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*Stock Advisor returns as of February 24, 2025

Actual events or results could differ materially. Therefore, I refer you to the discussion under the heading Risk Factors in Geron's most recent periodic reports filed with the SEC, which identifies important factors that could cause actual results to differ materially from those contained in the forward-looking statements and our future updates to those risk factors. Geron undertakes no duty or obligation to update our forward-looking statements. With that, I'll turn the call over to Chip.

Chip.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Aron, and good morning to everyone on the call. Thanks for joining us today. 2024 was a terrific year for Geron and for Rytelo, our first-in-class telomerase inhibitor. Rytelo has a unique mechanism of action that represents a highly differentiated treatment with blockbuster potential in this high unmet need, lower-risk MDS population.

The FDA approved Rytelo in June of 2024 for the treatment of certain lower-risk MDS patients, including patients in the front line who are ESA ineligible, second-line ESA relapsed and refractory patients, and third-line plus patients, regardless of RS status across lines of therapy. In addition, in August of 2024, Rytelo received favorable placement in the MDS NCCN guidelines, including a Category 1 treatment recommendation in second-line RS-positive and RS-negative patients, regardless of prior treatment. We've also been pleased with further validation for Rytelo in lower-risk MDS in Europe, where the CHMP adopted a positive opinion in December, recommending the approval of Rytelo for the treatment of ESA ineligible and ESA relapsed/refractory non-del 5q adult patients with transfusion-dependent anemia due to lower-risk MDS. The European Commission is expected to make a final decision on our Rytelo marketing authorization application in the first half of 2025.

Beyond lower-risk MDS, our development efforts in myelofibrosis also continue to progress in 2024. We have now achieved 80% enrollment in our pivotal imetelstat phase 3 IMpactMF trial in Jak-i relapsed/refractory myelofibrosis. Many of you will recall, this is the first myelofibrosis phase 3 trial with overall survival as the primary endpoint. This study assesses the potential to alter the course of myelofibrosis with imetelstat.

Based on our current enrollment rate and number of death rates, we expect the interim analysis may occur in the second half of 2026, while we expect the final analysis may occur in the second half of 2028. We believe that if this trial is positive, imetelstat could transform the treatment landscape for this high unmet need, relapsed/refractory myelofibrosis patient population, that has such a dismal survival today; and in doing so, to potentially double the Rytelo commercial opportunity. We're proud of these robust 2024 accomplishments. Since launching in the U.S.

lower-risk MDS market beginning at the end of June of 2024, we've seen positive uptake of Rytelo. In the fourth quarter of 2024, our second full quarter on the market in the U.S., we achieved $47.5 million in Rytelo net product revenue. Since product availability at the end of June 2024 and through year-end, we achieved $76.5 million in net product revenue, which exceeded our internal expectations. From a financial perspective, we ended the year with a strong cash position of approximately $503 million, which we expect will enable us to reach profitability without additional financing if our internal sales and operating expense expectations are met.

However, despite achieving this revenue in the first two quarters of launch, we have observed flat revenue trends over the last few months. As many of you will recall, beginning a few months into launch, we changed our commercial and medical affairs leadership. Jim Ziegler, our chief commercial officer; and Joe Eid, our EVP of R&D, will discuss their assessments and actions in more detail later in this call. Before I hand the call over to Jim, however, I want to reinforce our confidence in the potential commercial opportunity of Rytelo, which is supported by robust clinical and scientific evidence that Rytelo is a highly differentiated product.

We believe that the compelling phase 3 data, along with the favorable FDA label and NCCN guidelines, support Rytelo's establishment as a standard of care for high unmet need, eligible lower-risk MDS patients, particularly in the second line. Most importantly, many hematologists that we speak with have the same assessment. So, with that, I'll turn the call over to Jim for our commercial update. Jim.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Thank you, Chip, and good morning, everyone. Today, I will address Q4 commercial performance and recent revenue trends, highlight our assessments and actions to focus on our key value drivers, and thus help us realize the significant commercial opportunity we have with Rytelo in this high unmet need patient population. As described previously by Chip, we achieved $47.5 million in Rytelo net product revenues in the fourth quarter of 2024. This demand for Rytelo was supported by strong payer access.

Payers responsible for approximately 80% of U.S. covered lives have implemented medical coverage policies for Rytelo that are consistent with the FDA label, clinical trials, and/or NCCN guidelines. New patient starts and duration of treatment are the key primary drivers of revenue. For duration of treatment, it is important to note that even the longest treated patient in the commercial setting are just sitting the median of approximately eight months observed in the phase 3 IMerge trial, and our market research suggests the duration of treatment in commercial Rytelo patients treated to date appears consistent with that observed in IMerge.

However, with respect to new patient starts, we have observed flatness over the past few months. Specifically, even though we see Rytelo being utilized across RS-negative and RS-positive first-line ESA ineligible, second-line ESA relapsed/refractory, and third-line plus patients, the majority of new patient starts have come from the third-line plus patient segment, with the second-line new patient starts lower than our expectations. Our priority is to drive new patient starts across the breadth of population and our FDA label so that we are not niched to a third-line treatment. We are particularly focusing on ESA relapsed/refractory RS-negative patients, where we believe Rytelo's benefit are notably differentiated and where there is substantially unsatisfied patient population.

There are other factors we are also addressing which we believe will help accelerate uptake in earlier line patients. First, below the national level trend, we see variability in regional, territory, and account-level performance. Some territories and accounts are performing very well and competing and winning at the local level. Other territories and accounts have opportunities for improvement where we are refocusing our support and sales training efforts.

Second, we believe the lower-risk MDS market is promotionally sensitive, with time in front of the healthcare providers, or HCPs, being a key factor to changing their prescribing behaviors. We are taking steps to optimize our engagement with target HCPs. Joe will also highlight educational efforts by our medical affairs team to increase HCP awareness and education. We expect that as HCPs gain successful clinical experience with Rytelo in later lines and often difficult-to-treat patients and as we work to raise awareness and increase engagement, they will choose Rytelo in earlier lines of treatment.

Third, as Chip mentioned earlier, our organization changed commercial and medical affairs leadership a few months into launch. We have a balanced sense of urgency and a thoughtful approach in implementing changes to quickly drive operational excellence and minimize launch disruption. We have augmented the team with experienced senior leadership to support these efforts. Dawn Winn joined in October 2024 as senior vice president, commercial strategy and operations.

Prior to joining Geron, Dawn was at Gilead Sciences for almost 20 years and most recently served as vice president, commercial operations, where she led a team of approximately 150 people responsible for supporting the U.S. business. Dawn brings a deep background in commercial analytics to Geron. Jim Hassard joined in November 2024 as senior vice president, sales and marketing.

He is another strong commercial leader with a 30-plus-year successful track record. His prior experiences include roles as chief commercial officer at two publicly traded biotech companies after spending most of his career at Amgen in senior sales and marketing leadership roles, including a country manager role. Together, Dawn and Jim and their teams are working to improve insights, strategies, and execution. We are also assessing other possible root causes for the flat revenue trends and have implemented or are in the process of implementing several changes such as scaling up our analytics capabilities, refining our segmentation and targeting, and improving our promotional and sales force effectiveness, which we believe will help us more fully capture the significant commercial opportunity for Rytelo in lower-risk MDS, which I will speak to on the next slide.

As shown on Slide 8 in our earnings deck, we estimate that, in 2025, the U.S. Rytelo total addressable lower-risk MDS patient population is approximately 15,400 patients and includes patients recommended in the NCCN guidelines. This includes approximately 3,400 first-line ESA ineligible patients, approximately 7,600 second-line, and 4,400 third-line plus patients, with approximately 75% of patients with RS-negative and 25% of patients with RS-positive status. As I mentioned, our efforts are particularly focused on the eligible RS-negative population where Rytelo is the only drug approved for ESA relapsed/refractory patients.

Assuming the duration of treatment observed in IMerge and based on the current net price, there is potential to achieve blockbuster status by treating approximately one-third of the U.S. Rytelo total addressable patients. I want to thank our dedicated commercial team and the cross-functional teams at Geron for their hard work to ensure that treatment-eligible patients have broad and timely access to Rytelo. I will now turn the call over to Joe for a medical update.

Joe.

Joseph Eid -- Executive Vice President, Research and Development

Thank you, Jim, and good morning, everyone. As Jim mentioned, we are excited about the opportunity to bring Rytelo, an innovative and first-in-class drug, to as many eligible patients as possible. I joined Geron in November. And working with the medical and commercial teams, we have now identified areas for improvement.

Similar to Jim's approach in the commercial organization, we are continuing to build and enhance our medical organization. As a first-in-class drug with a unique mechanism of action, Rytelo requires a steady flow of data to raise awareness and manage knowledge and data gaps at launch. To that end, we have actively prioritized our publication strategy and are targeting key medical congresses to reach the medical community to help increase awareness. Together with commercial, we are also investing in market development and KOL engagement, which is particularly important in this launch given that 70% of the phase 3 IMerge investigators were ex-U.S.

At ASH in December, new analyses from IMerge phase 3 were presented but are a good example of our proactive approach to bring data to the medical community to increase awareness, address potential knowledge gaps, and educate on key data that provide insights to physicians on how they can use Rytelo in their clinical practice. The KOL engagement at ASH was robust and encouraging, and the data presented there reinforced Rytelo's potential as a standard of care second-line treatment for lower-risk MDS patients, regardless of prior therapy. In addition, the feedback we received at ASH has informed our plans to refresh our clinical development plan with the goal of generating data that will expand the application of Rytelo in MDS and other potential indications and support our scientific engagements. I expect our market development activities, data generation, and publication activities to make a positive impact as they continue to roll out.

Before I turn the call over to Faye, as a hematologist who has treated MDS patients for many years, I'd like to share my excitement for Rytelo. I believe Rytelo is truly an innovative drug with a unique mechanism of action that will change how MDS patients are treated and managed. I will now turn the call over to Faye for clinical update. Faye.

Faye Feller -- Executive Vice President, Chief Medical Officer

Thank you, Joe, and good morning, everyone. Today, I will provide an update on our ongoing myelofibrosis development programs. First, I will speak to our phase 3 IMpactMF clinical trial, the first with overall survival as a primary endpoint. We have conviction in this first-of-its-kind trial based on significant imetelstat clinical experience myelofibrosis.

Starting with the pilot study out of Mayo Clinic, which was eventually published in The New England Journal of Medicine and was the basis for our phase 2 IMbark study. In IMbark, we enrolled participants with Jak-inhibitor relapsed/refractory myelofibrosis to evaluate the efficacy and safety of two dose regimens of imetelstat, with overall survival as a key secondary endpoint. We found that the median overall survival in the 9.4 milligram per kilogram arm compared favorably to historical controls, which are around 11 to 16 months. To further validate the OS signal, we conducted a real-world data study to compare best available therapy of closely matched patients in the Moffitt Cancer Center's database to the 9.4 milligram per kilogram imetelstat arm in IMbark.

In this analysis, we found that median overall survival more than doubled versus those on best available therapy. This gave us the confidence to design a phase 3 trial IMpactMF with an OS primary endpoint and 2-to-1 randomization imetelstat to best available therapy. As Chip mentioned, this trial is now 80% enrolled. Based on the enrollment rate and death rates, we now expect the interim analysis from this study in the second half of 2026 and the final analysis in the second half of 2028.

This trial was designed to confirm the strong OS signal observed in the phase 2 study. And if that reads out positively, it would be a paradigm shift and transformational for patients with Jak-inhibitor relapsed/refractory myelofibrosis who have limited treatment options and dismal survival. We are also sponsoring the phase 1 IMproveMF clinical trial, from which we presented the first results at ASH, suggesting tolerability of imetelstat combined with ruxolitinib as first-line treatment in patients with myelofibrosis. We presented data from Part 1 of the study showing that imetelstat was well tolerated, with no dose-limiting toxicities reported at any imetelstat dose level within the first 28 days of Cycle 1.

The PK profile for imetelstat and ruxolitinib in this study were consistent with previous monotherapy studies. Importantly, preliminary results showed variant allele frequency reductions in driver mutations associated with MF across all four dose cohorts. Additionally, patients treated with imetelstat 9.4 milligram per kilogram experienced stable hematology values over time. Imetelstat 9.4 milligram per kilogram every four weeks was selected for dose confirmation and expansion, and we are actively enrolling patients in this Part 2 of the study.

Initial results from Part 2 are expected in 2026. I look forward to continuing to keeping you updated on our clinical development progress. And with that, I'll turn the call over to Michelle for a financial update. Michelle.

Michelle Robertson -- Executive Vice President, Finance, Chief Financial Officer, and Treasurer

Thanks, Faye, and good morning, everyone. The detailed Q4 and full year 2024 financial results, please refer to the press release we issued this morning, which is available on our website. As of December 31, 2024, we had approximately $502.9 million in cash, cash equivalents, restricted cash, and marketable securities. Total product revenue net for the three and 12 months ended December 31, 2024 was 47.5 million and 76.5 million, respectively.

There was no product revenue in the prior-year periods given that Rytelo was approved by the FDA in June 2024. Total net revenue for the three and 12 months ended December 31, 2024 was 47.5 million and 77 million, respectively, compared to 23,000 and 237,000 for the same period in 2023. Total net revenue includes license fees and royalties, in addition to any net product revenue. Total operating expenses for the three and 12 months ended December 31, 2024 were 67.6 million and 250.7 million, respectively, compared to 54.3 million and 194.2 million for the same period in 2023.

Cost of goods sold was approximately 783,000 and 1.3 million for the three and 12 months ended December 31, 2024, respectively, which consisted of costs to manufacture and distribute Rytelo compared to no cost of goods sold in the prior-year periods. Research and development expenses for the three and 12 months ended December 31, 2024 were 23.4 million and 103.7 million, respectively, and 32.9 million and 125 million for the same period in 2023. The decrease is primarily due to manufacturing and quality costs that were capitalized in the current period due to FDA approval of Rytelo compared to being expensed in the prior period. The decrease is partially offset by an increase in personnel expenses related to increased headcount and incentive and stock-based compensation expense recognized for the vesting of performance-based stock options upon FDA approval of Rytelo.

Selling, general, and administrative expenses for the three and 12 months ended December 31, 2024 were 43.4 million and 145.7 million, respectively, and 21.4 million and 69.1 million for the same periods in 2023. The increase in general and administration expenses in 2024 as compared to 2023 primarily reflects an increase in personnel expenses related to increased headcount to support the commercial launch of Rytelo in the U.S. and stock-based compensation expense recognized upon FDA approval of Rytelo due to the vesting of performance-based stock options. For fiscal year 2025, we expect total operating expenses to be in the range of approximately 270 million to 285 million, which includes noncash items such as stock-based compensation expense, amortization of debt discounts and issuance costs, and depreciation and amortization.

We expect to reach profitability without additional financing if our current internal sales and operating expense expectations are met. Based on our current operating plans and assumptions, we believe that our existing cash, cash equivalents, and marketable securities, together with anticipated net revenues from U.S. sales of Rytelo, will be sufficient to fund our projected operating requirements for the foreseeable future. I will now turn the call back over to Chip.

Chip.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Michelle. To close, we're very pleased with our accomplishments in 2024, in which we secured U.S. regulatory approval for Rytelo in lower-risk MDS and commercially launched the product in June. We're confident that the strategic and leadership changes we put in place early in the launch, combined with our differentiated product and the high unmet need lower-risk MDS population, will position us to increase our growth trajectory as these investments start translating to results.

We also progressed the U.S. regulatory review process for imetelstat in lower-risk MDS, which positions us to receive EU approval in the first half of 2025 and potentially launch in select EU countries in 2026. Also, in 2026, we expect key readouts from our MF clinical programs, with an expected interim analysis from phase 3 IMpactMF in the second half of 2026, as well as a primary analysis from phase 1 IMproveMF in the same year. Lastly, we believe we're in a strong financial position, thanks to the nonequity financings executed in November of 2024 and the commercial opportunity of Rytelo in the U.S., which we believe position us to reach profitability without additional financing, assuming we meet our operating expense and revenue expectations.

While it is clear that we still have work to do to present Rytelo as a strong treatment option in the patient populations where the needs are greatest and the potential patient benefits are clear, I and my colleagues are confident that refining our sales strategies and execution, investing further in our medical affairs functions, and continuing to increase awareness and engagement with HCPs and patients will allow us to meet our goal of Rytelo becoming a highly valued standard of care across treatment-eligible lower-risk MDS patients. We will now open the line to questions. Operator.

Questions & Answers:

Operator

Thank you. [Operator instructions] Your first question comes from Peter Lawson of Barclays. Your line is open.

Peter Lawson -- Analyst

Great. Thanks. Thanks for the update. Maybe first question would just be around how we think about revenues, your commentary around flat revenues over the last few months, whether you're seeing any week-over-week growth.

And I assume that comment kind of captures January and February. And then the other component would just be around how we think about 1Q revenues themselves, whether that's flat or growing versus 4Q. And then anything you can tell us around revenues and costs as we think about 2025? Thank you so much.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Peter. Appreciate the question. So, Jim will take this question, which obviously relates to both the prior revenues and also for -- you know, you had some questions about potential future revenues in the first quarter. So, Jim.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Good morning, Peter. So, our revenues week over week have had some variability, but what I would say is our four- and eight-week rolling averages underscore the flatness that I characterized on the call. And that flatness continued into the prior week leading up to this call. So, it may be a little bit too early to make a full call on Q1 revenues, but I would characterize and reinforce what we said on the earnings call that the past couple of months have been relatively flat week over week in the four- and eight-week averages.

Peter Lawson -- Analyst

And anything you can say around kind of costs or even revenues for 2025?

Chip Scarlett -- Chairman and Chief Executive Officer

Michelle.

Michelle Robertson -- Executive Vice President, Finance, Chief Financial Officer, and Treasurer

I'm sorry, I didn't hear the question.

Peter Lawson -- Analyst

Yeah. Just any guidance you can provide around revenues for 2025 or indeed cost for 2025? Just kind of marrying up your comment around getting to profitability.

Michelle Robertson -- Executive Vice President, Finance, Chief Financial Officer, and Treasurer

Right. Yeah. I mean, we're -- we have said that we're not providing guidance on the revenue just yet. You know, we have always said that we wanted three or four quarters under our belt.

And I think that just remains consistent with how we're going to talk about guidance for revenue. On the opex, we feel pretty good about our 270 to 285. We've got levers that we can pull, as well as stage-gating expenses. So, we'll manage that as the quarters go on.

And right now, we have no changes to our forecasts, our internal forecasts around profitability.

Peter Lawson -- Analyst

Gotcha. OK. Thank you so much.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Peter.

Operator

The next question comes from Tara Bancroft with TD Cowen. Your line is open.

Tara Bancroft -- TD Cowen -- Analyst

Hi. Excuse me. Good morning and thanks for taking the questions. So, I was hoping you could give us maybe some more detail on the seasonality or patterns, in general, not only that you're seeing with Rytelo, but it appears to be impacting MDS as a whole with luspatercept, too.

So, I'm curious to get your thoughts on what's happening at a higher level in this indication. And then separately, maybe Jim, if you could tell us more about the expected cadence of growth this year that we could see with your implemented changes that you suggested? Thanks so much.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Sure. Thanks, Terry. Good morning.

Chip Scarlett -- Chairman and Chief Executive Officer

Go ahead, Jim.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Sorry, Chip.

Chip Scarlett -- Chairman and Chief Executive Officer

No, go ahead, detail on the seasonality and expected cadence.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Great. So, we have started -- or we saw some seasonality beginning around the holidays, Thanksgiving more specifically, and there is some hesitancy in the market to start some of these products that require, in our case, some monitoring. So, there was a little bit of a delay. I agree with you that as we've looked at other products in this market and ran correlations between our trends and others, there was a very high correlation.

So, it didn't just affect Rytelo, it affected a primary product that's used in this space as well. In terms of the expected cadence, it's really driven off of our business driver, right? We characterize the most important business driver for us as new patient starts. You know, with launch products often start in later line, third-line plus, which we characterized on this call as seeing -- that's where the majority of our use was, even though we saw earlier line, second-line, first-line use. So, it really depends on our effectiveness in driving market share, not just in third-line plus, but in earlier line, second-line, and first-line opportunities.

And our expectation is that as we increase our share of voice, our reach, and frequency and, together with medical affairs, increase the education and awareness, we hope to see, you know, greater impact and use across all lines of therapy. But it's not going to happen overnight. Share of voice and increasing the prescribing behaviors will take some time.

Tara Bancroft -- TD Cowen -- Analyst

OK. Great. Thanks so much.

Operator

The next question comes from Faisal Khurshid with Leerink Partners. Your line is open.

Faisal Khurshid -- Analyst

Hey, guys. On the trends that you've been seeing lately, could you comment on how much of that was impact on new patient starts as opposed to like discontinuations or dose modifications and holidays? I guess the reason for the question is like even if you're starting mostly in third-line patients, right, like shouldn't you be kind of like adding patients at a consistent rate? And I guess like people are also wondering like the duration of therapy should still be, you know, longer than like the time you've been in the market in third line as well or is that not the way to think about it?

Chip Scarlett -- Chairman and Chief Executive Officer

Jim.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Hi, Faisal. Good morning. You know, I think the way you're thinking about it is exactly right. The primary drivers are new patient starts and duration of treatment.

What I said on the call is that duration of treatment at this point, while still early in that, we're only approaching, you know, the median duration of treatment seen in IMerge about right now. That does not appear to be an issue based upon our own market research and KOL. As you know, there isn't perfect data that we can, you know, cite, only data that we triangulate around. But right now, at this point, we don't believe that duration of treatment is inconsistent with that seen in IMerge.

And so, we have seen some softness, and it's related to new patient starts. I think the way to characterize it is, you know, we saw uptake in unmet need, and the treatment was really with some of these early adopters who believe -- who understood and believed in the product. And it's our obligation to really increase the reach and frequency, the share of voice among the majority of physicians who have yet to treat patients with Rytelo.

Faisal Khurshid -- Analyst

Got it. Thank you. And then in terms of like the inflection or potential inflection this year, like you guys have visibility that you should be kind of like at a bottom on new patient growth now? And then like how confident are you that like the new sales strategy will cause an inflection and what kind of timing would -- should we expect on that?

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

That's a great question. I wouldn't characterize it as an inflection. I think others characterized it in the past as a bolus. What we're looking for is steady growth, a steady growth in third line leading to earlier lines, you know, second line and first line.

So, what we anticipate is that with great execution, great targeting, great messaging that as we increase our share of voice and awareness with these physicians, that we would see uptake across the board. Inflections are often associated with new indications, unique publications, things along those lines. So, right now, this is pure execution in order to increase market share and to begin to increase the adoption, if you will, across all lines of treatment.

Faisal Khurshid -- Analyst

Got it. Thank you.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Faisal.

Operator

The next question comes from Greg Harrison with Scotiabank. Your line is open.

Greg Harrison -- Scotiabank -- Analyst

Hi. Good morning. Thanks for taking the question. What feedback are you getting from KOLs and other providers around why they're not using Rytelo as much in earlier lines of therapy and are there any differences based on setting as far as academic versus community? It sounds like from your comments just now that the bulk may be in academic.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Thanks, Greg. I think the first message that I would share with you is that our MD and our KOL feedback that have used Rytelo very simply can be summarized as Rytelo works. And we see that in our market research, in our one-on-one engagements with the KOLs. I think the biggest opportunity for us is to really increase the reach and frequency, our education and awareness, and share of voice, especially, as you point out, with the community.

I'll just give you a very simple, you know, mathematical equation. So, if you think about the 15,400 patients that we characterized as treatment-eligible and you divide that by the number of MDS-treating physicians in the U.S., it only leads to a couple of patients on average that each one of these physicians have. So, it's really important for us to make sure that we get out to as many of these physicians in a cost-effective way through our sales team, our medical affairs team, and our nonpersonnel efforts to really increase the share of voice.

Greg Harrison -- Scotiabank -- Analyst

Great. That's helpful. Thanks again.

Chip Scarlett -- Chairman and Chief Executive Officer

Thank you, Greg.

Operator

The next question comes from Stephen Willey of Stifel. Your line is open.

Stephen Willey -- Analyst

Yeah. Good morning. Thanks for taking the questions. Can you guys maybe just comment a little bit on the patient mix that you've been seeing over the last couple of months, specifically in the second-line setting, both with respect to RS status and prior therapy? And I guess is it safe to say that given the majority of new patient starts are occurring in third-line plus patients, does that imply that Rytelo is primarily being sequenced post-HMAs?

Chip Scarlett -- Chairman and Chief Executive Officer

Jim, do you want to take that?

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Yup. Thanks, Stephen. So, we haven't disclosed exact numbers, but what I can tell you is like most product launches, we're seeing higher use in later lines. But I would underscore that we're seeing utilization in both second line and first line, as you point out.

We have an opportunity to really sharpen our product differentiation, especially in the RS-negative patient population, which many physicians will acknowledge that, you know, second-line RS-negative is one of the areas of high unmet need. I don't know that our messaging has been as specific as it could be, and that's one of the things that we're refining with our segmentation, targeting, and messaging going forward. So, we are seeing utilization across both RS-positive and especially RS-negative. I think we can have a greater uptake in RS-negative given that that's about 75% of the underlying status.

Stephen Willey -- Analyst

OK. And then can you also maybe speak to some of the data that you're now contemplating generating to build on the value proposition of the product profile?

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Maybe I'll turn that to --

Chip Scarlett -- Chairman and Chief Executive Officer

Joe.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Joe and Faye.

Joseph Eid -- Executive Vice President, Research and Development

Can you repeat the question, please?

Stephen Willey -- Analyst

Yeah. Just wondering what data you're now contemplating generating to build on the value proposition of Rytelo.

Joseph Eid -- Executive Vice President, Research and Development

Yeah. I mean, so, you know, the first thing, we have to look at the existing data from the phase 3 program, the IMerge, and respond to questions from physicians about the full spectrum of the benefit for patients from this drug. We are also looking at advancing within the MDS different lines of treatment, whether it's in the first line or sequencing or combination. So, those are potential, you know, ideas that we are pursuing, and we have investigators who are interested in collaborating with us.

Beyond MDS, there's obviously the ongoing myelofibrosis phase 3 program, where we're treating patients who are in the relapsed/refractory setting. But in parallel, we also have a first line in combination with the Jak-inhibitor study that is also in the second part of that development. Beyond that, there are obviously many different areas that the mechanism of action is applicable that we are also looking at collaborating with investigators to advance Rytelo development.

Stephen Willey -- Analyst

OK. Then maybe just last question, I guess, is what is happening in the U.S. just given the flatness in the trajectory of new patient starts? And I know you're not looking to commercialize in Europe until 2026, but does that now kind of change the cadence of perhaps expansion plans outside of the U.S.? Do you need to get the U.S. on track and kind of growing in a new patient start direction before you embark on anything outside the United States? Thanks.

Chip Scarlett -- Chairman and Chief Executive Officer

Yeah. Steve, it's Chip. I think that it would be very easy for us to put our hands on our hearts and say our number one, two, and three focus is on the U.S., the U.S. -- getting the U.S., you know, on track, new patient starts on track, appropriate utilization throughout the areas of high unmet need.

And we are absolutely taking care to look at a variety of different options and to start some of the pre-work for Europe. But I think it would be very, very easy to say that our -- you know, 90-plus percent of our focus is on the U.S. right now.

Stephen Willey -- Analyst

All right. Thanks for taking the questions.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Steve.

Operator

The next question comes from Emily Bodnar with H.C. Wainwright. Your line is open.

Emily Bodnar -- Analyst

Hi. Good morning. Thanks for taking the questions. I guess the first one, in terms of new patient starts, are you mainly seeing prescribers who have already used Rytelo kind of represcribe it to new patients, or is it mostly coming from new prescribers and new centers? And then maybe if you could comment a bit on what factors are contributing to the slower enrollment in myelofibrosis and the potential for any guidance on when you expect to reach full enrollment.

Thank you.

Chip Scarlett -- Chairman and Chief Executive Officer

OK. So, Jim, why don't you comment about the new patient starts and cadence there with various prescribers, and then we'll ask Faye to comment on the enrollment status?

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Great. Thank you. On new patient starts, we're seeing repeat prescriptions among the early adopters, largely at many of the academic medical centers. In the community, it's a little bit more diffuse.

So, there, we're seeing more breadth and depth. But over time, as with other product launches, I expect that both breadth and depth will continue to grow, especially as physicians gain clinical experience and success with Rytelo.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Jim. And, Faye, could you make a comment on sort of the cadences you see for enrollment and how you sort of judge that today? And, Emily, if you want to refine that question for Faye, please feel free to do so.

Faye Feller -- Executive Vice President, Chief Medical Officer

Sure. Thanks, Emily. We're talking about the enrollment in MYF3001 in the phase 3, right? And that's --

Emily Bodnar -- Analyst

Yeah.

Faye Feller -- Executive Vice President, Chief Medical Officer

Yeah. OK, just to be sure. So, the enrollment in the phase 3 studies is proceeding along well and has been, you know, steadily and as expected. Is there --

Emily Bodnar -- Analyst

Any like timeline you could provide for when you expect to complete enrollment?

Faye Feller -- Executive Vice President, Chief Medical Officer

I don't think we've released that publicly, but I'll remind you also that the interim analysis and the final analysis projected dates are not dependent necessarily on the enrollment timing but more on the event dates. So, we can reach those milestones without necessarily enrollment being closed.

Emily Bodnar -- Analyst

Got it. All right. Thank you.

Operator

The next question comes from Kalpit Patel with B. Riley Securities. Your line is open.

Kalpit Patel -- B. Riley Financial -- Analyst

Yeah. Hey. Good morning and thanks for taking the questions. Maybe first on the flattening over the past few months, can you comment on exactly which month you started to see flattening? Was it the beginning of this year or was it the beginning of fourth quarter last year?

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Hey, Kalpit. It's Jim here. I would say, based upon the rolling four- and eight-week, we started to see, right, let's call it around the holidays, Thanksgiving holiday going forward. We do see, as you know, in the weekly data a lot of variability, which is why we anchored more to the four- and the eight-week rolling averages.

Kalpit Patel -- B. Riley Financial -- Analyst

Got it. And I appreciate the color here into the more usage in the third-line setting, but I'm curious to hear if there are any other specific subgroups of patients that are more heavily targeted by doctors. For example, is this mostly used in high transfusion burden patients?

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

We don't have perfect data on that, so a lot of it is gathered through market research. But as you know, based upon our indication statement, we stay consistent with that. As physicians gain experience, they have the ability to use physician discretion, medical justification in areas that may go beyond the label.

Kalpit Patel -- B. Riley Financial -- Analyst

Got it. OK. And then one last one for me. You know, I think we've had that slide in your deck saying that there are 15,000-plus patients eligible, potential 1 billion-plus in net revenue.

Do you still stand by that 1 billion-plus number?

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Yes. The bottom line is for physicians that have used Rytelo and based upon our KOL feedback, as well as market research, Rytelo works. It's that simple. It's our obligation and opportunity to help educate and increase the awareness with a much broader group of physicians across the country, but we absolutely do believe in it.

I think our opportunity is to also drive market development and KOL development. As Joe highlighted, there's a significant opportunity for us to increase the awareness, therefore leading to initial trial. Initial trial will lead to reinforce success in broader use. It would just take a little bit of time.

Kalpit Patel -- B. Riley Financial -- Analyst

OK. Got it. Thank you very much for taking the questions.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Kalpit.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Thank you.

Operator

The next question comes from Gil Blum with Needham. Your line is open.

Gil Blum -- Analyst

Good morning, everyone, and thanks for taking our question. So, we noted that the financial opex guidance remains unchanged. Maybe just as a strategic question, you know, given you guys plan on investing more in outreach here, doesn't this affect your estimates as it relates to operational expenses for 2025? Thanks.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Hi. Jim here. Potentially, right? If we kept the spend exactly the same and increased our nonpersonnel spend, it would. But the way we've managed our budget is to reallocate based upon opportunities and, you know, directed our spend by shifting funds within.

Gil Blum -- Analyst

All right. And maybe --

Chip Scarlett -- Chairman and Chief Executive Officer

Michelle, any other comment? Sorry, I just want to make sure.

Michelle Robertson -- Executive Vice President, Finance, Chief Financial Officer, and Treasurer

I'm sorry, I didn't --

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Go ahead with your second.

Chip Scarlett -- Chairman and Chief Executive Officer

Yeah. So, the question was related to the opex unchanged, and Jim gave the commentary that we were reallocating within various portions of our budget there. I didn't know if you had any other comment on our opex and change going forward.

Michelle Robertson -- Executive Vice President, Finance, Chief Financial Officer, and Treasurer

Yeah. I mean, Gil, I guess what I can say is we had already accounted for in our budget for 2025 additional investments in medical affairs and some other programs that we didn't get to in 2024. So, we've got flexibility.

Gil Blum -- Analyst

OK. And maybe as a follow-on here, I know maybe this question was addressed previously, but just to better understand, people who go on Rytelo seem to stay on Rytelo, at least up until what we would have expected from the IMerge phase 3. So, it's just convincing physicians that they should give it a try. Is this where the problem is? Thanks.

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Yes, I'd actually expand upon that. You know, we have a lot of early adopters that we've seen prescribed and gained that success. There's a lot more patients and physicians that have not used Rytelo. So, it's really us increasing the education, the awareness, and driving that initial clinical experience.

That's really where the opportunity is on new patient starts. It's continuing to drive the breadth, and the breadth obviously leading to depth over time.

Gil Blum -- Analyst

All right. Thanks for taking our questions.

Chip Scarlett -- Chairman and Chief Executive Officer

Thanks, Gil.

Operator

This concludes the question-and-answer session. I'll turn the call to Aron Feingold for closing remarks.

Aron Feingold -- Vice President, Investor Relations and Corporate Communications

Thank you so much for joining us today. We appreciate your interest in Geron and look forward to keeping you updated.

Operator

[Operator signoff]

Duration: 0 minutes

Call participants:

Aron Feingold -- Vice President, Investor Relations and Corporate Communications

Chip Scarlett -- Chairman and Chief Executive Officer

Jim Ziegler -- Executive Vice President, Chief Commercial Officer

Joseph Eid -- Executive Vice President, Research and Development

Faye Feller -- Executive Vice President, Chief Medical Officer

Michelle Robertson -- Executive Vice President, Finance, Chief Financial Officer, and Treasurer

Peter Lawson -- Analyst

Tara Bancroft -- TD Cowen -- Analyst

Faisal Khurshid -- Analyst

Greg Harrison -- Scotiabank -- Analyst

Stephen Willey -- Analyst

Steve Willey -- Analyst

Emily Bodnar -- Analyst

Kalpit Patel -- B. Riley Financial -- Analyst

Gil Blum -- Analyst

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Geron (GERN) Q4 2024 Earnings Call Transcript was originally published by The Motley Fool