Geron Corporation (GERN) Earnings Call Transcript & Summary

All right. Good morning, everyone. Thank you for tuning in B. Riley's Oncology Conference. I'm Kalpit Patel, a research analyst here on the biotech team at B. Riley. Our next fireside chat is with a company called Geron, and we have the company's CEO, John Scarlett. Chip, thanks very much for joining us today.

Maybe we can get started with you had a major clearing event with imetelstat recently in lower-risk MDS. And maybe we can just start with your overall take on hitting the primary endpoint in IMerge. Were there any surprises relative to what you've seen in the Phase II, maybe both on the positive and on the negative sides of the equation?

Yes, sure. Thanks, Kalpit. I'll answer that question in a second. First of all, thanks to you and the bank for inviting us to this conference. I really appreciate the opportunity. I am going to do a quick forward-looking statement. So during the course of this fireside chat, there will be forward-looking statements regarding future events, performance, plans, expectations and other projections, including those related to the therapeutic potential of and potential regulatory approval of imetelstat, the anticipated clinical and commercial events and related time lines, the sufficiency of Geron's financial resources and other statements that are not historical fact. Actual events or results could differ materially. Please refer to the discussion under the heading Risk Factors in Geron's current report on Form 8-K filed on January 5, 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. So to your question, the overall take on the readout of IMerge, look, there were no surprises from our perspective. I think based on the strong Phase II data that we saw in low-risk MDS and the similarities in the patient population, the study protocol procedures, we actually had a lot of confidence that we'd have a positive readout. And as you've seen, that confidence was pretty clearly rewarded.

Okay. And what stands out to you maybe from the -- some of the subgroup analysis that you showed in IMerge? And how does that sort of explain the market opportunity ahead in low-risk MDS given these results?

Yes. So maybe I could start by just summarizing what we thought were 3 key differentiators for imetelstat that came out of this study. First, I think we showed that imetelstat had remarkable durability of hematologic benefit, including, of course, compelling transfusion independence. So we met both the 8-week and 24-week TI endpoints, actually very similar to the Phase II results. It's notable that among those people who achieved 8-week TI as of the data that cut off for the analysis, the median duration of transfusion independence for those responders approached a year. Similarly, those who had a 24-week TI, the duration of total transfusion independence approached 80 weeks. And so the depth and durability of these TI data in such a heavily transfused population was really pretty unprecedented from our perspective, and we're really thrilled. Also, I just would be remiss to not point out that for all patients, not just responders, there were statistically significant increases in both hemoglobin levels and reductions in transfusions. And remember, these patients started at a baseline transfusion burden of -- sorry, baseline hemoglobin level of about 8 grams per deciliter. And on imetelstat, there was a median hemoglobin rise amongst responders of 3.6 grams per deciliter, with a median peak of over 11. That's pretty darn good. And also in a lower-risk MDS population that had a baseline median transfusion burden of 6 units per 8 weeks, there were -- those were remarkable rises in hemoglobin. So if we then take your direct question second, as you alluded to, imetelstat showed really broad, statistically significant efficacy across subtypes, including both RS+ and RS-. And specifically, the rates for 8-week and 24-week TIs were statistically significant for both RS+ and RS- treated patients compared to placebo. Again, very compelling efficacy. So I think that gave us a lot of confidence in accessibility into the market, which I suspect we'll talk about that in a few minutes. And third, the trial also provided really strong evidence for clinical -- both clinical and molecular evidence supporting the potential for disease modification. Clinically, that 1-year TI duration for the 8-week responders and the median rise that we just talked about in hemoglobin of 3.6 grams per deciliter, these don't happen if you are not really changing the course of the underlying disease. Just think about that. And then from a molecular perspective, we saw greater than 50% variant allele frequencies or VAF decreases in mutations characteristic of lower-risk MDS. So that included SF3B1, TET2, DNMT3A and ASXL1. So maybe the point I'd make here, again, we may come back to it, but these changes demonstrate reduction in the underlying driver of disease. These are all acquired mutations that indicate a malignant origin of the circulating white cells in which the mutation is identified. So a reduction of greater than 50% in one or more of these variant alleles indicates suppression of the malignant stem and progenitor cells responsible for the disease. That's clearly the [indiscernible] So that's sort of the way we saw all of that and clearly, both the subgroup analysis that looked at good statistically and clinically significant results for both high and very high transfusion burden patients and both RS+ and RS- patients [indiscernible].

Okay. And I've -- since your data set was revealed, I've received some inbounds from investors on the placebo responses in the trial. It has been higher than historical trials in the same setting. That said, obviously, the active arm significantly and maybe meaningfully outperformed the placebo arm. So what I guess I'm trying to ask is, is there anything else you want to highlight that might give these investors some additional comfort on the placebo responses?

Sure. Yes. I mean, first of all, we agree with your primary observation that the differences for both the primary and the key secondary efficacy end points were both highly statistically significant and clinically meaningfully different from placebo. I think the other thing I'd point out, and there's a plethora of data if you look at our TLR response deck. When you go to observation periods of 16 weeks or greater, the placebo response rate is really within expectations. So I think without diving in deeply to all of the rationale for why we saw an opportunity for a little bit higher placebo response rate in the earlier periods, once you get to the longer periods, the placebo responses just drop away and so -- but I think that's [indiscernible].

Okay. And give us an impression or what are the KOLs saying on the 24-week TI rate? I know you mentioned durability was an important component in the secondary end point. But what -- have you engaged with the KOLs? And what's the feedback primarily been like?

Yes. We had -- I don't know if I'd call it an outpouring. But we certainly have had a lot of communications from investigators, in particular, many of whom are considered [ lead clinics' ] KOLs, investigators in the study and others, lots of virtual high fives. And I think that the thing that they were really thrilled with, which we are thrilled with, is that durability of transfusion independence. And the 24-week is really unprecedented and certainly very compelling. So again, key differentiators that they cited, durability of effect, that everybody was thrilled to see the broad statistically significant efficacy across subtypes, especially with the RS+ and RS- and really good indications of disease modifications we just talked about. So I think we had a really, really good response and they were as thrilled as we are.

Okay. And any commentary on the mean change in red blood cell transfusion units over time, and how impactful this might be for patients who have an underlying transfusion burden?

I'm really glad you asked that question, Kalpit, because we've moved to a primary analysis set in this disorder of transfusion independence, which couldn't have even been contemplated 10 years ago or so, right, 10, 15 years ago. So that's great. But while we and others would love to get everyone transfusion-free, even those patients who don't achieve true transfusion independence, a reduction in the number of transfusions over time can be really important. I mean you have decreased morbidity associated with [indiscernible] we see the more transfusions you have, the more opportunity and risk you have of iron overload, organ failure associated with that, even lower -- there's statistically a lower overall survival for patients who have meaningful number of transfusions. And obviously, a big improvement in quality of life when you reduce the time spent in infusion chairs. So in and of itself, reducing the transfusions with or without achieving transfusion independence is really useful. And as you saw in the IMerge data, there is a statistically significant difference in the mean number of RBC units transfused compared to placebo. And that was true across the board for all patients. And then, for example, at week 41, there was a difference of more than 4-unit drop in transfusion units versus 1 for placebo. So I think overall, we're really pleased across the board, and it goes beyond just pure transfusion independence.

Okay. And is there anything you wish to communicate about the adverse events, specifically the cytopenias? I know some individuals have expressed some level of concern with the numerical rates of -- the high numerical rate of cytopenias, despite not having any differences in clinical consequences like febrile neutropenia or bleeding events. So any more color on that?

Yes. I think you have to go back to our many conversations about this with both community hematologists as well as academic hematologists. I'd like to begin by reminding everyone that even cytopenias are on-target cytopenias. They reflect the mechanism of action of the drug. Remember, we selectively affect the malignant stem and progenitor cells driving the disease. That means we affect the malignant hematopoiesis more selectively than normal hematopoiesis. So that's one of the reasons that we see this. It's not a broad myelosuppressive effect, it's really very targeted at the origin of the disease. Second of all, I think our data showed that these cytopenias occur predominantly early in the treatment cycles and generally resolve within a treatment cycle. Hematologists remind us that they're accustomed to seeing cytopenias. Many of the drugs they use in lower-risk MDS have even higher rates of persistent thrombocytopenia and neutropenia than they're seeing here, including HMAs, venetoclax, other drugs used in these settings. And of course, there is some level of cytopenias that eventually occur in the background of some patients with the disease. And finally, what we overwhelmingly hear are that what's important for these hematologists are the clinical consequences, as you mentioned, Kalpit. And for imetelstat, this study showed these clinical consequences are quite limited. And they were similar between the imetelstat and placebo arm. We haven't seen any bleeding events associated with a greater reduction of [indiscernible]. So I think we feel very good overall about the AE profile and believe that this is, as we've always said, manageable and again give us comfort with [indiscernible] responses.

Okay. And maybe another way to look at these cytopenias and what impact they're having is just to simply look at the discontinuation rate or treatment interruption rate. I guess, can you remind us if that has deviated, the treatment discontinuation rates from other trials in lower-risk MDS in this sort of late-line setting?

Sure. Well, I think that there are some trials that we don't need to get into all the nitty gritty details of, but some trials actually dropped patients who were not responders, right? So we allowed everybody. I think I'd like to just point out that we allowed -- this was a very classic Phase III -- IMerge was a very classic Phase III study. It studied patients in a practice setting that we believe is very similar to what would be the case if the drug were approved and on the market. So nobody forces patients off of the drug. Nobody forces transfusions. It's up to the, in this case, investigator. It would be up to a practicing hematologist [ more to show ]. And so if we talk specifically though about the discontinuation rates, I mean, at the end of the day, all of the key endpoints we know favored imetelstat and favored a very significant value proposition of the drug in lower-risk MDS. With regard to your specific question about discontinuation rates, I'd just point out a couple of important reminders. Discontinuation rates for the 2 arms were certainly similar. I agree. But the reasons for discontinuation were different. For the placebo arm, there were -- there was about a twofold higher rate of discontinuation due to lack of efficacy compared to the imetelstat arm. And similarly, discontinuation rates for AEs were higher in the imetelstat arm than placebo. But remember, cytopenias were responsible for less than 10% of the total discontinuation rate in the imetelstat arm. And finally, I'd note progression to AML was similar in both arms and was really quite low. It was only 1.7% in each arm. So I think we're feeling pretty comfortable about the overall viewpoints upon discontinuation of patients and [indiscernible]

Okay. Fair enough. And one of the other important questions that I get from investors is surrounding where imetelstat fits into the treatment landscape for lower-risk MDS. With luspatercept in the mix, it's moving into the frontline, where do you see imetelstat ultimately end up in this market?

Sure. Well, let's just recap what we saw in the Phase III IMerge study. We saw a strong benefit in ESA-ineligible patients. So these are patients with serum EPO level rates greater than 500. Those are the definition usually considered frontline patients, but it's a small proportion of frontline patients. We also, of course, saw a benefit with relapsed patients, relapsed and refractory to ESAs, again, including both RS+ patients and unlike other drugs, also RS- patients. We saw 4-plus transfusion burden patients, which are a very significant part of the market, and imetelstat was effective in both high and very high transfusion burden patients. So I think overall, we believe that imetelstat will become a very valued standard of care in lower-risk MDS, including all of these settings.