Karyopharm Therapeutics (KPTI) Q4 2021 Earnings Call Transcript

Karyopharm Therapeutics (KPTI 0.06%)
Q4 2021 Earnings Call
Feb 08, 2022, 8:30 a.m. ET

Contents:

• Prepared Remarks
• Questions and Answers
• Call Participants

Prepared Remarks:

Operator

Good morning. My name is Sarah, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics' fourth quarter and full-year 2021 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 Sarah Connors, vice president, corporate communications. Please go ahead.

Sarah Connors -- Vice President, Corporate Communications

Thank you, Sarah, and thank you all for joining us on today's conference call to discuss the top-line results from the Phase 3 SIENDO study, as well as Karyopharm's fourth quarter and full-year 2021 financial results. Today, I am joined by Mr. Richard Paulson, president, and chief executive officer; Ms. Sohanya Cheng, chief commercial officer; Dr.

Jatin Shah, chief medical officer; Mr. Michael Mason, chief financial officer; Mr. Stephen Mitchener, chief business officer; and Sharon Shacham, chief scientific officer. Earlier this morning, we issued two press releases, one announcing top-line results from the Phase 3 SIENDO study in endometrial cancer, and one detailing Karyopharm financial results for the fourth quarter and full-year 2021.

These releases, along with the slide presentation that we planned to reference during today's call, are available under the events and presentations section of our website at karyopharm.com. Before we begin our formal comments, I'll remind you that various remarks we'll 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 two. These include statements about our future expectations, clinical developments, and regulatory matters and timelines. The potential success of our products and product candidates, including our expectations relating to the commercialization of XPOVIO, and next year financial projections, and our plans, and prospects.

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 Factors section of our most recent quarterly report on Form 10-Q, which is on file with the SEC, and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views 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 date subsequent to today.

If you turn to Slide three, you can see our agenda for today. I will now turn the call over to Richard. Please turn to Slide four.

Richard Paulson -- President and Chief Executive Officer

Then you, Sarah, and good morning, everyone. As we work to defeat cancer and improve patient survival, I'm very pleased to report that the Phase 3 SIENDO study met its primary endpoint of a statistically significant improvement in median progression-free survival compared to placebo. Selinexor-treated patients had a median PFS of 5.7 months compared to 3.8 months for patients on placebo. Representing an improvement of 50% with a hazard ratio of 0.70 and a P-value of 0.0486.

Additionally, selinexor demonstrated a sustained and a long-term improvement in progression-free survival. At 12 months, there was an improvement in patients in remission from 25.8% to 35.3%, representing a 37%t increase in probability that selinexor-treated patients will be in remission compared to patients on no treatment, or today standard of watch and wait. In this study, selinexor was well tolerated with no new safety signals identified, and a low discontinuation rate of 10.5% due to adverse event. Karyopharm will work with investigators and the FDA to complete a full evaluation of SIENDO data.

Importantly, the preliminary data also identified a pre-specified subgroup wild-type p5,3 known as the guardian of the genome, which achieves a statistically significant reduction in the risk of disease progression or death. In this pre-specified subgroup currently consisting of 103 patients. The data showed an almost four-fold improvement in progression-free survival. For selinexor-treated patient, with a median progression-free survival of 13.7 months, compared to 3.7 months for patients on placebo.

The hazard ratio of 0.38 and a P-value of 0.0006. We plan to submit a supplemental new drug application to the FDA during the first half of 22, and also plan to submit the detailed results from the study for presentation at upcoming medical meetings in the first half of 22. I would like to acknowledge the exceptional work done by a lot of very dedicated individuals who both carry a farm, and that the SIENDO clinical trial site. I wish to express our sincere gratitude for everyone involved, especially the patients and their family.

On slide five, I will present an overview of our five key pillars, the driver underlying value, and will provide opportunity for what we believe will be substantial future growth. First, we are successfully building upon our existing US Multiple Myeloma Foundation, as our lead oncology asset XPOVIO, generated $29.8 million in net product revenue in the fourth quarter of 21, representing growth of 47% year-over-year. For the full year 21, we generated net product revenue of $98.4 million, representing growth of 29% compared to the prior year. We expect to continue growing sales in 22 through strong execution, and proven commercial capabilities, creating value for both patients and shareholders.

We are striving to become the standard of care in second-line plus, and anti-CD38, and establish XPOVIO as a novel effective modality in the multiple myeloma treatment landscape. Globally, I am very pleased we have brought on board a new commercialization partner for Europe, Latin America, and other key territories with our mentoring partnership that was finalized in December. In the near term, we are expecting the Europeans to attempt to complete its review of the selinexor MAA in second-line plus, and issue an opinion during the first half of 22. With Menarini and her other global partners, we will increasingly bring XPOVIO to patients worldwide.

Second, and just outline, our near-term opportunity, and solid tumors took a huge step forward, and SIEDO met its primary endpoint with a statistically significant 50% improvement in median progression-free survival versus placebo. Third, we are advancing a clinical pipeline that is being purposely built and strategically focused on targeting cancers with high unmet needs. Where science enables us to make the biggest difference in the lives of patients in an area with high probability of success. To that end, we have rapidly initiated new phase 2 trials in myelodysplastic syndrome and myelofibrosis, where we believe we have the potential to achieve approvals over the next three to four years.

Our fourth pillar is our people, and we have the right people in place, along with a strong leadership team with an exceptional ability to achieve both scientific and commercial excellence in executing on our key corporate objectives. Most recently, we bolstered team even further with the promotion of Sohanya Cheng, the chief commercial officer, and the addition of Peter K Honig to the board of directors. If and finally, to support our strategic and focused growth plan, we are well-capitalized to fund our operations into early 2024. In Karyopharm, everything we do is driven by our mission to positively impact patients lives and defeat cancer.

Our foundation is in our science. And we are the global leader with our first in-class science technology. Against this backdrop, we believe we have a strong organization which allows us to begin 2022 prime to support patients and deliver for shareholders this year and beyond. Turning now to slide six, driven by our vision, our innovation, as well as our scope and range of data, we are focused on our core program, Multiple myeloma, endometrial cancer, myelofibrosis, and myelodysplastic syndrome.

As we now turn to Slide seven, I would like to turn the call over to Sohanya for her to review the commercial results for the quarter. Sohanya.

Sohanya Cheng -- Chief Commercial Officer

Thank you, Richard, and good morning, everyone. As Richard mentioned, we have maintained strong growth in the fourth quarter, and continue to make excellent progress across key indicators since our second-line plus launch at the beginning of 2021. Please now turn to Slide eight. On this slide, we show how we have rapidly evolved XPOVIO dosing in three important ways over the past two years to improve efficacy and the patient experience.

On the left from a high dose administered at 160 mg per week to lower doses of 60 to 100 mg. In the center, from twice weekly to once-weekly dosing, and on the right, evolving from a double doublet in later line to triplets in early line. While XPOVIO in combination with Velcade is the approved indication and the only indication we promote to, XPOVIO in combination with pomalidomide, bortezomib, and daratumumab are also included as part of the NCCN guideline for the treatment of second-line plus multiple myeloma. This evolution is an important part of the drug life life cycle, and we have worked rapidly to explore different doses and combinations as we continue to expand the breadth and depth of XPOVIOs' life-cycle.

Turning now to slide nine, it is clear that over the last few quarters we positively changed the growth projectory, and continued to make steady progress across key indicators. We continue to see a positive shift from the temporary factory setting toward early aligned with the most rapid growth this year in the third line, as we continue to focus our messaging on XPOVIO as a new class of therapy in the white space, a second to fourth-line in the myeloma treatment journey. We are also expanding in the breadth and depth of use of XPOVIO, with strong growth in the community setting. We continue to add more accounts every quarter and increase penetration at top myeloma accounts.

In addition, I intend to prescribe data continues to show sustained improvement in the efficacy and safety perception of the product and growing confidence in utilization in earlier line, as physicians have been increasingly positive experience with the lower dose once weekly exposure of triplet regimen. While we continue to see the impact of COVID on oncology patient visits compared to pre-COVID baseline, our field team achieved a high level of life engagements with physicians in the fourth quarter. As we've all observed in January, the Omicron variant has added pressure on the healthcare system and our access to providers. We will continue to adapt to this and remain focused on strong execution, and positioning XPOVIO as a standard of care in second-line plus.

Building on our momentum in 2021, and with a rapidly advancing myeloma pipeline, we expect to continue to drive steady growth in the near, mid, and long term. If you'll advance to Slide 10, I will now turn the call to Jatin to discuss the positive update from a Phase 3 SIENDO study evaluating selinexor in patients with endometrial cancer. Jatin.

Jatin Shah -- Executive Vice President and Chief Medical Officer

Thank you, Sohanya. First, I would like to send a thank you to our teams, the SIENDO investigators, our lead global investigator, and committee chair, Dr. Farragut in the University of Leuven Cancer Institute in Belgium, and the lead US principal investigator, Dr. Vicki Macher from Memorial Sloan Kettering.

As well as our partners, the European Network for Gynecologic Oncology Trials, and the GOG Foundation, and, of course, the patients who participated in SIENDO trial and their families. Now, please turn to Slide 11, we'll recap the positive SIENDO results covered by Richard. I am very pleased to report the Phase 3 SIENDO results demonstrate selinexor significantly extends remission in patients with advanced or recurrent endometrial cancer. Selinexor-treated patients had a median progression-free survival of 5.7 months, compared to 3.8 months for patients on placebo, representing an improvement of 50%.

Hazard ratio .70 with a P-value of 0.0486, representing a 30% reduction in the risk of death, disease progression, or death. In addition, selinexor demonstrated a sustained and long-term benefit in progression-free survival, as seen at 12 months, with a 37%t increase in the probability that a selinexor-treated patient will be in remission compared to patients on no treatment for today's current standard of care of watch and wait. In this study, selinexor was well-tolerated with no safety signal, no new safety signals identified, and no discontinuation rate of 10.5% due to adverse events. Additionally, the preliminary data also identified in a pre-specified subgroup, wild-type p53, again known as a guardian of genome.

We achieved a statistically significant reduction in the risk of disease progression or death. In this prespecified subgroup of patients with wild-type p53, currently consisting of 103 patients. The data showed almost fourfold improvement in progression-free survival for selinexor-treated patients. The median progression-free survival of 13.7 months, compared to 3.7 months for patients on placebo.

With a hazard ratio of 0.38 and a P-value of 0.0006. In addition of XPO1 by selinexor leads to the nuclear accumulation of p53, which is a well-established tumor suppressor protein, which we believe allows p53 to carry out its function again because selinexor inhibits XPO1. So why is this top-line data so significant? Because there is no current treatment to extend their time in remission for patients in the maintenance setting, which is simply unacceptable. As you can see on Slide 12, endometrial cancer is the most common gynecologic cancer with significant unmet needs for patients with advanced disease.

Is projected there will be nearly 66000 new cases in the US, and more than 130000 new cases in Europe in 2022. The current treatment landscape consists of first-line treatment with chemotherapy, typically a taxane plus platinum, response rates can be as high as 67%. However, following a response from chemotherapy with no available treatments, the NCCN guidelines recommend a watch and wait approach until disease progresses. The prognosis is poor with this approach, the progression typically within four months for those who have responded to chemotherapy.

Now, let me turn the call back to Sohanya, talk in more detail about the market opportunity in patients' selinexor benefit if approved.

Sohanya Cheng -- Chief Commercial Officer

Thank you, Jatin. We have a meaningful market opportunity in front of us. Turning to Slide 13. While most of the 66,000 cases in the US are diagnosed with early stage disease and have a good prognosis after surgery alone, approximately 14,000 patients each year in the US will present with advanced or recurrent is the.

Of those patients, up to 67% of those treated with chemotherapy will respond, translating to approximately 9,000 patients being eligible to benefit from selinexor in the maintenance therapy in the front line. Further driving and enhancing that opportunity are several factors. First, maintenance therapy is already well established with physicians that treat multiple solid tumors, including breast and ovarian cancer. Second, progression-free survival of 5.7 months demonstrated by selinexor in SIENDO is superior to the watch and wait approach used today.

Third, patients are treated until progression in the maintenance setting. Forth, selinexor is an oral medicine that is well-positioned to be the first and only treatment post-chemotherapy in the maintenance setting that has the potential to extend time in response and remission. And finally, Karyopharm has an established and strong commercial and medical affairs footprint, which is rapidly engaging in preparing for a potential launch. In summary, as we turn to Slide 14, we believe selinexor has the potential to become an exciting new standard of care for women with advanced or recurrent endometrial cancer.

This belief is driven by powerful faith, free results, a dire unmet need in the maintenance setting, and a significant market opportunity. In short, a paradigm shift for patients living with advanced endometrial cancer. Turning to Slide 15, I'd like to now turn the call back to Jatin, to discuss highlights from some of our other core programs.

Jatin Shah -- Executive Vice President and Chief Medical Officer

Thank you, Sohanya. Turning to Slide 16 will, now turn to our other core programs, which are focused on blood cancers. We are confident in our programs with a proven track record with robust clinical data. Selinexor has demonstrated strong response rates, both as a single-agent and in combination in many hematologic indications.

First in myeloma, and diffuse large B-cell lymphoma, and more recently in myelofibrosis and myelodysplastic syndromes. Single-agent activity is one of the key factors in predicting positive-based results and regulatory approvals. And selinexor has been no exception. In multiple myeloma, there's an increasing use at least 80% and growing in the first two lines of an anti-CD38 based therapy.

Limited data in one to four lines of therapy, from trials on how to manage patients with disease progresses after an anti-CD38 based treatment. This is where we are focused and generated data where selinexor based combinations that include pomalidomide, [inaudible], and bortezomib with a goal of solving that data gap. As you can see on Slide 17, the design of our Phase 3 SPd continues to build this data gap and further evaluates and entrenches selinexor based combinations post anti-CD38. This study will compare the triplet regimen [inaudible] dexamethasone or EPd versus SPd.

This will be our global study expected to recruit up to 280 patients who received one to four prior lines of therapy. We expect to dose the first patient in the first quarter of 2022, and top-line data is expected in 2024. If approved, the SPd tripled with the second world triplet combination approved in relapsed refractory multiple myeloma. Turning now to the XPOVIO regulatory expansion beyond the US on Slide 18.

We continue to see increased access to selinexor worldwide through regulatory filings made by healthcare reform and our global strategic partners. In Europe, the marketing authorization application based on clinical data from the Phase 3 Boston study, has been validated and is currently under review by the CHMP. We expect this review to be completed during the first half of 2022. Our partner, antigen received conditional approval for exposure for relapsed multiple myeloma in China.

There are also new drug submissions or applications for SPd admitted or on file in Canada, and multiple Asia-Pacific markets through our strategic partners. We look forward to keeping you up on those approvals as they happen. Now turning to Slide 19, and we review myelofibrosis, we believe selinxor has the potential to improve outcomes for patients with JAK inhibitor refractory disease. And as seen on Slide 20, there are approximately 5000 patients per year in the US diagnosed with myelofibrosis.

Disease is characterized by significant anemia, weakness, fatigue, and splenic enlargement. The only class of drugs approved in myelofibrosis are JAK inhibitors. Unfortunately, these are not curative, and 60% of patients do not respond. Among the 40% of patients who do respond, initially, the response left at most four years.

There is no other class of drugs approved, and survival is short, typically less than 14 months. But those patients, once JAK Inhibitor stops working. In it in this setting with promising data would once weekly low dose selinexor. Turning now to Slide 21.

Recent data, the report of 2021 showed that for patients on study for at least 24 weeks, 40% of patients achieved an SVR35, And 60% of patients achieved SVR25. These are very compelling results in this patient population. As you can see on Slide 22, the median duration of treatment was 11 months, with a range of 2.8 to 28.8 eight months. On Slide 23, you can see that among patients with anemia or transfusion dependence at screening defined as a hemoglobin less than 10 grams per decilitre.

50% of patients achieved either an improvement in their hemoglobin levels or became transfusion independent as of the time of this data readout. Looking at Slide 24, based on all these data, we have rapidly moved into a global randomized phase two trial that's recruiting patients with at least six months, or prior JAK inhibition, and randomized them to once weekly low dose selinexor for physicians choice. 112 patients are expected to be enrolled, and the first patient was dosed in late 2021. Top-line data from this trial is expected in the second half of 2023.

Turning now to slide 25, with our program in MDS and our second novel compound, we believe eltanexor has the potential to improve outcomes in patients with hypomethylating agents refractory MDS. On Slide 26, we show that approximately 15,000 patients are diagnosed each year in the US with intermediate to high-risk MDS who need therapy. Again, currently, the only class of drugs that are approved are hypomethylating agents Once the disease progresses on each may there are no other approved therapies. Survival is very short along the line of 4 to 6 months.

There's a clear, high unmet need and an opportunity to improve outcomes for patients with MDS that's refractory to HMAs'. Turning to slide 27, our Phase 1 study of single-agent eltanexor reacting in patients with MDS refractory with HMA. In that study, eltanexor demonstrated a 53% overall response rate and a median overall survival of 9.9 months, doubling historical controls of 4 to 6 months. In addition, new results as 2021, demonstrate that the response rates also correlated to improved overall survival.

The median overall survival for patients with a complete response with nearly 12 months compared to 3 months for patients with progressive disease, a hazard ratio of 0.023. Based on this promising signal observed in the Phase 1 study on Slide 28, shows our ongoing Phase two expansion and we've initiated in 2021, topline data from 2023. Also of note, just a few weeks ago, the FDA granted orphan drug designation for eltanexor for the treatment of MDS. We believe this designation reinforces eltanexor potential to improve clinical outcomes for patients with HMA refractory MDS.

With that, and I will advance this by 29, and turn the call over to Mike Mason, to review the strategic partnerships driving our global footprint, as well as our quarterly and full-year financials. Mike.

Michael Mason -- Chief Financial Officer

Thank you, Jatin. Turning now to Slide 30, our business development activities continue to focus on leveraging strategic partners to support commercialization outside the United States. As Richard mentioned earlier, in December 2021, we signed an exclusive license agreement with the Menarini Group. Whereby Menarini will develop and commercialize XPOVIO in the EU, UK, and Latin America, among other territories.

In exchange, Karyopharm received an upfront payment $75 million and is eligible to receive an additional $202.5 million in future milestones based on regulatory and sales performance, plus tiered double-digit royalties on that. Menarini is a strong EU-based partner, there were $4 billion in annual revenue. They operate in over 140 countries and have a deep commitment to the developing treatment, addressing oncologic and hematologic diseases. This deal adds to the growing global footprint, bringing XPOVIO to patients worldwide with partners for Karyopharm in Canada, Neopharm in Israel, and Antengene in Asia Pacific.

With Antengene, Karyopharm recorded $19.5 million in milestone revenue from Antengene in the fourth quarter 2021, with cash payment expected one year from the anniversary of their launch. Turning to our financial, since we issued a press release earlier today with the full financial results, I will just focus on the highlights begin on Slide 31. Total revenue for the fourth quarter of 2021 was $126.3 million, compared to $35.1million for the fourth quarter of 2020. Net product revenue, from US commercial sales of exposure for the fourth quarter of 2021 was $29.8 million, compared to $20.2 million for the fourth quarter of 2020, representing a 47% increase year-over-year.

The estimated gross to net discount for XPOVIO in the fourth quarter was 15%. We expect gross to net discounts to be in the 15% to 20% range for the full year 2022. We recognize $96.5 million of license and other revenue in the fourth quarter of 2021, including the upfront payment of $75 million entering. R&D expenses for the fourth quarter of 2021 were $44 million, compared to $37.2 million for the fourth quarter of 2020.

SG&A expenses for the fourth quarter of 2021 were $34.6 million, compared to $33.9 million for the 2020. Cash, cash equivalents, restricted cash, and investments as of December 31, 2021, total $235 million, compared to $276.7 million as of December 31, 2020. Based on our current operating plan, we are expecting net product revenue of $135 to $145 million for 2022, reflecting approximately 40% growth compared to 2021. Non-GAAP R&D investment expenses, which excludes stock-based costs, best to be in the range of $265 to $280 million for the full year of 2022.

And finally, that our existing cash, cash equivalents, and investments, as well as the revenue expect to generate from a XPOVIO product sales and other license revenues will be sufficient to fund our planned operations into early 2020 for. I'll now flip to slide 32 and turn the call over to Richard for some final thoughts, Richard. 

Richard Paulson -- President and Chief Executive Officer

Thanks, Mike. 2021 was a very strong year for Karyopharm, and I'm excited about our future, especially following the positive Phase 3 SIENDO study, plus our progressing and focus pipeline. We are maintaining strong momentum with a number of key near-term catalysts and corporate milestones for us to deliver on, as we continue to deliver for patients with high unmets need and strengthen our organization as outlined on p53. For the multiple myeloma program, we expect to leverage our commercial capabilities, striving to become the standard of care in second line plus both anti-CD38 and increase US XPOVIO of sales throughout the year.

Those are the first patients in our Phase 3 study evaluating selinexor, pomalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma in the first quarter, and receive a decision from the CHMP and EMA, under MAA requesting approval for selinexor, bortezomib, and dexamethasone in patients with multiple myeloma following at least one prior therapy in the first half of 2022. We're the enemy through a cancer program. We plan to submit the detailed results from the study for presentation at upcoming medical meeting in the first half of 22. The plan to submit a supplemental new drug application to the FDA during the first half of 22.

And finally, we plan to conduct pre-launch activities in anticipation of a potential approval and launch in the first half of 23. For the myelofibrosis program, we expect to report top-line Phase 1 data in combination with JAK inhibition, in treatment naive male fibrosis during the second half of 22 and report top-line Phase 2 data in previously treated myelofibrosis during the second half of 23. And finally, for the MDS program, we expect to report preliminary Phase 1 out facts or data in combination with HMA, and frontline MDS in 22, and report top-line Phase 2 data in HMA, refractory MDS in the first half of 23. In closing, I would like to give a heartfelt thank you to our teams, especially all the dedicated people who serve to move the [inaudible] trial forward during COVID and deliver our data rapidly.

I look forward to updating the investment community on our continued progress in the months and quarters ahead. And with that, I would now like to ask the operator to open the call up to the question-answer portion of today's call. Operator.

Questions & Answers:

Operator

Thank you. We will now begin the question and answer session.[Operator instructions] We will pause momentarily to assemble our roster. My first question comes from Maury Raycroft with Jefferies. Please go ahead.

Maury Raycroft -- Jefferies -- Analyst

Hi. Good morning, everyone, and congrats on the updates today, and thanks for taking my questions. I'll start off with myeloma guidance. Can you tell us what's going into your assumption of $135 to $155 million and the 40% growth for XPOVIO in 2022? What proportion of earlier line patients are you assuming and is there anything built in to your assumptions on durability?

Richard Paulson -- President and Chief Executive Officer

Thanks, Maury. Just to correct that, our guidance is $135 to $145 for the year, and maybe I let Sohanya talked to what's going into that because of that guidance, Sohanya.

Sohanya Cheng -- Chief Commercial Officer

Great, thanks Maury for the question. So, yeah, we feel very confident about the annual guidance of $135 to $145, which is roughly 40% growth year over year, and it's in line with many best-in-class launches in the multiple myeloma's phase. As far as growth drivers, we look at what drove growth in 2021, and it was strong execution and the new positioning in the wide phase of second to fourth line, and we'll continue to focus in these areas. There are three key growth drivers.

The first is the continued shift into early align, where we anticipate being the most continued rapid growth in the third line. In fact, in 2021, XPOVIO was the fastest-growing multiple myeloma product in the third line, and we anticipate continuing to see this shift into early alliance. We're approaching roughly about half of our patients now in the second to fourth line. And then the remaining half in the fifth line plus.

The second growth driver is the continued expansion in the breadth and depth of use of the product. So we continue to add more accounts, as well as increase our penetration at our top myeloma account. The third growth driver is the continue to move the need on I intend to prescribe data and the perception of the product. And as the community is building confidence in our use of our new lower dose, Once XPOVIO-base triplet regimen, that shift will continue to happen.

So those are the kind of the key ingredients driving growth and part of the guidance for next year.

Maury Raycroft -- Jefferies -- Analyst

Got it. That's really helpful, and I also wanted to ask you a question on SIENDO. So, if you can talk more about the proportion of endometrial maintenance that is wild-type p53, and how does that population fit into your regulatory and commercial strategy?

Richard Paulson -- President and Chief Executive Officer

Yeah. Thanks so much for that, Maury. So, when you look at patients with p53 wild-type, approximately 50% of patients with advanced individual cancer who have this, and we look at within our study approximately 50% as well in our study have wild-type p53 so consistent with what we see in the broader patient population. I think the second question comes to the regulatory kind of forward with that.

So I think I want to be very clear and remind folks, that we have a positive Phase 3 study for the overall patient population. So we have ongoing discussions with the agency, and we'll continue to have that to be part of that discussion for the final label negotiation.

Maury Raycroft -- Jefferies -- Analyst

Got it. And also for the 103 patients, that number with wild-type p53, is that a two to one ratio to for this study? Or can you say more about how many patients were in the treatment versus placebo? And just clarifying, does that number represent the number of events? Or is that the PFS for the p53 population still maturing?

Richard Paulson -- President and Chief Executive Officer

Yeah, so those 103 patients, I would say, the final top-line results are based on 104 patients, and same thing for the subgroup analysis. So that itself is fixed, and so will present the full data set at a major medical meeting.

Maury Raycroft -- Jefferies -- Analyst

Got it. OK. Congrats again, and thanks for taking my question. 

Richard Paulson -- President and Chief Executive Officer

Thanks, Maury.

Operator

Our next question comes from Peter Lawson with Barclays. Please go ahead.

Peter Lawson -- Barclays -- Analyst

Hey, thanks for taking my question. And congratulations to all. On the SIENDO study, just as we think about the p53 separate. Is that something you push in the label, or you going for a broader label? That means testing an individual can. 

Richard Paulson -- President and Chief Executive Officer

Thanks, Peter. I think we just touched on the overall study, obviously, as we've shared as positive and as a positive statistical significant improvement in patients in the maintenance setting. And so when we look at this area right now, there are no other approved therapies for these patients. So as we look at that, we need to understand that the full data sets as we continue to do the analysis on this, and we'll engage with the FDA, over the near term to work on reviewing the data and determining what the final label will be. 

Peter Lawson -- Barclays -- Analyst

Will we get a p53 mutant breakout for whether it's PFS or hazard ratio?

Richard Paulson -- President and Chief Executive Officer

They absolutely will provide the full dataset as we presented a major medical meeting. 

Peter Lawson -- Barclays -- Analyst

Gotcha. OK. Thanks for taking the question.

Operator

Our next question comes from Mike Hall with Morgan Stanley. Please go ahead.

Mike Hall -- Morgan Stanley -- Analyst

Hey, guys, thanks for taking the question. Just to follow-up on XPOVIO 2022 guidance, and just thinking about the quarterly progression here, should we consider maybe any seasonality in 1Q or continued maybe pressure from Omicron that persists in 1Q? Thanks.

Richard Paulson -- President and Chief Executive Officer

Sohanya, you want to take that?

Sohanya Cheng -- Chief Commercial Officer

Yep. Thanks for the question, Mike. So we are not disclosing quarterly guidance. We've provided the annual guidance of the $135 to $145 million.

As far as quarterly seasonality, given the variances we see in the market in the different quarters, to your point, we will focus on year-over-year performance moving forward for that quarter. And again, we feel positive about the annual guidance we've given. To answer your question on Omicron variant. So in Q4 and 2021, we did see the impact of COVID on oncology patient visits compared to pre-COVID baseline.

However, in January, the Omicron variant has now added pressure on the healthcare system and our access to providers. But we continue to leverage a very nimble and patient-centric sales force, and strong digital and commercial capabilities, and we continue to see strong support across our key growth drivers. We remain laser-focused on strong execution, and positioning XPOVIO as the standard of care in the second-line plus.

Mike Hall -- Morgan Stanley -- Analyst

Thank you.

Operator

Our next question comes from Brian Abrahams with RBC. Please go ahead.

Steven Duong -- RBC Capital Markets -- Analyst

Hi, this is Steve, I'm for Brian. Congrats on the progress, and thanks for taking our question. Which areas do you plan to revisit any other indications in the science study to look for a possible effect of p53 in ovarian or cervical cancer? And maybe as a follow-up, are there any differences in the adverse event profile between the wild-type p53 population and the overall population? Thank you.

Richard Paulson -- President and Chief Executive Officer

Yes, I'm sorry, the first question was on adverse event profile, and so I think we can comment is that we don't expect to see any differences right in the biology between those two patient populations and will provide that full dataset to move along. With key though, is that what you need is something that's well-tolerated in the maintenance study. And the biggest indicator is that 10.5% discontinuation rate, which is very low in that setting and really speaks to the tolerability of once weekly low dose selinexor in the maintenance setting. 

Jatin Shah -- Executive Vice President and Chief Medical Officer

Can you repeat first question for me?

Steven Duong -- RBC Capital Markets -- Analyst

Is on looking at other indications on science? with the science that we're [inaudible] study

Jatin Shah -- Executive Vice President and Chief Medical Officer

Yeah, so looking at ovarian cancer and endometrial cervical cancer, so those are the two other histology in the science study, ovarian and endometrial. So we're clearly committed to gynecologic malignancies and we'll have further discussions. But again, our four key programs is going to be myelofibrosis, MDS, myeloma, and endometrial cancer, and we'll continue to build upon this platform. 

Steven Duong -- RBC Capital Markets -- Analyst

Great, great thank you.

Operator

Our next question comes from Eric Joseph with J.P. Morgan. Please go ahead.

Eric Joseph -- J.P. Morgan -- Analyst

Hi, good morning. Thanks for taking the questions. I'm curious if you guys are relieved to see, know, I'm curious whether you've taken a preliminary look at OS trend. Appreciating that it's not a primary, it's going to be a secondary point here, just wondering whether it might be a gating factor to this NSDA submission, and whether this might be part of the overall package that you would submit to FDA.

And then secondly, as it relates to the the the primary endpoint analysis of the PFS, does this statistical analysis plan make any distinction between intent to treat and per protocol population? And if so, what population is reflected in this [inaudible]

Richard Paulson -- President and Chief Executive Officer

Yes. Absolutely. So number one, no overall survival is not a gating factor, the submission of the US FDA. Number two, too early, with too few events with overall survival events to make any conclusions.

And number three, for the primary PFS statistical analysis plan agreed and reviewed by the FDA. It is primary is progression-free survival by investigator on an intent to treat. And that's the data that we have presented.

Eric Joseph -- J.P. Morgan -- Analyst

OK. Great. And perhaps we could follow-up on just one XPOVIO question. Commercial questions related to the guidance and also for Q performance.

Can you just comment on how patients that were new to brand trended in fourth quarter compared to third quarter? And as part of the guidance for this year, how should we be thinking about that metric new to brand trending sequentially?

Richard Paulson -- President and Chief Executive Officer

Thank you, Eric, maybe I'll turn that to you, Sohanya.

Sohanya Cheng -- Chief Commercial Officer

Yeah, thanks, Eric. So we continue to show strong new patient starts, and we also showed improvement in our refill rate, with patients being on therapy longer because of the earlier line trip. Think as we move into 2022, those three key growth drivers of the earlier lines to the increase in the breadth and depth of use, and the improvement in I intend to prescribe data should all contribute toward increased momentum with our new patients as well as our refill rate.

Eric Joseph -- J.P. Morgan -- Analyst

OK. OK. All right, thanks for taking the question, guys.

Operator

Thank. Our next question comes from Jonathan Chang with SVB Leerink. Please go ahead.

Jonathan Chang -- SVB Leerink Partners -- Analyst

Hi, guys, thanks for taking my questions and congrats on SIENDO. First question, what is your strategy for commercial success in SIENDO? Are there lessons learned from the multiple myeloma and DLBCL experience that are applicable here? And second question, can provide any color around the duration of treatment that you're seeing in multiple myeloma?  And are you seeing a difference in duration between earlier line versus the penta in multiple myeloma treatment? Thank you.

Richard Paulson -- President and Chief Executive Officer

Thanks, Jonathan. Maybe I'll take the first question. So I think again, when you look at the SIENDO patient population, obviously we're still going to be engaging very much with regards to our action and our plans forward. I think this is very different than multiple myeloma because there are currently no approved therapies in a maintenance setting.

So we have the potential to be the first and only therapy, we believe in this by itself is a real significant market opportunity because I think it's so and you talk to the engines of 14,000 patients in frontline, with about 67% responding to chemotherapy. So those numbers obviously are different than the multiple myeloma market in the different areas. So now in the maintenance setting, the difference here is you're really treating through progression, and as we have shared in here, the median PFS for the total population is 5.7 months, but also in that in that p53 wild-type population, it's 13.7 months. We're showing through that with the discontinuation rate of 10.5%, that's really been well tolerated for those 13 months.

So, as we know in our study, approximately 50% of the wild-type p53 patients are in the study. And that's the p53 status is a very known and actionable mutation as part of the kind of standard evaluation of workup for when people are looking at their patients. So as we move forward, we need to continue to do more work on this, but it's well understood, well documented, well measured. And physicians, I think, are patients are really looking for looking away from the watch and wait and being in a move to treat their cancer and obviously extend their time in remission.

So, you know, very excited about it and also kind of a very different opportunity. And then the last point I would close with on that is and here we're taking our established teams, which are well-established, which are delivering excellent results, and are going to be able to move forward rapidly and engage with with healthcare practitioners following the potential approval and a label. And for the second part of the question to will turn to Sohanya to talk overall about what we're seeing in terms of evolution for patients being on therapy.

Sohanya Cheng -- Chief Commercial Officer

Thanks, Richard. So multiple myeloma duration of therapy, so preliminary data is showing more patients are staying on therapy longer. And again, that's driven by a shift into earlier line and better side effect management. Now it's important to remember this data is still maturing.

We're still in the early stage of our second line plus long, so we cannot definitively guide to duration at this time. And we're also in that dynamic phase of our transition into earlier lines of use. But as we evolve into early align, and we are now approaching the 50 50 split between second and fourth line and fifth line plus in our patient population, with our greatest growth happening in our third line, we we will continue to see these patients in early line therapy longer.

Jonathan Chang -- SVB Leerink Partners -- Analyst

Got it. Thanks for taking the question.

Operator

All right, next question comes from Ed White with H.C. Wainwright. Please go ahead.

Ed White -- H.C. Wainwright and Company -- Analyst

Good morning, thanks for taking my question. Can you just give us perhaps the youth, the prescribing under the label with Velcade versus what you're seeing with the other drugs under the NCCN guidelines? How is that breaking out? And how's the growth been under with the NCCN guideline?

Sohanya Cheng -- Chief Commercial Officer

Yes. So XPOVIO-based Triplet use as an overall trend that is rising significantly. And to break it down, 60%t or so from the data that we see of XPOVIO-based Triplet are a XPOVIO combination with Velcade and death. And again, this is our approved indication and the only triplet regimen we promote to.

But we also know to your point, there are other combinations with pomalidomide, carfilzomib, and daratumumab on the NCCN guidelines. For those that remaining 40% or so of that triplet from the data that we see where it is, those other combinations, but an overall rapid rise in that trend from doublet to triplet.

Ed White -- H.C. Wainwright and Company -- Analyst

Great. Thanks for taking my question.

Operator

Our next question comes from Arlinda Lee with Canaccord. Please go ahead. 

Arlinda Lee -- Canaccord Genuity -- Analyst

Thanks for taking my questions. I guess I had another one on the duration. Can you comment maybe on the duration of treatment? Is that a contributing on the growth in sales? or is it an improved duration versus what proportion can you help us understand the improved duration versus the patient? And then on the standard side, can you remind us when you initially started the trial, what were kind of the ongoing regulatory discussions then and maybe what FDA was looking for, and how you think about that?

Richard Paulson -- President and Chief Executive Officer

Sohanya, you want to take the first part.

Sohanya Cheng -- Chief Commercial Officer

Yeah, thanks. Thanks, Arlinda. Again, the earlier line trip right, it's got to drivers here. One is there's a larger addressable population in the earlier line, and hence XPOVIO see that remains a focus for us to establish in the second to fourth line setting.

But in addition, the growth driver is as these patients move into earlier lines, they do stay on therapy longer. So a second line patient will be on therapy longer than a fourth line patient. So preliminary data is showing that more patients are gradually seeing therapy longer, and that's driven primarily by that shift into earlier line, but also the better side effect management. Again, data is still maturing.

We're still a year into our Boston launch, and so we can't definitively guide to mean duration also that we are still in that dynamic phase into the earlier line shift. But we're seeing kind of good progress as that early line shift happens with those patients staying on therapy longer.

Richard Paulson -- President and Chief Executive Officer

And Jatin, if you can just address the second part of Arlinda's question.

Jatin Shah -- Executive Vice President and Chief Medical Officer

Yeah, absolutely. You know, we're engaged with the agency throughout the entire lifecycle of the trial from the beginning and continuously. And the one key point in the regulatory discussions is it's clear that the primary endpoint is progression-free survival by investigator on intensive training that has not changed. And that's what the results report positive these results from the end of.

Operator

[Operator instructions] Our next question is a follow-up from Peter Lawson with Barclays. Please go ahead.

Peter Lawson -- Barclays -- Analyst

Thanks for the follow-up. Just on the wild-type p53 population. Does that make you rethink in any way the use endometrial in the sense of potentially using an earlier line or combinations, etc.?

Richard Paulson -- President and Chief Executive Officer

 Yeah, great question. Thanks for that, Peter. Obviously, we share the same excitement on p53, as well as the entire population. We'll dive more into this with additional data analyzes with our investigators and the agency for future trials.

Peter Lawson -- Barclays -- Analyst

Gotcha. And just maybe a question on the [inaudible], just what was the stock option expense in 2021 of just trying to back out the guidance? 

Michael Mason -- Chief Financial Officer

[Inaudible] expense was just about $30 million

Peter Lawson -- Barclays -- Analyst

Perfect. Thank you. And just on the p53 mutant population, are you going to break that now or just wait for a conference? And would that be? Would you have to break down the label as well for the p53 mutant population?

Michael Mason -- Chief Financial Officer

 It'll be broken out at a conference as the data is presented, and then I think as referred to, we have to engage with the FDA and look at the totality of the data and determine the outcome is looking at the label 

Peter Lawson -- Barclays -- Analyst

How should we think about pricing in the endometrial population?

Michael Mason -- Chief Financial Officer

And this is I mean, our products already on the market, so it's going to be remaining at the same price, I think that the key thing again to look at is maintenance setting patients are really treating themselves through progression. With physicians and patients, they want to, you know, and extend the time in remission. And I think that's where it's really important to looking at those mediums, as we talked to, but also looking at big part to the real importance that over over that long tail. When are seeing that, you know, about 35% of patients are still in remission one year after starting therapy, and that'll be very important in the duration of therapy.

And as we've talked to, we see with the discontinuation, it's been very well tolerated for a long period of time and for instance, the 13 months that we see in the wild-type p53 population. So all those factors will obviously look at, you know, the total value of the market. But from a pricing perspective, you know, we're at the same price. We're already in the market.

Peter Lawson -- Barclays -- Analyst

OK. Thank you. Just a final question on the guidance. I know you're not doing quarterly guidance, but there are any headwinds or tailwinds that we should be thinking about year over year, when we're kind of doing the model.

Sohanya Cheng -- Chief Commercial Officer

Yeah, I think that the tailwinds are really the key growth drivers where we continue to sustain our momentum as far as headwinds, I think the wild card continue to remain the impact of Omicron variant. But as I mentioned earlier, we are adapting to it and we've got strong commercial digital capabilities and we'll we'll see how that evolved. But our focus remains on strong execution and positioning XPOVIO as the standard of care in second-line plus.

Peter Lawson -- Barclays -- Analyst

OK. Thanks so much, thanks for taking all the questions.

Operator

This concludes our question and answer session. I would like to turn the conference back over to Richard Paulson for any closing remarks.

Richard Paulson -- President and Chief Executive Officer

Thank you, operator, and thank you for all of our participants today in the call. With that again, we look forward to being able to share our ongoing progress as how we're moving forward with our pipeline and now working forward to continue to focus on trying to defeat cancer and benefit patients' lives who are fighting cancer. So thank you very much, operator.

Operator

[Operator signoff]

Duration: 60 minutes

Call participants:

Sarah Connors -- Vice President, Corporate Communications

Richard Paulson -- President and Chief Executive Officer

Sohanya Cheng -- Chief Commercial Officer

Jatin Shah -- Executive Vice President and Chief Medical Officer

Michael Mason -- Chief Financial Officer

Maury Raycroft -- Jefferies -- Analyst

Maurice Thomas Raycroft -- Jefferies -- Analyst

Peter Lawson -- Barclays -- Analyst

Mike Hall -- Morgan Stanley -- Analyst

Steven Duong -- RBC Capital Markets -- Analyst

Eric Joseph -- J.P. Morgan -- Analyst

Jonathan Chang -- SVB Leerink Partners -- Analyst

Ed White -- H.C. Wainwright and Company -- Analyst

Arlinda Lee -- Canaccord Genuity -- Analyst

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