Q3 2025 Karyopharm Therapeutics Inc Earnings Call

Good morning. My name is Ludy and I will be your conference operator today.

At this time, I would like to welcome everyone to the Karyopharm Therapeutics third quarter 2025 financial results conference call. There will be a question-and-answer session to follow. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Brendan Strong, Senior Vice President of Investor Relations and Corporate Communications. Please go ahead.

Good morning, and thank you all for joining us. On today's conference call to discuss Karyopharm Therapeutics' third quarter 2025 financial results and recent company progress.

We issued a press release this morning detailing our financial results for the third quarter of 2025.

This release, along with the slide presentation that we will reference during our call today, is available on our website.

For today's call, as seen on slide 2, I'm joined by Reshma Rangwala and Lori Macomber, who will provide an update on our results for the third quarter of 2025 and discuss recent clinical developments.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on slide 3.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factor section of our most recent Form 10-Q or 10-K on file with the SEC, and in other filings that we may make with the SEC in the future.

As of today, only.

While we may elect to update these forward-looking statements at some point in the future, we specifically, disclaim any obligation to do. So, even if our views change,

Therefore, you should not rely on these forward-looking statements as representing our views as of any later date.

I'll now turn the call over to Richard. Please turn to slide 4.

Thank you, Brandon and thank you all for joining us today for Carrier Farms Q3 2025 earnings call.

As we turn to side 5, I'm pleased to share that this has been a very productive quarter for Cario Farm.

1 defines by meaningful clinical programs and strengthened financial flexibility that together set the stage for our next chapter of growth.

in Q3, we completed enrollment in our phase 3, entry trial in Frontline, Mi fibrosis,

Marking a pivotal moment for Karyopharm.

Sentry represents a significant opportunity to redefine the standard of care for patients with mild fibrosis.

Through the combination of cell and XOR, plus Rock Solid nib.

As a potential all-oral treatment option.

With top-line results expected in March, we believe this trial could establish a new paradigm for how myofibrosis is treated and further validate the relevance of XPO1 ambition in hematological malignancies.

The power of XPO1 inhibition is multi-dimensional.

It simultaneously targets multiple pathways that enable malignant cell growth and proliferation.

Targeting these relevant pathways concurrently overcomes the limitations of targeted therapies such as ROCK-solid nib, a JAK inhibitor that mostly delivers symptomatic benefits, which many consider palliative.

this unique and potentially foundational mechanism could establish XPO1 inhibition as a key mechanism in myofibrosis, with further potential across the broader MPN landscape.

In October, we made significant progress in getting our financial foundation.

Through comprehensive refinancing and capital restructuring, we secured approximately $100 million of financial flexibility and additional capital, extending our cash runway into the second quarter of 2026.

Turning to our financial performance, our profitable multi-million dollar commercial organization provides a solid foundation on which to build.

In the third quarter, we delivered total revenue of $44 million, an increase of 13% year-over-year.

And U.S. net product revenue grew 8.5%, reaching $32 million.

This growth reflects the continued strength of exposure in multiple myeloma and the disciplined execution of our commercial and operational teams.

Importantly, we delivered this level of growth, which will continue to reduce expenses.

As we look ahead, our recent financing enables us to continue with focus and conviction around three core priorities.

First, advancing our late-stage clinical programs.

10 Tree and Eco 42, which we believe have the potential to be truly transformative for patients and the company.

Second driving continued growth across our Expo franchise.

And third, maintaining financial discipline as we execute on our strategy and position Karyopharm for sustained success.

Taking together, these underscore the momentum and transformation underway at Cario Farm.

We are executing with Clarity and purpose as we advance our mission. The Pioneer Innovative cancer therapies that can meaningfully improve the lives of patients and deliver long-term value for all our stakeholders.

As our next major Milestone is the Topline Mi fibrosis data from century.

We will focus much of today's discussion on the science supporting this program and the significant commercial opportunity ahead.

Now, I'd like to turn the call over to rishma to review our science.

Thank you, Richard.

There is a substantial need to develop new treatment options for patients with myelofibrosis, as shown on slide 7. This disease is heterogeneous and is defined by four hallmark defining features.

These hallmarks include an enlarged spleen, normal blood cell production, bone marrow fibrosis, and constitutional symptoms.

Overall, survival, for intermediate to high-risk Milo, fibrosis patients is only 4 to 5 years.

Lastly, Jak Inhibitors are the only approved therapy for Milo fibrosis and while they may, decrease symptom, burden and lead to very modest spleen reduction relevant, Jak Inhibitors including Rexall lip the standard of care and Frontline. Milo, fibrosis do not Target. All of the relevant Pathways implicated in Milo fibrosis, including NF Kappa P 53 and fibrosis, inducing pathways

As a result treatment of Frontline. Milo fibrosis patients with monotherapy, Jak Inhibitors, do not adequately address. The relevant drivers of pathogenesis in Milo fibrosis.

on slide 8, our confidence in selling next Source potential in Milo fibrosis, is based upon a growing body of pre-clinical, non-clinical translational and clinical efficacy and safety data sets,

These data suggest XPO1 inhibition is a key mechanism that may facilitate potential synergy with ruxolitinib and other drugs relevant in myelofibrosis.

This multi-targeted approach enables treatment of the underlying mechanisms that lead to Milo fibrosis, and we believe it may lead to meaningful efficacy across the key treatment drivers, as well as a generally safe and manageable side effect profile.

This is supported by our blinded safety data, which I will take you through in a few slides, as well as our substantial safety database with Stellin XOR, where approximately 30,000 patients have been treated in clinical trials and in the post-market setting.

this underscores our confidence in the ongoing, phase 3, Sentry trial,

Seen on slide 9, while JAK inhibitors directly inhibit the JAK-STAT pathways, multiple other pathways downstream of JAK's deaths support malignant clone proliferation and survival. The marrow fibrosis, cytokine storms, and proliferation of abnormal megakaryocytes.

These pathways include NF Kappa Beta, PI3 Kinase AKT, mTOR, and TGF Beta. A multifaceted approach with dual XPO1 and JAK inhibition, simultaneously targeting upstream and downstream sectors of the JAK-STAT pathway, ultimately enables apoptosis, or cell death, of the malignant clones.

Let's now focus on the key treatment drivers in Milo fibrosis as seen on slide 10.

Clean reduction, symptom, Improvement and lower rates of grade, 3 plus anemia.

First, spleen volume reduction. As a reminder, note that only approximately one-third of patients achieve a spleen volume reduction of greater than 35% with ruxolitinib alone. In contrast, our Phase 1 data suggests that the combination could more than double the SVR 35 rate to 79%.

The substantial proportion of patients achieving an SBR of 35 is coupled with very encouraging durability. Specifically, there is a 100% duration of response as of the date of cutoff.

Second is symptom, Improvement data from this trial? Also showed an average 18.5 Point Improvement in absolute TSS at week 24, which suggests this combination could provide a meaningful improvement over the 1100 to 14 points achieved by patients on ruxolitinib as observed in the phase 3 manifest 2 and transform 1 trials.

Third is lower rates of grade, 3 plus anemia.

The data that we presented in June at EHA from our Phase 2 035 monotherapy trial should lower rates of all grade and grade 3 anemia in myelofibrosis patients previously treated with JAK inhibitor therapies.

Blinded safety data from the ongoing Phase 3 Sentry study suggests a similar trend.

Meaningful improvement of these treatment drivers requires disease modification or the elimination of the underlying mechanisms leading to the development of an enlarged spleen, constitutional symptoms, and worsening cytopenia.

Data observed, from cell and xor monotherapy, studies in a pre-treated, Milo fibrosis population as well as our Phase 1 combination data and Jak inhibitor naive Milo fibrosis, suggests meaningful, reductions in keyside of kinds that are critical to Milo fibrosis. Pathogenesis symptom, development and anemia as well as improvements in bone. Marrow fibrosis increases in arthritis progenitors and mutational burden.

Turning to slide 11, we are super excited that our Phase 3 Century trial has completed enrollment, with topline data expected in March 2026.

Which are tested sequentially, as we have discussed before. It is important to re-emphasize based on learning from other myofibrosis trials that we believe we have optimized for success.

In alignment with the FDA we changed, the co-primary endpoint of TSS 50 to Absolute TSS and exclude the fatigue domain, in the primary analysis of absolute TSS, due to the ambiguity of patients assessment of their fatigue. We are certainly not the first to exclude fatigue. In fact, both the pivotal trials that led to ruxolitinib and fedratinib approvals also excluded fatigue in their TSS 50 analysis.

Encouragingly, amongst approximately 350 patients enrolled in Century, the mean baseline TSS, excluding fatigue, is approximately 22.5.

Note that the 21.9 that you will see in our ASH abstract today was preliminary data and before enrollment was completed.

Our mean baseline of approximately 22.5 compares favorably to other comparable trials.

Importantly, as you compare our number to other trials, please remember other Phase 3 trials may include fatigue in their baseline scores.

How does the fatigue domain affect the score?

In the Phase 3, MANIFEST 2 trial, the average fatigue score at baseline was approximately 5 points. Our baseline score, if we included fatigue, would be approximately 5 points higher, which gives us confidence in the patient population that we have enrolled.

Shifting back to our trial design, absolute TSS. In the Phase 3 Sentry trial, we will be analyzed using the mixed models repeated measures approach, or MMRM, which is viewed as a more sensitive and potentially more robust method by which to analyze absolute TSS.

Now, let's review the encouraging preliminary blinded aggregate, safety data from this trial as these are preliminary and blinded data. Please keep in mind that this data may not be reflective of the trial's. Actual Topline results.

The data on Slide 12 are from the first 61 patients that enrolled in the Phase 3 portion of Sentry, who have now been followed for a median of over 12 months. These patients were included in the successfully passed utility analysis conducted at the beginning of the year.

We have continued to track the safety events over time and took a snapshot of the blinded safety data from these 61 patients on July 1, 2025, which continued to look favorable.

The most common tea is provided for the first 61 patients randomized to the trial and includes patients randomized to both the combination of Selinexor plus ruxolitinib or ruxolitinib arms in a 2 to 1 ratio.

Because these are blinded data, we do not know the rates by each arm.

In an effort to improve comparability, we then took our analysis one step further. Knowing that the 61 patients were randomized 2 to 1, we used the historical data on RX to extract the preliminary safety data for the approximately 40 patients that received the combination, which is shown in the orange boxes in the middle of the slide.

The number that I am most optimistic by is the extrapolated rate of grade 3 for anemia at approximately 26%. The extrapolated rate of grade 34 anemia for the combination is meaningfully lower than the 37% historically reported for ruxolitinib.

Grade 34 thrombocytes are relatively similar, with 9% suggested for the combination-treated patients, compared with the approximately 6% reported for ruxolitinib alone.

Finally, the extrapolated rate of treatment-emergent adverse events leading to discontinuation is approximately 5% to 7%, which is lower than the 6% to 11% range that has been historically reported for ruxolitinib. We view this as an encouraging observation.

We are very encouraged about these data and what it could mean for patients. If we see something similar in the top line results in the Phase 3 Century trial,

Specifically, it could suggest a combination therapy that has a safety profile similar, if not potentially better than standard of care, ruxolitinib, given that both grade 3 or higher anemia and thrombocytopenia are similar, if not better than ruxolitinib alone. This could suggest decreased blood draws for the patient and reduced monitoring burdens for physicians and healthcare staff.

On the study treatment for over 3 and a half years.

This 81-year-old female was diagnosed with myelofibrosis secondary to polycythemia vera.

She initiated treatment with Selenexor for 60 mg in combination with Ruxolitinib in March 2022.

Her baseline spleen volume was 2,058 cubic cm.

For TSS without fatigue at Baseline was 7 and variant, allele frequency burden or valve was 83%. Meaning that 83% of our cells had a cancer driving mutation

She achieved an SVR of 35 and TSS of 50 at week 24, with complete resolution of her symptoms by approximately week 52.

Furthermore, her VAP levels decrease, with zero signifying eradication of the cancer-driving mutation to this day. She still continues on therapy with minimal side effects, with more than 3.5 years on therapy.

This patient exemplifies the potential a multi-pathway approach can deliver in a disease as complex as myofibrosis.

P1 inhibitors have a unique ability to simultaneously target multiple relevant pathways, suggesting their foundational potential in all patients with MS, as well as other myeloproliferative neoplasms. I will now turn the call over to Sohanya.

Thank you rishma as shown on slide 15, our commercial organization executed. Well, this quarter within the highly competitive, multiple Myoma Market Expo. Net product, Revenue in Q3 grew 8.5% year-over-year to 32 million.

Demand for exposure was consistent year-over-year within the community setting, continuing to drive approximately 60% of total U.S. sales.

Exposure is positioned in both the community and academic settings as a flexible therapy with a differentiated mechanism of action, an orally convenient option, and increasingly used in the third line in patients before T-cell therapy or in patients who cannot access these complex therapies.

Additionally, it is used in the fourth line plus setting. Once patients progress on a T-cell therapy,

based on our results here to date, we are confident in our ability to deliver within our full year, guidance range of 110 million to 120 million

Now turning to malafibrosis outlined on slide 17, we are excited to be working towards a potentially transformative commercial launch that we expect will redefine the way that frontline malafibrosis patients are treated.

Our conviction is driven by the high unmet need in myelofibrosis, combined with the fact that there has been no real innovation in the market beyond JAK inhibitors over the past 14 years.

Roxel is an EV and has been the standard of care for more than a decade, being used in the vast majority of intermediate to high-risk patients. Even though fewer than 35% of these patients achieve an SVR, 35.

Physicians and patients want to see deep and durable reduction in spleen volume. As Reshma discussed, the data from our Phase 1 trial highlights our potential in this area with selinexor plus Roxy, helping more than twice as many patients achieving a spleen volume reduction of 35% or more.

In addition, many patients experience constitutional symptoms and anemia, both of which negatively affect patients' quality of life. These are areas where we believe the selling X or Plus rule, in combination, may make a meaningful difference.

So, this presents us with a significant opportunity to improve upon the standard of care in combination with the market leader.

Slide 18 provides an overview of our potential commercial opportunity. We have the opportunity to redefine the standard of care, expand, the market and lead with a new Frontline, combination therapy, that may offer very differentiated results for patients.

This isn't an incremental change in the treatment landscape. It is a potentially transformational change for patients.

Here are some figures that help inform our view. That selling Exorcist Peak. Revenue opportunity could be up to approximately a billion annually in the US.

Marketplace.

As we look at the opportunity for patients that can benefit from selling X or plus Roxy Soliton, there are approximately 4,000 newly diagnosed patients each year in the U.S. with intermediate to high-risk MDS that have a platelet count above 100,000. This is our target market. Most of these patients receive Roxy Soliton today.

Seventy-five percent of U.S. physicians showed an intent to treat with combination therapy based on third-party market research.

There is a clear appetite among Physicians to evolve from a monotherapy to a combination treatment approach.

Finally, the real world duration of therapy for Rock Solid is approximately 13 months. Our assumption is that the combination of selling X or plus Rock Solid and it would be used for at least 13 months.

Looking at all of this together, you will see that our peak revenue opportunity may approach $1 billion annually in the U.S. alone.

As we prepare for potential commercialization, we have spent the past year speaking with leading KOLs at academic medical centers, as well as community-based physicians, and have received overwhelming support for the need to improve upon the current standard of care.

Our position in the market, if approved, will be very clear and focused. If you're going to prescribe Roxel as an N to a patient with newly diagnosed male fibrosis, prescribe Selenex or plus Roxy Lisb instead.

Finally, our existing commercial capabilities are highly synergistic in mallow fibrosis and prepare us for a rapid and successful launch. As shown on slide 19, we have market access, a patient support hub, scientific and medical affairs, marketing, and a sales team with deep relationships with potential prescribers.

In the academic setting. We already call on all the key institutions in the community setting where a majority of newly diagnosed Malo fibrosis. Patients are treated. There's Approximately 80% overlap with our existing customer base.

Pending positive data and subsequent regulatory approval, our commercial team will be ready to drive rapid and strong uptake. As we bring this transformative therapy to patients,

Now, I'll turn the call over to Lori.

Good morning, everyone, and thank you, Saha.

Turning to our financials. Since we issued a press release earlier today, with the full Financial results, I will focus on the highlights and reviewing our guidance for 2025 on slide 21.

Total revenue for the third quarter of 2025 was $44 million, an increase of 13.4% compared to $38.8 million in the third quarter of 2024.

US exposure: Net product revenue for the third quarter of 2025 was $32 million.

an increase of 8.5% compared to 29.5 million in the third quarter of 2024,

Gross and net provisions for Expo were 27% in the third quarter, consistent with the second quarter of 2025 and down from 31% in the third quarter of 2024.

We expect growth in net provisions to remain relatively consistent with the third quarter levels in the fourth quarter of 2025.

Licensed and other revenue was $12 million in the third quarter, up nearly 30% from the third quarter of 2024.

Primarily driven by higher Milestone revenue from our partner merini.

This included the final amount of revenue that we will record from Meteren related to the $15 million of annual R&D reimbursement.

In the fourth quarter.

Our licensed and other Revenue will primarily be royalty Revenue.

Since we do not expect to achieve any significant additional milestones in Q4 2025,

Turning to expenses.

We continue to be very disciplined in managing our operating expenses and prioritizing our pipeline Investments, including additional cost reduction initiatives that we implemented in the third quarter.

2024 decrease was primarily driven by lower clinical trial and related costs for cell and xor in multiple Myoma reflecting the reduced scope of our phase 3 trial as well as lower personnel and stock-based compensation expenses resulting from previously implemented cost reduction initiatives.

Selling, general and administrative expenses were $26.6 million for the quarter, down 4% compared to $27.6 million.

The decrease was primarily attributable to the continued realization of our cost reduction initiatives.

Taken together, our loss from operations improved by approximately 42% in the third quarter of 2025 compared to the third quarter of 2024.

Interest expense was 11 million in the third quarter of 2025 compared to 11.4 million in the third quarter of 2024.

Other expense was $7.4 million in the third quarter of 2025.

Compared to $3.8 million of other income in the third quarter 2024.

This non-operational item is primarily driven by reoccurring, non-cash fair value remeasurement of embedded derivatives and liability costs by common stock. Warrants related to the refinancing transactions completed in the second quarter of 2024.

We reported a net loss of $33.1 million or 382 cents per share on a GAAP basis.

More than half of this loss is driven by below-the-line items, including interest expense, which is almost entirely non-cash at this point, and the $7.4 million of non-cash mark-to-market adjustments that I just mentioned.

Excluding, these items are underlying operating performance continues to show meaningful Improvement.

Finally, prior to the receipt of our approximately $36 million of gross proceeds from the financing transactions that we announced in October.

We ended the third quarter with $46.2 million in cash. Cash, equivalents, restricted cash, and investments compared to $109.1 million as of December 31, 2024.

On a pro forma basis, after deducting transaction-related expenses, we would have had approximately $78 million in cash.

Importantly, from a cash perspective, our interest payments do not start again until June 2026, and our royalty payments do not begin again until the third quarter of 2026.

Based on our current operating plans, our guidance, for the full year of 2025 is as follows.

Total revenue of 140255 million consisting of us exposure, net product Revenue.

And licensed royalty and Milestone Revenue expected to be earned from our partners primarily Metairie, and antigen.

US exposure, net product revenue is expected to be in the range of $110 million to $120 million.

We are lowering our range of R&D and sgna expenses, to 235 to 245 million down from 240 to 250 million.

With the financing that we announced last month. We expect our existing liquidity, including the revenue. We expected generated from Expo. Net product sales, as well as revenue generated from our license agreements will be sufficient to fund our plan operations into the second quarter of 2026.

I will now turn the call back to Richard for some final thoughts.

Thank you Lori, before we close on. Slide 23. I want to emphasize. How far onario Farm has come? And where we're heading?

This quarter reflects clear execution against our priorities, and the progress we've made has positioned us to enter 2026 with confidence.

With sentri enrollment completes.

A strong commercial foundation and a reinforced balance sheet. We are focused squarely on what matters most

With myo fibrosis and endometrial cancer.

Our team dedication.

Scientific rigor and focus on patients, continue to drive everything we do.

We believe the opportunities ahead of our significant and we are executing with purpose and discipline to realize them.

Thank you for your continued support and confidence in kareo farm. We look forward to updating you as we advance towards these important milestones.

I would now like to ask the operator to open the call up to the Q&A, portion of today's call, operator,

Thank you. And take a listen, gentlemen, we will now begin the question and answer session to answer the question. You may press the star, followed, by the number 1 on your telephone keypad. If you're using a speaker-phone, please pick up your handset before pressing the keys. You will draw your question. Please press star, followed by the number 2 and we kindly ask you to please limit yourself to 1 question and 1 follow-up with that. Our first question comes from the line of Peter Lawson with Barclays. Please go ahead.

Great. Thank you, thanks for the updates. And thanks for taking that questions. I guess this is just around the MS. Um, based that we're seeing in March 26th, as you can just kind of walk through what we should see if it's like a sprss and rs Trends, or if that's going to be staged across other medical meetings in in 2026. And then a follow-up question, would just be around.

And, um, the size of the sales force, I know you've kind of talked about 80% overlap, but it’s interesting to see how many you would add or dedicate to MF and also the kind of the Exas strategy. Thank you.

Thanks Peter. So maybe the first part Peter are you asking about when we plan to share the data post March, or it wasn't quite clear that the question in the first part. Oh, just the the level of detail would see in, um, for Ms. You know, whether it's svr, TSS, OS Trends, and then, or if it's kind of spread across the year kind of thing,

Sure. Yeah, I'll turn to rash for that first part and then I'll turn to sahana for for the second part with regards to our commercial capabilities

Peter, this is rajma. Um,

The Top Line results you're correct, you know, expected March of 2026. You know, I anticipate at this point, really just providing again, sort of those Topline details. So, you're correct, you know, the primary end points of svr, 35 at week 24, absolute TSS, uh, potentially write some other, uh, secondary end points, um, including hemoglobin and or disease modification. And then, of course, we'll touch upon safety. Um, but we'll get granular as we get closer to that milestone.

Hey Peter, as far as the sales force, as you mentioned, uh, very strong overlap, uh, particularly in the community setting, of course, uh, with our current organization and in the academic setting, we already call on those uh, those accounts. So we expect, uh, really minimal, uh, additions to our commercial structure. Our capabilities are already highly synergistic, as far as um, xus will continue to work with our xus partners, to drive launches, uh, in each of the countries and, and additional royalty, and, and Milestone revenues, uh, globally.

Thank you.

And your next question comes from the line of Ted Tanto with Piper Sandler. Please go ahead.

Great, thank you very much and congrats on all the progress for on the clinical side and financial side, can you remind us, are there any Milestones, um, associated with data, um, for um, warrants or things like that from the recent, um, Financial restructuring, that could extend that, uh, Capital Bond. Um,

Uh the second quarter and are there any geographies where uh you don't currently have uh, distributors in place? Thank you, or for For Milo fibrosis. Thank you.

Thanks. Yeah, maybe on the first part, we just asking about Milestones from a financing perspective with regards to positive data or maybe just clarify that part of the question. Yes. So Milestones, or were there any warrants or anything like that? That could, um, trigger to extend the June or the um, 22 deadline, thanks. I was trying to remember back.

You know, warrant or financing perspective. No, no specific triggers with regards to to positive MF data. Obviously, you know, pending positive data. You know, we think that would be a very, very strong, you know, inflection and Value Point for us. Yeah. You know, and on the second part, you know, with regards to, you know, our Partnerships globally know. Uh, you know, we have well established partners for selling X or globally, you know? And as, uh, Sonia mentioned, I think they're very excited and engaged and looking forward to positive data, and moving forward with a, you know, registration strategy and commercialization strategy globally. Which, uh, we would be able to do with the exception 1 market. We still don't have, uh, partnered is Japan because that would be the only additional Market. You know, we would look to to partner with in the future moving forward.

That's that's really helpful. And I appreciate all the color. Uh, going into the data readout, best of luck.

Thanks Dad.

And your next question comes from the line of clean. Custody with bird, please go ahead.

Great. Good morning. Congrats on all the progress and thanks for taking our questions, um, hopeful for the, the Baseline. TSS number 22.5, I think you said rishma, um, quite a lot higher than what you had enrolled in the phase 1, I believe. Um, and based on the data that you had at ACR in 2023, it actually looks like fairly similar response for TSS above and below 20, um, which could just be due to the small end, but just curious how you would expect that might impact the read through from Phase 1 to the pivotal phase.

3, and then I'll have a call.

Yeah, it it's a great question Colleen. Um, you know, I think we're very encouraged by how the Baseline TSS is evolving. As you as you mentioned 22.5, approximately 22.5 in almost the full ITT. Um, I think you're right. You know, sort of the phase 1, it's small. So, you know, we're very encouraged by those numbers. Clearly it suggests that absolute TSS, as well as TSS 50 can be achieved with a combination um relative to historical recall data. I think what we were trying to accomplish in the phase 3 was to drive that Baseline TSS without fatigue as high as possible. And so again very encouraged with that 22.5, especially as I compare it to other contemporary trials in which that 22.5 likely is higher than even those. So it really suggests that we could see a potentially meaningful Improvement for absolute TSS with our combination versus rucks alone.

Great, that's super helpful. And then in that same AEC update, it looked like there was some variability in response for platelet count above and below 200,000, which again could just be driven by small N, but curious if you have the baseline platelet count and what your thoughts are on the.

Um, activity based on platelet count.

Yeah. Um, we're seeing, um, you know, more than half of the patients with Baseline platelet counts above 200, um, which again is what I would expect. Um, you know, there's nothing biological or mechanistic. That would suggest that platelet count is a key variable that would, um, impact the overall svr 35 rate or even the absolute PSS. Um, so again, it's a, it's a number we're watching, it's a baseline characteristic that I think is very consistent with other phase, 3 trials. Um, in general that variable as well as all the other variables, you know, are in line with what we would expect. And again, very encouraged with how this patient population is enrolled in and who they represent across the Frontline, mile of fibrosis is population.

Okay, great, thanks so much for taking your questions.

Thanks Colleen.

And your next question comes from the line at Mario Rey crop with Jeffrey. Please go ahead.

Hi, good morning. Uh congrats on the progress and thanks for taking my question. Um and so Ash, abstracts are coming out pretty soon. Uh just confirming it sounds like you're phase. 3 Baseline data is going to be at Ash. Um, can you talk more about what's in the abstract? And then what is going to be at the conference?

I mentioned, you know, on my prepared remarks, as well as with some of the questions today, just very encouraged with, you know, how that patient population has evolved and again, very consistent with what we would expect.

Got it. Okay. And maybe as a follow-up, for the slightly lower treatment emerging adverse events leading to discontinuation for the 61 patients in the blinded safety review, can you comment on whether that rate is mostly in line with what you're seeing for the full study? I guess, any additional perspective there that you could share.

Yeah, great question. So you know, 1 of the things that I'm

Very encouraged by is that we've followed, the 61 patients, um, and taken a snapshot across their AE summary, including their treatment discontinuation rates as well as the specific aees, as well as a couple of grade 3 plus aees. And what I'm encouraged by again is that, you know, despite whether we look at a 7 7 months including treatment emerging discontinuation rates are remarkably stable, right? So it really suggests that a majority of the events including discontinuation is potentially, our current early. And we don't continue to see this accumulation as the patients are followed over time. Now, you know what the Top Line results are going to show, um we'll see, you know, at the top of the top at the

Time to report the top line results. But again, we are very encouraged by how the 61 patients are evolving.

Your next question comes from the line, Brian Abrams. With RBC Capital markets, please go ahead.

Hey, good morning. Thanks for taking my question and uh, congrats on all the progress. Um,

I wanted to drill down a little bit more on some of the market research, um, findings. Um, in particular the um, the high 75%, uh, intent to treat with the combo. And in Frontline MF, I'm curious if you could talk a little bit more about sort of the, the types of patients that you're hearing. Uh, Physicians would just try on an, on a combo, uh, Roxy uh initially, um, whether or not some of the payer feedback, maybe you've been getting the early payer feedback uh, has been, uh, has been aligned with what you're hearing from Physicians uh, in terms of the degree of uh, a Frontline use. And then, you know, with the space expected to evolve and more targeted treatments like em calr and more targeted Jax. What impact do you think that might have on the way, uh, Sally is ultimately, uh, positioned. So to be successful in the phase 3. Thanks.

Yeah. Thank thanks, Brian. Maybe I'll I'll, I'll start kind of with, with the second part of your question, and I'll turn it over to to Sonia.

You know, to to talk to, I think broadly, you know, in in my old fibrosis, you know, as you know, and as so, when you talked about, there's been really you know no new innovation in the front line, only Jack inhibition in in Milo fibrosis. So there's significant opportunity across the whole Space to improve outcomes for patients.

And to bring new innovation to patients, which is exactly what we're focused on are bringing up, you know, a novel MOA such as selling X or an Excel 1 in addition. Uh, you know, which we think can have, uh, a really meaningful benefit to, to patients.

And when we look across the space again, I I think the data we've shown, as we've talked about, we've been working on myio fibrosis for over 7 plus years rashma talked about the breadth of our data.

Uh, and showing impact as a, as a monotherapy, and obviously, it's a combination.

I think what we're excited about obviously, is to work to deliver that positive phase 3 trial and and then to continue expanding and mpns as well. As we're selling next door with Elton xor, our novel, uh you know, second generation xpl 1 inhibitor and and a whole Suite of Expo on Inhibitors that we have, which we think may be able to have an impact across a broad range of of mpns.

You know, with regards to, you know, the car we need to wait, we haven't seen any data in in Milo fibrosis. So again, I think there's a lot of opportunity for for Innovation and Improvement. And what we're excited about again, is in the very near term, you know, to read out, uh, potentially positive trial and a combination with such an impact for patients and, and I'll let Sonia talk to that because that's really what our our Market Research indicates when we talk about the you know 75% intent to prescribe that combination therapy up front you know for treatment naive patients.

Greater than 100,000 platelets, and the market research, kind of just a little bit of background, was comprised of both community and academic physicians. The proportions were in line with what we see in the real world, a majority of community physicians that are treating newly diagnosed male fibrosis patients. So, the value proposition for selling Xor is very simple, clear, and focused.

If a prescriber is already prescribing or planning to prescribe Rovax alone for a newly diagnosed Malo fibrosis patient, upon approval, they will then just do a Silly plus Rovax combination. So, we are not competing with Rovax in it, which is the standard of care. Go-to treatment for our target patient population. We're simply an addition, um, with rules. And if the current market leader,

Um, as as we look at the sort of pair environment, we don't anticipate any kind of push back. Um,

Uh, with the pairs, uh, and generally, as Richard pointed out, there really has been little, uh, innovation beyond the Jack inhibitors. So, there's a tremendous appetite to move these physicians from a monotherapy to a combination treatment approach.

Thanks.

Thanks Brian.

And our last question will come from Jonathan Chang with living. Please go ahead.

Hi guys. Good morning. Thanks for taking my question. Just regarding the commercial potential launch in myelofibrosis, could you discuss any relevant learnings from the multiple myeloma experience? Thank you.

Yeah, I I think broadly Jonathan um, you know, the learnings from our multiple experience really have been built in into the trial design where, you know, in multiple wilmo came to the marketplace. As, you know, at at a much higher dose at, uh, 80 milligrams twice, weekly or 160 milligrams.

And what we've learned, you know, over the past number of years, is the importance and the ability to use cell and extra at a lower dose. And we've obviously built that in with our trial. Now, being a 60 milligrams, once a weekly. And we've also learned the importance of the Dual Antics, uh, to use for the first couple Cycles, uh, as patients, uh, you know, initiate therapy on next. We will want inhibition. We know that the, the nausea is transient and gets better over time. So we've seen both those earnings over our multiple experience. Uh, we've built that in already to the design of the trial. And so I think moving forward and and what we've seen already in, what rashma has shared

When the blinded safety data is is really the benefit to patients the benefit overall to the tolerability profile. And as we saw from the the variable Tae discontinuation to benefit for patients and I think the case study may talk to you with a patient, you know on the combination for over 3 and a half years and still benefiting really talks to the outcomes for patients from those learnings we built in. So we feel very positive about the learnings, we've built in and the potential to, you know, transform outcomes from my fibrosis patients in the front line.

Yeah, I would add that, the big kind of biggest differentiating, uh, point between the 2 Landscapes is the, the degree of competition Myoma. Highly competitive with overlapping competitors, across classes, very different situation, in Milo fibrosis, uh, really little to no innovation beyond the Jack Inhibitors. Also, I would say, the mallow fibrosis space is primed to be what the myeloma space was over a decade ago, over a decade ago, in maloma, they were using mono therapies and then evolving to dubs, that is the level of transformation. I think we're about to see in mallow fibrosis. The second point is given that we have established a um a commercial organization that has worked very closely with community physicians, who will be the majority of prescribers for these new diagnosed patients with a

High degree of synergy and we expect to launch rapidly with Malo fibrosis.

Understood, thank you.

Thanks Jonathan.

Thank you. And that concludes today's question and answer session. I would like to turn this back to Richard Paulson for closing remarks.

For the majority of frontline Myelofibrosis patients, we look forward to sharing topline data with you in March, pending future regulatory approvals. Our organization is well prepared to rapidly deliver on the commercial opportunity. Once again, thanks for joining today.

thank you, and ladies and gentlemen, this