BBOT Announces First Patient Dosed with BBO-11818, a PanKRAS Dual Inhibitor, in the Phase 1 KONQUER-101 Trial for Advanced Solid Tumors
BBOT has announced the dosing of its first patient with BBO-11818 in the Phase 1 KONQUER-101 trial for advanced solid tumors. BBO-11818 is an orally bioavailable small molecule that acts as a panKRAS dual inhibitor, binding to both 'ON' and 'OFF' states of KRAS with picomolar affinity.
The drug demonstrates sub-nanomolar to single-digit nanomolar potency in cellular assays for pERK inhibition in KRAS G12D and G12V-mutant cell lines. It shows effectiveness in reducing cell viability across KRASG12D, KRASG12V, and KRASG12C-mutant cell lines, with over 500-fold selectivity for KRAS over H- and NRAS.
This marks BBOT's third molecule entering clinical trials, positioning the company to potentially deliver combination therapy through MAPK and PI3Kα/AKT co-inhibition for patients with RAS-driven cancers.
BBOT ha annunciato la somministrazione del suo primo paziente con BBO-11818 nel trial di Fase 1 KONQUER-101 per tumori solidi avanzati. BBO-11818 è una piccola molecola bio-disponibile per via orale che funge da inibitore duale panKRAS, legandosi sia agli stati 'ON' che 'OFF' di KRAS con affinità picomolare.
Il farmaco dimostra una potenza da sub-nanomolare a nanomolare a singolo numero in saggi cellulari per l'inibizione di pERK in linee cellulari mutate KRAS G12D e G12V. Mostra efficacia nel ridurre la vitalità cellulare in linee cellulari mutate KRASG12D, KRASG12V e KRASG12C, con oltre 500 volte di selettività per KRAS rispetto a H- e NRAS.
Questo segna il terzo composto di BBOT ad entrare in sperimentazione clinica, posizionando l'azienda per potenzialmente fornire terapie combinate attraverso l'inibizione co-attiva di MAPK e PI3Kα/AKT per pazienti con tumori guidati da RAS.
BBOT ha anunciado la dosificación de su primer paciente con BBO-11818 en el ensayo de Fase 1 KONQUER-101 para tumores sólidos avanzados. BBO-11818 es una pequeña molécula bio-disponible por vía oral que actúa como un inhibidor dual panKRAS, uniéndose tanto a los estados 'ON' como 'OFF' de KRAS con afinidad picomolar.
El fármaco demuestra potencia de sub-nanomolar a nanomolar de un solo dígito en ensayos celulares para la inhibición de pERK en líneas celulares mutantes KRAS G12D y G12V. Muestra efectividad en la reducción de la viabilidad celular en líneas celulares mutantes KRASG12D, KRASG12V y KRASG12C, con más de 500 veces de selectividad por KRAS sobre H- y NRAS.
Esto marca la tercera molécula de BBOT que entra en ensayos clínicos, posicionando a la empresa para potencialmente proporcionar terapia combinada a través de la co-inhibición de MAPK y PI3Kα/AKT para pacientes con cánceres impulsados por RAS.
BBOT는 고급 고형 종양을 위한 1상 KONQUER-101 시험에서 BBO-11818의 첫 환자 투여를 발표했습니다. BBO-11818은 경구로 생체 이용 가능한 작은 분자로, KRAS의 'ON' 및 'OFF' 상태 모두에 결합하는 panKRAS 이중 억제제로 작용하며, 피코몰 수준의 친화력을 가지고 있습니다.
이 약물은 KRAS G12D 및 G12V 변이 세포주에서 pERK 억제를 위한 세포 분석에서 서브-나노몰에서 단일 자리 나노몰의 효능을 보여줍니다. KRASG12D, KRASG12V 및 KRASG12C 변이 세포주에서 세포 생존율을 감소시키는 데 효과적이며, KRAS에 대해 H- 및 NRAS보다 500배 이상의 선택성을 보입니다.
이는 BBOT의 세 번째 분자가 임상 시험에 진입하는 것을 나타내며, RAS 주도 암 환자에게 MAPK 및 PI3Kα/AKT의 공동 억제를 통한 병용 요법을 제공할 수 있는 가능성을 지닌 회사로 자리매김하고 있습니다.
BBOT a annoncé l'administration de son premier patient avec BBO-11818 dans l'essai de Phase 1 KONQUER-101 pour les tumeurs solides avancées. BBO-11818 est une petite molécule bio-disponible par voie orale qui agit comme un inhibiteur dual panKRAS, se liant à la fois aux états 'ON' et 'OFF' de KRAS avec une affinité picomolaire.
Le médicament démontre une puissance allant de sub-nanomolaire à nanomolaire à un chiffre dans des essais cellulaires pour l'inhibition de pERK dans des lignées cellulaires mutantes KRAS G12D et G12V. Il montre son efficacité à réduire la viabilité cellulaire dans les lignées cellulaires mutantes KRASG12D, KRASG12V et KRASG12C, avec plus de 500 fois de sélectivité pour KRAS par rapport à H- et NRAS.
Cela marque le troisième composé de BBOT à entrer dans des essais cliniques, positionnant l'entreprise pour potentiellement fournir une thérapie combinée grâce à l'inhibition co-active de MAPK et PI3Kα/AKT pour les patients atteints de cancers liés à RAS.
BBOT hat die Dosierung seines ersten Patienten mit BBO-11818 in der Phase-1-Studie KONQUER-101 für fortgeschrittene solide Tumoren bekannt gegeben. BBO-11818 ist ein oral bioverfügbares kleines Molekül, das als panKRAS-Dualinhibitor wirkt und sowohl an die 'ON'- als auch an die 'OFF'-Zustände von KRAS mit pikomolarer Affinität bindet.
Das Medikament zeigt eine Sub-Nanomolar- bis Einzelstellennanomolar-Potenz in zellulären Assays zur pERK-Inhibition in KRAS G12D- und G12V-mutierten Zelllinien. Es zeigt Wirksamkeit bei der Reduzierung der Zellviabilität in KRASG12D-, KRASG12V- und KRASG12C-mutierten Zelllinien, mit über 500-facher Selektivität für KRAS gegenüber H- und NRAS.
Dies markiert das dritte Molekül von BBOT, das in klinische Studien eintritt, und positioniert das Unternehmen potenziell, um eine Kombinationstherapie durch MAPK- und PI3Kα/AKT-Co-Inhibition für Patienten mit RAS-gesteuerten Krebserkrankungen anzubieten.
- First patient dosed in Phase 1 KONQUER-101 trial, advancing clinical development
- Drug shows high potency with sub-nanomolar to single-digit nanomolar effectiveness
- Strong selectivity with 500-fold preference for KRAS over H- and NRAS
- Potential for combination therapy with other targeted treatments
- Early-stage Phase 1 trial with uncertain outcomes
- Faces competition in crowded KRAS inhibitor market
Insights
BBOT's announcement of first patient dosing in the Phase 1 KONQUER-101 trial represents an important early clinical milestone for their novel panKRAS dual inhibitor. This development, while still in early stages, is significant due to the strategic importance of KRAS as a target, which has been historically challenging to drug effectively.
The molecule's dual inhibition mechanism targeting both "ON" and "OFF" states of KRAS offers potential advantages over single-state inhibitors. The impressive preclinical potency (sub-nanomolar to single-digit nanomolar) and high selectivity (500-fold for KRAS over related proteins) suggest a potentially favorable efficacy and safety profile, though this remains to be proven in humans.
Notably, this is BBOT's third molecule to enter clinical trials, demonstrating the company's ability to advance its pipeline. The company appears strategically positioned to explore combination therapies targeting both MAPK and PI3Kα/AKT pathways, potentially addressing resistance mechanisms that often limit single-agent approaches.
While this news signals pipeline progress, investors should recognize that Phase 1 trials primarily establish safety, with efficacy data still distant. The KRAS inhibitor landscape has become increasingly competitive following Amgen's Lumakras approval for KRAS G12C mutations, though BBOT's compound targets additional mutations (G12D, G12V) that represent larger patient populations.
The collaboration with prestigious national laboratories adds scientific credibility to the program, but ultimately clinical data will determine its value proposition.
BBOT's BBO-11818 represents an intriguing addition to the emerging field of direct KRAS inhibitors. The compound's dual-binding mechanism targeting both the GTP-bound "ON" and GDP-bound "OFF" states of KRAS differentiates it from first-generation inhibitors that typically target single states.
This approach could potentially overcome limitations seen with current KRAS G12C inhibitors, which only bind the inactive state. By targeting both states, BBO-11818 might achieve more complete target inhibition and address acquired resistance mechanisms. Additionally, while first-generation KRAS inhibitors primarily target G12C mutations (found in ~13% of lung and ~3% of colorectal cancers), BBO-11818 demonstrates activity against G12D and G12V mutations, which are more prevalent in pancreatic cancer (~41% G12D, ~34% G12V).
The preclinical data showing potency in the picomolar range and demonstrating 500-fold selectivity for KRAS over H- and NRAS suggests a potentially favorable therapeutic window. The oral bioavailability adds to its clinical practicality.
The KONQUER-101 trial will provide crucial safety data and early signals of clinical activity. If successful, this compound could address significant unmet needs in multiple KRAS-driven malignancies where current treatment options remain suboptimal.
Their strategic positioning to deliver combination MAPK and PI3Kα/AKT pathway inhibition is scientifically sound, as these parallel signaling pathways often mediate resistance to single-pathway inhibition in RAS-driven cancers.
- The first patient has been dosed with BBO-11818 in the KONQUER-101 first-in-human clinical study
- BBO-11818 is an orally bioavailable small molecule panKRAS dual (“ON” and “OFF” states) inhibitor that directly binds to KRAS with picomolar affinity
- BBO-11818 is expected to provide significant benefit to patients with tumors driven by these oncogenes by safely achieving optimal target inhibition
“The dosing of the first patient is a major milestone in assessing BBO-11818’s potential benefit for patients with tumors driven by mutant KRAS,” said Dr. Ignacio Garrido-Laguna, MD, PhD, Principal Investigator at Huntsman Cancer Institute at the University of
BBO-11818 was designed to non-covalently bind both the inactive GDP-bound “OFF” and active GTP-bound “ON” forms of KRASG12D and KRASG12V. In cellular assays, EC50 values for pERK inhibition in selected KRAS G12D and G12V-mutant cell lines range from sub-nanomolar to single-digit nanomolar potency. BBO-11818 is similarly effective in reducing cell viability in KRASG12D, KRASG12V, and KRASG12C-mutant cell lines. Further, NRAS and BRAF mutant cell lines show insensitivity to BBO-11818, and the molecule exhibits more than 500-fold selectivity for KRAS over H- and NRAS.
“There is a great need for new therapies that can safely treat patients with tumors driven by KRAS mutations, as the current standard of care lacks satisfactory options as monotherapy or to enable combinations of KRAS targeted therapies with other targeted agents,” said Yong (Ben) Ben, MD, Chief Medical and Development Officer of BBOT. “BBO-11818 marks the third molecule entering the clinic for BBOT, further proving our capability to advance novel programs into the clinic. Of note, our portfolio is uniquely positioned to deliver the combination of MAPK (BBO-8520 and BBO-11818) and PI3Kα/AKT (BBO-10203) co-inhibition, with a therapeutic index. We hope this will bring unprecedented benefit to patients with RAS-driven cancers.”
The discovery of BBO-11818 was the result of a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT.
About BBOT
BBOT is a clinical-stage biopharmaceutical company advancing a next-generation pipeline of novel small molecule therapeutics targeting RAS and PI3Kα malignancies. Initially formed as a subsidiary of BridgeBio Pharma, Inc. (Nasdaq: BBIO), BBOT has the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information, visit bridgebiooncology.com.
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BBOT Contact:
Idan Elmelech
Senior Vice President, Strategy & Business Development
Contact@bridgebiooncology.com
(650) 405-7021
Media Contact:
Jake Robison
Inizio Evoke Comms
Jake.robison@inizioevoke.com
Source: BridgeBio Oncology Therapeutics
FAQ
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