C4 Therapeutics 3rd Annual Guggenheim Healthcare Innovation Conference

Yeah. Thanks for having us. So first, for those of you who are unfamiliar, cemsidomide, it is a cereblon-modulating protein degrader of two transcription factors, IKZF1 and three, which are critical in multiple myeloma. In fact, they are foundational biology. Our vision for cemsidomide is to become a backbone therapy for myeloma across the evolving landscape, and it is really based on the fundamental MOA, which is really, there are two mechanisms. The first mechanism is around plasma cell proliferation. It blocks that. The second and equally critical mechanism is immune cell expansion and activation, and that is critical in the evolving landscape. How cemsidomide differs from others in the class is really around its pharmacology.

It has a longer half-life, it is less protein-bound, and that enables us to dose in a different schedule, much lower doses, which manifests itself in a differentiated safety and efficacy profile, which we think gives it a potential for a best in class across all of the next-generation cereblon-modulating degraders.

Yeah. Len, you want to tackle that?

Yeah, sure. I've been doing this a long time, and I've had the privilege of working with a lot of drugs that are now successful. cemsidomide has, in my view, the most robust de-risk proof of concept safety signal, certainly of the class, but of many drugs to come along, and let me give you the evidence for that. Andrew alluded to this in his first comments. cemsidomide was built from the ground up to be a better molecule, and the clinical data supports that thesis. How does it support the thesis? We can start with the top-line summary, that in a first-in-human study where we treated 72 patients with cemsidomide plus dex, we have an overall response rate of 53% at the highest dose level, which is our RP2D, 100 micrograms, 40% at the next dose level.

Impressively, we have a 36% response rate regardless of what dose they saw in the study. Importantly, that response rate signal is differentiated in the class in terms of early development, because fully 75% of our patients in that first-in-human study had either had CAR-Ts or BiTEs or both. This is an incredibly important clinical signal in the most contemporaneously refractory population to date. That signal would be not so impressive if it wasn't also associated with the most impressive safety signal in the class. Importantly, this class of drugs, the reason for the break in dosing is they all must be given a break in dosing because of the neutropenia, and more importantly, neutropenic-associated side effects. But with the 14 days on, 14 days off dosing, we also have, in fact, notwithstanding the clinical potency, we actually have the most favorable safety profile.

In particular, we have the lowest rate of grade 4 neutropenia. We have the lowest rate of G-CSF use. This is really crucial in conversations we had today. If you look at early drug development, you're trying to predict future success in larger-scale studies. We have very, very few dose reductions or dose delays. In fact, you can deliver cemsidomide on schedule with the lowest need for G-CSF and the most modest neutropenic signal. Taken together, that's the sort of thesis for what we're building on. How we're building on that is obviously in our next generation of trials, which we can talk about, which exploit both the direct anti-myeloma effects, but also importantly address the issue that Andrew brought up in terms of the secondary mechanism of action of immune enhancement.

Sure. Let's talk about it in two ways, because there's two questions. There's how to use it with dex as a late-line refractory drug, and then potentially how to combine it with other drugs in the class, which is also equally important. Let's do the late line first. One of the things that we've done with our dataset is we really have an incredibly powerful dataset, both in the points of dose effect and outcome, but we also have a pop PK model. That model doesn't get much attention, but it actually was disclosed and published as a poster at the American Conference on Pharmacometrics meetings last October. What does the model show? The model shows for cemsidomide, unequivocally, that you are going to get higher rates of anti-myeloma control with higher exposures. That's not rocket science. But it pushes you to give the highest dose possible to get there.

But what's in that model, which is the differentiating piece, is over the range of doses we tested, there's only a very modest increase of cemsidomide's risk of neutropenia as you got to higher exposures. It goes up a little bit, but it does not dramatically go up. It's statistically a very weak correlation. So why does it matter? It gets back to the original thesis. You've got potency with safety. So when we made the case for our recommended phase II dose, because we also don't have dose reductions and we don't have patients coming off for safety events, we discussed and got alignment on a dose of 100 micrograms as the dose for late-line refractory.

Now, that dose may end up being the combination dose, but as you know, you have to, in a combination thesis, usually you start out by saying, "I'm going to go at least one dose lower." We've done that, and we've actually shared the top-line outcome of that with their combination with elranatamab, a BiTE. What's that top-line number, the thing that we shared? It was a press release at IMS. We cleared 75 micrograms for safety, and now we've escalated back up to 100.

Okay. But the unique piece of the 75, which is already differentiating, is 75 micrograms, remember I told you, that's a 40% response rate.

So we've already been able to give a dose that has a 40% response rate in late-line refractory, including BiTE refractory, cleared it for safety, escalated, and are now expanding at 75. So we'll have a more detailed discussion about the combo dose for things that aren't dex, but we're off to a really, really good start, which is already differentiated from some of the other communications that have come out for combinations with BiTEs for the class of drugs.