BeOne Medicines Ltd. American Depositary Shares Morgan Stanley 24th Annual Global Healthcare Conference

That's great. Thanks, Sean, for having us. It's great always to be here at the Morgan Stanley conference. It's hard to go through everything that's changed in the last 10 years. I mean, 10 years ago, the company was nascent. It was a company that had very little revenue, a couple hundred employees, and just really had no significant commercial or manufacturing capabilities to speak of. So much has happened over that 10-year period with where today we are a leading global oncology company. I think the hallmark of that capability difference is the investment across the value chain in our fully integrated business model from research with our high throughput research organization through ultimately what we believe is a key differentiating advantage for the company, our wholly-owned global clinical development infrastructure, what we call our global development superhighway.

Then pulling that through the remainder of our value chain into manufacturing, into commercial, and behind incredible brands like BRUKINSA, bringing innovative oncology medicines to as many patients around the world as we can. Now our goal is to leverage that incredible capability and do so repeatedly with the cost and time advantages that we've created through that global development superhighway, for the next wave of innovation that I'm sure we'll spend a lot of time talking about today.

Yeah, thank you. It's a great question. I think if you step back, it's worth reminding everyone how we developed the molecule and designed the molecule. The molecule was designed to be the most potent against CDK4 in the class and also the most selective. Ultimately, the therapeutic hypothesis behind that was could you hit CDK4 the hardest while also sparing CDK6 and therefore sparing the CDK6-mediated hematologic toxicity that you know impacts many of the real-world dose reductions and dose discontinuations that you see with the CDK4/6 class, including the three that are approved. What we saw in the ASCO data was that that preclinical profile was really translating into the clinic.

Just to remind everyone, at ASCO, we showed in the frontline hormone receptor-positive HER2 negative setting, a response rate roughly around 70%, which compares favorably to what you see for the CDK4/6 inhibitors, which is roughly around the low 50s, and a hematologic toxicity profile that is clearly differentiated. So we had, at the recommended phase III dose, zero cases of grade 3 neutropenia, which to provide some context, if you think about a drug like IBRANCE, the rates of grade 3 neutropenia are in the mid 60% range. Even for the competitive CDK4 molecule from Pfizer, at ESMO last year, they showed rates of grade 3 neutropenia of 26.5%. We think that's a function of our greater selectivity, again, for CDK4 over CDK6. What we also showed at ASCO is how the GI profile can be ameliorated with the co-administration with food.

It turns out when you administer the drug with food, you substantially reduce the rate of GI AEs, and it really transforms the GI profile from that perspective. Of course, these are small patient numbers at this stage, but we are in the phase III that is up and running now and enrolling very nicely. We are co-administering the drug with food. Ultimately, this is a frontline trial. The market, as you're aware of in the frontline hormone receptor-positive setting, is quite large. If that profile translates into phase III, it'll be a very commercially relevant profile. GI tolerability that is no different, hopefully, than other agents with a very differentiated heme tox profile that also, by the way, enables combinations with other assets in our own internal pipeline, such as CDK2 degrader, CAT6, and the ultra-potent BCL-2 inhibitor for solid tumor we're developing.

All these are in phase I, each of which, or in some cases, has its own intrinsic heme tox. We feel like with our CDK4 inhibitor, we have the ability uniquely to combine with some of these other agents because we do not have a heme tox profile- Heme tox that the other agents have.

Sure. That's an asset that we're very excited about. I think the reason why we're excited about it, you have to, again, you look at our data we presented at ASCO in an oral presentation. HCC is a very high unmet medical need indication. The five-year survival for HCC is on the order of what you see with pancreatic cancer. There unfortunately has not been a tremendous amount of innovation in this space. What we've developed here is a first-in-class, a GPC3 by 4-1BB bispecific antibody, and 4-1BB is a target that I think many folks are aware of. What's interesting about our 4-1BB is we really feel like we've cracked the code from a scientific perspective on how to engage this axis, and do so with a novel binder, novel biology.

We really spent some time pre-clinically to design this appropriately, and ultimately how that's translating into clinical data, we saw roughly in the late-line HCC setting, 30% response rate. For context here, the IMbrave251 trial was presented at ASCO. That's a second-line TKI. The response rate was 5.8%. The response rate in the frontline setting with the standard of care, which is PD-1 nivolumab, is about 30%. So we're seeing response rates in the late-line setting that are roughly comparable to what you see in the frontline setting. We also announced at earnings recently that we fully enrolled a potentially registrational cohort in China in roughly around 2 months.

We plan to start a phase III global trial in the second-line setting by the end of this year, and of course, we're looking beyond the second line and trying to move to the frontline setting as early as possible. From a market size perspective, this market is not small. It's actually a much bigger opportunity than many think. In the U.S., for example, there's about 35,000 patients across all lines. Roughly equivalent incidents to CLL, just for some context. Of course, the difference here is the duration of therapy, and that's the area that we hope to improve upon with this next-generation agent. In Asia, the prevalence of HCC is quite large. There's almost 300,000 patients with HCC in Asia. So it is a very substantial opportunity for us, and it's a first-in-class asset. We're moving as fast as possible. We're excited about it. Thank you.

Maybe I can touch first on PRMT5, and Aaron, you can transition. I think what we've developed is a molecule that is the most potent against PRMT5, but critically is brain penetrant. We think that's critical differentiation, particularly in lung cancer, where upwards of 30%-40% of patients develop brain metastases. It's a critical unmet need, and it's an area where we believe we will be the only brain-penetrant molecule, assuming all three end up making it to lung, and that's going to be a very important area of competitive differentiation.