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

Good day, everyone, and thank you for joining the H.C. Wainwright 25th Annual Global Investment Conference. My name is Steve [ Berce ], I'm an equity research associate here at H.C. Wainwright, and it is my pleasure to welcome Richard Paulson, President and Chief Executive Officer of Karyopharm Therapeutics; and Reshma Rangwala, Chief Medical Officer. So I'll turn it over to Richard Paulson.

Thanks, Steven. Thanks, H.C. Wainright for having us here today. We're pleased to be joining you and showing some more about the Karyopharm story. Just a little housekeeping before we begin. As you know, various comments we make today will be forward-looking statements, so please refer to our most recent 10-Q. So Karyopharm is an innovation and patient-focused company, which is passionately driven in the submission to positively impact patient's lives and defeat cancer. And we're an organization and that is a leader in the science of the selective inhibition nuclear export with our lead molecule selinexor, and multimyeloma is our foundation that we have built over the last few years. And as we look and talk to our story moving forward, we believe we are very strongly positioned for our next stage of growth, building on our multimyeloma foundation. Right now, selinexor is approved in over 40 countries around the world in multimyeloma and DLBCL. Total revenue expected for the year is $145 million to $160 million. And in our foundation of multimyeloma, we continue to drive uptake in earlier lines in multimyeloma therapy, and I'll touch on that in a few slides. So could our Q2 results, where we continue to drive year-over-year demand growth. Now as we move forward, we have a very focused and near-term clinical pipeline with 3 Phase III pivotal studies in multimyeloma and in endometrial cancer and in myelofibrosis. And Reshma will go into those. And what's very exciting about all 3 of those studies is we expect to have readouts on those studies in the '24 to '25 time frame, really setting us up, as I mentioned, for a very strong next stage of growth, and we have the financial strength to deliver on these 3 pivotal data readouts. Our cash position at the end of Q2 was $238 million. Also in August, we implemented a reduction in force of about 20% to further strengthen our cash position, enabling us to deliver on our programs with a cash runway into late 2025. And so if you look at the programs as we move forward, as I mentioned, today, we are focused on multimyeloma, and that's our current label in second-line plus enabling a class switch with a novel mechanism of action. As we move forward, we have 3 pivotal Phase IIIs, which combined together, give us the potential for U.S. revenue in excess of $2 billion. Each opportunity by itself is a significant opportunity. When you look at XPd on all oral, second line plus post anti-CD38, that data readout is expected in the second half and will enable us to continue driving sustained growth, the convenient all-oral option in multimyeloma. Next, if we look at endometrial cancer in patients whose tumors are TP53 wild type with endometrial cancer, we really have the opportunity to transform outcomes for these patients, and Reshma will go into that in more detail, especially as we continue to see our data positively evolving from our earlier SIENDO trial. This data we expect to read out in late 24, early '25 with our EC-042 trial. And then a myelofibrosis, a really exciting first-line trial in combination with ruxolitinib where we have the potential to transform first-line treatment with rapid, deep and sustained responses. So together, building on our current label, the potential to deliver over $2 billion in U.S. peak revenue. If we look at where we are today, today, we are very focused in multimyeloma, physician clearly in the second to fourth line with 3 key areas of focus. The first is in the community setting. We're post anti-CD38 in the second to fourth line. We have an opportunity to dramatically improve outcomes for patients through the very strong and continual improvement treatment outcomes that patients have in multimyeloma with a number of novel new classes where the importance of a novel mechanism of action, the importance of data post anti-CD38 and the importance of being able to combine with a product like Velcade, which is as well used and also with NCCN, other available combinations that physicians can look at. In the institutions or academic settings, we're clearly positioned also in a pre or post T-cell engaging therapies. And as we continue to see a number of these therapies come on board, we know it's incredibly important for patients and for physicians to continue to look at the treatment paradigm there and going in their journey the treatment paradigm, which again, we believe selinexor has the potential to offer significant benefit. And also, there's patients in institutions and academics who can't access or do not choose access T-cell therapy, more elderly and frail patients. Again, we believe selinexor has a significant opportunity. And as I mentioned earlier, moving forward with our Phase III trial, the all oral SPd will enable us to only strengthen our position in multimyeloma. And if we look kind of specifically our latest cube, we had delivered 9% demand growth in Q2 year-over-year. And within that demand growth, 2/3 of our revenue is now in the community setting. So we're seeing strong uptake in the community, which is what our strategy is and where we're focused on. And also, as you saw from the previous slide, where the majority of patients are. Now our revenue in Q2 was adversely affected by patient assistance programs, really free drugs, which has grown to about 14% versus last year in 2Q, it was about 5%. We do expect this to kind of normalize moving forward into next year as we see IRA-related changes to Part D beneficiaries and the elimination of the kind of 5% beneficiary copay. Also, if we look at the continued impact moving forward, we now see that in second to fourth line, over 60% of our new XPOVIO patients are in the second to fourth line with the fastest growth in the third line. We see our guidance for the year, which we reconfirm again of $110 million to $125 million for 2023. And building on top of that, again, is our opportunity globally where with approval in over 40 countries, we're continuing to move forward through the pricing and reimbursement cycles in these countries. And as we move forward, we have the opportunity for kind of royalties, double-digit milestones in the range of about $400 million over the future years. And we're excited to see our progress as we continue to launch globally and make selinexor available for more patients globally. So with that, I'll turn it to Reshma to really talk about our exciting pipeline that has potential for 3 readouts over the next couple of years. Reshma?

Yes. Thank you, Richard. So before we go into the pipeline, I just want to touch on the mechanism for both selinexor as well as eltanexor. So selinexor is XPOVIO, again, approved in multiple indications, including multiple myeloma as well as diffuse large B cell. We also have a second-generation compound known as eltanexor, both selinexor and eltanexor inhibit XP01 and are known as selective inhibitors of nuclear export. In general, their mechanism is very basic in that they inhibit the transport of proteins between the nucleus and the cytoplasm. And these proteins, by and large, include tumor suppressors as well as oncoproteins, again, fundamental tumor genesis and are at the foundation impact apoptosis as well as cellular proliferation. Given this fundamental mechanism and foundational mechanism, both selinexor and eltanexor may have the benefit -- may have benefit across multiple different cancers, including both hematologic as well as solid cancers. Given this foundational mechanism, we have an opportunity to really focus on a very prioritized pipeline. And you can see that prioritized pipeline on the slide here. So we have multiple programs, including the Phase III trials that Richard just mentioned, with selinexor in multiple myeloma in which we're evaluating selinexor in combination with pomalidomide and dexamethasone. We have a second Phase III trial in myelofibrosis specifically in JAK-naive myelofibrosis in combination with ruxolitinib and a third Phase III trial now in a solid cancer endometrial cancer, specifically in TP53 wild type. So again, it leverages our unique mechanism to be able to provide benefit across a wide array of different cancers. Our fourth program is specifically with eltanexor again, this is our second-generation compound, and we're evaluating this compound in a population of very high unmet need. This is our high-risk relapsed refracturing myelodysplastic neoplasm patient population. One of the areas that we've been aggressively focused on is optimizing the dose with selinexor. So when selinexor XPOVIA was first approved in 2019, the dose in combination with dexamethasone was 80 milligrams twice weekly or 160 milligrams weekly. While obviously, there was benefit with this dose in this very hard-to-treat patient population, we know that toxicity was aggressive. And what we've done over the course of the last year, 1.5 years was really to look at the data and be able to use that data to optimize the dose and therefore, the benefit risk. In fact, you'll see across all of these 3 Phase III trials that are currently enrolling the dose of selinexor is 1/4 to 1/3 of that originally approved dose. They're at that 40 and 16 milligrams lower doses that optimizes not only the efficacy, but clearly the safety as well. With that said, let's transition to multiple myeloma. Again, we have an ongoing Phase III trial in multiple myeloma. Specifically, this is a patient population that has received 1 to 4 prior lines of therapies. All patients must have received an anti-CD38 in their most immediate line of therapy. These patients are randomized in a 1:1 fashion to either selinexor at the 40-milligram dose in combination with pomalidomide and dexamethasone or elotuzumab in combination with pomalidomide dexamethasone. A total of approximately 220 patients will be enrolled and the primary endpoint is progression-free survival, and we anticipate top line data in the second half of 2024. Now let's move on to endometrial cancer. Again, a really unique opportunity with selinexor in endometrial cancer. This would represent our first solid malignancy in which we have an opportunity to show a significant benefit for our patient population of high unmet need. We have very robust subgroup data, specifically from the SIENDO trial. The SIENDO trial was evaluating selinexor across all patients who are advanced recurrent endometrial cancer and was evaluating selinexor in the maintenance setting. What we observed from this trial was a very important subgroup in that the greatest benefit, right, I should say all the benefit was specifically observed in patients who are TP53 wild-type. We all know TP53 is probably the most important tumor suppressor. In patients who have an intact TP53, we see very robust benefit in those patients who are [ mutant ], we see new benefit. Therefore, supporting, again, selinexor's mechanism of action. P53 is found in approximately 50% of all endometrial cancer patients, which gives us a significant opportunity to develop selinexor in a large patient population of high unmet need. Given the fact that we have an opportunity in P53 to identify a very important predictive biomarker, we also have an opportunity to continue the development of personalized medicine. In endometrial cancer, there are a few molecular subgroups that are important to physicians, including MSI high, MSS, in this trial, we have an opportunity to now develop the third unique molecular subgroup in P53 wild-type. Again, P53 is seen approximately 50% of all advanced recurrent patients. If you look amongst the patients who are P53, we also know that approximately 70% are going to be MSS or proficient in MMR. And the small subgroup is going to be MSI DMMR at 30% of all patients. So again, a real opportunity to provide benefit in a large subgroup of patients. These long-term PFS data we recently presented at the ASCO plenary on July 25 of this year. After a median follow-up of approximately 25 months, we see unprecedented benefits, specifically in the TP53 wild-type subgroup. At this data cut, we see a median PFS for selinexor of 27.4 months compared to only 5.2 months in placebo, equating to a hazard ratio of 0.42. Again, this is a very important predictive biomarker, specifically in that P53 is identifying the patients who best respond to selinexor. We know that because in the TP53 mutant subgroup, which is seen in the Kaplan-Meiers on the right-hand side of the slide, the benefit for selinexor was the same as placebo at 4.2 and 5.4 months, respectively. Again, P53 is the biomarker that identifies the patients who can respond. We further looked at the benefit specifically in patients who also MSS and P53 wild type. On the left, you see in the TP53 wild-type MSS subgroup now an unprecedented benefit. We now see a median PFS that has not been reached as well as a median PFS for placebo of only 4.9 months now equating to a hazard ratio of 0.32. Again, this is unprecedented data. I say that because with the checkpoint inhibitors, the benefit is largely seen in that MSI high sub group. So this now allows us to clearly identify a superior therapy for this large group of patients who are MSS or PMMR. In the P53 wild-type MSI, we did see a meaningful benefit. So with selinexor median PFS of 13.1 and a placebo median of 3.7 equating to a hazard ratio of 0.45. Across these 2 subgroups, again, it really continues to highlight the importance of P53 and identifying patients who can best respond to selinexor. There was a very generally tolerable and manageable side effect profile despite a longer follow-up duration. The side effect profile has not meaningfully changed. We continue to see GI side effects, including nausea and vomiting as well as hematologic side effects, including thrombocytopenia as well as anemia. Despite these AEs, by and large, again, it was generally manageable and patients were able to stay on therapy. Only 15% of patients had to discontinue due to toxicity. These data together really suggests we have an opportunity to really embed selinexor in this P53 wild-type subgroup where we believe selinexor is going to fit into the evolving paradigm is likely in those patients who are going to be P53 wild-type and MSS. Again, to reiterate, those data are unprecedented with the hazard ratio of the 0.32 and a median PFS that has not been reached. This is our ongoing EC-042 Phase III trial. This is specifically evaluating selinexor as a maintenance therapy in patients who are P53 wild-type. They'll be randomized 1:1 to either selinexor 60 milligrams or placebo. The primary endpoint is PFS, and we expect top line data in late 2024 beginning of 2025. Lastly, I'll touch upon myelofibrosis. So again, this is a unique opportunity now evaluating selinexor in combination with ruxolitinib. Ruxolitinib is a JAK inhibitor, has been the standard of care for over 10 years, and yet the efficacy is very limited, with less than 50% of patients achieving a spleen volume reduction of 35% or symptom improvement of 50% or greater. Furthermore, we know that there are multiple subgroups who do not benefit, specifically male patients as well as patients who need to start on lower doses of ruxolitinib. Based upon Phase I data in which we identified 60 milligrams as the recommended Phase III dose, we saw unprecedented SVR and TSS 50 data, specifically with this combination, we saw 79% of patients achieving an SVR35 at week 24 and 58% achieving a TSS50 again at week 24. This represents almost a doubling of the efficacy seen with rux alone. We also see a very unique opportunity. And with subgroup data that suggests that selinexor is a foundational mechanism in myelofibrosis specifically in patients who were treated with very low suboptimal doses of ruxolitinib still see very profound TSS and SVR improvements, again, suggesting that XPO1 inhibition is the fundamental mechanism driving the efficacy in treatment naive myelofibrosis. We see a very generally tolerable and manageable side effect profile. Similar to our other programs, the main toxicities are going to be GI in nature as well as hematologic in nature, regardless of these AEs, patients stay on therapy. And this ability to stay on therapy is what drives efficacy. Only 2 patients at the 60-milligram dose needed to discontinue their therapy due to toxicity, specifically thrombocytopenia as well as neuropathy. This is our ongoing Phase III trial evaluating selinexor and ruxolitinib in a JAK-naive patient population, a total of 306 patients will be enrolled. The primary endpoint is going to be SVR35 as well as TSS50. This trial was just initiated and at this we expect top line data sometime in 2025. That said, I'll hand it back to Richard.

Thank you, Reshma, having exciting data for us moving forward with 3 Phase III programs and great data and able to really deliver for patients, I think, transformative outcomes as we continue to move forward with those trials. Looking at the balance sheet. I think as an organization, we've been very diligent and very focused on our capital allocation and just a couple of highlights here in the first half of this year versus first half of last year, bringing down our non-GAAP R&D and SG&A expenses by 12%. Also in August in order to enhance our financial strength and really to deliver a prioritized pipeline. We put in place a reduction across the organization of about 20% in our workforce. And so together with that, if you look at our non-GAAP R&D and SG&A expenses have been reduced guidance for the year of $240 million to $255 million, and a cash runway to fund our planned operations into late 2025. And as I mentioned, finished the end of Q2 was $238 million in cash. So if we move forward, again, easy as being very focused on delivering a prioritized pipeline on core programs. A lot of work across our organization to really optimize our cost structure and at the same time, advance 3 Phase III programs which target large indications with high unmet need, significant commercial opportunity with that $2 billion in peak revenue in front of us for selinexor. To think these initiatives really position us and strengthen us to deliver through the end of 2025 with multiple readouts in '24 and '25 as we continue to work to really drive the next phase of growth for Karyopharm. And with that, these are the milestones we have in front of us across multimyeloma, endometrial cancer, myelofibrosis and MDS. Thank you for joining.

Thank you, Richard and Reshma for taking the time to present. And thank you to everyone listening in on the presentation. Have a great day.