAK-naive myelofibrosis patients remains an area of high unmet need with more than 20,000 myelofibrosis patients in the U.S. alone. Ruxolitinib remains the standard of care for the majority of JAK-naive patients. However, there is an opportunity to improve benefit given that the efficacy with ruxolitinib remains limited, given that only approximately 35% of patients achieved an SVR35. This is important given that spleen volume reduction is correlated with overall survival. We are evaluating the potential for selinexor in combination with ruxolitinib to provide benefit across all of the hallmarks of this disease, which includes spleen reduction, symptom improvement, disease modification as well as stabilization, if not improvement of cytopenias. XPO1 is a fundamental mechanism in myelofibrosis, given that it targets both the JAK and non-JAK pathways, underscoring selinexor's additive or potentially synergistic activity when dosed in combination. The non-JAK mechanisms include inhibition of NF-kappa B, induction of cell cycle arrest, as well as P53 driven cell death. Together, XPO1 inhibition increases malignant cell death, decreases malignant cell proliferation and reduces inflammation. We presented updated data last year from our trial evaluating selinexor in combination with ruxolitinib in JAK-naive myelofibrosis patients, which showed a very meaningful SVR35 and TSS50 improvement with 60-milligram selinexor, including a 79% SVR35 and a 58% TSS 50% rate at week 24 in the intent-to-treat population. Importantly, amongst the evaluable patients, 100% of those patients achieved an SVR35 at any time. When we look at patients, the percentage of patients who achieved both an SVR35 and TSS50, we see that 50% of patients experienced both of these responses at week 24, and 75% experienced an SVR35 and TSS50 at any time. Albeit the numbers are small, these rates are the highest I have seen with a novel therapy currently in Phase III development in patients with JAK-naive myelofibrosis. Building upon these impressive data are the durability data. As of the most recent data cutoff, none of the week 24 SVR35 responders dosed at selinexor 60 milligrams, had observed radiographic progressions. And none of the TSS50 responders at week 24, had observed symptom progressions. While I acknowledge the apparent limitations and cross-trial comparisons, contrast these data to ruxolitinib alone, in which only approximately 70% of responses were ongoing at 78 weeks. Together, these data illustrate the rapid, deep and now durable spleen and symptom improvement achieved with selinexor in combination with ruxolitinib and further demonstrate the potential for this combination to change treatment paradigms for JAK-naive myelofibrosis patients. This profile in conjunction with this subgroup analysis, indicate SVR35 and TSS50 responses despite treatment with suboptimal doses of ruxolitinib are suggestive of potential monotherapy activity. We also observed very important stabilization in the hemoglobin levels of patients on the selinexor 60-milligrams dose level when dosed in combination with ruxolitinib, which is further suggestive of disease modification. This trend is unique with the addition of selinexor, given that with ruxolitinib alone, hemoglobin levels drop after treatment initiation and tend to stay low. The biomarker analysis from this Phase I study is also suggestive of disease modification, rapid and sustained reduction as early as week 4 has been observed in multiple cytokines evaluated from the study. Although not presented on this slide, data also indicate that more profound cytokine reduction is seen with selinexor 60 milligrams as compared to 40 milligrams. All of these data combined underscore our confidence in the ongoing Phase III trial, which is evaluating the combination of selinexor 60 milligrams with ruxolitinib versus ruxolitinib alone in approximately 300 JAK-naive myelofibrosis patients. We see a high level of excitement from investigators for our data and the study. Now let's turn to multiple myeloma. We are expanding our multiple myeloma franchise with the ongoing Phase III trial that is evaluating selinexor at the low dose of 40 milligrams in combination with a well-established backbone therapy of pomalidomide and dexamethasone post anti-CD38, which will ultimately drive earlier use. Selinexor 40 milligrams in combination with pom-dex has been evaluated in a cohort of relapsed refractory multiple myeloma patients and an impressive median PFS of 18.4 months has been observed. This all-oral combination has the potential to benefit a significant number of patients across the multiple myeloma treatment journey. The Phase III trial is enrolling patients with relapsed refractory multiple myeloma, who have received an anti-CD38 as part of their most recent therapy. Approximately 220 patients will be randomized to either the oral regimen of selinexor, pom-dex or elotuzumab/pom/dex. In summary, we have near-term late-stage opportunities supported by compelling data in our rapidly advancing pipeline that will potentially benefit multiple cancer patient populations of high unmet need, building on our approved indications. With that, I'll now turn it back to Richard.

Thank you, Reshma. So in closing, with $192 million in cash and equivalents at the end of 2023, we have a projected cash runway into late 2025, putting us in a solid financial position to deliver on our Phase III clinical trials. We're excited about our innovation and growth strategy with Phase III clinical trials in multiple myeloma, endometrial cancer and myelofibrosis, each of which would be transformative for patients and our organization. With data expected in multiple myeloma in the second half of this year and in endometrial cancer in the first half of 2025, the next 18 months are going to be an incredibly exciting time for our organization. We're focused on accelerating momentum as we look to deliver on the next phase of growth and our people continue to strive each and every day for patients with high unmet needs as we work to generate value for patients and shareholders. So thank you again for joining us today, and let's open it up for the questions.

All right. Great. So I can start up by way of Q&A. First question really is just around ahead of additional life cycle expansion opportunities ongoing. With [indiscernible] in this back half of the year, I guess how should we be thinking about the core commercial strategy right now with XPOVIO in multiple myeloma? You kind of mentioned -- and we've heard physician feedback in this regard as well and kind of use as a bridge to CAR T. Is that something that you're sort of leaning into or -- I'll leave the question there. And just get your sense of sort of where you think the core opportunities are ahead of life cycle expansion opportunities?

Great. Thank you. So with our multiple myeloma business in 2024, we're working to grow our myeloma business. We're really focused in 3 areas. So the primary one is the community. And in 2023, 2/3 of our business came from the community. That's where 70% of myeloma patients tend to be treated. We increased our breadth in 2023 by 20%. So as we brought on new accounts in the community, we want to drive increased utilization there. We've also increased our depth in our top prescribing community accounts. So we want to accelerate our uptake there in the community. Also, an interesting trend that helps us is the anti-CD38 class is increasingly used upfront in the frontline and that opens up an opportunity in the second to fourth line for a novel mechanism of action that's an oral combinable option such as selinexor. Finally, in the community, we are armed with some new data and NCCN Guideline updates in the second half of last year, the NCCN elevated us to preferred and Category 1. We also came out with new PI naive data, which essentially shows a tripling of our PFS versus the control 30 months of PFS for a patient that potentially progresses from a regimen like DRD, again, [indiscernible] regimens growing in the front line opens that opportunity for us in the community in the second line. The second area of growth for us is the shift of the patient mix into earlier lines. We made tremendous progress on that in 2023, about a 30% increase in the proportion of patients in the second to fourth line. So about 70% of our XPOVIO new starts are in the second or fourth line. The reason this is important is you see the benefit of the duration increase. So we're seeing an upward trend in the patient's weeks on therapy. The last area of growth for us is building that body of evidence, the data to build upon the foundation of data that we already have. So firstly, SPd, our Phase III study, an all-oral community-friendly potentially cell sparing regimen. Secondly, our selinexor/mezigdomide combination in partnership with BMS, again, another all-oral potentially T cell sparing option out there. Finally, we're generating more data pre- and post T-cell therapy. So we're building the body of evidence. To answer your final question around the bridging in the academics, in the academics, highly competitive in the late-line setting. A couple of, I think, interesting things happening there. Obviously, last year, the bispecifics came in, new class, 3 new entrants into the late lines. We are seeing some use as we're building this body of evidence in the [indiscernible] bridging as well as in the post T-cell therapy space. And that will continue to rapidly evolve in the late lines.

Maybe just setting expectations for the SPd Phase III study. What -- what -- I guess, how would you frame expectations? What's the trial powered to detect in terms of benefit over the [indiscernible] alone? And -- yes, I'll leave the question -- really what benefit would -- do you think would be compelling and commercially competitive in the [indiscernible]?

Sure. So the Phase III is evaluating selinexor/pom-dex versus elo/pom-dex. The primary endpoint is going to be progression-free survival. So we don't usually disclose our powering assumptions. With that said, all of our Phase III trials are powered greater than 80%. And I think if you look at the data, especially around elo PD sort [indiscernible] in that post anti-CD38 setting, it really suggests that efficacy is quite marginal, about 5 to 6 months. What we see with our data with SPd is more than a doubling of that benefit where which from a clinician really find this very meaningful in that patient population.

I think from a commercial standpoint, again, being an all oral drug, it's currently listed on the NCCN but to be able to actively promote a low-dose [indiscernible] community, really is a catalyst for us to help strengthen our myeloma business.

Okay. And on endometrial, you're -- I mean, going by the size of the study, the data that you've generated, I believe, already in the original SIENDO trial of -- excuse me, PFS was standard of care, basically -- I would think the -- your Phase III study is perhaps over -- not overpowered, but very well powered at full enrollment to succeed. So I guess in guiding to data first half of next year, I guess how should we be thinking about -- you haven't yet completed enrollment there, if I understand correctly, is full enrollment required to perhaps solidify that readout expectation?

Sure. So no, we have not announced full enrollment for the trial. We anticipate being able to disclose full enrollment later this year. With that said, you're absolutely correct that the primary endpoint is progression-free survival. I mean based upon the data on the positively evolving data, we're very confident that we're going to show a very meaningful benefit in terms of PFS relative to the control arm. With that said, our key secondary endpoint is going to be overall survival. And so we do need a sufficient number of overall survival events in order to show that no detriment. So it's going to ultimately be sort of clinically and statistically meaningful PFS benefit, no detriment for overall survival in the context of a very tolerable safety profile. Those data, again, the top line results are anticipated in the first half of 2025.