Geron Corp (GERN) 2023 Q3 法說會逐字稿

Good morning. My name is Audrey, and I will be your conference operator today. At this time, I would like to welcome everyone to the Geron Corporation Third Quarter 2023 Earnings Conference Call. Today's conference is being recorded. (Operator Instructions)

At this time, I would like to turn the conference over to Aron Feingold, VP of Investor Relations and Corporate Communications. Please go ahead.

Good morning, everyone. Welcome to the Geron Corporation Third Quarter 2023 Earnings Conference Call. I am Aron Feingold, Geron's Vice President of Investor Relations and Corporate Communications. I'm joined today by several members of Geron's management team: Dr. John Scarlett, Chairman and Chief Executive Officer; Michelle Robertson, Executive Vice President and Chief Financial Officer; Dr. Faye Feller, Executive Vice President and Chief Medical Officer; Anil Kapur, Executive Vice President of Corporate Strategy and Chief Commercial Officer; and Dr. Andrew Grethlein, Executive Vice President and Chief Operating Officer.

Before we begin, please note that during the course of this presentation and question-and-answer session, we will be making forward-looking statements regarding future events, performance, plans, expectations and other projections including those relating to the therapeutic potential and potential regulatory approval of imetelstat, anticipated clinical and commercial events and related timelines, the sufficiency of Geron's financial resources and other statements that are not historical facts. Actual events or results could differ materially.

Therefore, I refer you to the discussion under the heading Risk Factors in Geron's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023, which identifies important factors that could cause actual results to differ materially from those contained in the forward-looking statements. Geron undertakes no duty or obligation to update our forward-looking statements.

With that, I'll turn the call over to Chip. Chip?

Thanks, Aron. Good morning, everyone. Thanks for joining us today. This quarter, we continued to make important progress and build momentum along our planned path to develop and commercialize imetelstat, our first-in-class telomerase inhibitor. This path, we believe, represents a great opportunity for both near- and longer-term value creation.

2023 has been a signal year for us. The imetelstat NDA for the treatment of transfusion-dependent anemia in patients with lower-risk MDS was submitted and subsequently accepted for FDA review in August. The FDA assigned a PDUFA action date of June 16 of 2024. This was followed by validation of the MAA for the same indication in September of this year.

Now that our MAA is under review, we expect the earliest potential approval could occur in late 2024 with a European launch potentially in 2025. We are continuing to evaluate our strategic options, including self-commercialization or partnering, and expect to be able to provide an update later in 2024. If approved, we believe the imetelstat commercial opportunity in this indication is both differentiated and compelling for 3 reasons:

First, imetelstat has been shown to be highly effective in several key patient subgroups, where today's available treatments did not satisfactorily address the needs of patients with this disease. These include RS-negative patients, patients with high transfusion burdens and patients with high serum EPO levels.

These key clinical attributes of imetelstat have been further reinforced by the ASH abstracts published this morning. New analyses using data from the Phase III IMerge trial in transfusion-dependent lower-risk MDS continue to show a significant durability and breadth of transfusion independence across subgroups, including patients whose needs are not being met by current treatments.

Second, there is a very large market opportunity for imetelstat in lower-risk MDS patients with transfusion-dependent anemia, which we estimate represents a total addressable market or TAM of approximately $3.5 billion by 2033 in the U.S. and the EU4 as well as the U.K.

And third, this is a market that's seen low competitive intensity and relatively little innovation in the last decade. Despite the recently approved luspatercept label expansion, just last month, the National Comprehensive Cancer Network, or NCCN, published a revised version of its MDS guidelines, which still point to limited treatment options available to hematologists as they manage their transfusion-dependent lower-risk MDS patients.

Moving beyond lower-risk MDS, another key component in Geron's path to value creation is an expected interim analysis in IMerge, which is a Phase III study in JAKi relapsed and refractory MF that's currently anticipated in the first half of 2025. IMpactMF is the first and only Phase III trial with overall survival as a primary endpoint. If the expected interim analysis in 2025 or the final analysis expected in 2026 is positive, these data could be transformational for patients with relapsed/refractory MF, which also represents an underserved, very substantial market opportunity with an estimated $3.5 billion TAM by 2033.

Together, our lead indications represent a potential TAM of $7 billion in 2033. And beyond that, we continue to investigate the potential of imetelstat in other hematologic malignancy indications and combination trials that could build additional value for the company.

Given that opportunity, we've been preparing at an enterprise level for transitioning to a commercial company for several years. This has enabled us to efficiently hire and onboard our commercial and medical affairs leadership teams, scale our internal systems and operations and build the competencies needed to succeed as a commercial company.

Anil will speak further to the commercial opportunity later during this call. We also have a strong cash position of approximately $382 million at the end of the quarter, which, based on our current plans and expected available resources, we expect, will enable us to fund a potential successful launch in transfusion-dependent lower-risk MDS in the U.S. and fund our planned operations through the end of the third quarter of 2025.

Finally, we have outstanding individuals to lead our organization through this transformation from a development stage to a commercial company. These individuals now include Michelle Robertson, who we recently appointed as CFO following the retirement of our long-time CFO, Olivia Bloom.

We're thrilled to have Michelle on board at this very important moment in our history. Michelle brings with her over 30 years of financial and commercial operations experience, most recently as CFO of Editas Medicine, and before that, as CFO of Momenta before its acquisition by J&J. She also spent over 13 years in the finance and commercial operations group at Genzyme.

Her deep command of financial operations, her experience with managing the financial and organizational needs of a biotech company preparing to potentially launch its first commercial product, and her prior experience with investors, analysts, investment bankers, as well as her hands-on experiences with commercial launches in the past will all be extremely valuable to our organization going forward.

With that, I'll turn the call over to Faye for a regulatory and clinical update.

Thanks, Chip, and good morning to everyone on the call. As Chip mentioned, we accomplished critical regulatory milestones this quarter with the acceptance of our regulatory filings in the U.S. and EU for review of imetelstat for the treatment of transfusion-dependent anemia in patients with lower-risk MDS who have failed to respond or have lost response to or are ineligible for ESAs.

The FDA assigned a PDUFA action date of June 16, 2024. The FDA also informed us that they are planning to hold an advisory committee meeting. We have no further details at this time about a potential date or agenda for this meeting.

As is best practice in our industry, we are working with a consultancy group who has expertise and advisory committees to complement our deep in-house regulatory experience, and we expect to be highly prepared. We believe we have an important medicine in imetelstat, and we look forward to the opportunity to discuss it with experts.

As Chip also mentioned, we are pleased that the ASH abstracts published this morning continue to demonstrate what we believe are the unique and differentiated qualities of imetelstat in lower-risk MDS seen in the IMerge Phase III study, including the breadth of effects across MDS subgroups and the unprecedented durability of transfusion independence.

I will now provide a brief overview of the abstracts. Please note that we issued a press release this morning at 9:00 A.M. Eastern Time, which describes the abstracts in more detail and that all abstracts are available on the ASH website.

The first abstract was accepted for an oral presentation and characterizes TI responses in imetelstat and placebo-treated patients using various risk classification systems. This subgroup analysis demonstrated that imetelstat consistently had higher TI response rates than placebo across different risk subgroups irrespective of risk classification system.

Using the most recent and precise IPSS-M classification system, which takes into account the prognostic effect of molecular mutations, over 13% of IPSS low or intermediate one-risk patients enrolled in the IMerge Phase III were upstaged to have moderate high, high or very high-risk MDS.

Notably, despite having MDS that would be classified as higher risk under IPSS-M, these patients benefited from imetelstat treatment compared to placebo. For example, as you can see in the last few rows of the table on the slide, among the M IPSS high, very high group, the 8-week RBC-TI rate was 40% for imetelstat and 0 for placebo. This shows that TI with imetelstat treatment is achievable regardless of risk classification.

The next abstract was accepted for poster presentation and examined the efficacy of imetelstat versus placebo across underlying mutations associated with MDS. Results show consistent TI responses in imetelstat-treated patients across different molecularly defined subgroups, regardless of the presence of mutations associated with poor prognosis, including ASXL1 or TP53 or the number of mutations.

For example, the 8-week TI rate for patients who had 3 or more mutations, a group with known poor outcomes, was 56% with imetelstat and 14% with placebo. These results complement the data I just described for the IPSS-M classification and, we further believe, support telomerase inhibition as a mechanism that can address the many different clones and causes of lower-risk MDS.

The next abstract was also accepted for poster presentation and focuses on the patients who achieved continuous 1-year TI with imetelstat treatment, an unprecedented clinical outcome in lower-risk MDS, which recapitulates what we saw in IMerge Phase II. Among the nearly 20% of imetelstat-treated patients who achieved a 1-year TI, the median duration of TI was over 2 years, and the median increase in hemoglobin was over 5 grams per deciliter.

Of the 18 imetelstat-treated 1-year TI responders with mutation data available, nearly 3/4 achieved greater than 50% reduction in variant allele frequency. And importantly, nearly half experienced reduction of MDS-associated mutations to an undetectable variant allele frequency. We believe these cases of long-term uninterrupted TI, accompanied by robust increases in hemoglobin and the elimination of MDS-associated mutations, suggest the potential of imetelstat to have disease-modifying activity.

The next abstract accepted for poster presentation summarizes results of the Geron-sponsored study in collaboration with the Moffitt Cancer Center. This population-level analysis was based on a large U.S. healthcare insurance claims database that included over 5,000 patients with lower-risk MDS.

This real-world data analysis showed durable transfusion independence after second-line treatment is associated with improved survival. The median overall survival from the start of second-line therapy was 23.4 months overall, and 37.9 months versus 9.3 months among 16-week TI responders versus non-responders.

This difference in OS was clinically and statistically significant, with its p-value less than 0.001. For transfusion-dependent patients, achievement of TI with the second-line treatment is associated with improved OS, supporting the clinical benefit of TI and underscoring the importance of TI as a clinical trial primary endpoint. We look forward to all these presentations and discussions in San Diego this December.

Turning now to our Phase III trial of imetelstat in relapsed/refractory MF. Enrollment is progressing, and we anticipate completing 50% enrollment by the end of this year.

We continue to expect an interim analysis in the first half of 2025, which will occur when approximately 35% of the planned enrolled patients have died. A final analysis is expected in the first half of 2026 when over 50% of the planned enrolled patients have died. We look forward to continuing to keep you updated on this important study.

In addition to our Phase III programs, we are also evaluating imetelstat in a Phase I study as combination therapy with ruxolitinib in patients with frontline myelofibrosis. This study was informed by data from preclinical studies describing that the sequential treatment of ruxolitinib followed by imetelstat has a selective inhibitory effect on malignant myelofibrosis stem cells while sparing normal hematopoietic stem cells.

Our main goal for IMproveMF is to determine the safety profile of the combination regimen of ruxolitinib and imetelstat. And in addition, we plan to explore any potential activity in the frontline MF disease setting.

Last month, the IMproveMF Safety Evaluation Team or SET, which is comprised of study investigators, evaluated patient data from the first cohort of patients. No dose-limiting toxicities were identified, and the SET made a unanimous decision to escalate to the second dose cohort. We are very pleased with this progress and look forward to providing future updates.

With that, I'll turn the call over to Anil for a commercial update. Anil?

Thank you, Faye, and good morning, everyone. We have made significant progress regarding our commercial efforts in this quarter. We remain on track for launch readiness in the U.S. in early 2024 and are looking forward to the opportunity to bring this important new option to patients as they fight their disease.

I'll start by highlighting the recent updates to the NCCN treatment guidelines for MDS. This follows the recent FDA label expansion for luspatercept in the frontline space. As you may be aware, the NCCN guidelines, along with publication of the results from randomized trials, remain among the most important factors that influence clinical and payer pathways and significantly inform prescribing behavior.

This next slide with a simplified schematic reflecting the revised NCCN guidelines, shows that for the largest segment of the frontline RS-negative patients, ESAs remain the preferred treatment for patients. There also continues to be limited treatment options for patients with serum EPO levels greater than 500, and participation in clinical trials is encouraged for those patients.

Given these revised guidelines, we expect that the frontline, lower-risk MDS space will evolve towards the use of both ESAs and luspatercept. It is important to remember that the majority of the patients with symptomatic anemia are treated today with ESAs in the frontline setting, and most will fail treatment in approximately 2 years.

From our perspective, these updated guidelines reflect a lack of effective new treatment options, in particular, for the RS-negative lower-risk MDS patients, who constitute 75% of the market, and for those whose serum EPO levels are greater than 500. This is a need we believe imetelstat can powerfully address.

And given the lack of effective treatment options, we expect imetelstat to be adopted for these patients for the treatment of lower-risk MDS by the prescriber community. We believe that the lower-risk MDS market is ripe for a new, innovative and durable treatment that can be used broadly across MDS subtypes.

We expect this large attractive market opportunity for imetelstat across 3 main patient segments across both the U.S., EU4 and U.K., highlighted on the right-hand side of the slide. These segments include frontline patients who are ESA ineligible given their high baseline serum EPO levels, ESA-failed RS-positive patients where there are limited treatment options, including luspatercept and HMAs.

Lastly, there is also a very large segment of approximately 24,000 ESA-failed RS-negative patients who tend to have worse prognosis than RS-positive patients and where there is a significant need for durable treatment. Together, these 3 market segments represent a significant commercial opportunity for imetelstat, with a total addressable market of $3.5 billion by 2033 in the U.S. and these key European markets.

This slide highlights the key attributes of imetelstat in the Phase III IMerge trial that resonated more strongly with community and academic hematologists. Our unprecedented IMerge Phase III data that highlights totality of clinical benefit, achievement of transfusion independence regardless of RS subtypes and meaningful durability of response, along with the PRO data that highlighted improvement in fatigue when treated with imetelstat, resonate highly with physicians and serve as critical differentiators and inform our value proposition.

We continue to work towards bringing all of these elements, along with the real-world analysis of the importance of achieving transfusion independence, to our payers and prescribers through appropriate channels to highlight the imetelstat value proposition.

This next slide highlights key aspects of our market research with hematologists from both the U.S. and key European markets.

First, imetelstat's first-in-class mechanism of action is seen as a key driver for future market adoption. Together with the durability of response, physicians view the opportunity for a new and novel mechanism as highly compelling.

Second, imetelstat is projected to be part of the standard of care across both RS-negative and RS-positive patient subgroups. Physicians express a clear preference to use imetelstat first for their frontline RS-negative ESA-ineligible patients and across all luspatercept prior-treated patients.

Third, in the ESA relapsed/refractory patient segment, physicians note that imetelstat demonstrates significant improvements in long-term response, that is, the 24-week transfusion independence over available options, especially in the RS-negative patients.

Fourth, for high-transfusion burden patients, relapsed and refractory lower-risk MDS patients, physicians believe imetelstat may be a compelling option over currently approved therapies.

This next slide highlights the results from the survey we conducted post-luspatercept frontline COMMANDS data release. This was done with 50-plus practicing hematologists in the U.S. across both community and academic settings to understand how they would use imetelstat, if available, as compared to other available therapies.

On the left-hand side of the slide, you can see that the responses indicate strong enthusiasm for imetelstat to be integrated across the 3 different patient segments in the lower-risk MDS treatment landscape upon potential approval. The graph on the right-hand side shows the responses further segmented for RS-positive and RS-negative patients within these subgroups.

The responses, as you can see here, indicate that imetelstat is not only expected to be broadly adopted for the treatment of lower-risk MDS, but that it is especially likely to become a new standard of care for second-line RS-negative patients. As a reminder, the RS-negative patient segment is approximately 3x larger than the RS-positive patient segment, and treatment options for RS-negative patients remain suboptimal.

Holistically, we believe that the qualitative market research shown earlier and quantitative survey highlighted here are highly aligned with the updated NCCN guidelines. These results emphasize the significant unmet treatment needs across the lower-risk MDS patient population. Therefore, we strongly believe that imetelstat, if approved, can play a meaningful role in the treatment paradigm of lower-risk MDS moving forward.

We believe that we are well-positioned to execute against this tremendous potential commercial opportunity. I have described in detail in the past the robust internal planning to prepare imetelstat, the market, and Geron as an organization, so that we can deliver a seamless customer experience to all stakeholders while ensuring broad reimbursement for imetelstat.

With regards to U.S. launch planning, with our PDUFA date of June 16, 2024, in hand, we expect to be ready to launch upon potential FDA approval. Significant progress on multiple fronts is highlighted on this slide.

We have been highly successful in attracting deeply experienced talent to Geron, with significant operational and U.S. launch experiences. Our non-field-facing commercial organization is now fully deployed and deeply engaged in bringing imetelstat to the U.S. market.

We plan to hire our field-facing teams, including our sales force, in quarter 1 2024 to ensure proper time for onboarding and training. We have already identified many talented and experienced individuals who are eager to join the team and are very much looking forward to welcoming this critical function to Geron next year. We are pleased with our progress to date and look forward to sharing updates in the future.

I will now turn the call over to Michelle for a financial update. Michelle?

Thanks, Anil, and good morning, everyone. As this is my first earnings call at Geron, I wanted to start by saying how very excited I am to be part of this amazing team and how privileged I feel to lead the finance function through this pivotal time for the company.

With regards to Q3 financials, for detailed results, please refer to the press release we issued this morning, which is available on our website. I will now review some highlights from the quarter.

At the end of Q3, our cash, cash equivalents and marketable securities were $381.9 million. This balance includes approximately $28.3 million in proceeds from warrant exercises in the third quarter. There are approximately 2.5 million warrants outstanding, and the potential proceeds from these warrants is $3.2 million.

R&D expenses for the 3 and 9 months ended September 30 were $29.4 million and $92.1 million, respectively, compared to $24.6 million and $67.3 million for the same period in 2022. Expenses have increased year-over-year, primarily related to supporting our clinical trials, IMerge Phase III and IMpactMF. Both personnel and consulting costs increased to support regulatory submissions and increased investment in manufacturing as we prepare for the potential commercialization in transfusion-dependent lower-risk MDS.

G&A expenses were $18.4 million and $47.7 million for the 3 and 9 months ended 9/30/2023 compared to $15.6 million and $29.8 million for the same period in 2022. The increase in G&A expense is primarily attributed to headcount and external expenses to support the commercial readiness activities. At the end of September 30, the company had headcount of 137 employees, which we project will grow to approximately 160 by the end of 2023.

Our projected full year 2023 GAAP operating expenses are expected to be between $200 million and $210 million. Moving forward, we plan to provide only GAAP guidance for consistency with our SEC financials.

Based on our current operating plans and expectations regarding the timing of potential approval of our imetelstat NDA that is currently under FDA review and subsequent potential U.S. commercial launch, we believe that our current cash runway, together with projected revenues from U.S. sales of imetelstat, proceeds from the exercise of outstanding warrants and funding under our loan facility, will be sufficient to support our operations through the end of the third quarter of 2025.

I will now turn the call back over to Chip.

Thank you very much, Michelle. With our strong IMerge Phase III data and with our regulatory submissions based on these data currently under review by both the FDA and EMA, we believe there is a robust market opportunity in front of us in transfusion-dependent lower-risk MDS.

In addition, we remain excited by our second Phase III readout in JAKi relapsed and refractory MF, for which we expect an interim analysis in the first half of 2025 and a final analysis in the first half of 2026. These programs represent important opportunities for the patients we serve and for our shareholders, whose interests we represent.

We look forward to keeping you updated on our progress, and we'll now open the line to questions.

Operator?

Thank you. (Operator Instructions). We'll go first to Stephen Willey at Stifel.

Can you guys hear me okay?

Yes, we can.

Okay.

Yes.

Hey, guys. Yes. This is Tuuli on for Steve. We have 3 questions on our end. Firstly, can you guys give us any additional color on the dose level 1, basically, what does those dose level -- first dose level was in IMproveMF study? And maybe more color on the dose escalation scheme, whether the dosing was higher or about the same dose level as lower-risk MDS dose and whether -- maybe like dosing schedules, that would be helpful.

And second, can you guys talk a little bit about whether FDA's granting of broad label to luspatercept in the first-line patients impacts your perception of risk-benefit of imetelstat?

And lastly, are you guys planning on actually disclosing or announcing when the enrollment hits 50% target in IMpactMF study? That would be it.

Great. This is Chip though. I'm going to invite Faye to make any comments that she can about the IMproveMF dosing and how that might relate to some of our other dosing in, for example, lower-risk MDS or MF as single-agent use. Faye?

Thanks, Chip. The dosing for the IMproveMF study is mostly based on -- this is a safety study, so it starts at a lower dose and then dose escalates to our highest dose that we used in MF. The dosing scheme is publicly available on ct.gov and I think within the corporate deck appendix.

The first dose level was 4.7 milligrams per kilogram of imetelstat, and the next is 6 milligrams per kilogram. Importantly, again, this study is really to assess the safety of combination therapy in a frontline MF setting.

Great. The second question related to -- is that -- did you have any follow-up questions? Or shall we move on to the FDA -- or sorry, the broad label commentary? Okay. Let's move on.

So, the second question I'm going to invite Anil to address. I believe the question was, did the assignment of a broad label to the luspatercept frontline use -- does that read in any way on, from our perception, on the risk-benefit for imetelstat? I believe I got that right. Anil?

Yes.

Sure. The frontline indication and the frontline population is very different from the population that's been studied for imetelstat in IMerge. We -- our focus was ESA relapsed/refractory patients who are transfusion dependent. And so, that's a very different population from the frontline COMMANDS, which looked at the front - ESA-naive patient population that got treated.

So, as a non-clinician, my feeling would be that it does not have a risk-benefit impact to our trial, but I would invite Faye to provide her clinical judgment as well.

Agree, Anil. The patient population studied in the COMMAND has minimal, if any, overlap with any patient population within IMerge. So, impact on risk-benefit is negligible or nonexistent, in my opinion.

And then, the third question was, do we plan on disclosing when 50% enrollment is hit in IMpactMF?

The answer is yes, we do. That's historically been our practice with all of the clinical studies we've run for the last many years. I'm not sure exactly the form that that will take. It kind of depends on timing around other activities, et cetera. But we do plan to make that publicly available.

Okay, maybe we can go to the next question.

We'll move next to Corinne Jenkins at Goldman Sachs.

This is [Craig] on for Corinne. So one question from us. You previously announced the initiation of your EAP and I guess, now having some time under your belt. Can you give us some color on the types of patients that have enrolled in that and maybe some of the feedback that you've received so far on the use of imetelstat through it?

That's a great question. I think the question was, what kind of feedback or what are we seeing with the types of patients who are being proposed for the EAP. Maybe, Faye, you could talk a little bit about that.

Sure. Thanks for this question. Just a reminder that the EAP is similar to a clinical trial in that the enrollment criteria and site initiation criteria is similar to that that we used on the IMerge Phase III study. However, it's different from a clinical trial in that we cannot recruit for it.

It is based on investigator request. So as the trial is still in progress and ongoing, we're really assessing enrollment and the types of patients, and we are not providing further details at this time.

Got it. That's helpful. And one more from us. So how are you guys all preparing for the advisory committee meeting with the FDA? And what sorts of topics do you anticipate will be in focus at the event?

I'll let Faye take that and I'll supplement as needed. But Faye, why don't you take the first crack at that?

Sure. Thanks, Chip. So regarding the ODAC, we've contacted -- we've been -- as is common in industry, to prepare for an ODAC ahead of time. So even before the announcement or the communication from the FDA, we have been working with an accredited -- like a very well-known vendor, who specializes in ODAC preparation, in order to anticipate or game-plan any types of questions or issues that may be of relevance.

Overall, as with most ODAC, it will be -- come down to a clinical question of risk versus benefit. And other than that, we don't have any further details.

Yes. Thanks, Faye. I think I'd like to make a couple of other points about the ODAC. Just to remind people, we were told that the FDA is planning an ODAC, but we don't know if that will actually occur. There's historical information about other products in which ODACs had been planned. They've actually been scheduled, and they've been canceled at the last minute. So I think we'll just have to wait and see on that.

We often get a question, Craig, about when do the most ODACs occur? I think in general, our research shows that they occur 4 to 6 weeks before the PDUFA date, something like that.

And I think the other comment is that we have a variety of consultants. So, as well as the consultant that Faye was describing, who is a very specialized ODAC and advisory committee consultant, we have other broad regulatory consultants. So, I think we feel like we will be very prepared through this process for whatever may come. And as we've commented in the past and she commented today in her prepared remarks, I think we look forward to discussing the opportunities for treatment with imetelstat in this space. Next?

We'll go next to Kalpit Patel at B. Riley.

Yes. Maybe, first, related to an earlier question. I know we have the updated guidelines here. But I'm curious if we have a sense of how Reblozyl is being utilized in the real world based on your engagement with KOLs.

Is the preference to use Reblozyl only for RS-positive patients in that frontline ESA-naive group? And does that utilization -- at least what you're seeing so far, does it look consistent to the survey data that you highlighted?

Anil, that's definitely for you. Reblozyl in the real world, and is it consistent with what we've seen from survey data?

Thank you for the question, Kalpit. I think our survey data, which are focused on the second-line space, you clearly saw where things are. But when we talk to physicians and start to dig into frontline use, what we see clearly is both ESAs and luspatercept to be part of the treatment paradigm. When we are speaking to physicians, both academics and community, I think you will see a preference for RS-positive patients heading towards luspatercept.

But there are also important nuances that need to be kept into effect, especially serum EPO levels. Greater than 200 typically favor luspatercept; less than 200, ESAs are also very much in play. And then for ESA-ineligible patients -- COMMANDS, as you know, Kalpit, did not study those patients in particular with that study, but they do have a broad label. But physicians continue to cite unmet need for that patient population.

From our perspective, I think we see both. I think the degree of adoption depends upon dissatisfaction or satisfaction with ESAs in a particular prescriber's experiences, and we will see both these drugs be used. But it will not be a replacement or a displacement issue for ESAs to the best of our judgment today, as we go forward.

And these patients need a lot of new treatments, and imetelstat does get referred as well as part of the future treatment paradigm when we show them all the data. So hopefully, this will answer your question, Kalpit.

Yes, yes. That's helpful. And then, Chip, you mentioned partnering earlier. I guess, any more color on how you're thinking about partnering. It could be useful to investors. Maybe is it just for ex-U.S. territories or both U.S. and ex-U.S.?

Sure, Kalpit. Yes, look, partnering is part and parcel of our business. It's an arrow that every company would hopefully have in their quiver. And it's a conversation that needs to continue to develop and mature as you move closer and closer to potential approvals and subsequent commercialization. So I think that we have always been open to partnering.

What we commented on today was specifically around European commercialization. And I think that, of course, we have the goal to bring imetelstat to patients in that marketplace as efficiently and as effectively as possible.

And given that the MAA is now under review and we have a better feel for timing, I think that we tried to point out that the earliest potential approval would be in quite late 2024. And that means, a European launch would be potentially in 2025.

So we're going to continue to evaluate our strategic options, which include not only partnering but also self-commercialization, as we go into and progress through 2024. And I would hope we would be able to give an update -- we expect to give an update later in 2024 in that specific part of the world.

Okay. Perfect. And one last question, you have this abstract that shows the differences in overall survival between the responders and non-responders for transfusion independence. I guess, have you done any sort of early analysis for your own patients in the IMerge study, and whether that data is consistent with what you're showing in that claims data from the ASH abstract?

Well, I think that claims data -- first and foremost, I think that claims data is what I would call very mature data, right? And it was a large number. I don't remember the exact ends, but it is very large number.

I think the purpose of that study was to provide additional insights across various platforms and across various drugs as to the -- supporting the value of transfusion independence, right? And I don't -- I think that that's been a staple of belief amongst most practitioners and also, for that matter, academics.

But I do think that since we interact with claims databases all the time in doing our own assessments, we thought this was really valuable and interesting, and collaborated with Rami Komrokji and the Moffitt to produce -- to help them analyze these data and make this presentation. So I think it stands on its own, honestly, as an overview of the value in this marketplace of transfusion independence -- achieving transfusion independence. Next?

Next, we'll move to Gil Blum at Needham & Company.

Hi. This is Ethan Markowski on for Gil. Thank you for taking our questions. So just 2 quick ones from our side. First one, maybe a little bit of a follow-up from one of the previous questions. And I did try to look quickly, but I was unable to find it. Can you give any color on the rux dosing that was used in IMproveMF? I know you've mentioned imetelstat dosing.

And then the other question, I'm looking at Slide 10 of the presentation, so the ASH abstract regarding mutations. And you can definitely see a pretty clear efficacy across the various mutations. I was just wondering if there's any biologic rationale why, in particular, ASXL1 appeared to have a little bit lower effect than the others? Or if you think it's just small numbers.

Yes. Ethan, they're both really interesting and good questions. I will invite Faye to comment on the rux dosing first and then riff a bit on the efficacy across the different mutations and how our old friend ASXL1 appears to be a difficult -- patients with that mutation appear to be particularly difficult to treat. Faye?

Sure. Regarding the -- I'll start with ASXL1 first. Regarding ASXL1, yes, I do believe that it appears to be a smaller magnitude of benefits, and that's mostly due to a low number of patients with the ASXL1 mutation.

That mutation, in particular, portends a very poor prognosis and a quick transformation to higher-risk disease or AML. So it was even a bit surprising that we had patients with these mutations in the lower-risk population. And that speaks further to the relevance of the IPSS-M classification and the results that we are showing at ASH regarding that abstract as well.

So, it all fits together that because of the mechanism of imetelstat that's directed at telomerase, and telomerase is overexpressed in malignant cells and drives the malignant phenotype, by targeting the disease itself, we have activity across the broad mutations, regardless of what prognosis they portend for patients.

To address your second question -- or it was actually your first. To address your first question about ruxolitinib dosing, the aim of the study is to assess safety and make -- assess the safety in the context of real-world use. So patients are -- enter the study on ruxolitinib at whatever dose was most beneficial and tolerable for them. So, the ruxolitinib dose varies per patient in the same exercise.

Next question?

We'll go next to Joel Beatty at Baird.

In considering the market research data that shows a larger market share for imetelstat than luspatercept, do you expect that upon launch, there could be some movement from luspatercept to imetelstat, some switching? Or would use upon launch mainly be in patients who are either like newly diagnosed or failing their previous therapy?

Again, I think this is Anil's area to comment on, whether there's possibility for at least switching, et cetera, at launch. Anil?

Sure. I think, Joel, just one fact to keep in mind as I answer the question is, there are very few treatment options in lower-risk MDS. As Chip spoke to earlier, I think, the words he used was competitively less intense.

In practice, physicians only have a handful of choices. So, what we feel is, while we may expect or want a patient, I think the key need here is for patient to really be best treated with whatever option the physician thinks for them till they no longer see benefit. So, if it's the case of a patient not seeing benefit and there is a more effective option, I think physicians will consider switching the patient over.

But if the patient is responding, our belief and typical clinical practice is to allow that patient to benefit fully through that disease -- through that treatment choice and then, consider other choices for that patient for where they are. So hopefully, that answers that part of the question.

The last remark I'll make here is to have a completely new novel mechanism of action with the level of durability and all the clinical effectiveness that we have shown, I think, will become a really important tool in armamentarium for physicians to consider and continue to optimize a patient therapy. So I'll stop here and say, if there are any clinical remarks from your side, that might be good.

Okay. Thank you. Any further questions, Joel, or did that --

No, that's great.

Okay, great. Next question?

And there are no further questions at this time. I would like to turn the conference back over to Aron Feingold for closing remarks.

Thanks so much, operator. Thank you, everyone, so much for your participation today. We look forward to keeping you updated on our progress. Thanks so much.

And this concludes today's conference call. Thank you for your participation. You may now disconnect.