C4 Therapeutics Inc Aktie

Good day, and welcome to the educational KOL webinar Alliant. [Operator Instructions]. Please note, this event is being recorded.

I would now like to turn the conference over to Leah Gibson, Vice President of IR and Corporate Communications. Please go ahead.

Good morning, and thank you for joining our educational webinar to discuss the multiple myeloma landscape, including the role of IKZF1/3 degraders and the emerging profile of site. We will be making forward-looking statements today, and Slide 2 contains our legal disclaimer on this matter. Those presenting on today's call are Andrew Hirsch, our President and CEO; and Nisha Joseph, Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine; and Len Reyno, our Chief Medical Officer.

Andrew will begin with opening remarks and then hand it over to Dr. Nisha Joseph, who will go over the multiple myeloma landscape and IKZF1/3 degraders Foundational biology. Len Reyno will discuss some Cemsidomide's potential best-in-class profile. We will end today's call with a Q&A session. Andrew, over to you.

Thank you, Leah, and good morning, everyone. Thank you for joining us. As you know, C4 Therapeutics is a leading clinical-stage biopharmaceutical company advancing the novel modality of targeted protein degradation to treat patients with cancer as well as inflammatory neuroinflammatory and neurodegenerative diseases. Our lead asset, Cemsidomide, is a next-generation IKZF1/3 degrader in development for relapsed/refractory multi myeloma, where it has demonstrated a potential best-in-class profile in a Phase I study recently presented at EHA.

There has been exciting data recently presented on next-generation IKZF1/3 degraders, bringing the importance of this mechanism in multi-myeloma into focus. As the next-generation IKZF1/3 degrader, Cemsidomide is designed to be highly potent and deliver a wider therapeutic index, which was reinforced by the updated data that we presented at EHA last week. We're very excited to have Dr. Nisha Joseph on the call with us today, an investigator on the Cemsidomide program and a recognized expert in relapsed/refractory multiple myeloma from [indiscernible] Winship Cancer Institute.

The multiple myeloma landscape has evolved rapidly with a focus on immune-directed agents like T cell engagers and CAR-Ts across different lines of treatment with potential for various combinations. In our view, the question that many are asking, given recent shift is what anchors combination therapy and what therapies will remain relevant as the landscape evolves. Given that context, we felt it was critical to bring in a leading clinician to provide an independent perspective on how the landscape is evolving, what's resonating in clinical practice and where IKZF1/3 degradation fits.

Dr. Joseph brings deep experience in treating multiple myeloma patients and a strong understanding of IKZF1/3 degraders in clinical practice. So with that, I'll turn it over to Dr. Joseph to walk through the evolving landscape.

Thank you so much, Andrew, and thank you so much for the kind invitation to speak to today. So to get going here, I thought I'd start by walking you through really what is my Lamont and talk you through a little bit about the very rapidly evolving treatment landscape in multimyeloma specifically relapsed and refractory myeloma. So for those of you who are not as familiar, multi myeloma or myeloma does that get most common hematologic malignancy.

So even though it's overall a rare disease is still the second most common key malignancy that we see and it is classified or defined as a clonal proliferation of plasma cells, and that manifests clinically in the patient's body with 4 main symptoms. So elevated calcium, kidney dysfunction or renal failure, anemia analytic bone leases. And in addition to these symptoms that patients can present with, they're also often prone infection because they have a disorder of their immune system, they often have decreased antibodies in their system.

And so it's very common for these folks to either present at initial diagnosis with infection or to develop infection along the way. So that's a really important piece of myeloma therapy is to also make sure that we are supporting patients so they did not get life-threatening infections while we're attempting to treat their myeloma. So myeloma, we expect around 30,000 to 40,000 new cases of myeloma each year. And even though things are getting markedly better in terms of outcomes and survival. We still expect roughly 10,000 to 11,000 deaths in 2026, and we still are seeing about 40% of patients that are not surviving beyond 5 years. So even though we have a significant we've had significant advancements in treatment.

We have a lot of new treatments and classes of drugs. There's still a large chunk of patients who are not experiencing the significant benefit that some patients are. Sometimes these patients have high-risk disease, so whether that is defined cytogenetically. So if there are genetic changes that we know signal more aggressive myeloma, sometimes we're able to detect that at the onset. Sometimes they develop or require some of these genetic abnormalities every time they relax or the longer they have myelomas.

But there is also a class of patients who might not even have any of these high-risk features of diagnosis. But they are functionally high risk. They don't respond to therapies the way that we expect them to. So there's still an ongoing need to find safe and effective therapies for many myeloma patients who still relapse and need effective treatments in the relapse setting. So here, you can see really kind of the evolution of myeloma therapies across the last, what, 70, 80 years. And so before -- long before I was trading myeloma, there really wasn't a lot happening. If you look there in the 60s and 70s really into the early 2000s, there was a few drugs that we had and patients had very limited survival. When I was in medical school, we learned that myeloma survival was 2 to 3 years.

The therapies we had were toxic, and it was just not a diagnosis that you want it. And you fast forward now in 2026 and looking ahead, we have so many effective and well tolerated there. So not only have we had now the proteasome inhibitors, so portezamib and carfilzomib, ixazimib, we have several monoponal antibodies in daratumumab and etuximab with ilium. But now, more recently, as I'm sure you're familiar with, we now have more of these T cell redirecting therapies.

So there's 2 FDA approved CAR-T cell therapies in myeloma, iDose and sites really to cell is the CAR-T cell therapy we have access to in the relapsed setting, early relapse setting that target something called BCMA or B-cell maturation antigen that's highly expressed on the surface of malignant plasma cells. And then we have several bispecific antibodies. So we have several bispecific antibodies that target BCMA, so limboseltumab, [indiscernible] and we also have one bispecific antibody that targets something called GPRC5D which is also another antrigen that's highly expressed on the surface of malignant plasma cells.

And then with that, there are other classes like selinexor, which is an XPO1 inhibitor and other drugs in clinical trial development. that offer different mechanistic approaches to myeloma death. And what we are learning is how to best sequence and combine these agents to be the most effective. So even though we have these drugs, patients will relapse. So vast majority of patients relapse. So how do we make sure that when they relapse, we still have really effective options for them that are safe and well tolerated and how do we know which one to use and in what combinations?

So there's a real explosion of not only clinical trial activity with new classes of drugs that are still very much in need but also with the drugs that we already have, either in combination with each other or in combination with some of these novel therapies to try to make them even more effective at each line of treatment at each time the patients relapse. So here, you're looking at just examples of some of the drugs that we think about at each time point in the myeloma patient journey.

So for a standard myeloma patient, when I meet a newly diagnosed myeloma patient, I tell them unfortunately, we have not yet cured this disease. We're working on it, but the silver lining is we turned this into more of a chronic disease. The natural history of this disease is we're going to treat you. We're going to try to get the longest remission possible, but for most patients, this disease, unfortunately, will come back.

And so my role as your physician is to make sure that I'm selecting the most appropriate treatment at each relapse to maximize your depth of response, which will correlate to your emission time. And I want to take into account not only the disease factor, so that would be genetic factors, high risk factors, how the disease is presenting. But also what therapies that patient or that myeloma -- excuse me, has seen previously because that will affect how we respond to this next slide, and we have to take into account patient direct factors. So for a vast majority of myeloma patients, the average age of diagnosis is 67 to 69. So many patients in my clinic are in there are 70s and 80s. They might have other health problems and may have other comorbidities.

They might have limited mobility, limited social support transport. Many of the folks that I see in Georgia, in the Atlanta area, we have a large case area they were very far from the center. So a vast majority of my patients, I don't actually treat on a day-to-day basis. I check in with them, but they have local community oncologists several hours away that I coordinate with and they receive their care there. And so I have to take all those things into account every time they relapse, every time we're selecting therapies. So here's an example showing you of some of the drugs that we use or classes of drugs that we use exciting.

So in the newly diagnosed setting, what really is standard of tariff for both transplant eligible and transplant ineligible patients. is a quadruple therapy with a monoclonal anti-CD38 antibody. So that's either daratumumab, isatuximab, often in combination with what we call an or a KRD backbone. So lenalimide, bortezomib and dexamethasone. So you can see their lenalidomide, which is a trader or an amid is very integral and very important, really, in all lines of therapy, but particularly in combination with PI, the combination of an IMiD with the PI and then adding that monoclonal anti-38 has really revolutionized responses in newly diagnosed myeloma.

It's such an important component of that quadruple regimen. And then when patients relapse, depending on how they relapse and manner in which they relapse, the time at which they relapse, we start thinking about what would be best at their -- for them next. And so for example, if I have a standard-risk patient, I treat them with a quadruplet, they have a transplant, they're on maintenance therapy. And then 1 year later, they relapse. That's not what we would expect, right?

When we look at the pure colo patients who get their RVD, transplant and maintenance, we're expecting remissions. I don't know if I believe some of the projections of 17 years, but I would say it's reasonable to say over 10 years. That's very impressive. But again, that is clinical trial data, that is not real world, and that's not what we see. I think it's an effective argument, but we often have folks relapsing a few years after transplant. So then we start thinking about things like should we do another medical therapy-based combo with some of our standard therapies. So using another anti-CD38 using it again, daratumumab perhaps with another image like pomalidomide or maybe lenalidomide if they weren't online maintenance-based therapies, should we combine that dara with carfilzomib, so that's data from the IKEMA or the CANDOR trials looking at a monoclonal antibody with proteasome inhibitor.

And those are often regimens, particularly for folks who are in the community that are very effective because those are all drugs that community oncologists are very familiar with and they're able to deliver them. They have a lot of experience with those kinds of drugs. We also have things like anti-SLAMF7, which is ilituzumab, the XPO1 inhibitor selinexor and then the anti-BCMA antibody-drug conjugate is belimataolanzumab acidian which we have no access to an early relapse in combination with bortezomib. And that's also an option, I think, that is reasonable in the community setting but it still can be challenging with some of the ocular toxicity or eye toxicity that they're seeing with the drug.

I think for community really, they have more familiarity with those combinations of monoclonal anti-CD38 with either an or a PI. And then certainly at an academic setting, where I am, particularly after some of the data, of course, with CAR T cell therapy in early relapse, if you're familiar with the CARDI trial showing efficacy of filters in early relapse and now kind of the newest excitement in the myeloma world, particularly in the U.S., is the Majestic 3 data looking at teclistamab in combination with daratumumab or even as monotherapy and early relapse, that's certainly an interesting option to use T cell engagers or bispecific antibodies and CAR-T cell therapies.

But as that's a small portion of patients, 20% to 30% of my patients who are able to receive those therapies with me here in an academic setting. Those patients were thinking about even clinical trial, right? That's a smaller subset of the patients. Many of the patients were talking about some of these other therapies that they can receive closer to home. And then as we kind of look forward, what's on the horizon, certainly some came a novel class of drugs going really high potency, particularly what's really interesting about [indiscernible] contrast to the image and even the [indiscernible] is we're looking a lot of the post BCMA. Many of the patients enrolled in the early trials had received BCMA and T cell redirecting therapy.

There's a novel cost of drugs that I think are really interesting with P300 inhibitors in development, either in really more in combination. There is some single-agent activity, but in combination with -- there is some development of allogeneic CAR T cell therapies. I think there's been some limited efficacy there, but certainly an interesting concept and being further explored. And there's also, I think, interestingly, in the CAR T space, ongoing investigation of dual-targeted CAR T cell therapy. So looking at BCMA and GPRC5D or BCMA and CD19, which so far in early trials are showing really interesting efficacy. And then, of course, ongoing work looking at bispecific antibodies in a late relapse.

So there are specific -- there is a bispecific, for example, called savoimab, looking at FcRH5 and then price specific. So now using -- we had bispecifics, now we have trispecifics, looking at CD3 and 2 targets on the myeloma cell surface. So a lot of really interesting and exciting novel classes of drugs. That we absolutely need to make sure that all patients matter their disease type or no matter where they're being treated have access to really effective, well-tolerated drugs.

And not only are these drugs in clinical trial development but they're in clinical trial development in combination with other drugs, whether those are other novel agents or other standard myeloma therapy. So really a lot happening in the myeloma space is moving very rapidly, which sometimes can make these questions of sequencing and what to do challenging, but it's a good problem to have.

Okay. So now a little bit on some biology at a very high level. Why did IKZF1/3 degradation matter? SP-6 So when we think about IKZF1/3, but we're talking about our cross -- and then subsequently, IRS 4, which is a downstream transferation factor. And basically, what all we're saying here, these are very important transcription factors or components of minicell survival. They're needed to make sure that, that myeloma cell lives and lives and lives. When you cut those things off at the needs, when you degrade those proteins, you are enhancing myeloma cell death.

Without those important transcription factors, the myeloma cell has a hard time surviving. And so that's why these drugs are so affected, whether it was done with IMS or CAM when you degrade these proteins, and that's what Cemsidomide can do or any of these degraders can do, they target these important transcription factors for destruction, and once you start decreasing or destroying the amount of crisis in the cell, that leads to enhanced myeloma solid death. So it's a very critical component of myeloma therapy using these types of drugs.

And not only what we have learned with these classes of drugs, whether it's MD or AMoD or Cemsidomide, is this very interesting T cell activation data as a byproduct. So you're leading to a personalit degradation. You have enhanced myelomas. But as a byproduct, you're actually seeing increased cytokine production, you're seeing less T cell exhaustion and so you're having T cell stimulatory effects just by using the drug in the first place. It's not necessarily what's happening to the myeloma, but it's a nice side effect. It's a nice byproduct. And I think this becomes particularly rather than an important in a field where we're using so many T-cell redirecting therapies or we're seeing so much T cell redirecting use in clinical trial development.

Not only can we potentially pair these types of drugs, the IT degraders with T-cell redirecting therapies to enhance their efficacy. I think that's one really important pathway, but we can also use them in between T cell redirecting therapies. That's another really interesting place to put them. So for example, after someone receives a bispecific antibody, you feel a lot of T cell exhaustion or dysfunction. It's challenging to move directly into another T cell redirecting therapy. You need to give time for their T cells to recover essentially.

And so potentially, that's a space for these classes of drugs. Their T cell simulatory -- they don't require functional T cells to work, but you see really nice efficacy and nice safety profile, and you're positioning that patient well in case they do need a next-line therapy. So here is showing you examples of how IKZF1/3 degraders are incorporated across the myeloma treatment landscape. So you can see here for patients in the second and third line and then patients in the fourth and fifth line. And you can see here, there's multiple options in these spaces.

But ICFI and 3 degraders are integral in many different combinations. So you can see them in combination with CD38 and proteasome inhibitors or monoclonal antibodies. And moving forward, we're seeing more and more combination with those in clinical trial development in combination with bispecific antibodies or even as a maintenance therapy or even before T cell apheresis for CAR T cell therapy. So they're really a critical component of relapse across every sector from second to fifth line, we can use is in combination with our standard agents. We can use them in combination with our more novel T cell redirecting type therapies or bispecific antibodies or CAR-T cell therapies or we can use them in between.

So they're really -- they maintain a really important role in the treatment of Myeloma. So as we look ahead to the future of multiple Myeloma treatment, again, things are changing and moving so quickly, but there's still a significant unmet need in the late-line setting, particularly not only for an effective, well-tolerated treatment. And I'll point out, particularly in late relapsed, these patients can be a little up. They've seen a lot of therapy.

So it's important to have not only an effective therapy, but one that they can tolerate, one that they can be consistent with and does not negatively impact their quality of life. And then I think another really nice aspect of these types of drugs is that they're oral. And so particularly for older patients, particularly for patients who don't live near a large city or near an academic setting. Having an oral option is really convenient and really allows them access to effective drugs that wouldn't otherwise have access to if they're all going to be T cell redirecting therapies that have to be delivered in academic.

The other thing we think about when we think about what to select and relapse is we want to make sure there is a known attrition in myeloma therapy, meaning. As you look at first-line patients, second-line patients, third-line patients, there's a drop off. Even though patients are doing better, there's a drop-off. So there's side effects, there's ability to continue with treatment, et cetera. So we really want to make sure each relapse for using absolutely the best, most effective therapy that we have, the most potent.

We want to use that early, and we want to use that in combination in a way that's effective and against seeing for these patients. We're seeing a huge shift in these novel immune therapies into earlier lines of therapy. But these therapies are not curative. So even though we're using these therapies earlier, the vast majority of patients are relapsing, they often have T cell dysfunction or exhaustion, and it's important to still have regimens that are effective for those patients.

And as we think about CAR T cell therapy, I think there's another really important unmet need and how do we make CAR T cell therapy even more effective? How can we add maintenance therapy there's ongoing trials not only with maintenance post CAR-T, but even using these types of drugs that have T cell simulatory effects in patients who might have an exhausted T-cell phenotype to use these drugs prior to apheresis. So there's a lot of work, and I think interesting ideas but how can we use these important class of drugs to make CAR T cell therapy even more effective to help with persistence and help with duration of response.

And so I think what I tried to talk about in the last few minutes here is this is a really effective cost of drugs. And it might be easy to think that moving forward, we have all these novel immunotherapies. Is there a role for these therapies? And there absolutely is, okay, the therapies that we have that are using T cells, the bispecifics, the CAR T cell therapies, they're not curative, there is room for improvement. These drugs can potentially fill that space.

We're seeing in its predecessors and in some of the early data, there's a real mechanistic advantage combining these classes of drugs with other standard myeloma therapies and some of the new novel therapies are seeing enhanced potency, enhanced myeloma cell death without a significantly worse safety profile. We're seeing that we can use these drugs across multiple different treatment lines. So again, in combination in between in really each setting, there's a specific role for these drugs to make sure that we're getting good myeloma depth of response and long-term remissions.

So I think this is a really important cause of drugs. I'm really excited about some of the clinical trial data that we're seeing and looking forward to seeing more data as we start to combine these drugs with some of the T-cell redirecting therapies and novel therapies in our field. And so with that, I will conclude. I thank you so much for your attention, and I'll turn it over to Len, C4 Therapeutics Chief Medical Officer to discuss Cemsidomide's profile.

Thank you, Dr. Joseph for the excellent summary, and we appreciate you joining us today. With the context just outlined, I'm excited to discuss Cemsidomide's potential best-in-class profile as a next-generation IKZF1/3 degrader for multiple myeloma. To start, it is helpful to understand how IKZF1/3-degraders have evolved low time. IMiDs, CELMoDs, and Cemsidomide all have the same mechanism of action. Lenalidomide and pomalidomide were first-generation IKZF1/3 degraders, i.e., IMiDs and they have been clinically relevant for over 20 years.

However, when IMiDs were developed, their mechanism was not understood and there's a clear need for next-generation IKZF1/3 degraders because of the limitations in terms of potency, selectivity and durability. Mechanistically, these original drugs primarily block proliferation and did not drive multiple myeloma cell death, which ultimately allows resistance to emerge. But they did very effectively establish the importance of the pathway.

Next-generation agents, iberdomide, mesignamide, also known as CELMoDs and Cemsidomide were designed to address these limitations by not just inhibiting proliferation but actively driving myeloma cell death and overcoming resistance. Importantly, Cemsidomide is built on novel chemistry with a well-understood and validated mechanism, and we believe it is uniquely positioned as a potential best-in-class IKZF1/3 degrader as we move into later-stage development.

Let's think about Cemsidomide as a molecule and its potential for best-in-class in multiple myeloma. [indiscernible] was designed from the bench up as a highly potent and selective IKZF1/3 degrader. In this regard, it has uniquely highly targeted specicity. It does not degrade off-target neo substrates, including CK1 alpha and GSPT1. Important for patient care, where 50% of patients with myeloma have some degree of renal impairment. Subside has no renal clearance. It also has low protein binding, which maximizes the availability of free circulating drug to deposit deep in the tissues, including the bone marrow. In patients, Cemsidomide has a 2-day half-life. This 2-day half-life is important because it sustains free drug at therapeutic concentration while maintaining efficacy and allowing neutrophils to recover during a break in dosing. In this regard, Cemsidomide is uniquely dosed on a 14-day on, 14-day off dosing schedule.

This break in dosing allows the potency of Cemsidomide to maintain anti-myeloma control, but also enabling full neutrophil recovery. These features make Cemsidomide an ideal backbone for combination regimens. We've taken this information and launched it into a differentiated label-enabling strategy from other IKZF1/3 degraders. We are particularly focused on how to incorporate the potency of Cemsidomide with its class-leading safety and efficacy into the evolving multiple myeloma landscape.

Now let me take a moment to walk you through the data that has demonstrated some Cemsidomide potential for a best-in-class profile from our first-in-human Phase I trial. This Phase I trial, which is schematically illustrated on this slide, completed enrollment in September of 2025. And last week, we presented further analysis from the trial at the European Hematology Association. In total, 73 patients were enrolled on the study across multiple dose levels, including stand expansion cohorts. 100 micrograms was declared as our RP2D.

Patients enrolled in this trial were extremely heavily pretreated with 7 median prior lines of therapy and important in the current evolving context, 75% of these patients had prior CAR T or T-cell engager with therapy. The fact that we've been able to show an impressive response rate in this population confirms that the mechanism of action of targeting IKZF1/3 remain foundational regardless of prior treatments. Cemsidomide was extremely well tolerated across the dose levels tested.

There were no discontinuations related to Cemsidomide and minimal dose reductions, well-tolerated safety profile also included manageable neutropenia. It should be noted that all drugs in this class require a break in therapy to allow neutrophils to recover. On this study, Grade 3/4 etropenia rate was 22%, and the grade 40-ton rate was 36%. But more importantly, there were very low rates of neutropenic complications, including low rates of federal neutropenia across all dose levels with only 4% at Grade 3 and 1% at Grade 4. Equally importantly to patient care, there were also incredibly limited Grade 3 or 4 nonhematology side effects. It's also important to note that the risk of neutropenia did not increase over time on this study. there was limited G-CSF use.

And in fact, there was a minimal impact of the neutropenia on the patient's clinical experience and patients did not come off drug for side effects of [indiscernible]. Across all doses, only 45% of patients ever receive G-CSF. And in fact, most of the neutropenic events occurred in the first 2 cycles, where in later cycles, when the disease was controlled, the patients enjoyed excellent tolerability. The exciting safety profile of Cemsidomide is supported by an equally and more exciting evidence of anti-myeloma activity. On this slide, we summarized reductions in serum-free light chain levels across the doses tested in the first-in-human study.

What you can clearly see on the graphic that we had deep degradation of serum free light chains across all doses, but most especially at the 2 highest doses. Of course, serum free light chains as a prerequisite to demonstrate IMWG responses. And on this slide, you can see that our highest dose level 100 micrograms that in 19 patients we had a 53% response rate. We had two patients who achieved the [indiscernible] and the CR also achieved MRD negativity. From a drug development point of view, it's also important to note that the drug is active at all doses studied. And in fact, we had a 40% response rate at the next lowest dose level.

And in fact, over all those levels enteritated for Cemsidomide plus dexamethasone, the response rate was 36%. It's important to put this anti-myeloma activity for Cemsidomide in context. On this slide, we compare the Phase I results of Cemsidomide against the other next-generation IKZF1/3-degraders currently in development. let's first consider the population studied. The populations are not the same in that the Cemsidomide first-in-human study enrolled patients where 75% of the patients received prior BCMA-directed therapy.

1% of patients had BCMA-directed therapy for mesignamide, and none of the patients had BCMA-directed therapy on the abertamide first-in-human study. Notwithstanding these differences in the pretreatment populations, Cemsidomide across all dose levels has the highest overall response rate of 36% and at the dose level of greatest interest, the RP2D, our response rate of 53% compares favorably with mezignamide and is almost double the response rate of Iberdomide. As you can see from the available data, Cemsidomide has the potential to be a foundational treatment across multiple lines of multiple myeloma therapy.

Based on this emerging profile, we've designed a development strategy that is both differentiated and aligned with how the treatment landscape for multiple myeloma is evolving. First, in the late-line setting, there remains a clear unmet need for safe and effective therapies, highlighted by our Phase I trial that despite new emerging therapies, patients are still progressing and seeking disease-modifying care. We're enrolling the Phase III MOMENTUM trial now with the potential for accelerated approval. This is a setting where other IKZF1/3 degraders, including next-generation degraders are not currently pursuing label-enabling strategies. Second, in the earlier line setting, we're focused on combination strategies.

Our initial development strategy is in a combination with the BCMA. The rationale for this combination to combine Cemsidomide T cell activation with deep anti-myeloma activity which should drive higher and more durable responses. We've initiated a Phase Ib study with elranetinab with plans to advance into a Phase III trial. This Phase III trial has the potential to support accelerated approval based on MRD-negative CR rates as well as confirmatory for the broader program. And third, we're exploring ways to include Cemsidomide as a possible broader image replacement strategy.

These activities include a Phase Ib trial with a proteasome inhibitor in CD38. The trial is expected to initiate in the first half of next year. The goal here is to establish a consistent predictable dose of Cemsidomide that can be combined with agents that are used frequently to treat multiple myeloma in standard of care regimens. We are currently not planning to use this data to embark on a registrational trial, but rather to increase the body of knowledge of how to combine Cemsidomide safely with other drugs.

Overall, these three strategic paths are designed to maximize both near-term and long-term value by addressing unmet need in late-line disease while building toward broader use in earlier settings. With that, I'll turn it over to Andrew for closing remarks.

Thank you, Len and Dr. Joseph for this highly informative session regarding the evolving multiple myeloma landscape. As you heard this morning, despite the rapid emergence of new therapies, IKZF1/3 degradation remains a foundational mechanism that continues to underpin treatment across lines. At the same time, the limitations of first-generation agents create a clear opportunity for next-generation degraders that can deliver improved tolerability, deeper and more durable responses and better address resistance mechanisms.

Based on the data we've generated to date, we believe Cemsidomide is well positioned to deliver on that opportunity with the potential to be a best-in-class IKZF1/3 degrader. Our goal is to establish Cemsidomide as a foundational backbone therapy across multiple lines of treatment and believe Cemsidomide is well positioned to play an important role in the future multiple myeloma treatment landscape. We're encouraged by the progress we've made and remain focused on advancing this program through later-stage development.

This year, we plan to provide additional commentary on how our Phase Ib trial with elranetinab is progressing, and data is expected mid-2027. Our Phase II MOMENTUM trial is on track to complete enrollment by the end of Q1 2027 with initial ORR data expected in the second half of 2027. With that, we're happy to open the line for Q&A.

[Operator Instructions]. Our first question comes from Tyler Van Buren with TD Cowen.

Thanks very much for the presentation. I thought it was very well done. A couple for you all. The first is, as we think about the higher the 75 and 100-microgram doses, what do you think median PFS and median duration of response might be trending towards?

And then for the second question, just can you discuss the significance of the successor to data at ASCO for the class as well as how we should benchmark the control arm for the successor 1 trial reading out some months from now, which could be even more important for the class.

Yes. Thanks, Tyler, for those questions. I'll have Len address the [indiscernible].

Thanks, Tyler. Obviously, they're good questions and yet they're difficult to answer. So let's start with first principles, though. Obviously, we have small cohorts right now at any given dose level and they do not represent or anything remotely as a randomized comparison. But I would say the following: we know overall in the population that we have a PFS that's around 4 months, and we also know and not be irrespective of response rate irrespective of dose you received.

We also showed in the webinar you just saw that as you increase the dose, you get deeper degradation of the transcription factors, and better response rates. So one would anticipate that we have an opportunity at the highest 2 dose levels in particular, to improve on that. I think it's really difficult would be pure conjecture to try to say what the size of that improvement is.

But I would suggest that overall, the data supports that we have a compelling signal to start with, and as we optimize our dosing of patients at the RP2D and/or 1 dose reduction, if necessary, I think we'll see improvements there. The second piece of the puzzle that you alluded to in terms of XR2 data. So just to align with everybody on the call, that represents a randomized trial where mezigtimide was added to a 2-drug regimen and has an incredibly compelling hazard ratio.

And we are really happy to see that hazard ratio because it provides an initial read through on the class, meaning a potent degrader can be done in a global Phase III trial safely and successfully can be associated with a high efficacy signal. And we congratulate the patients who enrolled on the study and BMS for conducting it. However, what we also see there is an important read through to how it fits to symptom.

What's unique perhaps about this class of drugs, IKZF1/3 degraders is how well early first in human data predicts future outcomes. And so if we think about where gas mezignomide was at the time of its original first-in-human data, which we summarized briefly in the webinar. -- we're at there or better. And the part where we're better is actually on not having fewer dose reductions and less need for supportive care.

Well, why does that matter? They had a positive study? Well, because in that positive study, what's really important to note is it was positive despite the fact that 40% of patients had dose reductions, and we don't know what they were dose reduced, too. In addition, there was evidence in the study that some patients on study, the cause of death was actually not myeloma, but we don't know details for. So we think Cemsidomide can do at least as well or better. in that.

And then finally, to your next question with respect to the successor 1, which is comparing a 3-drug regimen and swapping pomalidomide foreside. Again, we would anticipate as the positive study. I would anticipate the effect size is smaller because you're actually just augmenting a class of drugs. And we wait to see that data with interest.

Yes. And I'll just add, I think the two comparative sort of points we can point to for what that kind of Palm KD arm is going to look like? Or is this IT called the SELECT study of 52 patients where there was an 11.1-month PFS. And then if you look at the comparator arm to the Majestic 9 study, which is a very similar patient population. We saw that have about an 8-ish month PFS. So that's another way to handicap success or 1 to see what is that palm triplet arm going to do versus the doublet that was in success or 2.

Thank you. The next question comes from Brad Canino with Guggenheim.

Great. Thanks for the question and for the overview this morning. question for me is how do you think about the ability for these next-generation IKZF1/3 degraders to be more effective than pomalidomide and earlier lines of therapy. And really the question behind the question I'm thinking about is why a T cell engager combination in second, third-line therapy might be better with a drug like Cemsidomide instead of a generic drug like pomalidomide?

Thanks, Brad. Nisha, I'm actually going to ask you to address that.

Sure. everyone. Happy to be here this morning. So I think the question was why would we think that Cemsidomide might be more potent with T cell engagers than the classic image that we have currently, is that correct?

Yes. Yes, roughly. Yes.

Yes. I mean I think we don't have the data, but I mean my answer to that would be an extrapolation from what we're seeing in the late line. So when we look at pomalidomide in this -- if we looked at that in this combination or we looked at Cemsidomide in this late relapse population, the Cemsidomide data looks more potent. So the depth of essie were not supposed to do cross-trial comparisons, but we do all the time.

And the depth of response, particularly in a much heavily pretreated population looks so much better. And so when we compare them, we're expecting to see better efficacy than them is that we have currently. And I think it's encouraging the data that we see with them is that we use IMiDs in combination with bispecific antibodies, both on trial and really in the rural world practice all the time, and we see those preclinical effects in patients all the time. There's immune stimulatory effects able to really deepen the responses that we see with bispecific antibodies in late relapse and even in early relapse in several clinical trials that we have here.

So I mean, for me, again, we have the Phase Ib open here looking at [indiscernible] in combination with Densan we're enrolling the first patient on [indiscernible] looking forward to see that data. But for me, it's just a very simple answer of it looks more potent than the late relapse. And we're seeing that efficacy with in so we would expect to see at the very least the same, but I would imagine improved efficacy given what we're seeing in the late relapsed population.

If I could add to that, at. Just 1 other point that is embedded in what Nisha said, so it's not different, but just as more illumination, if you will, is for us, our starting dose with our L recombination is 75 micrograms. And what's unique about that dose is we obviously know it has T cell enhancement features, and that's great. But that dose has a 40% response rate. And if you think about the first 2 cycles, in particular, when you're giving a bite, you're trying to get the patient into response.

So we're hoping -- and the data will be the data. And I want to make sure I'm clear on it. I'm hypothesizing, but at the end of the day, we're hoping what Cemsidomide can bring because we can give it at a dose that has its only independent anti-myeloma effects that it will really help drive getting the patient into a really clinically important response quickly. as well as the T cell enhancement effects than sort of supporting the back end for long-term durability and increasing depth of response over time. So we're really excited about the trial.

And certainly, we have great investigators participating on it.

And I'll add one other comment is what's really also important is the selectivity of Cemsidomide. When you think about the first gen, right? No one do the mechanism so they can't be selective. They -- they rate a number of other NeOsubstrates like GSPT1 and CK1 alpha. And when you think about combining them with a bite, you really want to do the safest, most tolerable one because there can be overlapping toxicities and bites alone have some toxicity.

So to be able to maximize the anti-myeloma effect and give the maximum dose possible, you want the cleanest sort of broad on target and really based on kind of the data that's out there, that's really subside.

Yes. On that aspect, if you could hear Dr. Joseph's perspective on how much TCEs can actually get out into the community and penetrate that patient population over time as the community continues to learn how to give them. And then also the feasibility of combining with a drug like EMC and the potential for overlapping neutropenia. Is that going to be a challenge? Or can that be administered there as well?

Yes, of course, happy to address those. And I think really good questions. I think at least in our region of the country, we have been seeing bispecific uptake in the community. At a slower rate, maybe than other regions, but it's definitely happening. And I think what's also been really helpful recently is Tecan Tech, and I think it's kind of becoming unavoidable that community physicians need to become familiar and learn how to get bispecific antibodies, and they want to, right?

They want to keep patients. So what they don't want to do is having to send patients to us often, right, even with CAR T cell therapy. They don't want to lose the patient. And they're worried that they come to an academic center. They won't get the patients back. So they want to be able to give BCMA therapy. They have belantamab, that can be a trickier 1 for them to give because of some of the ocular toxicity. So they want to be able to give a drug in their clinic that's effective and they can keep their patient. And I think given some of the data looking so effective in early relapse, I really think we're going to see even more shifts.

I think another thing that we've been working on here at Emory, we've been doing this now across the country. is how do we make administration more feasible for the community practice. And so right now, what we're currently doing is we do the ramp-ups for them. There's a lot of anxiety about CRS and IgAN. But we've also started, I'm sure we've heard and we started doing this in clinical trial practice now is just routinely using prophylactic cola we've made folks have published on this, it markedly reduces the rates of CRS and we're not seeing a lot of ICANS.

And so it's really a lot of education that we all do about the role of prophylaxis, how to use it and how limited those effects are into the first cycle in terms of CRS and ICANS. I think that is getting better. I think community doctors are becoming more comfortable. At the very least, we did the ramp-up and we send it back. That's -- it won't be forever, but that's what we're doing. And I'm seeing more people comfortable picking up with cycle 2. So I do think that's going to continue to shift just because it has to sets are coming in earlier line trispecifics are coming. I mean they just are going to have to start making this shift.

This is becoming standard of care for myeloma patients in early relapse, and it's going to become I think, standard in newly diagnosed, at least for certain populations. So that's just an inevitability, I think. And then in terms of the feasibility piece, about neutropenia, right, in combination with Cemsidomide. And again, let's see the data. I mean, certainly, when we look at CELMoDs in combination with bispecifics we saw a good amount of neutropenia, but with some dose finding, I mean that's certainly improved.

I think the thing you have to remember is even with community docs who are giving these regimens, they are hematologists. So there are side effects that are not good that we really can't tolerate and then there are side effects that we can, and those tend to be hematologic. And so hematologic even with significant rates of neutropenia, that's very familiar community [indiscernible]. So giving GCSF holding drug or doing dose reductions, I'm not particularly worried about that. I mean I think it's on us to make sure we find a dose that is appropriate and that we're not seeing high rates of federal neutropenia or opportunistic infections and things like that. But outside of that, I think it's quite manageable, certainly for academics but even for the community.

Okay. The next question comes from Etzer Darout with Barclays.

Great. Thanks for conducting this webinar. A couple of questions for Dr. Joseph. Just again, if these data hold, I would love to hear your thoughts around how you would use instead? And would you use it ahead of other IKI, the greater image or Cemsidomide? And then also, are you seeing patients that have progressed on BCMA modalities and how you're currently treating these patients? And maybe the success or lack thereof you're having with those patients?

Sure. Yes, happy to. I'll start with the last 1 first. meaning the question about, are you seeing post BCA how those patients are doing. So we have -- that's the most rapidly growing population in our practice as post-BCMA. We're giving so much more sale in early line starting to get more bispecifics.

So not only are we seeing a post-BCMA population, we're seeing a post-PC growing post GPRC5D population, and that's going to grow as we start using trispecifics and other dual-targeted CAR T cell therapies in early line, which are coming also. In terms of how they do or what I do currently, I mean that's -- that depends certainly on the case, but I think that really highlights the efficacy or the role of these classes of drugs because often coming off, certainly of a bispecific antibody, as you know, we tend to have a dysfunctional T cell phenotype, going to another bistate isn't going to work going into CAR T cell therapy is usually not the ideal.

So I think that's a role for these types of drugs. In current practice outside of clinical trial, if someone was coming off of CAR T cell therapy, I might consider a bite, but if someone is coming off of a bit, I'm trying to scramble to find some other regimen that I think would be effective. So some kind of if they haven't had carfilzomib or even maybe selinexor, I mean we're kind of limited outside of clinical trial in that space. lineal trial, we go for things like this.

C4, sometime, excuse me, or other P300 inhibitors, things that don't require T cells. So I think that's 1 phase that these herbs are very helpful. In terms of how they do, it just depends. If this is an early relapse patient, I think there's so many options. This is a late relapsed patient. It does get harder and harder for these patients to find options. I'm sorry? Okay. And -- I'm sorry?

There was no one interrupting. Keep going.

Okay. I'm sorry. And then I think the other question was how do I see using Cemsidomide. Is that correct? Forgive me.

Yes. That's correct.

Yes. I mean I think, again, I guess I just addressed this. I think the role of these types of drugs are either in a post T-cell redirecting space, where you have. You don't need functional T-cells and you have this potential immune similar to our effect, or in combination. So I mean we were talking -- we've talked about [indiscernible]. I'm sure you all a familiar with CAR-T data. I referenced this in the talk. These drugs are effective, but they're not curative. There's significant room for improvement.

So to be able to not only improvement but improve safety, which was referenced early, and we're moving towards fixed duration also. To be able to give bispecifics forever and ever, is really not feasible. You saw the infection data in -- so if we can try to get deeper, more durable responses early and then back off on the bispecific and maybe continue an oral drug or whatever. I mean, there's so much earn there. But there's a significant room for improvement. In terms of efficacy, duration of response and safety. So I mean, in the current landscape, if you gave me [indiscernible] right now, I'd probably be using it in a post BCMA space.

I mean that would be the approval. But post CAR-T or post bispecific in between bispecifics. But I think there's a lot of potential as we learn about how to combine with bispecifics and other standard therapies, as you heard about, I would imagine it's coming earlier in terms of what would I do with CELMoD versus side that's all very hypothetical. I think certainly, we see activity with incentivized in the post-allo space and the sawlogs are going to move up and everything is moving up. So it's hard for me to kind of wax poetic on what's going to come.

But ultimately, the best drug wins. The most ton drug, the safest drug for patients. And I think particularly when you talk about an oral agent that we're going to be giving the community more safety matters, the amount of dose reductions matter, how much supportive care matters. Because community oncologists, I see motions today, they see 1 to 5 every 6 months. So we have to find drugs that are effective and easy to dose. So I hope that answers the question.

And the next question comes from Derek Cilla with Wells Fargo.

This is Jacob on for Derek. So just thinking about De step-up dosing, G-CSF usage and other approaches to mitigate some of the safety issues with this class in BCMA bispecifics, can you talk a little bit about the differences between your study with [ ELRA ] and then those of [indiscernible]? And then how might the differences affect the dosing intensity and reductions compared to the Cemsidomide.

I'll let Len answer address that one.

Yes. So the data that precedes us with ELRA, in particular with ibernomide, which was seen at ASH, if you remember that presentation, there was a learning curve, if you will, during that study vis-a-vis how to give the and, in fact, how to even define DLTs. And so we've been able to learn from how that trial was actually designed and try to mitigate the risks that we will get into a situation where were caught off guard by unexpected findings.

So we have proceeded to start the study with ELRA, which is in the dose of administration, the way it was finessed in that study. We've redefined the DLTs carefully and made it very clear how to use supportive care, in particular in the safety evaluation period to make sure patients all get maximum supportive tariff needed. Also a key feature is that, of course, we don't start Cemsidomide during the step-up dosing. So the step-up dosing, obviously, is there's a unique set of risks related to bite therapy to ELRA therapy.

And we want to make sure the patient gets through that safely, so that we don't contaminate our ability to understand any safety issues before we introduce Cemsidomide. So the trial is very well designed and it benefits from the knowledge that's been gained before us. We're super excited about it. And as I said, it's open and recruiting. But we have benefited from being second with this combination actually.

and this concludes our question-and-answer session. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

Good morning, everyone. Welcome to Barclays 28th Annual Global Healthcare Conference. I'm Etzer Darout, Senior Biotech Analyst at Barclays. It's my pleasure to have C4 Therapeutics with us this morning to kick us off. I have Andrew Hirsch, CEO; Len Reyno, Chief Medical Officer from C4 Therapeutics. And Andrew, maybe you can just get us going with just an overview of C4 Therapeutics and then the upcoming milestones that you think are key and are worth noting to investors?

Yes, absolutely, and thanks for having us. It's great to be here. So for those of you who are not familiar with C4, C4 is a targeted protein degradation company. And we use our degradation platform with the goal of developing medicines in areas of high unmet need. We have 2 programs currently in the clinic. Our most advanced is Cemsidomide, and I'm sure we'll spend some time talking about that today. That is an IKZF1/3 degrader, that's targeting in development for multiple myeloma. Last year, we completed a Phase I study, and we've now started the next phase of development. We started a Phase II study called MOMENTUM. We started dosing patients last month, and that's underway and enrolling.

And then we expect to start in Q2, a Phase Ib study in combination with elranatamab, which is the BiTE from Pfizer, and we're excited to get that underway. And so that forms the basis of what we think is an exciting and differentiated registrational path. The other program we have in the clinic is a CFT8919 that's an EGFR L858R degrader for non-small cell lung cancer, that's in a Phase I study in China run by our partner, Betta Pharmaceuticals. And we expect to have data this month that will enable us to make a decision on the path forward for that program.

In addition, we have a robust discovery effort that combines both internal programs as well as collaboration programs. Our internal programs are really focused now on an area sort of outside oncology, we're focused on inflammation, neuroinflammation, neurodegeneration, we call out INN, and we're excited that really leverages some of the key elements of our platform as well as 10 years of learnings of degraders and what degraders can and can't do. And then in addition, we have collaboration partners. We're working with Roche, with Merck KGaA and with Biogen on developing degraders against targets of interest for them and more recently, Biogen has 2 molecules in Phase I that we've delivered as part of that collaboration.

And then we have a strong balance sheet. We ended the year with just under $300 million, which provides us runway through the end of 2028, which should get us though a number of important milestones, including an early look at data from the MOMENTUM study, which will be in the second half of 2027. And then through the Phase Ib and start-up of a potential Phase III with the BiTE combination. So lots of exciting milestones coming up is really a key year of execution as we get these studies underway and launch the cemsidomide development plan as well as pursuing our Discovery targets.

Great. Lots going on in multiple myeloma, obviously, even yesterday, we saw an update success 2 trial from Bristol-Myers Squibb. Just maybe give us some projective in terms of what cemsidomide could deliver to sort of the multiple myeloma disease armamentarium and what you believe is achievable with that molecule? And maybe highlight as well some of the data that you've generated to date there as well?

Yes. Maybe I'll start at a quick high level and Len get into some of the data. Look, I think the IKZF1/3 pathway for multiple myeloma is foundational. I think that's lost on a lot of people because these are targets that have been drugged through the IMiD class, which we've had for a long time. But if you remember, the IMiD class are not optimized degraders. In fact, when they were discovered we didn't know that they were degraders. And now that we've learned that they were degraders, we're able to develop and optimized degrader. And so we think that cemsidomide has a potential best-in-class profile based on the data that we shared last year. And that's based on the fact that we've really optimized both the catalytic activity as well as the selectivity and PK of the molecule. I think it gets lost on people that we're dosing in micrograms. People seem to forget that, which is incredible to me that we're able to do that. Len, I don't know if you want to...

Yes, I don't know if I could build on that because, obviously, people are interested in the evolution of the myeloma space and it's undergone a fundamental disruption with the advent and the penetration of immune-based strategies. But it's a really important part to map back to what Andrew just said. IKZF1/3 degradation remains a fundamental mechanism of action. And it's really important to think about what that actually means in practice. And in that regard, our first-in-human study is incredibly informative because what we show in that study where we had patients who had a median of 7 lines of prior therapy.

In fact, 75% who have been exposed either to CAR-Ts or T cell engagers or both. We showed that at our highest exposure, we still had a 53% response rate. Why does that matter? It matters because what it tells you is notwithstanding all the other things the patient has been through, there remains a foundational role for targeting these transcription factors, mapping back to IRF4. So that's sort of the top line summary of the trial, but why are we positioned for success is, I think, really important to both patients and investors.

What's unique about our data set is that we were able to show really very elegantly that at every dose level we tested with dexamethasone, we had meaningful anti-myeloma responses with a very manageable and class-leading potentially safety profile. Why maps back to what Andrew just said, we were able to optimize the PK/PD relationships. We're differentiated in the class because we have a 48-hour half-life. That 48-hour half-life with the potency, we're the most potent drug in the class, more potent preclinically than Mezigdomide is with that 48-hour half-life we're able to achieve anti-myeloma effects over a range of doses, clearly goes up as you increase exposure, but we're able to release the break in time to allow for neutrophil recovery.

And so taken together, we have a data set that I would refer to as a broad permission slip that cemsidomide can be developed in really in the future in any line of myeloma care. And our plan moving forward is a very efficient plan to address 2 parts of that spectrum with MOMENTUM, late line, fourth line plus. And with the 1B BiTE anticipating further development in the Phase III earlier lines of therapy pivoting on the move to immune-based strategy.

Right. Great. Maybe with that, talk a little bit more about MOMENTUM of the trial, maybe the trial design there. And then maybe some of the nuances to relative to the Phase I/II, right, in a highly refractory population, if you can kind of talk...

Yes. So in some respects, the MOMENTUM trial mirrors almost exactly what we did in the Phase I first-in-human study with some important changes. One is simply operationally now that's going to be a study that we conduct both in the U.S. and Western Europe. So that increases us because obviously, in the end, cemsidomide should be and will be a global asset. That will affect the population we recruit. So I told you a few minutes ago that we had 7 prior lines of therapy. The eligibility criteria is fourth line plus. What that will map because of the 2 continents is that probably in the U.S., there'll be relatively more prior lines of therapy with more patients who have actually progressed after T cell directed therapy.

And in Western Europe, we anticipate they may have had relatively fewer lines of therapy. That's an important premise because, in fact, one of the things that we don't want to do is pigeonhole that patients have to have failed everything and anything to get value. Patients don't take [ end-line ] therapy that's approved for various reasons, including access. So it will find kind of trial on the high level. But I don't anticipate at the end that the median prior lines of therapy will necessarily still be 7.

The other thing, of course, that's different is now we've really understood how to give the drug, and so we can manage the drug in terms of dosing and decision-making vis-a-vis optimizing safety and opportunity for efficacy in a programmatic way, consistent with driving the drug forward for potential accelerated approval. And that's the other difference is the trial will be conducted with what I would describe as regulatory intent. Really, the main issue is we always follow the protocol, but we will follow the protocol and in addition, have the indices of safety and efficacy reviewed by an independent committee. And that will increase the potential rigor of the data set that we anticipate will support ideally an accelerated approval discussion.

Great. I guess with that, can you talk about what you view as sort of a hurdle rate for response rate for that, again, highly refractory population? And also maybe sort of coming to sort of quorum with the FDA around what sort of that bar, if you will, could be for success?

Yes. I think the FDA is always very cautious in trying to -- and giving an arbitrary bar for what success will be, especially if you are having a discussion regarding accelerated approval. And contextually, it's always how does the data look in the context of what else is happening in the space at the time you present the data, that's it. There are some principles that I think are reliable that we can think about. And one is we know from experience, most accelerated approval drugs are going to have to have a meaningful response rate with meaningful duration and also safety that's acceptable, manifested in particular, by not having patients come off drug for safety issues.

So we've modeled the study that with 100 patients we can reliably detect a response rate of 40% or greater. And we anticipate that the duration of that response benefit will be at least 6 months, more being better. We're higher than that in our IMS presentation and that the drug will be safe. And there, again, where we're really proud of and happy about from the first-in-human study, we have almost no discontinuations of cemsidomide for any safety-related events. So that's the sort of context of the study. Historically, it's compared against what the background rate of an effect might be. And we know that no off-label use in various lines is active. But typically, we statistically modeled that, that signal wouldn't be greater than about 25%. And with 100 patients we can distinguish between those 2.

Got it. Great. And I guess with the increasing use of anti-BCMA therapy, maybe you can also speak to how important is that post-BCMA activity we're observing with cemsidomide especially put in the context where the comparator IKZF1/3 degraders really didn't have that sort of -- that hurdle that you guys have with the anti-BCMA therapy. So can you speak to that...

It's a great question and an important observation that people obviously are always making comparisons with us in terms of emerging the class of BMS is calling CELMoDs, which are essentially optimized degrader. And that's a really important distinction. CELMoDs are nothing different in terms of mechanism of action than cemsidomide. What they are, are potent optimized degraders. And the difference is that when people talk about what folks have seen with those drugs, those drugs were developed. It's not a question of they didn't offer to include those patients. Those patients didn't exist. And in fact, when I joined the company 3 years ago, I had initial conversations with some investors saying, does this MOA even matter anymore?

And what our data just resoundingly showed that it does matter, that patients who get state-of-the-art care still progress and they still show up seeking disease-modifying care. And we are the only drug in the class that is actually articulated and defined and really impressive response rate with that exposure history.

Yes, I think that patient population is growing because as the CAR-Ts and the BiTEs move into earlier lines of treatment, what happens is patients are living longer, but they're still progressing. So if you look at the CARVYKTI data, I think 2/3 of patients kind of relapse around within 5-year mark. So for 1/3 of patients, it's close to a functional cure, but there are still 2/3 of patients who now have a great treatment option that can prolong keeping their disease in check, but they will progress too. And that just expands the number of patients available in this late-line setting as we see that migration of these newer therapies to earlier more immunocompetent patients.

Great. And between now and when you sort of get to the response rate, duration of response endpoint, are there any interim updates that you could provide on that trial before we get to that? Or is it just sort of heads down, if you will, until we get to that response rate?

No. I mean, so as Len said, we're conducting it for regulatory intent. And so we're blinded to the data. That's why we have the independent safety data monitoring committee. So we're trying to be as clean as possible. We don't want to bias the outcome of the study at all. And so we're not going to see anything so we won't really be able to provide an update until, as I mentioned, really that second half of '27, where we'll be able to share an investigator-assessed response rate. The regulatory endpoint will be that centrally assessed as well as some indices of durability, and that really won't happen until about mid-28, and we'll have that data set. But the first look that we'll be able to see and potentially share would be that second half of '27.

Got it. Great. Maybe we can shift to the second-line plus setting in combination with T-cell engagers. We've obviously seen data from Bristol there, from Iberdomide as well as mezigdomide. Maybe first, just your thoughts around where cemsidomide could differentiate from those combinations and I guess, relative to what...

Yes, it's easy. It's going to differentiate by being more effective. But you really want to know is what's the evidence for that. And I think it's important to think about why you're doing the combination in the first place. So you're doing the combination in the first place because we know that BiTE-directed therapy suffers from T cell exhaustion as well as lack of optimized T cell effect that does 2 things. It contributes to relapse, but it also reduces the depth of the response.

So if you think about the data we presented in our first-in-human study, there are 2 buckets that data that are important. One, we already talked about, and that is that we have the most active compound of the class. And then the second piece that we didn't spend any time on yet is that we also know from our translational data in that study that at every dose level we study. We have a beneficial effect on the T cell population and the concomitant related effect on cytokines that are associated with immune activity. So taken together, the promise of that combination is the following: that because we have at every dose level and every dose level that we have has anti-myeloma effects as well, we're hoping that we can both augment the anti-myeloma effects, which will appear very early in the first 2 to 4 cycles of therapy, and that would manifest with hopefully, higher quality, i.e., more CRs, deeper CRs, more MRD-negative CRs.

And then at the end, that will also manifest as prolonged progression-free survival and ultimately survival. Unique differences from the data that's already been presented for us. If you look at the data that was presented at ASH for Iberdomide combination with [ ELRA ] which is our combination partner. We benefit from that data because when that trial was started, the sponsor Pfizer was still figuring out how to give a BiTE with the combination and dosing schedule, as well as how to define the safety events and the response to the safety events. We have the luxury of learning from that and actually making sure that as we incorporate our combination strategy, that we're only really focused on the dose of cemsidomide and that we have appropriate indices of both safety and efficacy. And in addition, that we have optimized the support of care because, as you know, with BiTEs, there is a very real issue. The good news is it's manageable, but it needs to be optimally managed. So we benefit from that data.

Another key difference though is when I talked about the data that we had from our first-in-human study, that signature with the immune enhancement is with dexamethasone. So if you look at the Iber data from ASH, that was not with dexamethasone. And I think partly that's simply because the data to generate that hypothesis was lacking. So that's another key difference because we know dexamethasone does has augmented anti-myeloma effect, it will also reduce the side effects, risk of CRs. It also has an augmented safety benefit in terms of supporting neutrophil counts, especially in the first 2 cycles. So there's a lot of key differences.

We're excited about the data that was presented though because the data that was presented, notwithstanding, we think it's not the optimal combo is it did show a beneficial effect on a higher response rate. It really is a very small study and really doesn't have the ability to drill down into quality of CRs, et cetera. But as an out-of-the-gate data set, really supportive of our hypothesis and the design we have. So we're super excited about it, and it really enables us, I think, to move quickly because obviously, we need to be agile, and we need to move fast to get these trials done to get the data to the environment we need to get ultimately to design a Phase III in this instance.

And I think some people sort of looked at that data and said, well, like the bar is higher for C4. But actually, to Len's point, sort of derisked our hypothesis around can these classes of drugs be combined and managed safety? And the answer was yes. And you saw the increased ORR that really put it on par with CAR-Ts. But what it didn't do is increase the sort of CR and greater rate to be able to put that. And that's really the name of the game in myeloma today. It's not necessarily ORR because we think with these new combinations and these novel immune directed agents, you can get close to 100% response rate. It's really how you drive that MRD negative depth of response, and that's the opportunity for cemsidomide, which is, again, we think best-in-class in terms of both potency and tolerability.

And so we think that the potency of cemsidomide can actually drive that CR+ rate higher and maybe we haven't seen the MRD-negative rate for that study. And I don't know if they're going to present it at some point, but -- and then hopefully have a quality MRD negativity as well. So that's really the opportunity that, that data set opened for us.

Yes. And so as you think about the Phase Ib study that you're going to be this year? Is it really more around sort of the safety of the combination? Or are you going to sort of embed the ability to look at sort of the deepening of responses, the durability within that study?

So of course, by definition, it's safety, but obviously, it's got to be efficacious. And it's not going to be statistically powered to actually have a reported reliable response rate. But we will obviously look at and share the quality of response, the depth of response. And we'll be looking at that data and making decisions vis-a-vis how to design Phase III trial. So we anticipate that the regimen will be safe because we think we have the optimized drug vis-a-vis safety. It will be clearly very active. We won't be in a position to have 100 patients at a dose of interest quickly, but we will get data as quickly as possible at relevant doses.

And in that regard, I think what's really important to note we're starting with our starting dose of 75 micrograms of cemsidomide. A great question is why? And that reflects our confidence in the safety signal. We know the drug is safe across a range of doses. If we look at the data from our first-in-human study, we have a modest side effect signal at 75 purely manageable. When we look at the effect on neutrophils as well as the supportive care that would be administered with a BiTE, we're cautiously optimistic that, that dose will be clear safety hurdle. And that will do 2 things based on the design of our trial. It will allow us to go higher. We're not -- we have to define whether 100 is the right dose when you're using a combo partner that's not just [ Dex ]. But will also allow us to expand the 75 level and if need be an interest to look at 50.

So again, our job is to obviously do right by patients and to do safe regimens. But our job is also to bring efficacy to patients as fast as possible, and then, therefore, to bring data to who we need, which is our investor audience to give confidence that our plan is working and on our time line that's efficient to get the drug to market.

Yes. Great. I think one point I think that sort of maybe missed on folks to is sort of the innovation around the 14 days on, 14 days off that you ended up implementing for that versus sort of the legacy 21/7. Is that a moat, you think, in terms of for this molecule for this program? Is this something others can try to replicate? Or do you think that it's really the quality of the molecule that allowed you to do that?

They can. For a drug with a 24-hour half-life, you can give sort of a lower thing. But the question is I think I would frame back is our 14-day on, 14-day off schedule is pharmacologically optimized for this drug. And for a drug with a 24-hour half-life that won't -- anything less than the 21/7 if you're looking for the anti-myeloma effect, it's not going to be an optimal regimen. It will likely be safe and tolerable. But if you ask a different question, would it likely optimize the anti-myeloma effect, I think the answer would be it doesn't make sense. It wouldn't based on the understanding of how the drug actually works.

Right. Great. Maybe lastly on CFT8919, just your lung cancer program. And just the opportunity there and maybe the progress that the program is making currently?

Yes. So when we set out with this program, I think that we observed that when you look at osimertinib, which is a fantastic drug. There was really a gap in efficacy from [ DL19 ] versus LR patients. And we thought making a degrader against selectively against the LR segment, was going to lead to improved outcomes for patients with that LR driver mutation. And so that was the goal of the program, and we started a Phase I study in China with our partner, Betta. So we'll have the data -- some of the data from that Phase I study this quarter. And that will enable us to look at what does that mean and then kind of plug that back into our market assumptions the same.

There's been certainly some advances in that space that has shrunken the gap between the [ osimertinib ] data and in terms of [ DL19 ] versus LR. And then we will also, as we always do, will evaluate what does the development path look like to really capture the opportunity. The bulk of the opportunity we believe is in the frontline setting, and that will go into the calculus of what does that look like? How complex is that? And is that a study for us to do assuming the data supports it? Or is that something that may be better suited for a partner. And so we'll put all that together and make a decision internally this month and we'll communicate at the right time, but we're on track with that.

Right? So we're up on our time. Andrew, Len, thank you so much for this discussion. And then we'll be back with our next session. Thank you.

Great. Thank you.

Thank you.

Good day, and welcome to the C4 Therapeutics' Phase I trial data of cemsidomide in multiple myeloma presented at IMS 2025 Conference Call. [Operator Instructions]

Please note this event is being recorded. I would now like to turn the conference over to Ms. Courtney Solberg, Associate Director of Investor Relations. Please go ahead, ma'am.

Good afternoon, and thank you for joining our call to discuss our Phase I data of cemsidomide in multiple myeloma. These data were presented at the IMS Annual Meeting earlier today. We will be making forward-looking statements today, and Slide 2 contains our legal disclaimer on this matter. Those presenting on today's call are Andrew Hirsch, our President and CEO; and Len Reyno, our Chief Medical Officer.

We will begin with opening remarks and then walk you through the clinical data for cemsidomide in multiple myeloma and next steps in clinical development. We will end today's call with a Q&A session. This will include Kendra Adams, our CFO; as well as Dr. Binod Dhakal, a clinical investigator for multiple myeloma. Dr. Dhakal presented the Phase I clinical results at IMS earlier today. I will now turn the call over to Andrew Hirsch for some introductory remarks.

Thank you, Courtney. While the focus of today's call is on the Phase I data for cemsidomide in multiple myeloma and the next steps in development, I wanted to take a few moments to highlight key elements of our strategy to create a new generation of medicines that transforms patients' lives by delivering on the promise of targeted protein degradation.

First is to advance our clinical stage assets through the development stages as data warrants to the commercial setting. Cemsidomide is our most advanced and derisked program and remains our top priority. We also continue to advance CFT8919 in collaboration with our partner, Beta Pharmaceuticals.

The second pillar of our strategy is to leverage the learnings from 10 years as a leader in TPD science to advance a preclinical portfolio of degraders against novel targets in areas of high unmet need. Under the leadership of our new Chief Scientific Officer, we've expanded beyond oncology into other indications that build upon the learnings of the early stages of this new modality. We will update you in the future as these programs advance.

Lastly, we continue to advance our established collaborations in both oncology and non-oncology indications as a way to expand the application of TPD, but also achieve financial milestones that can contribute to our capital formation plan. We're excited about the recent news from Biogen that the IND for BIIB142 and IRAK4 degrader has cleared and clinical trials will start soon.

Taken together, we're excited about the potential here at C4T and look forward to updating you on our progress across all 3 elements of our strategy. As I mentioned, our top priority is to quickly advance cemsidomide through the clinical development process to targeted high-value labels that address important segments of the multiple myeloma market. While degrading IKZF1/3 are not new therapeutic strategies, given the biology of multiple myeloma, this therapeutic approach is fundamental to halting the disease, which is why the on-market degraders have had significant market penetration.

However, it's important to remember that these are not optimized degraders, whereas cemsidomide is, and the data we'll present today will demonstrate that cemsidomide has a potential best-in-class profile. Based on the data and our perspective on the evolution of the multiple myeloma treatment landscape, we've identified an efficient development plan that we can execute with a differentiated label-enabling strategy and other next-generation IKZF1/3 degraders are pursuing.

That strategy leads to potential $2.5 billion to $4 billion peak revenue opportunity across 2 market segments, in combination with the BCMA BiTE in second line or later and in combination with dexamethasone in fourth line or later. As some of the new immune-directed therapies move to earlier lines of treatment, multiple myeloma patients will live longer, but since these therapies are not cures, there will ultimately be a growing late-line multi-refractory patient population, similar to the one we studied in the Phase I.

Additionally, while the efficacy of new immune-directed treatments has been impressive, there is an opportunity to enhance both the rate and depth of response by boosting T-cell activity through the addition of a highly selective IKZF1/3 degrader with class-leading tolerability. Everyone at C4T is excited about the potential for cemsidomide, and we're in execution mode to begin the next set of studies in early 2026.

Now I'll turn it over to Len to share more detail about the cemsidomide data and the path forward.

Thank you, Andrew. I want to start off by emphasizing the importance of Ikaros and Aiolos, also known as IKZF1 and IKZF3, respectively. As Andrew mentioned, these targets are central to multiple myeloma biology and are well established in the treatment landscape. IKZF1 and 3 are transcription factors essential to cancer cell growth and regulate the activity of IRAK4, another transcription factor that multiple myeloma is dependent on for survival.

As a result, multiple myeloma has strong dependencies on IKZF1 and 3 and degrading these targets leads to plasma cell death. Neutropenia is an inevitable consequence because IKZF1 and 3 play a role in early neutrophil maturation. And neutropenia is observed with this class of medicine because of reduced replenishment of neutrophil populations over time rather than a direct effect on neutrophil cell viability.

Incorporating a dosing holiday period allows us to balance both cell kill and neutrophil replenishment. With cemsidomide's half-life of approximately 2 days, the 14 days on, 14 days off dosing regimen is optimal. As seen on the right graph, IKZF1/3 degradation also stimulates the immune system by activating fully differentiated T cells and preventing T-cell exhaustion. This is an important concept as we think about combinations, especially with bispecific antibodies.

With a potentially best-in-class profile, cemsidomide is well positioned to be a backbone therapy in multiple myeloma across multiple lines. To orient ourselves, this slide describes the progress we've made and where we are going. This data enabled us to advance to the next phase of development. With cemsidomide dose escalation complete and the data presented at the IMS today, demonstrating class-leading anti-myeloma activity, a differentiated safety profile as well as compelling evidence of immune activation.

To that end, we are on track to initiate a Phase II evaluating cemsidomide plus dexamethasone in a fourth line or later setting with the potential for accelerated approval. We are also on track to initiate the Phase Ib trial in combination with BiTE in the second line or later. If the Phase Ib trial is supportive, we would trigger a Phase III trial for cemsidomide in combination with a BiTE.

This Phase III trial has potential for accelerated approval and will serve as a confirmatory trial for both combinations. This slide demonstrates all of the comprehensive dose escalation work we have completed to get us to this path. Based on the data generated to date, the 14 days on, 14 days off schedule remains the optimal dosing schedule for cemsidomide. We have escalated up through 5 dose levels with the 100-microgram dose level declared safe and is the maximum administered dose. Based on our discussions with investigators, we believe if we dose escalated higher, we would have exceeded the MTD, making further dose escalation not warranted.

It should be noted that dose escalation and subsequent dose level expansion decisions use the BLRN methodology. Safety was initially determined in cohorts of 3 to 9 patients and then dose levels were expanded to include up to 20 patients. Also, as a reminder, during cycle 1, routine G-CSF use was not permitted in the escalation cohorts determining safety, but could be used at investigator discretion in all subsequent cycles.

There was no restriction on G-CSF use in any cycle for patients enrolled during dose level expansion. On this slide, we describe the characteristics of the multiple myeloma patients enrolled on the Phase I trial of cemsidomide in combination with dexamethasone. The median age of patients enrolled was 67, which is typical for relapsed/refractory multiple myeloma with a range -- age range of 39 to 90 years.

32% of patients have extramedullary disease, a marker of more difficult-to-treat disease. Importantly, all of these patients are heavily pretreated. Indeed, patients had a median of 7 prior therapies ranging from 3 to 22 and 79% of patients were Penta-class exposed. Note in the green boxes, the population treated in this trial also included patients who had progressed despite prior CAR-T or T-cell engager therapy. 75% of the patients had one or the other therapies, including 75% with prior BCMA therapy, 47% with prior GPRC5D therapy and 29%, who had both CAR-T or T-cell engager therapy.

Despite the success of these novel therapies, as the enrollment data from our trial shows, these patients are still progressing and continue to need more treatment options, representing the current high unmet need. Let's now examine the safety and tolerability profile of cemsidomide plus dexamethasone.

To summarize, cemsidomide plus dexamethasone demonstrated a differentiated safety and tolerability profile in a highly refractory late-line population. This supports late-line development as well as the possible combination with other anti-myeloma agents. Notably, neutropenia was manageable, supported by no discontinuations related to cemsidomide and minimal treatment of emergent adverse events that led to dose reductions. This is important for 2 reasons. First, the #1 reason patients came off of this study was due to progressive disease and not due to safety.

This supports the fact that cemsidomide is well tolerated for those that derive benefit, and this bodes well for full development. Secondarily, this is a key differentiator compared to other IKZF1/3 degraders in the clinic. In addition, we'd like to highlight the risk of neutropenia did not increase over time, and we observed limited G-CSF use, which again supports the minimal impact of neutropenia on the patient experience.

I will now walk you through the cemsidomide plus dexamethasone safety data in more detail. As expected for all drugs in this class, the most common adverse event was neutropenia. 61% of patients experienced all grade neutropenia. However, only 33% of patients experienced grade 4 neutropenia across all doses. Febrile neutropenia occurred in only 6% of patients. Only 19% of patients experienced thrombocytopenia at any grade with 4% reported as grade 4.

Importantly, only 6% of patients had dose reductions due to treatment-emergent adverse events, and there were no discontinuations related to cemsidomide safety. This data continued to demonstrate cemsidomide's well-tolerated profile and that patients are not coming off treatment due to safety events. Let's now examine the common and important side effects across the individual dose levels tested. In general, rates of Grade 3 and 4 neutropenia were remarkably consistent across each dose level.

We do note the 75-microgram dose level has a numerically higher neutropenia rate, an outlier from the other dose levels. It's important to note, however, that 95% of the patients enrolled at this dose level had received prior stem cell transplant, which is known to increase the risk of neutropenia to any given myelosuppressive agent.

Regardless of the rate of neutropenia at any given dose level, the more significant question is what are the clinical consequences of neutropenia, bacterial infections and febrile neutropenia. In this regard, you can see the rate of Grade 3 or greater infections across all dose levels was only 25% and in fact, is a mixture of both bacterial and viral etiology and did not increase as dose level increased.

Finally, the incidence of febrile neutropenia was also low with no dose level having more than 1 patient with febrile neutropenia. On this next slide, we break down the incidence of myelosuppressive side effects, including the use of growth factor support and significant infections across multiple cycles of treatment. It is remarkable to note that the majority of myelosuppressive-related side effects occurs in the first 2 treatment cycles.

The risk of neutropenia does not, in fact, significantly increase over time with only 6% of patients experienced grade 3 or 4 neutropenia for the first time after cycle 2. This bodes well for further success in late-stage development and again, supports the notion that patients do not come off of therapy because of treatment-related side effects. As you can see from the green bars, the pattern of stable and modest myelosuppression is also not the result of increasing use of growth factor support.

In fact, only 40% of patients received G-CSF at any point during their course of therapy and G-CSF use did not increase in later cycles. And importantly, 32% of patients are still on treatment after cycle 8, consistent with clinical benefit from cemsidomide. Taken together, this data strongly supports the differentiated safety and tolerability profile of cemsidomide in combination with dexamethasone in this highly refractory population.

Now let's turn to the evidence of class-leading anti-myeloma activity. As summarized on this slide, IMWG objective responses were achieved across all dose levels. Patients enrolled at the highest dose levels, 75 and 100 micrograms, respectively, achieved a 40% and 50% objective response rate. This includes a patient who achieved an MRD-negative CR at the 100-microgram dose level.

Importantly, these responses were durable. The median duration of response across all dose levels was 9.3 months at the time of the data cutoffs with the median duration of response not yet reached at the 2 highest dose levels where a number of patients continue on therapy. While we observed compelling activity across multiple dose levels, it's clear there is dose-related response at our highest dose level of 100 micrograms.

Now let's examine how pharmacokinetic and pharmacodynamic data further support optimal therapeutic outcomes at the 2 highest dose levels. As a reminder, cemsidomide in combination with dexamethasone when given over a 14-day dosing schedule shows dose proportional increases at each dose level.

The half-life is approximately 2 days. On the right-hand side of this slide, at all dose levels tested, you see degradation of IKZF1 and 3 is observed. If we specifically look at IKZF3, which is the most cited in relationship to myeloma control, there is deepened and prolonged duration at 75 and 100-microgram dose level. This data further supports that cemsidomide is a highly potent degrader and at the 2 highest dose levels is associated with durable and meaningful degradation, which, in fact, persists over 21 days of the 28-day cycle.

In addition to deep degradation, secondary pharmacodynamics such as CD8 positive T-cell activation were observed at all dose levels treated as measured by significant elevation of cells with HLA-DR and CD838 markers after 7 and 14 days of doses. These activated T cells persist until day 21 of cycle 1. And this T-cell activation, as expected, is associated with IL-2 elevation.

It's important to note this immune enhancement is actually seen across all dose levels tested. This is an important concept as we think about the combination with BCMA BiTEs, bispecific antibodies exhaust T cells, which limits the durability of response. As a result, we believe with cemsidomide's immune enhancement profile that we can increase the quality of BiTE's response and durability. To better understand the relationship between cemsidomide exposure and objective evidence of anti-myeloma activity, a population pharmacokinetic analysis was conducted. On this slide, we plot the decrease of serum-free light chain in individual patients against the population PK-derived AUC for that same patient.

It's clear that the higher AUCs are associated with more predictable light chain reductions, which are a prerequisite for IMWG responses. In this regard, patients who achieved AUC in the highest exposure quartile achieved a 52% reduction in serum-free light chains. The likelihood of achieving this level of exposure is optimized at 100 micrograms, which we will show on the next slide.

Here on this slide, we plot the reductions of serum-free light chains as a pharmacodynamic parameter across each individual dose level. If you focus your attention on the blue and purple bars, which represent 70 and 100 micrograms, respectively, it is easy to tell that these 2 dose levels have the greatest reductions. Importantly, over all doses tested, 73% of patients demonstrated a decrease in light chains and 50% of patients with elevated light chains achieved at least a 50% decrease in serum-free light chains.

Finally, as expected, this reduction in light chain predicts evidence of objective responses uses IMWG criteria. Here, the data demonstrate that cemsidomide is highly active at a range of doses, achieving a 34% overall response rate across all the doses tested. There is also clear evidence that higher doses are associated with more predictable and deeper responses as seen at the 75 and 100 microgram dose level.

We achieved a 40% ORR at the 75-microgram dose level and a 50% ORR at the 100-microgram dose level, including 1 patient at 100, who achieved an MRD-negative CR. We should also note that as of September 5, which is after the data cutoff, 1 patient at the 100-microgram dose level who is not reflected on the graph became efficacy evaluable and achieved a PR.

Additionally, one patient who was included in the graph as a VGPR converted to a CR. Taken together, these data show, in fact, that cemsidomide plus dexamethasone has a class-leading anti-myeloma effect. Now let's turn to examine durability. The median duration of response across all dose levels was 9.3 months. At the 2 highest dose levels, we've not yet reached the median duration of response because 67% of patients here who achieved a PR or better remain on therapy as of the cutoff date.

Together, these data points demonstrate that patients who responded experienced a durable and clinically meaningful benefit. We recognize the importance of viewing the cemsidomide data set in context with other drugs that are in development in the class. We must caveat that there are inherent limitations in cross-trial comparisons, especially in Phase I study populations. And the data shown here is provided only as a benchmark for relative comparison.

No head-to-head trials have been run. Demographically, our patient population is quite different from mezigdomide and iberdomide Phase I populations. Our cemsidomide trial patients were the most heavily pretreated, especially as it relates to having previously received the BCMA-directed therapy. Our trial highlights the fact that despite novel treatments used in earlier lines of therapy, patients are still progressing. In fact, 75% of our patients had prior BCMA-directed therapy. While iberdomide's Phase I trial did not report patients progressing on BCMA therapy, these therapies have not been approved when this trial was enrolling.

Also, only 59% of their patients were triple class exposed. When we look at mezigdomide's dose escalation, 12% of patients had received prior BCMA therapy and only 56% were triple class exposed. Against this backdrop, cemsidomide has potential to be best-in-class based on both its safety and anti-myeloma characteristics. As it relates to safety, our clinical data supports a differentiated safety profile compared to the other degraders in development. If we examine neutropenia across all 3 trials, there were similar levels of Grade 3 neutropenia. As a reminder, Grade 3 neutropenia, while measurable, is rarely of clinical consequence. Grade 4 neutropenia, which is associated with clinical complications favor cemsidomide versus mezigdomide. In comparison to mezigdomide and iberdomide, cemsidomide demonstrated minimal disruptive events and had significantly fewer dose reductions due to AEs in a cross-trial comparison.

This safety signal supports the ability to give cemsidomide with manageable safety consequences and to give it at the attended dose across multiple cycles. Now let's turn to the anti-myeloma activity observed. Cemsidomide demonstrated compelling activity across all dose levels and especially at the 2 highest dose levels with durable responses that are ongoing. Taken together, we believe this profile differentiates cemsidomide from other IKZF1/3 degraders in the clinic, especially against the backdrop of a highly refractory population presenting for disease-modifying care in 2025.

The next 2 slides further illustrate this point in 2 patient vignettes. This first case relates to a 42-year-old male who achieved an MRD-negative CR response after 3 cycles at 100 micrograms. Prior to achieving this response, the patient had a 4-year history of multiple myeloma with extramedullary disease and prior to our trial had, in fact, received 17 prior therapies.

In the month prior to enrollment, the patient had progressed after therapy with talquetamab, a BiTE antibody directed against GPRC5D. At the time of the data cutoff, this patient remains in CR after 8 cycles. The second case demonstrates and describes the activity in a 90-year-old woman who was enrolled with light chain disease after 5 prior therapies. Her last prior therapy, in fact, was teclistamab with the best response of progressive disease. She has tolerated therapy well and in fact, had a VGPR after 2 cycles, which continues after the data cutoff currently post cycle 4.

To Summarize, cemsidomide has demonstrated class-leading anti-myeloma activity, a differentiated safety profile and immune enhancement, which derisks development in the next phases. With this data, along with feedback from the agency, we now have a clear and efficient path forward. On the next few slides, I will describe this path in more detail. We acknowledge that the multiple myeloma treatment landscape includes a multitude of currently approved options. But importantly, targeting IKZF1/3 is biologically relevant in any line of therapy due to its importance as a primary mechanism to inhibit plasma cell proliferation.

Commercially, this is manifested by the inclusion of the drug class in multiple lines of therapy and regimens, which you can see on this slide marked by orange boxes. Our all-oral regimen with cemsidomide has the potential to be used across multiple lines of therapy as a result, and C4T has identified 2 distinct near-term development opportunities.

The first is cemsidomide plus dexamethasone in the fourth line plus setting. And the second is cemsidomide in combination with the BCMA BiTE in the second-line plus setting. If we achieve labels for these 2 regimens, we project peak revenue opportunity in the range of $2.5 billion to $4 billion. The cemsidomide plus dex strategy in the fourth line or later is supported by the fact that despite high response rates of recently approved later-line assets and regimens, patients continue to progress, including after receiving BCMA BiTEs and CAR-T.

Now while many patients are living longer, the median survival of quad or Penta-class refractory patients is less than a year with a range of approximately 5.6 to 9 months. The next slide describes the rationale for cemsidomide plus BCMA in the second line or later. T-cell-directed therapies currently are an important segment of the multiple myeloma market and includes both BiTE and CAR-Ts.

While CAR-Ts have higher response rate, their widespread adoption is more challenging due to technical operations and clinical administration issues than BCMA BiTE. The use of BCMA BiTE may therefore be an even more attractive option if both the response rate and the quality of response could be increased.

It is now accepted in the literature that T-cell exhaustion limits the ultimate effectiveness of BiTEs. We and others have demonstrated the degradation of IKZF1 and 3 can reverse or limit T-cell exhaustion and thus enhance therapeutic cytokine production. That is why we believe with cemsidomide's ability to activate T cells and with potential best-in-class safety profile, the combination could increase the effectiveness of this T cell-directed strategy with the opportunity to pick up a portion of the CAR-T market share in a growing segment of the BiTE adoption in practice.

Based on this rationale, we've outlined a strategic and efficient development plan to registration to take advantage of the growing multiple myeloma population as well as changes in the treatment paradigms for this disease. First is a nonrandomized Phase II trial in the fourth-line plus population evaluating cemsidomide plus dexamethasone, which we believe has been derisked by the data set we shared today.

Second is a Phase Ib trial in combination with BiTE, which aims to characterize the safety and quality of responses. If the data from the Phase Ib trial supports it, we would then trigger a Phase III trial of cemsidomide plus a BiTE with the opportunity to use ORR from this trial for accelerated approval. The Phase III trial is designed to support full approval for both the second line or later combination with the BiTE and the fourth line and later combination with dexamethasone, where full approval would be triggered by a time-to-event endpoint.

We are on track to initiate the single-arm Phase II trial of cemsidomide plus dexamethasone in the first quarter of 2026 with a targeted enrollment of 100 patients. The RP2D for this trial will be finalized by year-end in consultation with the agency. We expect to share the initial ORR data resulting from this trial in the second half of 2027. The Phase Ib trial with the BCMA BiTE is on track to initiate in Q2 '26 with the goal to characterize safety and quality of the response in the combination and establish an optimal dose for cemsidomide. Doses of 50, 75 and 100 micrograms of cemsidomide will be tested starting at 75 and depending if it's declared safe, we would evaluate then simultaneously doses of 50 and 100 micrograms.

The first part of this trial is expected to enroll between 30 and 50 patients, and we expect to share data from the Phase Ib trial in the second half of 2027. To conclude, today, we have reviewed data that supports our thesis that cemsidomide has the potential to be a best-in-class IKZF1/3 degrader in the growing multiple myeloma market. Our clinical trial has demonstrated class-leading safety and anti-myeloma profile in a heavily pretreated population.

The data supports the differentiated development path we've outlined, which is designed to capture a significant portion of the growing commercial multiple myeloma marketplace. We are on track to declare the RP2D by the end of the year and initiate the Phase II trial in combination with dexamethasone in Q1 2026 and the Phase Ib trial in combination with the BCMA BiTE in Q2 2026. The operational path to achieving these goals is clear, and we've initiated all the appropriate activities to ensure we continue to advance cemsidomide towards value creation for both patients and our stakeholders. Operator, please open the lines for Q&A.

[Operator Instructions] And the first question will come from Sudan Loganathan with Stephens.

Congrats on achieving this crucial milestone with a very positive outlook for the cemsidomide program. My first question is regarding the upcoming cemsidomide plus BCMA bispecific trial. What magnitude of efficacy are you hoping to see to justify moving directly into a Phase III? And is the bar currently the teclistamab monotherapy outcomes of approximately 60% ORR to be met or exceeded to justify greenlighting a Phase III combo study? Additionally, can you share which BCMA BiTE you may plan to use, if it will be teclistamab or another agent and why if it's another agent? And I may have some follow-ups after.

Yes. Thanks for your question. I'll turn it over to Len to answer some of the technical design questions. At this point, we've not decided the BCMA BiTE that we'll be going with. We're currently evaluating that now, and we'll have hopefully update you when we've made that conclusion.

The second part or actually the first part of your question, but super important part. I want to speak to the strategy here. We do think that regardless of which BCMA BiTE we study that there is an opportunity to improve both the magnitude of the response, but actually increasingly importantly, the quality of the response. So what we'll be looking at is not just response rate, but actually, obviously, the CR rate and in fact, the MRD-negative CR rate.

In terms of predefining what those differences might be, we need 2 things. We need to then characterize it on the BiTE we're actually using and we need to get a breed of the initial data in small cohorts for qualitative decision-making. The assessment of the difference though will require randomization. And we think within the first 3 dose levels, we'll be able to get enough information in groups of patients that are around 15 or so at each dose level to make that qualitative decision and plan the Phase III trial.

But how big that trial is and what the eventual sample size is and the statistic around that, of course, will depend on data that we don't have yet in hand. But we think it's a viable strategy and in fact, provides an opportunity, as we said in the deck, for a second accelerated approval. So I remind you, in that regard, an early predefined look at the CR rate, in particular on a BiTE randomization trial provides an opportunity to go to the agency to discuss that for accelerated approval and then to use the data from the same trial on a time-to-event endpoint for full approval.

Great. I appreciate the color there. If I can squeeze in a follow-up. On the regulatory side, is the FDA expecting a confirmatory data from the BiTE combo Phase III to serve as a confirmation for the monotherapy accelerated approval? Or will there be maybe 2 separate confirmatory strategies to be required?

And then lastly, could you share what the median follow-up time was at the July 2025 cutoff? And how should we think about the maturity of the DOR signal, especially since it wasn't reached yet at the higher doses?

So I will tackle that in 2 parts. So on the regulatory part, the randomized time-to-event endpoint for full approval for the BiTE would also serve for full approval for the nonrandomized indication. So it would be one randomized trial that ultimately could drive full approval in 2 indications. To answer your second question, the median duration of therapy, I'm not sure if I have that number on top. So I'll actually turn it to Dr. Dhakal...

This is Dr. Dhakal. So for the median duration of follow-up for PFS is about 7 months, 7.5 months. And for the DOR is about 4 to 5 months. So it's still pretty early. As you know, if you recall the data about at 75 to 100, there are a lot of patients still on treatment, 67% of patients. So we're anticipating that median is going to be much longer than the median DR of 9.3 months. So that will continue to follow up the patients.

Got you. And also the median follow-up time, was there -- at the July 2025 cutoff, was there kind of a range for that as well?

So I would say the median follow-up was 7 months.

Okay. And again, congrats on the completion of this study with a positive outlook for cemsidomide program.

The next question will come from Brad Canino with Guggenheim.

Great to see this comprehensive data in the forward path outlined. The immediate question that comes to mind is how you're thinking about the right dose for the fourth-line dex combo. I mean you see great efficacy at 75, that improves at 100, but the DLTs also start to emerge at 100. So it would be helpful to understand why those DLTs don't immediately invalidate that dose and how you think this is with the optimized degrader still having a therapeutic index across the dose range that you've presented here today.

Thanks for the question, Brad. I'm going to answer part of it, and then I'm going to ask Dr. Dhakal to speak to it as well. So in terms of dose selection for the Phase II, our guidance that we're working on is that we do believe that 100 is the optimal dose, notwithstanding the observations you made from the data set.

First, with respect to the number of DLTs at 100, that's in 9 patients in a BLRM model. So that actually does not exceed the MTD per the statistics of the trial. And actually, per those statistical modeling, it recommended actual further dose escalation. But I think to your point, there is a sense that there is more evidence of complications, if you will, at a higher dose. However, what's important to note is those patients did not come off therapy. They continued on therapy. And I'm going to hand it over to Dr. Dhakal to speak to this more broadly.

Yes. So I think what we have seen here in this one is when you look at this with neutropenia, that is more kind of a prevalent in the first cycle. So after the first or second cycle, the patients really maintain this -- the counts pretty well. And I can tell you for sure, for a lot of patients being treated in this program, including all dose levels, not only on this in all dose levels, there are very few patients after cycle 2, they have -- we have to either reduce the dose or discontinue the dose because of Grade 4 neutropenia. So I think as Len said, I think in that 100 microgram, that didn't exceed the DLT based on the BLR and methodology. And I think that is the right dose in our opinion that we can expand the Phase II for the efficacy and safety.

To follow on from that, however, Brad, when you go into Phase II with efficacy-seeking trial, you need to have a recommended starting dose and obviously, a dose reduction strategy. And what I think is really important for successful development here is what you've already pointed out that we actually have compelling efficacy at 75 as well.

Just drawing on what Dr. Dhakal is saying, these are patients with late-line relapsed/refractory disease and no really viable options. And so getting their disease under control with the highest dose possible, we think makes the most sense. But we do have obviously a rational dose reduction strategy and our data collectively fully supports that obviously, higher exposure is associated with deeper degradation of the targets and ultimately, we think higher quality long-term responses.

And I'll just add, recall in the protocol, G-CSF use is not allowed during the DLT evaluation period. And so to me, more relevant is what's the Grade 3 or 4 neutropenia rate across all the doses, including all the patients, including the expansion because that's more relevant of what you would see in clinical practice as the dose is going to be used, and we wouldn't have that restriction in the Phase II and in future studies.

Got it. And maybe if I can just ask you to expand upon this a little bit. And I think additional commentary would be helpful about why you might not be seeing the sequelae of neutropenia like fevers and infections as much as you might see with other neutropenic agents, even Bristol's mezigdomide. Another way of asking the question is why the clinical consequences seem to be decoupled from the rates of high-grade neutropenia that you're reporting on the safety table?

I'm going to speak first, and again, I'm going to hand it over to Dr. Dhakal. I think one of the issues that we benefit from is the 14 days on, 14 days off schedule. And that what -- I see one of the theories is if you look at those degradation curves as it relates to IKZF3, you can see from day 14 to day 21, you get a gentle rise and then you get continue to day 28. At some point, we're able, I think, to get -- release the break enough to get neutrophil recovery. So the actual consequences are limited and the 14 days off really helps us. But Dr. Dhakal, please.

Yes. No, I agree. I think when you look at the mezigdomide, 3 weeks on, 1 week off. So it's a little bit long duration in my opinion. And the beauty of this schedule of 14 days on, 14 days off, what I have observed in during that 14 days off, sometimes we see -- we check the labs of these patients, and they have nicely recovered by third week, they've already -- most of them have nicely recovered the neutrophil count.

I think it has to do mainly with the schedule. We know that it's a class effect of delayed neutropenia, having neutropenia because of delayed granulocyte maturation. But I think giving the scheduled break, I think, really helps us the neutrophils to recover and so that didn't compromise the subsequent cycles. And that's what we saw in the clinical trial.

And as Andrew mentioned, in terms of G-CSF uses, it's not that very high. It's only 40% despite not letting cycle 1 G-CSF and dose escalation. So if you allow that literally from -- in the Phase II, I think that number is going to be much lower.

The next question will come from Etzer Darout with Barclays.

First one for me is you noted alignment with the FDA by year-end on the recommended Phase II dose. Just curious if you've had any initial discussions on sort of the fourth line plus trial and sort of endpoints? And then just a follow-up, if you could maybe give some guideposts around the potential cost of the Phase II for accelerated approval as well as the Phase Ib in combination with BCMA therapy, whatever color you could provide?

Len, you can start with the regulatory and Kendra you can weigh in on the cost.

Yes. So from a regulatory perspective, we just had really a robust and productive discussion at a Type C meeting earlier this summer. And during that discussion, we discussed our plans to interrogate late line, and we also discussed our plans to combine with a BiTE. So we got feedback on both.

As it relates to the late line, we got specific feedback to not limit it simply to people who are post T-cell engager or CAR-Ts and that felt that fourth line plus was the appropriate population to interrogate because of the lack of full penetration of those mechanism of action to all patients. So that was the first thing.

The second thing was agreement that in terms of selecting the dose for that trial that we would come back to them by year-end, but we agreed on the methodology of how we would recommend the dose. So in fact, many of the analysis the FDA asked for are actually in this deck, which will be presented in a robust way before the end of the year, along with the Phase II protocol, which has actually already been written. So did I miss part of your question? And Etzer, remind me if there was another part. I'll ask Kendra speak to cost.

No worries. So a couple of things to note, right? Generally speaking, the Phase II is going to be more expensive than the Phase Ib just because it's going to be a higher number of patients. The team has done a really nice job sort of mapping out our clinical trial sites. And of course, we'll try to be as efficient as possible utilizing the same trial sites potentially for both studies.

The other thing that I just want to remind you all, Andrew noted it, but we are currently exploring supply agreements for the cost of the BCMA or for use in the BCMA study, which would obviously help us to offset some cost.

The next question will come from Derek Archila with Wells Fargo.

Great data. So just two from us. I guess first, just in terms of like potential partnering strategy, how is that influencing potentially the BiTE you'll use in the combo trial? And just remind us, I mean, you're looking at potentially 3 doses to use in combination, just kind of thoughts on overlapping tox and what we should think there in terms of the 3 doses that you selected?

Yes, Derek, thanks, and I'll take the first part. So our focus right now is advancing the program as we've outlined in the slides in our presentation. Certainly, we think this is a development plan that we can execute, and we're planning to do that in ways that Kendra outlined. I think the profile is really exciting around this program, and I think there's a lot more we'd like to do, and that's really where our partner comes in.

Given the profile, I could see this used in a post CAR-T maintenance and a post-transplant maintenance given the activity and safety, but those are trials that as a small company, we're not going to do. And so I think our -- any partnering strategy would really be around how do we expand the opportunity beyond what we've outlined here today.

And to tackle your question with respect to overlapping toxicity with the BCMA BiTE, obviously, a crucial issue, which we thought a lot about. So I'll call your attention to the part of the slide presentation where we talked about the immune enhancement. And one of the exciting things about the immune enhancement, it occurred at every dose level that we studied.

So we think we have some latitude in terms of what dose we will select. In terms of how to do that, clearly, the most important overlapping toxicity potentially is neutropenia. And we think with the 3 dose levels we've identified that we'll have a Grade 4 neutropenia level that's low enough that won't interrupt the BiTE therapy.

That said, we have to show that with data. And so we're trying to show that as quickly as possible by interrogating the 3 dose levels as close as statistics will allow. And maybe I'll ask Dr. Dhakal to just comment on the dosing with the BiTE and your...

Yes. There are some trials that are already happening if you are aware that they are combining bispecific with the CELMOS or whatever is already being tested in the trial. And I have some experience of using mezigdomide with another BCMA BiTE. I must say that the overlapping toxicities are not that major concern.

I mean I would say the main thing that you worry about the cytopenia, but if you allow kind of close watching of this number, at least in the cycle 2 onwards, I think the cytopenia doesn't become a major concern. And I feel that this is going to be even less of a concern with the rates of Grade 4 neutropenia that we're seeing here. with the combination.

And I should add, I forgot in my answer that because of the step-up dosing and issues in cycle 1, we wouldn't introduce cemsidomide to cycle 2 so that we get through that loading of the BiTE before you introduce it to simplify.

Cytopenia are most common in the bispecific in the first cycle. So after the second cycle, it becomes less common.

The next question will come from Ian Zhu with Jefferies...

This is Yifan. Congratulations on the data. So first question on the durability. I found that the DOR seems much compelling compared to BMY's KCF degraders, while the PFS, median PFS was short. I'm wondering if you can elaborate on why these 2 durability, I mean, measurement have some divergence. Second question is that do you see better or worse efficacy among patients post BCMA CAR-T or T-cell engager?

So I think it's premature to conclude that we have final estimates on either PFS or duration. Both of them are still evolving, especially with the later enrollment of the 2 highest dose levels. That said, the 3.7 months PFS in all patients, all dose levels to date is actually approaching 4 months, which is very similar to what has been reported for other agents in a relapsed/refractory population.

So we think that data is just not quite mature yet to draw that conclusion. And we're confident really what's driving the duration of response, in particular, we think is the deep degradation of the targets combined with the fact that the patients do not have to come off drug for safety, in fact and don't have dose reductions.

No, I agree. I think if you look at the mezigdomide, I think what we're looking at is the whole patient population of 100-something patients. And there, if you look at it, the patients -- again, we're doing the cross-trial comparison that is probably a little bit limited in that regard. But the patients treated in this trial, I must say that is more heavily treated.

At the same time, we also don't have the full follow-up of the 7,500 micrograms. So I think that will probably -- once we have a little bit more longer follow-up, I think that will give a more idea about. But if you just look at the duration of response, I think that looks quite promising.

I think your other question was, do we see difference in responses based on prior therapy. I think we're sort of -- the answer is no when we slice it. But I think we're really stretching in terms of ends by doing that. So -- but we don't see that when we do slice the data. But again, it's a pretty small data set. So it's hard to really draw meaningful conclusions at this point.

The next question will come from Terence Flynn with Morgan Stanley.

This is Alex for Terence. Congrats on the data. We just have a quick one. For the cemsidomide and Phase II trial in the fourth-line settings, what is ORR and PFS bar required for accelerated approval? If you can comment here, that would be nice.

Yes. So there's never a predefined ORR for accelerated approval really for any indication. It's always driven by what's contextually the prevailing treatments and expectations at the time. However, what's important to say is we have to realistically plan a trial statistically that will detect a meaningful effect.

So we anticipate being able to achieve a 40% response rate and that, that would be statistically different from the background expectation of off-label use of other treatments. As it relates to duration, we know that typically for late-line multi-refractory indications of any type, you're going to want a duration of at least 6 months.

That's why, in fact, our current duration at 9 months. We're really optimistic about because it may well end up being higher than that. And so we already have a really compelling response rate in really the most difficult-to-treat patients with meaningful duration. And we think we can translate that into Phase II and ultimately have a discussion of both the response rate, the duration of therapy and the safety in due course with the agency to have an accelerated discussion.

This concludes our question-and-answer session. I would like to turn the conference back over to Mr. Andrew Hirsch for any closing remarks. Please go ahead, sir.

Thank you. So I want to close today just by thanking you all for joining us. I also wanted to thank the patients, their families and caregivers for participating in our study. We're very excited about cemsidomide's potentially best-in-class profile and believe that the data shared to date has derisked the next phase of development. As we continue to advance the program, we look forward to updating you on its progress. Thank you, and have a great rest of your weekend.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.