BeiGene Solid Tumor Portfolio 2023 by Solid Tumor CMO

From 2023 R&D Day Transcript.

Again for joining us this morning. My name is Mark Lanasa, and I'm very glad to present the progress and potential of our solid tumor portfolio. We have three areas of focus at our solid tumor portfolio. The first is that we continue to have very positive newsflow for Tislelizumab our PD1 antibody, and we're looking into turn that positive news flow into regulatory approvals and ultimately patient impact. From there, we want to build upon ticillicimab to develop best in class regimens with new IO targets in our next wave immuno-oncology portfolio including targets that we're disclosing today, including CCR8, DGK zeta, and PVRIG. From there, we want to expand into additional tumor types with novel agents, some of which we believe have blockbuster potential, such as a CDK4 selective inhibitor in breast cancer. Tislelizumab is an outstanding PD1 inhibitor and in fact is already a successful medicine. We have treated over 750,000 patients with commercial Tislelizumab to date, and we have enrolled over 12,000 patients in our global clinical development programs. We are developing a subcutaneous injection formulation for Tislelizumab that will achieve first human dose later this year so that we can bring the impact of Tislelizumab to more patients globally.

The data for Tislelizumab continues to be very positive. Indeed, every phase 3 study that we have initiated with Tislelizumab has met the primary endpoint. We have recently announced that the rationale 305 study in frontline gastric cancer met the primary endpoint of overall survival in the intention to treat population. Similarly, in the rationale 312 study, that study also met the primary endpoint of overall survival in the intention to treat population in the study of extensive stage small cell lung cancer. And again, we're working hard to turn these positive data into regulatory approvals. Our partner, Novartis, are happy to inform that the FDA has completed their online site GMP inspections for Tislelizumab Manufacturing, and the BLA review is progressing, as well as the regulatory reviews are also progressing in EMA. Importantly, regulatory submissions are now also underway to expand Tislelizumab to the rest of the world in markets such as Australia, Brazil, and South Korea. And as John mentioned to you earlier, this is all being accomplished at reduced cost through optimization, internalization, and scale.

So where do we go from here? At BeiGene, we believe that PD1 is the beginning of the story in immuno-oncology, but it's not the complete story. PD1 has definitively been a transformational mechanism within solid tumor oncology. One of the challenges that we have in solid tumors is that the human immune system is highly complex, and therefore, we have developed a rational but focused program whereby we are modulating different components of the human immune system in a way that can address different patient segments because the immune system is dysregulated in different ways across different tumor types.

And if you'll hang in there with me for a moment, I'm about to take you on a brief but deep dive of our current solid tumor portfolio in immuno-oncology. So to start with Tigit, while we acknowledge that the recent data flow with tiget has been mixed, we have completed enrollment in five randomized phase 2 studies, and therefore, we will have inhouse data that will allow us to understand the opportunity landscape for Ociperlimab. Additionally, our phase 3 study in PDL1 high non small cell lung cancer continues to enroll very well, and we will complete enrollment this year. In short, we're delighted to have retained the global rights for Ociperlimab. From there, for our next wave of molecules, we are working towards establishing proof of concept in a focused and cost effective manner. We are upscaling our Lag-3 program substantially this year with phase 2 studies underway in both frontline and resectable non small cell lung cancer, frontline esophageal cancer, head and neck cancer, as well as frontline colorectal cancer maintenance. Tim-3 is another co checkpoint inhibitor. We have established a phase 2 dose not only in combination with Tislelizumab, but also as a triplet in combination with Lag3. We are testing both that doublet and the triplet in frontline head and neck cancer. We're very excited about our OX40 molecule. The reason for that is that we have the only OX40 agonist monoclonal antibody that does not block the interaction between the 40 and its ligand, the OX40 ligand. We have established a phase 2 dose, both as monotherapy and in combination with Tislelizumab. And have started a phase 2 study in both front line and second line non small cell lung cancer, as well as additional evidence generation in immune sensitive tumor types, including bladder, renal cell and melanoma. HPK1, we believe, is a very important target. Our HPK 1, which was one of the first HPK1s to enter the clinic, has advancing well through early evaluation. We have again identified a recommended phase 2 dose, both as monotherapy and in combination with Tislelizumab and have recently opened expansions in non small cell lung cancer and esophageal cancer. Because we have seen activity with our HPK1 molecule, we think that this is a potentially important target in immuno oncology. It turns out that we have a second HPK1 inhibitor that is on an entirely different chemical backbone. We intend to bring that molecule into the clinic as well so that we can compare safety, efficacy, and pharmacodynamic effects of the two molecules. From there, we have three new enemies that will be entering the clinic prior to the end of the year. Our CCR8, we believe, has best in class potential because it binds a unique epitope, which may facilitate more potent ADCC. DGK zeta, like HPK1, is a kinase that sits downstream of the T cell receptor. This is a selective inhibitor of DGK zeta and a potent activator of T and NK cells. Finally, PVRIG is another co-checkpoint monoclonal antibody that we believe has best-in-class potential, given its strong binding, affinity, and ligand blockade potency.

The use of multi-cohort studies is core to our strategic and focused assessment of immuno oncology combinations. Umbrella trials evaluate similar treatment arms against the common reference arm with contemporaneous randomization to identify the most promising interventions. It really will allow us to establish prioritization across our relatively broad portfolio of immuno onc assets. They can be adaptive and allow for dropping ineffective interventions and flexible to allow new molecules to be added as they emerge from phase 1. We have already initiated umbrella studies in advanced and resectable non small cell lung cancer that are enrolling patients. We have an umbrella study in head and neck cancer that is in setup.

To transition to what's next in solid tumor onc at BeiGene, we are entering a transformative period with the application of new targets and novel methodologies across priority tumor types. You'll hear from Lai in some detail about seven new molecules that we will bring into the clinic over the next 18 months for non small cell lung cancer. From there, we are also bringing these novel methodologies and new targets across all of our priority tumor types. So in the lower left, you can see an upper GI. We have both a bispecific antibody and ADC targeting CEA and a novel ADC targeting B7H3. In colorectal cancer, we again have the two CEA targeting molecules as well as a small molecule inhibitor of pancreates. In head and neck cancer, our smac mimetic molecule continues to progress well through early investigation. And again, the B7H3 ADC. In breast cancer, we have recently announced an exclusive global option from Duality for their B7H4 ADC. We think that this is a great target that's highly complementary to our internal portfolio of ADC targets. You heard from Merhdad about the potency and selectivity of sonrotoclax, and we intend to test that in HR-positive breast cancer. And I'd like to spend a bit more time discussing in detail our selective inhibitor of CDK4.

Cdk4 inhibitors have had huge patient impact for women with breast cancer and have also been commercially very successful medicines. There are three approved CDK4/6 inhibitors, and all have dose dependent toxicities that are related either to CDK6 inhibition or to other off target effects. So although the adverse events of with these molecules are driven primarily by inhibition of CDK 6, efficacy is driven primarily by CDK4, and therefore having a CDK 4 selective molecule allows for improvement of both efficacy and safety. There's a single CDK4 selective inhibitor that is already in the clinic that is being developed by Pfizer.

Now, that said, we believe that we have the potential best in class medicine in that in a cellular proliferation assay, as you can see on the left hand side of this slide, what you can see is that our CDK4 selective inhibitor has the highest potency against CDK4 of any of the approved CDK4 inhibitors or Pfizer's investigational CDK4 selective molecule. What this conveys is the greatest selectivity for CDK4 over CDK6, which we think will provide the widest therapeutic margin for us with this target. We have showed pre clinical efficacy in a number of different pre clinical models, and I'm very happy to say that this molecule has already completed its GLP toxicologic studies, did not have significant neutropedia or GI toxicities. We are currently developing the IND and CTA submissions, and we'll have our first human dose by the end of this year.

So putting it all together, across our target tuber types of upper GI, lung, head and neck, breast, and colorectal cancers, crossed against a diverse set of therapeutic modalities, we have developed a compelling group of innovative molecules to address priority tumor types. There is a large addressable population and unmet medical need. Our B7H3 molecule across multiple indications, CDK4 in breast cancer and potentially additional indications. The EGFR CDAC will be our first bivalent degrader in solid tumor oncology. The PanRAS molecule in thoracic and GI malignancies, and the MTA cooperative PRMT5, again in multiple solid tumors.