BBO-11818: An Investigational PanKRAS Dual Inhibitor for Advanced Solid Tumors

I. Introduction to BBO-11818

A. Overview of BBO-11818 as an Investigational Agent

BBO-11818 is an orally bioavailable, small molecule therapeutic currently under investigation for the treatment of advanced solid tumors characterized by KRAS mutations.[1] Its development represents a focused effort to target KRAS, an oncogene that has historically presented significant challenges to drug developers, often being described as "undruggable".[2] The progression of BBO-11818 into clinical trials signifies a potential advancement in providing new therapeutic options for patients with these difficult-to-treat malignancies.

B. The Unmet Medical Need in KRAS-Mutant Cancers

Mutations in the KRAS gene are among the most frequently observed oncogenic drivers in human cancers. They are particularly prevalent in some of the deadliest malignancies, occurring in approximately 30% of non-small cell lung cancer (NSCLC) cases, 40% of colorectal cancer (CRC) cases, and an overwhelming 90% of pancreatic ductal adenocarcinomas (PDAC).[2] While the advent of first-generation KRASG12C-specific inhibitors marked a breakthrough, a substantial unmet medical need persists. This need encompasses therapies for tumors driven by other KRAS variants (such as G12D and G12V) and strategies to overcome or delay the onset of adaptive resistance, which can limit the efficacy of existing targeted agents.[1] For many patients with KRAS-mutant cancers, current standard-of-care treatments offer limited efficacy, underscoring the urgency for novel therapeutic approaches.[1]

C. Developer: BridgeBio Oncology Therapeutics (BBOT) and Key Collaborations

BBO-11818 is being developed by TheRas, Inc., which operates under the name BridgeBio Oncology Therapeutics (BBOT).[1] BBOT is a clinical-stage biopharmaceutical company, initially established as a subsidiary of BridgeBio Pharma, Inc. (Nasdaq: BBIO). The company's core mission is to develop therapies for RAS-pathway malignancies.[1] The discovery and early development of BBO-11818 were not undertaken in isolation; they were the product of a significant collaboration involving BBOT, the RAS Initiative at the Frederick National Laboratory for Cancer Research (FNLCR), and the Lawrence Livermore National Laboratory (LLNL).[1] BBOT's pipeline also includes other agents targeting the RAS pathway, such as BBO-8520 (a KRASG12C inhibitor) and BBO-10203 (a RAS:PI3Kα breaker), with BBO-11818 being the third distinct molecule from this portfolio to advance into clinical evaluation.[1]

The strategic direction of BBOT, exemplified by the development of BBO-11818, clearly focuses on addressing historically intractable targets within the RAS signaling cascade. This pathway has long been recognized for its complexity and resistance to therapeutic intervention. The decision to partner with esteemed national research institutions like FNLCR, which hosts the RAS Initiative, and LLNL for the discovery phase of BBO-11818, points to a deeply science-driven and collaborative strategy.[1] Such partnerships are often crucial for tackling challenging targets, as they can provide access to specialized expertise, unique screening platforms, and fundamental biological insights that may be beyond the scope of a single entity. This public-private collaboration model is increasingly vital for accelerating the translation of foundational scientific discoveries into viable clinical candidates, particularly for complex diseases like cancer.

Furthermore, the naming of the Phase 1 clinical trial as "KONQUER-101" [1] suggests a deliberate effort by BBOT to communicate its ambition in tackling KRAS-driven cancers. While not a purely scientific aspect, trial names are often chosen to be memorable and to reflect the therapeutic goal. The term "KONQUER" implies a direct challenge to an oncogene that has long been a formidable adversary in cancer treatment, contributing to the narrative around BBO-11818 and BBOT's commitment to this difficult therapeutic area.

II. Mechanism of Action and Pharmacology

A. PanKRAS Dual Inhibition Strategy

BBO-11818 is distinguished by its mechanism as a panKRAS dual inhibitor. This means it is designed to directly bind to and inhibit the KRAS protein regardless of whether it is in its active, GTP-bound ("ON") state or its inactive, GDP-bound ("OFF") state.[1] This dual-targeting capability is a significant departure from many earlier KRAS inhibitors, which predominantly or exclusively target one state, often the "OFF" state.[2] The interaction between BBO-11818 and KRAS is non-covalent.[1]

B. Molecular Interactions and Affinity

The drug candidate demonstrates high-affinity binding to KRAS, with reported picomolar affinity.[1] Data from Surface Plasmon Resonance (SPR) assays quantify this interaction, showing dissociation constants (KD​) of 17 nM for KRASG12D bound to GppNHp (a non-hydrolyzable GTP analog) and 18 nM for KRASG12V(GppNHp). The affinity for the GDP-bound form of KRAS is even tighter, with a KD​ of <0.1 nM.[7] Functionally, BBO-11818 acts as a KRAS:RAF1 protein-protein interaction (PPI) inhibitor. It achieves this by locking KRAS into an inactive "State 1" conformation, thereby disrupting the critical association between GTP-bound KRAS and its primary downstream effector, RAF1.[6] The half-maximal inhibitory concentrations (IC50​) for preventing this KRAS(GTP):RAF1 interaction are 65 nM for the KRASG12D mutant and 86 nM for the KRASG12V mutant.[7]

C. Specificity for KRAS Mutations

Preclinical investigations have confirmed BBO-11818's activity against a spectrum of KRAS mutations, prominently including KRASG12D, KRASG12V, and KRASG12C.[1] Reflecting this broad activity, the KONQUER-101 clinical trial is designed to enroll patients whose tumors harbor KRAS G12A, G12C, G12D, G12S, or G12V mutations, or exhibit KRAS gene amplification.[5] A key pharmacological feature of BBO-11818 is its high selectivity for KRAS over other RAS family isoforms, such as H-RAS and N-RAS. This selectivity is reported to be greater than 500-fold.[1] Correspondingly, cell lines driven by NRAS or BRAF mutations exhibit insensitivity or significantly lower potency (over 1000-fold less) to BBO-11818, underscoring its specificity for KRAS-driven signaling pathways.[1]

D. Pharmacokinetics and Pharmacodynamics (Preclinical)

BBO-11818 has been developed as an orally bioavailable compound.[1] Preclinical pharmacokinetic and pharmacodynamic (PK/PD) studies conducted in mouse models, specifically the GP2d subcutaneous tumor model, have shown that a single oral dose of BBO-11818 leads to robust, dose-dependent, and time-dependent inhibition of phosphorylated ERK (pERK), a key downstream signaling molecule in the MAPK pathway activated by KRAS.[6]

The dual "ON" and "OFF" state inhibition employed by BBO-11818 represents a critical mechanistic evolution from first-generation KRAS inhibitors. These earlier agents, such as sotorasib and adagrasib for KRASG12C, primarily engage the inactive, GDP-bound "OFF" state of the KRAS protein.[2] A well-documented mechanism of acquired resistance to these "OFF"-state inhibitors involves the reactivation of KRAS signaling, often through cellular processes that increase the proportion of the active, GTP-bound "ON" state.[2] By targeting both conformational states, BBO-11818 aims to achieve a more comprehensive and sustained suppression of KRAS oncogenic signaling, irrespective of the nucleotide bound to KRAS. This strategy holds the potential to elicit deeper clinical responses and to delay or circumvent the development of adaptive resistance. The ability of BBO-11818 to lock KRAS in an inactive "State 1" conformation and disrupt its interaction with RAF1 are fundamental to this comprehensive inhibitory effect.[6]

Furthermore, the non-covalent binding mechanism of BBO-11818, despite its high potency (picomolar affinity), distinguishes it from covalent KRAS inhibitors.[1] Covalent inhibitors, such as those targeting KRASG12C, form an irreversible bond, typically with a cysteine residue. While this can lead to prolonged target engagement, it also carries potential risks, including off-target covalent modifications or the emergence of specific resistance mutations that alter the targeted cysteine. BBO-11818's non-covalent approach relies on strong, yet reversible, binding interactions. This could translate to a different safety profile, potentially with fewer idiosyncratic adverse events linked to irreversible covalent binding, and may also lead to different patterns of resistance development. The high degree of selectivity for KRAS over other RAS isoforms and unrelated kinases is particularly vital for a non-covalent inhibitor to achieve a favorable therapeutic window, minimizing off-target effects.[1] The oral bioavailability of BBO-11818 further indicates desirable drug-like properties, facilitating patient administration.[1]

III. Preclinical Development and Efficacy

A. In Vitro Studies

BBO-11818 has demonstrated significant potency in preclinical in vitro settings. In KRASG12D and KRASG12V-mutant cell lines, it potently inhibits the phosphorylation of ERK (pERK), a downstream effector in the MAPK signaling pathway, with half-maximal effective concentrations (EC50​) in the sub-nanomolar to single-digit nanomolar range.[1] The compound also effectively reduces cell viability in cell lines harboring KRASG12D, KRASG12V, and KRASG12C mutations, achieving low nanomolar EC50​ values.[1] This activity is highly selective; BBO-11818 shows over 500-fold greater selectivity for KRAS compared to H-RAS and N-RAS.[1] Cell lines driven by NRAS or BRAF mutations are largely insensitive to BBO-11818, exhibiting over 1000-fold lower potency, which underscores the drug's specificity for KRAS-driven oncogenesis.[1] This high degree of selectivity is a critical attribute, as it suggests a lower likelihood of off-target toxicities.

B. In Vivo Efficacy (Monotherapy)

The anti-tumor activity of BBO-11818 has been robustly demonstrated in various in vivo preclinical models featuring KRASG12D and KRASG12V mutations.[2] As a monotherapy, BBO-11818 induced significant anti-tumor responses, including notable tumor regressions, at doses that were well-tolerated in cell-derived xenograft (CDX) models. These models represented diverse KRAS-mutant human cancers, including:

• Pancreatic cancer:
• HPAC model (KRASG12D): 81% tumor growth inhibition (TGI).[7]
• Capan-2 model (KRASG12V): 99% TGI.[7]
• Colorectal cancer:
• GP2d model (KRASG12D): 88% TGI and 37% regression.[7]
• Non-small cell lung cancer models were also tested, showing efficacy.[6]

C. In Vivo Efficacy (Combination Therapy)

The therapeutic potential of BBO-11818 appears to be further enhanced when used in combination with other anti-cancer agents. Preclinical studies have revealed synergistic or additive effects:

• With BBO-10203 (RAS:PI3Kα breaker): In the Capan-2 pancreatic cancer CDX model (KRASG12V), the combination of BBO-11818 (100 mg/kg BID) and BBO-10203 (100 mg/kg QD) resulted in 83% TGI and 40% tumor regression. This outcome was superior to that achieved with either agent alone. Mechanistically, this combination led to a marked decrease in tumor cell proliferation, as measured by BrdU incorporation, and a significant increase in apoptosis, indicated by cleaved caspase-3 levels.[6]
• With cetuximab (anti-EGFR monoclonal antibody):
• In the GP2d colorectal cancer CDX model (KRASG12D), the combination of BBO-11818 (30 mg/kg BID) with cetuximab (15 mg/kg BIW) yielded 89% TGI and 57% regression.[7]
• In the H441 NSCLC CDX model (KRASG12V), a similar combination regimen resulted in 82% TGI and 57% regression.[7]
• In the LS513 colorectal cancer CDX model (KRASG12D), the combination produced 89% TGI.[7]
• With anti-PD-1 antibody: In the CT26 colorectal cancer syngeneic model (KRASG12D), combining BBO-11818 (100 mg/kg BID) with an anti-PD-1 antibody (10 mg/kg BIW) led to improved survival compared to either monotherapy. This finding suggests that BBO-11818 may have immunomodulatory effects or can sensitize tumors to immune checkpoint blockade.[6]

D. Preclinical Safety and Tolerability

Across the in vivo studies, BBO-11818 monotherapy was reported to induce strong anti-tumor responses at "well-tolerated doses" in CDX models.[6] While specific details of the adverse event profiles from these preclinical investigations are not extensively described in the available information, this general statement suggests a manageable safety profile in animal models at therapeutically active concentrations.

The extensive preclinical activity of BBO-11818 across a range of KRAS mutations—notably G12D, G12V, and G12C—and its efficacy in diverse cancer types such as pancreatic, non-small cell lung, and colorectal cancers, strongly support its designation as a "pan-KRAS" inhibitor with broad therapeutic potential.[1] KRAS mutations are not uniform; different amino acid substitutions can lead to varied biological effects and differential sensitivities to targeted agents. The observed activity against major oncogenic forms like G12D and G12V, as well as G12C (the target of already approved drugs), is particularly significant.[1] Furthermore, demonstrating efficacy across distinct tumor histologies in preclinical settings implies that the drug's mechanism of action is fundamental to KRAS-driven signaling, largely independent of the specific tissue context.[6] If these broad activity profiles are validated in human clinical trials, BBO-11818 could potentially benefit a considerably larger patient population compared to inhibitors that are highly specific for a single KRAS mutation.

Moreover, the compelling preclinical data from combination studies—with a PI3Kα pathway breaker (BBO-10203), an EGFR-targeting monoclonal antibody (cetuximab), and an immune checkpoint inhibitor (anti-PD-1)—suggests that BBO-11818 has the potential to serve as a foundational therapy in the management of KRAS-mutant cancers.[6] KRAS-driven tumors are notorious for their signaling pathway redundancy and their ability to develop adaptive resistance to monotherapies. The PI3K/AKT pathway is frequently co-activated or serves as an escape route in KRAS-mutant cancers.[2] Combining BBO-11818 with a PI3Kα breaker like BBO-10203 directly addresses this by simultaneously inhibiting two major downstream signaling arms of the RAS pathway.[6] In colorectal cancer, EGFR signaling is often intricately linked with KRAS activity; thus, the observed synergy with cetuximab is clinically highly relevant for this tumor type and may help overcome resistance.[6] Additionally, KRAS-mutant tumors are often characterized as immunologically "cold," meaning they are less responsive to immunotherapy. The improved survival observed with the anti-PD-1 combination indicates that BBO-11818 might modulate the tumor microenvironment, rendering tumors more susceptible to immune attack.[6] These findings position BBO-11818 not merely as a standalone agent but as a potentially crucial partner for a variety of combination strategies aimed at achieving more durable and comprehensive anti-tumor effects.

The following table summarizes key preclinical efficacy data for BBO-11818:

Table III.A: Summary of Key Preclinical Efficacy Data for BBO-11818 (Monotherapy and Combination)

KRAS Mutation	Cancer Model Type	Specific Model	Therapy (BBO-11818 Dose; Combination Agent + Dose)	Key Outcome (e.g., EC<sub>50</sub>; %TGI, %Regression; Survival)	Source Document(s)
G12D, G12V, G12C	Cell Line	Various	BBO-11818 (various conc.)	Low nM EC<sub>50</sub> for pERK inhibition & cell viability reduction	1
G12D	CDX	GP2d CRC	BBO-11818 (30 mg/kg BID)	88% TGI, 37% Regression	7
G12D	CDX	GP2d CRC	BBO-11818 (30 mg/kg BID) + Cetuximab (15 mg/kg BIW)	89% TGI, 57% Regression	7
G12D	CDX	HPAC PDAC	BBO-11818 (100 mg/kg BID)	81% TGI	7
G12V	CDX	Capan-2 PDAC	BBO-11818 (100 mg/kg BID)	99% TGI	7
G12V	CDX	Capan-2 PDAC	BBO-11818 (100 mg/kg BID) + BBO-10203 (100 mg/kg QD)	83% TGI, 40% Regression	7
G12V	CDX	H441 NSCLC	BBO-11818 (30 mg/kg BID) + Cetuximab (15 mg/kg BIW)	82% TGI, 57% Regression	7
G12D	CDX	LS513 CRC	BBO-11818 (30 mg/kg BID) + Cetuximab (15 mg/kg BIW)	89% TGI	7
G12D	Syngeneic	CT26 CRC	BBO-11818 (100 mg/kg BID) + Anti-PD-1 (10 mg/kg BIW)	Improved survival vs monotherapies	7

TGI: Tumor Growth Inhibition; CDX: Cell-Derived Xenograft; PDAC: Pancreatic Ductal Adenocarcinoma; CRC: Colorectal Cancer; NSCLC: Non-Small Cell Lung Cancer; BID: Twice daily; BIW: Twice weekly; QD: Once daily.

IV. Clinical Development: The KONQUER-101 Trial (NCT06917079)

A. Study Identification and Phase

The first-in-human clinical trial evaluating BBO-11818 is registered under the identifier NCT06917079.[4] The study is named KONQUER-101.[1] It is a Phase 1a/1b, open-label clinical trial.[1]

B. Sponsor and Collaborators

The sponsor of the KONQUER-101 trial is TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics (BBOT).[1]

C. Study Objectives and Purpose

The primary objectives of a Phase 1a/1b trial like KONQUER-101 typically include the evaluation of safety, tolerability, and pharmacokinetics (PK) of the investigational drug, BBO-11818, to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D).[2] Secondary and exploratory objectives usually involve assessing preliminary anti-tumor activity.[2] The overarching purpose of the trial is to evaluate the potential clinical benefit of BBO-11818 in patients whose tumors are driven by KRAS mutations and to determine if the drug can safely achieve optimal target inhibition in humans.[1]

D. Patient Population and Eligibility (Key Criteria)

The KONQUER-101 trial is designed to enroll adult subjects with advanced solid tumors that harbor specific KRAS mutations.[1] The targeted KRAS alterations include G12A, G12C, G12D, G12S, or G12V mutations, as well as KRAS gene amplification.[5] The trial listings specify enrollment for patients with locally advanced unresectable or metastatic KRAS mutant solid tumors, with particular mention of Pancreatic Ductal Carcinoma, Colorectal Cancer, Pancreatic Cancer, Adenocarcinoma, and Non-Small-Cell Lung Cancer.[2]

E. Current Status, Timelines, and Enrollment

As of early April 2025, the KONQUER-101 trial is actively recruiting patients.[4] The first patient was dosed in the trial on April 1, 2025, with trial initiation reported as March 31, 2025.[1] The estimated total enrollment for the study is 287 patients.[4] The estimated primary completion date for the trial is August 1, 2027.[9]

F. Investigational Sites and Principal Investigators

The KONQUER-101 trial is a global study, planning to enroll patients from various international sites.[1] One of the known Principal Investigators is Dr. Ignacio Garrido-Laguna, MD, PhD, who serves as the Director of the Phase 1 Program at the Huntsman Cancer Institute at the University of Utah.[1]

G. Dosage and Administration (General)

BBO-11818 is administered orally as a small molecule drug.[1] Specific dosage levels to be used in the KONQUER-101 trial are not detailed in the publicly available information but will be determined through the dose-escalation portion of the Phase 1a study.

The global scope of the KONQUER-101 trial, combined with its inclusion of a wide array of KRAS variants (G12A, G12C, G12D, G12S, G12V, and KRAS amplification) from the outset of Phase 1, points to an ambitious and comprehensive development strategy.[1] This approach is geared towards rapid data generation across diverse patient populations and various tumor types. Enrolling patients internationally can significantly accelerate recruitment, which is particularly beneficial for a trial targeting multiple specific mutations within different cancer contexts.[1] Testing a "pan-KRAS" inhibitor against such a broad range of specified KRAS alterations in an early Phase 1a/1b setting, rather than initially focusing on a single mutation, allows for the early identification of efficacy signals across different genetic backgrounds.[5] This strategy can de-risk and expedite later-phase development by quickly highlighting which patient subgroups—defined by their specific KRAS mutation and/or tumor type—are most likely to derive benefit, thereby guiding the design of cohort expansions and future pivotal trials.

The projected primary completion date of August 2027 for a Phase 1 trial that commenced in the first half of 2025, along with an estimated enrollment of 287 patients, suggests a complex and thorough trial design.[4] A duration of over two years for a Phase 1 oncology trial is not uncommon, particularly for drugs with broad target populations and multiple planned cohorts. The substantial sample size of 287 participants for a Phase 1 study strongly implies that, beyond the initial dose-escalation phase aimed at determining the MTD or RP2D, the KONQUER-101 trial will incorporate several dose-expansion cohorts.[9] These expansion cohorts will likely concentrate on specific KRAS mutations and/or tumor types (e.g., PDAC with KRASG12D, NSCLC with KRASG12V) to gather more robust preliminary efficacy data and to further characterize the safety profile of BBO-11818 in more homogeneous patient populations. Such extensive data collection in Phase 1 is crucial for a drug candidate with pan-KRAS inhibitory potential, as it lays the groundwork for subsequent, more focused clinical investigations.

The following table summarizes key details of the KONQUER-101 clinical trial:

Table IV.A: Key Details of the KONQUER-101 (NCT06917079) Clinical Trial

Feature	Detail	Source Document(s)
NCT Identifier	NCT06917079	4
Official Title (derived)	A Phase 1a/1b Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of BBO-11818 in Subjects With Advanced KRAS Mutant Cancers	4
Phase	Phase 1a/1b	1
Sponsor	TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics (BBOT)	1
Primary Purpose (likely)	Evaluate safety, tolerability, pharmacokinetics (PK), determine MTD/RP2D	2
Key Endpoints (likely)	Safety (AEs, DLTs), PK parameters, preliminary efficacy (ORR, DoR, PFS)	2
Target KRAS Mutations	G12A, G12C, G12D, G12S, G12V, or KRAS amplification	5
Key Eligibility (general)	Adults with locally advanced unresectable or metastatic solid tumors with specified KRAS alterations	1
Targeted Tumor Types	Pancreatic Ductal Carcinoma, Colorectal Cancer, Pancreatic Cancer, Adenocarcinoma, Non-Small-Cell Lung Cancer	2
Estimated Enrollment	287	4
Start Date (First Patient Dosed)	April 1, 2025 (Trial Initiation: March 31, 2025)	1
Estimated Primary Completion Date	August 1, 2027	9
Known Study Locations/Regions	Global; Huntsman Cancer Institute (University of Utah) is a participating site	1
Key Principal Investigator (Known)	Dr. Ignacio Garrido-Laguna (Huntsman Cancer Institute)	1

MTD: Maximum Tolerated Dose; RP2D: Recommended Phase 2 Dose; AEs: Adverse Events; DLTs: Dose-Limiting Toxicities; ORR: Objective Response Rate; DoR: Duration of Response; PFS: Progression-Free Survival.

V. Therapeutic Potential and Competitive Landscape

A. Potential Advantages of a PanKRAS Dual Inhibitor

BBO-11818, as a panKRAS dual inhibitor, offers several potential advantages over existing or other investigational KRAS-targeted therapies. Its ability to target multiple KRAS mutations—including G12D, G12V, G12C, G12A, G12S, and KRAS amplification—could allow it to address a significantly broader patient population than inhibitors specific to a single mutation (e.g., KRASG12C inhibitors).[1] The dual-inhibition strategy, targeting both the "ON" and "OFF" states of KRAS, is designed to potentially overcome adaptive resistance mechanisms that can limit the efficacy of inhibitors targeting only the "OFF" state.[1] Furthermore, strong preclinical data suggests BBO-11818 may be suitable for combination therapies with other targeted agents, such as PI3Kα inhibitors like BBOT's own BBO-10203, EGFR inhibitors, and immunotherapies.[1] BBOT has highlighted that its portfolio, including BBO-11818 and BBO-8520 (another MAPK pathway inhibitor) alongside BBO-10203 (a PI3Kα/AKT pathway inhibitor), is "uniquely positioned to deliver the combination of MAPK and PI3Kα/AKT co-inhibition, with a therapeutic index".[1]

B. Targeted Tumor Types and Patient Populations

The primary focus for BBO-11818 is on patients with advanced solid tumors harboring relevant KRAS mutations. Key tumor types where KRAS mutations are prevalent and represent a high unmet need include pancreatic cancer (specifically PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC).[1] The KONQUER-101 trial is actively enrolling patients with these and other KRAS-mutant solid tumors.[4]

C. Brief Comparison with Other KRAS Inhibitors

The field of KRAS inhibition is rapidly evolving and becoming increasingly competitive. BBO-11818 enters a landscape that includes other pan-KRAS inhibitors as well as mutation-specific agents. Notable competitors in the pan-KRAS or broad-spectrum KRAS inhibitor space include Revolution Medicines' darovasertib (RMC-6236), which is a KRAS-ON multi-selective inhibitor, Mirati (a Bristol Myers Squibb company) with MRTX1133 (a KRASG12D selective inhibitor that also has broader preclinical activity), Eli Lilly's LY3537982 (formerly LY4066434, a KRASG12C inhibitor with potential broader activity), Pfizer's PF-07934040, and BeiGene's BGB-53038.[5] BridgeBio Oncology Therapeutics aims to differentiate BBO-11818 through its claimed "dual inhibitor" characteristic, emphasizing its capacity to target both the "ON" and "OFF" states of KRAS across multiple common mutations.[1]

The "dual ON/OFF" pan-KRAS inhibitory mechanism of BBO-11818 positions it distinctively against both highly mutation-specific inhibitors (such as the approved KRASG12C inhibitors sotorasib and adagrasib) and other investigational pan-KRAS agents that may not target both conformational states as effectively or across such a broad range of mutations. Mutation-specific inhibitors, while valuable, are limited to a subset of KRAS-mutant tumors, and resistance remains a significant challenge. If BBO-11818's dual-state targeting genuinely leads to more profound and durable KRAS pathway inhibition and can circumvent common resistance mechanisms that involve the shuttling of KRAS between its active and inactive states, it could offer a superior clinical benefit. The capacity to address a wide spectrum of G12 mutations (G12A, G12C, G12D, G12S, G12V) as well as KRAS amplifications, as planned for the KONQUER-101 trial, further broadens its potential therapeutic utility compared to inhibitors focused on a single KRAS variant.[5]

The collaborative nature of BBO-11818's discovery, involving the Frederick National Laboratory for Cancer Research (FNLCR) and Lawrence Livermore National Laboratory (LLNL), may have been instrumental in its design.[1] The RAS Initiative at FNLCR was specifically established to unravel the complexities of RAS biology and develop new therapeutic strategies against this challenging oncogene.[3] LLNL offers advanced capabilities in areas like computational modeling and high-performance computing, which are invaluable in modern drug discovery. Such public-private partnerships often enable biotechnology companies to leverage cutting-edge, publicly funded research infrastructure and fundamental scientific expertise that might otherwise be inaccessible. This early-stage scientific collaboration could be a crucial factor in the development of an inhibitor with BBO-11818's described dual mechanism and broad specificity, potentially providing it with a unique scientific foundation and a competitive edge.

VI. Regulatory Status and Intellectual Property

A. Current Understanding of Regulatory Designations (FDA, EMA)

Based on the available information, BBO-11818 has not yet received any specific special regulatory designations from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA), such as Fast Track, Breakthrough Therapy, Orphan Drug status, or PRIME (Priority Medicines) designation.[8] It is noteworthy that another KRAS inhibitor from BBOT's pipeline, BBO-8520, was granted Fast Track designation by the FDA for KRASG12C-mutated metastatic non-small cell lung cancer.[8] This indicates that BBOT is familiar with these expedited regulatory pathways and may pursue them for BBO-11818 if supported by emerging clinical data.

The absence of such special regulatory designations for BBO-11818 at this juncture is likely a reflection of its early stage in clinical development, having only recently dosed its first patient in the Phase 1 KONQUER-101 trial.[1] Regulatory agencies typically grant designations like Fast Track or Breakthrough Therapy based on a combination of compelling preclinical evidence and, crucially, early clinical data that suggests the potential for substantial improvement over available therapies or the ability to address a high unmet medical need. As BBO-11818 has just entered human trials, mature clinical data to support such applications would not yet be available. The precedent set with BBO-8520 suggests that BBOT is strategically aware of these regulatory mechanisms and will likely leverage them for BBO-11818 if the clinical findings are promising.

B. Overview of Relevant Patent Information

Information from PatSnap Synapse indicates that there are "100 Patents (Medical) associated with BBO-11818"; however, access to the specific details of these patents requires a subscription to the platform.[4] The provided research documents do not contain specific patent numbers or detailed claims related to the composition of matter or methods of use for BBO-11818. General patent searches for BridgeBio Oncology Therapeutics or TheRas, Inc. concerning KRAS inhibitors do not explicitly link to BBO-11818 within the text of the available snippets.[20]

While specific patent numbers for BBO-11818 are not publicly detailed in the provided materials, the reference to a significant number of associated medical patents on specialized databases like PatSnap strongly suggests that BridgeBio Oncology Therapeutics is actively cultivating a robust intellectual property (IP) portfolio around this novel pan-KRAS dual inhibitor.[4] For any new therapeutic agent, particularly one targeting a high-value and historically challenging oncogene like KRAS with a differentiated mechanism of action, comprehensive patent protection is critical for commercial viability. This protection typically covers the composition of matter (the chemical structure of the drug itself), methods of its use for treating specific diseases, manufacturing processes, and potentially formulations. The indication of numerous patents associated with BBO-11818, even if the specifics are not fully accessible in the provided documents, points towards a strategic and diligent IP effort by the company. Furthermore, the collaborative discovery process involving national laboratories like FNLCR and LLNL might also entail shared or licensed IP from these institutions, which would further secure the foundational patent protection for BBO-11818 and its applications.[1]

VII. Discussion and Future Directions

A. Synthesis of Current Knowledge on BBO-11818

BBO-11818 has emerged as a promising investigational agent characterized as an orally bioavailable, non-covalently binding, panKRAS dual inhibitor. It uniquely targets both the active "ON" (GTP-bound) and inactive "OFF" (GDP-bound) states of the KRAS protein. Preclinical studies have demonstrated its broad activity against multiple clinically relevant KRAS mutations, including G12D, G12V, and G12C, across various cancer cell lines and xenograft models derived from pancreatic, colorectal, and non-small cell lung cancers. This preclinical efficacy is observed both as a monotherapy and, notably, in combination with other targeted agents and immunotherapy. BBO-11818 is currently undergoing Phase 1a/1b clinical evaluation in the KONQUER-101 trial (NCT06917079), which aims to establish its safety, pharmacokinetic profile, and preliminary anti-tumor efficacy in patients with advanced KRAS-mutant solid tumors.

B. Potential Challenges and Opportunities in Development

A primary challenge in the development of BBO-11818 will be to demonstrate a favorable therapeutic index in human subjects. Given its pan-KRAS inhibitory nature, which targets a protein crucial for normal cellular functions, there is a potential for on-target toxicity in healthy tissues that express wild-type KRAS. Managing this potential systemic toxicity while achieving effective anti-tumor concentrations will be critical.

Conversely, the opportunities for BBO-11818 are substantial. If its broad efficacy and manageable safety profile are confirmed in clinical trials, it could address a wide spectrum of KRAS-mutant tumors. This includes malignancies for which no targeted therapies currently exist or those that have developed resistance to existing KRAS inhibitors. The dual "ON"/"OFF" state inhibition mechanism offers a distinct potential advantage in terms of overcoming resistance and achieving deeper responses. Furthermore, the robust preclinical data supporting combination strategies suggests that BBO-11818 could become a versatile backbone therapy, adaptable to various combination regimens tailored to specific tumor types or resistance mechanisms.

C. Future Research Directions

Future research will likely focus on several key areas. The identification of predictive biomarkers beyond the specific KRAS mutation subtype will be crucial for optimizing patient selection and maximizing therapeutic benefit. This could involve exploring co-mutations, gene expression signatures, or characteristics of the tumor microenvironment. As clinical data emerges from the KONQUER-101 trial, further exploration of rational combination strategies will be guided by observed efficacy signals and an evolving understanding of tumor biology. Investigating the mechanisms of potential acquired resistance to BBO-11818 will also be important for developing next-generation strategies or sequential therapies. Finally, based on efficacy signals observed in the expansion cohorts of the KONQUER-101 trial, development will likely expand into more focused studies within specific tumor types and patient populations.

D. Concluding Remarks on the Potential Impact of BBO-11818

BBO-11818 represents a scientifically sophisticated approach to targeting KRAS, one of the most formidable oncogenes in cancer biology. Its unique dual-targeting mechanism and broad spectrum of activity against multiple KRAS mutations hold considerable promise for patients with difficult-to-treat cancers. The ongoing KONQUER-101 trial will be instrumental in defining its clinical utility and potential to change the treatment landscape for KRAS-driven malignancies.

The ultimate clinical success of BBO-11818 will be critically dependent on its ability to demonstrate a favorable therapeutic index in human trials. Achieving a balance between its potent, broad pan-KRAS inhibition and a manageable systemic toxicity profile will be a paramount consideration, as this is a common challenge for inhibitors that target fundamental oncogenic pathways active in both cancerous and normal cells.[1] While preclinical models indicated that BBO-11818 was "well-tolerated" at effective doses [6], human physiological responses and tolerance can differ significantly. The dose-escalation phase and safety findings from the KONQUER-101 trial will provide the first crucial insights into this therapeutic window in patients.[2] The emphasis by BridgeBio Oncology Therapeutics on developing a portfolio that can deliver combinations "with a therapeutic index" underscores their awareness of this critical aspect.[1]

Looking forward, the development pathway for BBO-11818 will likely necessitate the implementation of sophisticated biomarker strategies that extend beyond simple KRAS mutation detection. Such strategies will be key to refining patient selection criteria, predicting which patients are most likely to respond, and guiding the rational design of combination therapies in the context of tumor heterogeneity and evolving resistance mechanisms. Even within a specific KRAS mutation subtype, such as G12D, tumor responses to targeted therapies can vary considerably due to factors like co-occurring genetic alterations (e.g., in TP53 or PIK3CA), redundancies in signaling pathways, and differences in the tumor microenvironment. The KONQUER-101 trial is designed to enroll patients with a range of KRAS mutations and diverse tumor types.[5] Identifying which specific contexts—for instance, KRASG12V mutations in PDAC versus NSCLC, or the presence or absence of key co-mutations—derive the most significant benefit from BBO-11818 will be crucial for its successful clinical translation. The promising preclinical data supporting various combination approaches already points towards a future where BBO-11818 is integrated into tailored therapeutic regimens, and robust biomarkers will be essential for determining the optimal combination partners for individual patients or defined patient subgroups.[6]

VIII. References

• [1]: BBOT Announces First Patient Dosed with BBO-11818, a PanKRAS Dual Inhibitor, in the Phase 1 KONQUER-101 Trial for Advanced Solid Tumors | BridgeBio Oncology Therapeutics.
• [2]: Platform | BridgeBio Oncology Therapeutics.
• [1]: BBOT Announces First Patient Dosed with BBO-11818, a PanKRAS Dual Inhibitor, in the Phase 1 KONQUER-101 Trial for Advanced Solid Tumors | BridgeBio Oncology Therapeutics (BridgeBioOncology.com).
• [4]: BBO-11818 Drug Profile | PatSnap Synapse.
• [3]: BBO-8520 Drug Profile | PatSnap Synapse (mentions BBO-11818 development context).
• [10]: Ozmosi | BBO-11818 Drug Profile.
• [5]: BridgeBio enters the pan-KRAS game | Evaluate.
• [9]: BBO-11818 in Adult Subjects With KRAS Mutant Cancer | Larvol Clin.
• [1]: BBOT Announces First Patient Dosed with BBO-11818, a PanKRAS Dual Inhibitor, in the Phase 1 KONQUER-101 Trial for Advanced Solid Tumors (BusinessWire).
• [11]: Ignacio Garrido-Laguna: Dosing first patient in the world with BBO-11818, a novel PanKras inhibitor - OncoDaily.
• [5]: BridgeBio enters the pan-KRAS game (OncologyPipeline.com, refers to Evaluate article).
• [4]: BBO-11818 Drug Profile | PatSnap Synapse (alternative access).
• [8]: BridgeBio Oncology Therapeutics (BBOT) Granted U.S. FDA Fast Track Designation for BBO-8520 for KRASG12C-Mutated Metastatic Non-Small Cell Lung Cancer (BusinessWire, context for BBOT regulatory strategy).
• [12]: BridgeBio Announces Commercial Progress, Program Updates, and 2025 Milestones (FirstWord Pharma, general company update, no BBO-11818 specifics).
• [4]: BBO-11818 Drug Profile | PatSnap Synapse (reiteration of patent info access).
• [13]: BridgeBio Oncology Therapeutics Reports the First Patient Dosing in P-I (KONQUER-101) Trial of BBO-11818 for Advanced Solid Tumors – PharmaShots.
• [14]: BridgeBio Oncology Therapeutics (BBOT) Enters into Business Combination Agreement with Helix Acquisition Corp. II to Develop RAS and PI3Kα-Targeting Drugs - PharmaShots (mentions BBO-11818 funding).
• [2]: Platform | BridgeBio Oncology Therapeutics (mentions BBO-11818 publication).
• [6]: Abstract 4378: BBO-11818, an orally bioavailable, highly potent and non-covalent pan-KRAS inhibitor demonstrates robust anti-tumor activity in KRAS-mutant preclinical models | ResearchGate.
• [1]: BBOT Announces First Patient Dosed with BBO-11818, a PanKRAS Dual Inhibitor, in the Phase 1 KONQUER-101 Trial for Advanced Solid Tumors (BridgeBioOncology.com, repetition).
• [13]: BridgeBio Oncology Therapeutics Reports the First Patient Dosing in P-I (KONQUER-101) Trial of BBO-11818 for Advanced Solid Tumors – PharmaShots (repetition).
• [20]: Patent UA119167C2 - Google Patents (general search result, not specific).
• [15]: BridgeBio Oncology to merge with Helix Acquisition Corp II (Pharmaceutical Technology, mentions BBO-11818).
• [16]: PharmaShots Key Highlights of First Quarter 2025 (PharmaShots, general news, no BBO-11818 specifics).
• [17]: BBOT Announces First Patient Dosed with BBO-11818, a PanKRAS Dual Inhibitor, in the Phase 1 KONQUER-101 Trial for Advanced Solid Tumors (BusinessWire, repetition).
• [18]: BridgeBio Oncology Therapeutics (BBOT) and Helix Acquisition Corp. II Announce Business Combination Agreement... (BusinessWire, mentions BBO-11818 funding).
• [21]: Patent EP3710439A4 - Google Patents (general search result, not specific).
• [19]: BridgeBio Oncology Therapeutics (BBOT) Granted U.S. FDA Fast Track Designation for BBO-8520... (BridgeBioOncology.com, context).
• [1]: Details on BBO-11818 mechanism of action, targeted KRAS mutations, KONQUER-101 trial, preclinical efficacy, and safety goals (BridgeBioOncology.com).
• [2]: Information on BBO-11818's mechanism as a pan-KRAS inhibitor, targeted mutations (G12D, G12V), preclinical activity, and development phase (BridgeBioOncology.com).
• [10]: BBO-11818 drug profile including mechanism, modality, route of administration, company, development phase, clinical trial details (TBBO11818-101), and targeted diseases (Ozmosi).
• [5]: Information on BBO-11818 as a pan-KRAS dual inhibitor, its entry into clinical trials, and comparison with other KRAS inhibitors (OncologyPipeline.com).
• [6]: Detailed preclinical efficacy, mechanism of action, safety/tolerability in animal models... from AACR Abstract 4378 (ResearchGate).
• [7]: Preclinical data, mechanism of action... for BBO-11818 from the RAS Symposium Poster (BridgeBioOncology.com PDF).

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