BridgeBio Oncology Therapeutics, Inc. (BBOT) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the BBOT Clinical Data Update Call. Today's program is being recorded. [Operator Instructions] I'd now like to introduce your host for today's program, Heather Armstrong, Head of Investor Relations. Please go ahead.

Thank you for joining us today. For today's prepared remarks, I am joined by Dr. Eli Wallace, CEO; and Dr. Yong Ben, Chief Medical and Development Officer. Also joining for the Q&A section are Dr. Pedro Beltran, Chief Scientific Officer; Uneek Mehra, CFO; and Dr. Adrian Sacher, Thoracic Oncologist and affiliate Scientist at the Princess Margaret Cancer Center and an Associate Professor in the Department of Medicine and Immunology at the University of Toronto. As we begin our presentation, I would ask that you review our legal disclaimer on Slide 2. And with that. I'll turn the call over to Eli Wallace, CEO. Eli?

Thank you, Heather, and thank you for everyone who has joined us today. I'll begin on Slide 3. We at BBOT are advancing the next generation of small molecule therapies targeting the RAS pathway, one of the most important and historically difficult areas in oncology. Our mission is to accelerate meaningful scientific and medical breakthroughs and to deliver medicines that are not only more effective, but also better tolerated for patients facing the deadliest cancers. We've designed our inhibitors with the goal of optimized target coverage for patients with tumors driven by RAS and PI3K Alpha, positioning us to address key resistance and durability challenges. Importantly, our portfolio is designed to be synergistic, enabling targeted KRAS combination strategies, both with standard of care therapies as well as within our own pipeline. With multiple clinical stage assets, we expect several meaningful value inflection points in 2026. And with our strong financial position, we are well funded to execute on this strategy and support operations into 2028. Moving on to Slide 4. Today's data, which Ben will walk you through shortly, underscore the strength of our precision oncology portfolio. By focusing on the active on state of RAS and leveraging differentiated chemistry, we are delivering on the promise of innovative RAS/PI3K Alpha inhibition through direct effector blockade. We believe our differentiated direct KRAS G12C on/off inhibition may position BBO-8520 as the combination agent of choice with immune checkpoint inhibitors in early-line non-small cell lung cancers. Ben will provide more details on the data, but in short, BBO-8520 monotherapy in patients with KRAS G12C non-small cell lung cancer showed a 65% overall response rate with 83% of patients with at least 6-month follow-up remaining on treatment greater than 6 months. It also showed a favorable safety profile, particularly as it relates to liver enzyme elevations compared to what has previously been shown with OFF inhibitors. We believe the improved therapeutic index observed with 8520 is a direct result of the on-state hit and run mechanism as we observed promising efficacy signals at substantially lower exposures than OFF inhibitors. As has been well documented, all OFF inhibitors are plagued by varying degrees of liver toxicity, including Grade 3, which we believe is likely due to the high exposures required for OFF-only inhibition. Combination therapy with pembrolizumab at a potentially optimally active dose of 8520 also showed early efficacy signals with a distinct tolerable safety profile without increased liver enzyme elevations compared with pembrolizumab alone. This contrasts with OFF inhibitor combinations, all of which have had to reduce their dose to suboptimal levels and nevertheless, still experience significantly increased toxicities, particularly liver toxicity. Taken together, the encouraging early safety and efficacy data positions 8520 as a compelling combination partner with pembrolizumab in earlier line non-small cell lung cancer patients. Additionally, we have also observed encouraging early efficacy signals in STK11 KEAP1 co-mutant tumors. This is a highly resistant patient population for which there is currently no effective therapy, and we are working to confirm this finding in additional patients. Moving on to BBO-11818, where dose escalation data demonstrate the potential of direct pan-KRAS inhibition in patients with KRAS mutant tumors, showing antitumor activity with a favorable and differentiated safety profile. This includes a partial response in a pretreated pancreatic ductal adenocarcinoma patient. To our knowledge, this represents the first publicly disclosed monotherapy pan-KRAS response in a patient with PDAC. 818 is a close cousin of 8520 and incorporates key learnings from that molecule into a reversible pan-KRAS inhibitor. It is designed to be a highly potent orally bioavailable inhibitor that targets both the on and off states of KRAS. We believe this approach has the potential to deliver a superior therapeutic index relative to many existing strategies by maintaining selectivity for KRAS over HRAS and NRAS while capturing multiple KRAS mutants as well as wild type. For those who have been following the BBOT story, you may notice that we have moved 818 earlier in the sequence. This reflects our decision to group our KRAS inhibitors together given their similarities and their large potential when combined with our breaker. We are encouraged by these findings as these data support continued dose escalation and progression into expansion cohorts. Next, clinical data support the approach we're taking on our novel RAS PI3K Alpha breaker, BBO-10203 in KRAS mutant and breast cancers. We have achieved our objectives of monotherapy dose escalation and the data aligned closely with our expectations and preclinical findings. Even without any restrictions on HbA1c status, we observed no hyperglycemia at dose levels that fully engage the target, and we rapidly established a recommended dose for expansion studies. It is important to note, to our knowledge, 203 is the only inhibitor of PI3K Alpha activity to both treat patients without HbA1c restrictions and observe no hyperglycemia. As has been reported, other inhibitors in the space have restrictions and still observe varying degrees of hyperglycemia. The observed monotherapy safety profile of 203 to date may portend well for our planned combination approaches. As a reminder, all inhibitors of this pathway have been developed in combination. Notably, because its mechanism is agnostic to mutational status, 203 has the potential to be effective whether RAS or PI3K Alpha is wild-type or mutated, significantly extending the population of patients who may benefit. Moreover, combination studies with standard of care therapies in KRAS-mutant colorectal and breast cancers have been initiated, and we expect to open internal combination studies with 8520 and 818 later this year. Slide 5 shows a high-level view of BBOT's portfolio of clinical stage RAS pathway inhibitors designed to enable direct dual inhibition of KRAS on and off states and pan-RAS inhibition of PI3K-alpha activation. We believe our portfolio uniquely positions us to safely achieve concurrent high-level inhibition of PI3K-alpha and MAPK through internal combinations for the first time. This strategy provides us the potential opportunity to treat a large number of patients with some of the most aggressive cancers. In fact, we estimate an annual incidence of approximately 250,000 patients in the U.S. across multiple indications. We are very pleased with these data and look forward to the next steps. I'll now turn it over to Ben to review the data in more detail. Ben?

Thank you, Eli. Starting on Slide 7 with BBO-8520, which is designed with a differentiated mechanism of action, binding directly to both the on and off stage of KRAS G12C. By targeting the active oncogene and directly blocking effector binding, this approach may help prevent adaptive resistance mechanism. It also fully leverages the covalent mechanism of action that allows for sustained pathway inhibition even as systemic drug levels decline, creating a favorable PK/PD profile. Together, these features support the potential for favorable safety and efficacy profile in combination with pembrolizumab in patients with KRAS G12C non-small cell lung cancer. As you can see on Slide 8, ONKORAS-101 is an open-label multicenter global Phase I study designed to evaluate the safety, tolerability, preliminary antitumor activity and pharmacokinetics of BBO-8520 as a single agent and in combination with pembrolizumab in patients with KRAS G12C mutant non-small cell lung cancer. Patients have been enrolled across dose levels ranging from 100 to 700 milligram once daily as monotherapy. Monotherapy and pembrolizumab combination cohort expansions are currently enrolling. Moving on to Slide 9. 8520 demonstrated robust monotherapy activity across dose levels in previously treated patients with KRAS G12C non-small cell lung cancer who had not received a prior G12C inhibitor. As of November 15, an objective response rate of 65%, 11 out of 17 patients was observed across all dose levels, including 10 partial responses and 1 complete response. We also saw a disease control rate of 100%. As you can see on Slide 10, responses appear durable with 83%, 10 out of 12 patients who were eligible for 6 months follow-up remaining on treatment for at least 6 months and the 6 months progression-free survival rate of 66%. Moving on to Slide 11. 8520 monotherapy has demonstrated a generally favorable safety profile with a differentiated liver safety profile compared with off-state inhibitors characterized by a low frequency and low grade of AST or ALT elevations has been transient and asymptomatic. Gastrointestinal events were the most commonly observed AEs and were mostly grade 1 or 2 and manageable. Importantly, there have been no dose-limiting toxicities, no Grade 4 or higher treatment-related adverse events and no treatment-related serious adverse events to date. The most common treatment-related adverse events were nausea, vomiting and diarrhea with few instances of Grade 3 diarrhea being mostly associated with suboptimal management. Slide 12 shows encouraging combination data with pembrolizumab in treatment-naive non-small cell lung cancer patients as well as in patients previously treated with G12C inhibitors, where it shows 3 PRs out of 3 patients and 2 PRs out of 5 patients, respectively. It's worth noting that all patients remain on study treatment, except for 1 patient who withdrew consent despite achieving a partial response. As shown on Slide 13, in terms of safety in combination with pembrolizumab, 8520 has demonstrated a generally favorable safety profile with largely low-grade treatment-related adverse events, mainly GI related. In terms of AEs of interest, the only AST/ALT elevation was reported as a Grade 3 in patients treated at a dose of 200 milligram of 8520 in combination with pembrolizumab and was assessed by the principal investigator as primarily related to concomitant medications. And the AST/ALT do not appear to be dose dependent. This patient previously treated with sotorasib, olomorasib and pembrolizumab achieved a confirmed partial response and has remained on study for more than 36 weeks with the AST/ALT levels having resolved. As of this cutoff, about half of the patients have been on treatment for over 12 weeks. On Slide 14, 8520 exposure is approximately dose proportional achieving predicted efficacious dose levels at the 200 milligram and above. Importantly, as we can see, 8520's on-stage inhibition enables efficacy at the low systemic exposure, which we believe is why we observed superior therapeutic index compared with off-state inhibitors. Relative to 8520 at 500 milligram once daily, exposures with adagrasib and sotorasib are more than 700-fold higher. MK-1084 and D3S-001 are more than 150-fold higher and olromasib and divarasib are more than tenfold higher. 8520's markedly lower exposure compared with what has previously been reported with off-state inhibitors is consistent with an on-state mechanism that creates a favorable PK/PD profile. We believe these attributes of 8520 may enable its combination with pembrolizumab at active dose levels to differentiate in earlier settings of the diseases, as shown on Slide 15. OFF inhibitors have had to significantly reduce their dose to suboptimal levels when combined with pembrolizumab due to liver toxicity. Even at the suboptimal dose levels, patients experienced Grade 3 toxicities from 30% to 70%. In comparison, we believe 8520 is well positioned to potentially differentiate in earlier settings where safety is critical. Lastly, as shown on Slide 16, Early 8520 monotherapy data in patients with STK11 and/or KEAP1 mutations demonstrated encouraging efficacy signals with all 5 initial patients showing a partial response, which appears favorable relative to standard of care and OFF inhibitor benchmarks. We're very pleased with these results and look forward to future updates on this program. Now moving on to BBO-11818 on Slide 18. As Eli mentioned earlier, 818 is a close cousin of 8520. It's an orally bioavailable reversible pan-KRAS inhibitor with activity against both the on and off states designed to deliver an optimal therapeutic index. 18 is mechanistically differentiated in that it targets KRAS, the active oncogene in the majority of the RAS mutant tumors and directly blocks effector binding. In addition, it's highly selective for KRAS and NRAS. We have also seen strong monotherapy activity and promising combination potential with anti-EGFR monoclonal antibody and BBOTs, RAS PI3K Alpha breaker BBO-10203 in mouse models. As you can see on Slide 19, KONQUER-101 is evaluating the safety and preliminary antitumor activity of 818 in subjects with locally advanced or metastatic KRAS mutant solid tumors. Monotherapy dose escalation is ongoing and expansions and combination cohorts are planned in patients with pancreatic cancer, non-small cell lung cancer and colorectal cancer. Slide 20 shows efficacy data to date. We are pleased with the encouraging early antitumor activity. Of note, one patient with pancreatic cancer previously treated demonstrated a PR. We also saw tumor reductions at the predictive efficacy dose levels across tumor types. Slide 21 shows that 818 monotherapy treatment in 13 patients appears generally tolerable and manageable with no DLTs treatment-related AEs were largely GI related, including 2 Grade 3 GI events of diarrhea and nausea in patients with preexisting GI conditions. Lastly, on Slide 22, 818 PK exposure was approximately dose proportional with 600 BID covering G12D and G12V mutant alleles. We are encouraged by the early antitumor activity and tolerability of 818 and look forward to future updates. Next, I will discuss BBO-10203, starting on Slide 24. As Eli mentioned, 203 employs a novel mechanism of action designed to inhibit the physical interaction between RAS and PI3K Alpha, thereby disrupting RAS-driven PI3K Alpha AKT signaling without inhibiting the kinase activity PI3K-alpha. It blocks binding of K, and RAS to PI3 Alpha and is agnostic to the mutational status of either partner. In preclinical studies, 203 demonstrated tumor growth inhibition in multiple mouse tumor models and excellent brain penetrant in mice with Kp,uu 0.468 was observed. Notably, no hyperglycemia was observed preclinically even at 3x the efficacious dose level. Consistent with the broader PI3K alpha AKT inhibitor class, the clinical development plan for 203 will focus on combination strategies. You can see the study schema on Slide 25. BREAKER-101 is a multicenter open-label Phase I study, evaluating the safety, tolerability, pharmacokinetics and preliminary antitumor activity of 203 as monotherapy and in combination with trastuzumab, [ fulvestrant ] or FOLFOX plus bevacizumab in patients with locally advanced or metastatic HER2-positive breast cancer, HR-positive HER2-negative breast cancer and KRAS-mutant colorectal cancers. As we have completed monotherapy dose escalation, where 24 patients, the majority of whom were heavily previously treated colorectal cancer patients were enrolled across dose levels from 150 to 750 QD. We have selected 500-milligram QD as the recommended dose for expansion based on safety, PK and target engagement, which we will cover in the next 2 slides. With the selection of a recommended dose for expansion, we have initiated 3 combination cohorts with standard of care therapies and expect to open combination cohorts with 8520 and 818 later this year. As shown on Slide 26, 203 achieved predicted efficacy exposure at the 500-milligram QD dose. Importantly, rapid target engagement was also observed across all dose levels with complete engagement across all dose levels at the steady state. Slide 27 shows 203 monotherapy has a highly differentiated safety profile compared to other PI3K Alpha targeting agents. There were no DLTs and no treatment-related SAEs and no hyperglycemia even with any restriction on HbA1c levels and glucose levels at study entry. All TRAEs were grade 1 or 2, except for one instance of asymptomatic hypokalemia lab abnormality. Notably, there were no dose reduction. Similarly, in early combination with trastuzumab and FOLFOX bevacizumab, it appears tolerable with no Grade 3 or higher adverse events observed. As for efficacy, clinical benefit was observed in patients with CRC, of which more than 80% were third line or beyond patients and HR-positive breast cancer who were previously heavily treated and tumor reductions were observed in some patients. As you can see on Slide 28, 203 has shown robust tumor regression in combination with standard of care therapies. and importantly, with our direct KRAS ON/OFF inhibitors across the panel for breast cancer and KRAS-mutant CRC, non-small cell lung and pancreatic cancer models. We are pleased with this early yet encouraging data, particularly that we saw no hyperglycemia even without any restrictions on HbA1c and baseline glucose levels. Now I will turn it over to Eli for closing remarks. Eli?

Thank you, Ben. As you can see on Slide 29, we have rapidly advanced our programs and achieved significant progress to date. Building on this momentum, we expect to announce updated data across all of our programs in the second half of 2026. Starting with 8520, we anticipate sharing additional efficacy and safety data from its combination with pembrolizumab. For 818, we plan to report further efficacy and safety data in both the monotherapy and combination setting. And for 203, we expect to announce combination data across multiple tumor types, including HER2-positive breast cancer, hormone receptor positive HER2-negative PIK3CA mutant breast cancer and KRAS-mutant colorectal cancer. I will conclude our prepared remarks by sharing that we are encouraged by the data across all 3 of our innovative and differentiated programs. These data support our portfolio-wide thesis that achieving meaningful clinical benefit requires driving high levels of target inhibition. Despite significant advances, there remains substantial room for improvement in both RAS and PI3K-alpha therapeutics. We believe we are well positioned to address this opportunity. Finally, I'd like to thank the patients and their families as well as our investigators. Without their belief in and support of our mission, none of this progress would be possible. I'll now turn the call over to the operator for the Q&A session.

[Operator Instructions] Our first question today comes from the line of Andrew Berens with Leerink Partners.

Congrats on all the progress. I think you guys had said, and I think we've heard the same thing from some experts, RAS experts that with the breaker, you might see some monotherapy activity in HER2-positive patients. So just wondering what's the rationale for the greater activity in that subgroup? And were there any HER2-positive patients that were treated in this data set?

Thanks, Andy, for the question. And yes, so for the Phase I monotherapy study, we really hit our objectives of showing differentiated safety and achieving our exposure targets, both from a PK perspective and then as well with target engagement. So we're very confident in the dose that we're fully targeting -- inhibiting the target. As far as the HER2 patients, in the monotherapy dose escalation, there were no HER2-positive breast cancer patients enrolled. You are correct that our preclinical data does support that, that is the most sensitive genotype that we've observed, and we're excited that the safety so far with trastuzumab looks very favorable. And I think where we're going to see that benefit in that patient population is in that expansion when we combine with trastuzumab.

Our next question comes from the line of Imogen Mansfield with Cantor.

Congratulations on the data. Eli, it would be great to hear a bit more about how you expect the development path to look in first-line G12C mutant non-small cell lung cancer? And are you planning to combine with chemo and pembro?

Thanks, Imogen. Yes. So for 8520, we're very encouraged with the data we've seen, we think the very promising overall response rate, early signs of nice durability and importantly, a very differentiated safety profile, particularly that we're particularly excited that, that monotherapy safety profile translated very well in combination with pembrolizumab. Our belief in the molecule is that, that profile will very -- will set us up very well for earlier line settings with patients with KRAS G12C non-small cell lung cancer. We'll have to see how the data matures going forward, but we would expect that with a very good G12C inhibitor, you should not need chemotherapy in that earlier line setting, but we'll continue to evaluate that as we generate more data into 2026.

Our next question comes from the line of Matthew Biegler with Oppenheimer.