tuxobertinib (BDTX-189) / Black Diamond Therap - LARVOL DELTA

MasterKey-01: A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=91 | Terminated | Sponsor: Black Diamond Therapeutics, Inc. | Phase classification: P1/2 ➔ P1

Phase classification • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2

Characterization and Identification of the Metabolites of Tuxobertinib in Rat, Dog, Monkey, and Human Liver Microsomes by Liquid Chromatography Combined With High Resolution Mass Spectrometry. (PubMed, Biomed Chromatogr) - "In human recombinant CYP3A4, 13 metabolites were detected, and CYP3A4 was the primary enzyme responsible for tuxobertinib metabolism. This is the first report on the metabolism of tuxobertinib, which provided an overview of the metabolism profiles of tuxobertinib in vitro, which is helpful in understanding its safety and action."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CYP3A4 • EGFR

BDTX-189, a novel tyrosine kinase inhibitor, inhibits cell activity via ERK and AKT pathways in the EGFR C797S triple mutant cells. (PubMed, Chem Biol Interact) - "Furthermore, BDTX-189 not only inhibits common EGFR triple mutations but also effectively inhibits EGFR L858R mutation and EGFR L858R/T790M mutation. These findings support the cytotoxic effect of BDTX-189 and its inhibitory effect on cell division and proliferation with the EGFR C797S triple mutation."

Journal • EGFR

Black Diamond Therapeutics Reports Second Quarter 2023 Financial Results and Provides Corporate Update (GlobeNewswire) - "Black Diamond continues to leverage its Mutation-Allostery-Pharmacology (MAP) drug discovery engine to advance its discovery-stage pipeline to bring therapies to underserved patients and expects to progress another undisclosed program in solid tumors to development candidate nomination in 2023....Research and Development Expenses: Research and development (R&D) expenses were $13.2 million for the second quarter of 2023, compared to $16.2 million for the same period in 2022. The decrease in R&D expenses was primarily due to reduced clinical trial activities stemming from the discontinuation of the development of BDTX-189 to focus on advancement of the Company’s pipeline programs, BDTX-1535 and BDTX-4933."

Commercial • New molecule • Oncology • Solid Tumor

[VIRTUAL] Prospective preclinical modeling to estimate clinical pharmacokinetics and doses of BDTX-189, an inhibitor of allosteric ErbB mutations in advanced solid malignancies (AACR 2021) - P1/2 | "This study demonstrates that a PBPK modeling approach and an understanding of the determinants of clearance can provide an effective framework for preclinical-to-clinical translation. BDTX-189 is currently under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465), and clinical PK will be reported in due course."

Late-breaking abstract • PK/PD data • Preclinical • Oncology • Solid Tumor • EGFR • HER-2

Identification of STX-721, an EGFR exon 20 mutant inhibitor with superior selectivity and a potential best-in-class profile (AACR-NCI-EORTC 2022) - "STX-721 demonstrates EGFR exon 20 mutant selectivity approaching the selectivity of Osimertinib in EGFR T790M mutants, warranting further exploration of this potential best-in-class exon 20 inhibitor in the clinic. Ba/F3: proliferation selectivity vs. EGFR WT Human cells: proliferation selectivity (vs."

EGFR exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

MasterKey-01: A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1/2 | N=91 | Terminated | Sponsor: Black Diamond Therapeutics, Inc. | Completed ➔ Terminated; The development of BDTX-189 was discontinued by the sponsor.

HER2 exon 20 • Trial termination • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2

MasterKey-01: A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1/2 | N=91 | Completed | Sponsor: Black Diamond Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Sep 2022 | Trial primary completion date: Jun 2023 ➔ Sep 2022

HER2 exon 20 • Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2

MasterKey-01: A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1/2 | N=91 | Active, not recruiting | Sponsor: Black Diamond Therapeutics, Inc. | Recruiting ➔ Active, not recruiting | N=200 ➔ 91

Enrollment change • Enrollment closed • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2

Black Diamond Therapeutics Announces Pipeline Prioritization and Workforce Realignment (GlobeNewswire) - "Black Diamond Therapeutics...announced that it is realigning its resources to focus on key near-term value drivers and to extend its cash runway into the third quarter of 2024, supporting the execution of important clinical and preclinical milestones....Black Diamond has discontinued the development of BDTX-189 and realigned its workforce to focus on progressing its pipeline through important upcoming milestones for BDTX-1535, BDTX-4933 and discovery efforts....Black Diamond initiated investigational new drug (IND)-enabling studies in the first quarter of 2022 and expects to submit an IND for BDTX-4933 in the first half of 2023....Black Diamond anticipates announcing a development candidate for its FGFR program in 2022 in addition to disclosing a new small molecule development candidate in 2023."

Discontinued • IND • Pipeline update • Oncology

LNG-451, a potent inhibitor of EGFR exon 20 insertion mutations with high CNS exposure (AACR 2022) - "While several small molecules have been approved (mobocertinib) or are in clinical development (e.g. CLN-081, BDTX-189) none have demonstrated meaningful CNS activity and they can be associated with treatment-limiting adverse events, including wild-type (WT) EGFR-mediated toxicities. An ex vivo imaging analysis of the brain and spinal cords from all animals at the end of the study showed a dose-dependent decrease in the bioluminescent signal in both brain and spinal cords from mice treated with LNG-451 relative to the vehicle control animals. Taken together, LNG-451 is a CNS-penetrant, wild-type EGFR-sparing, EGFR Ex20ins inhibitor that is expected to provide strong anti‑tumor efficacy for patients with advanced/metastatic solid cancers harboring oncogenic EGFR exon 20 insertions with reduced WT EGFR driven toxicities."

EGFR exon 20 • Lung Cancer • Oncology • Solid Tumor • EGFR

"$BDTX to discontinue development of BDTX-189 and reduce workforce by ~ 30%" (@BioStocks)

ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetration and antitumor activity in subcutaneous and intracranial NSCLC models (AACR 2022) - "In this subcutaneous model, ORIC-114 was superior to CLN-081 in efficacy and tolerability, and superior to BDTX-189 in efficacy...Once daily oral administration of ORIC-114 significantly regressed established intracranial NSCLC tumors and demonstrated greater efficacy than TAK-788, commensurate with the superior brain exposure of ORIC-114...Taken together, these data confirm ORIC-114 as a potent, selective, irreversible, brain penetrant exon 20 inhibitor, and a promising therapeutic candidate, including for patients with CNS metastases. Based upon these data, ORIC-114 is entering a Phase 1/1b clinical trial in genetically defined cancers."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

LNG-451 is a potent, CNS-penetrant, wild-type EGFR sparing inhibitor of EGFR exon 20 insertion mutations (AACR 2022) - "While several small molecules have been approved (mobocertinib) or are in clinical development (e.g. CLN-081, BDTX-189) none have demonstrated meaningful CNS activity and they can be associated with treatment-limiting adverse events, including wild-type (WT) EGFR-mediated toxicities. LNG-451 potently suppressed EGFR phosphorylation in tumor tissue (e.g. 99%, 3 h post 50 mg/kg dose) but had minimal-to modest suppression of phospho-EGFR in large intestine tissue (e.g. 4.2%, 3h post 50 mg/kg dose) and skin tissue (e.g 1.9%, 3h post 50 mg/kg dose). Taken together, LNG-451 is a wild-type EGFR-sparing, CNS-penetrant EGFR Ex20ins inhibitor that is expected to provide strong anti‑tumor efficacy for patients with advanced/metastatic solid cancers harboring oncogenic EGFR exon 20 insertions with reduced WT EGFR-driven toxicities."

EGFR exon 20 • Lung Cancer • Oncology • Solid Tumor • EGFR

Black Diamond Therapeutics Reports Third Quarter 2021 Financial Results and Provides Corporate Update (GlobeNewswire) - “Black Diamond remains on-track with preparations for initiating the Phase 2 portion of the MasterKey-01 Phase 1/2 study of BDTX-189 by the end of 2021. The Company completed the Phase 1 dose-escalation portion of the study and has selected the recommended Phase 2 dose for BDTX-189. Black Diamond continues to advance BDTX-1535 through IND-enabling studies and expects to file an IND application by the first half of 2022…. Black Diamond continues to progress its early-stage pipeline programs designed to target cancers driven by mutations in BRAF and FGFR. The Company anticipates IND filings for both programs in 2022.”

IND • Trial status • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology

[VIRTUAL] Safety and preliminary efficacy from the phase 1 portion of MasterKey-01: A First-in-human dose-escalation study to determine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and preliminary antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients (pts) with advanced solid malignancies. (ASCO 2021) - P1/2 | "BDTX-189 has a generally manageable safety profile with early evidence of anti-tumor activity . Enrollment is ongoing in non-fasting QD and BID cohorts, and the FE cohort, prior to RP2D identification."

Clinical • P1 data • P2 data • PK/PD data • Dermatology • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • HER-2

[VIRTUAL] Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study. (ASCO 2021) - P1/2 | "BDTX-189 demonstrated rapid absorption and a short PK half-life consistent with the desired PK/PD profile, with exposures in the efficacious target range based on preclinical data . The pilot high fat food-effect data and non-fasting QD dosing regimen show similar or improved systemic exposure relative to dosing in the fasted state . The MasterKey-01 trial is ongoing, including refinement of the dosing regimen and identification of the recommended phase 2 dose."

Clinical • PK/PD data • Oncology • Solid Tumor • EGFR • HER-2

[VIRTUAL] Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies. (ASCO 2020) - P1/2 | "Enrollment began 1/2020. Research Funding: Black Diamond Therapeutics"

Clinical • P1/2 data • PK/PD data • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR • HER-2

A Phase 1/2 Study to Assess the Safety and Antitumor Activity of BDTX-189 in Patients with Advanced Solid Malignancies (clinicaltrialsregister.eu) - P1/2; N=100; Ongoing; Sponsor: Black Diamond Therapeutics, Inc.

Clinical • New P1/2 trial • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2 • MRI

[VIRTUAL] Novel EGFR WT sparing, HER2 selective inhibitors for the treatment of HER2 exon 20 insertion driven tumors address a clear unmet medical need (AACR 2021) - "Here, we report the identification and pharmacological characterization of novel selective HER2 exon 20 mutation TKIs that differ from currently tested TKIs such as poziotinib, TAK-788 or BDTX-189. Our results suggest that HER2 exon 20 insertions can be effectively treated by a potent and highly selective HER2 inhibitor that spares EGFR wild type. These findings warrant the upcoming clinical testing in HER2 mutant NSCLC patients in order to effectively treat this aggressive type of cancer."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Black Diamond Therapeutics Presents Phase 1 Pharmacokinetic, Safety, and Preliminary Efficacy Data of BDTX-189 in Advanced Solid Tumors Harboring EGFR or HER2 Alterations (GlobeNewswire) - P1, N=200; MasterKey-01 (NCT04209465); Sponsor: Black Diamond Therapeutics, Inc; “The PK data for the BDTX-189 QD regimen demonstrated dose-dependent increases in exposure up to 800 mg QD, achieving the predicted efficacious exposure at 800 mg QD. BDTX-189 was rapidly absorbed, with a short elimination half-life of 1.3-4.4 hours, consistent with preclinical predictions. No apparent accumulation or change in exposure at steady state was observed….One confirmed partial response was observed in a patient who had previously responded and then progressed on poziotinib (at the data cut-off, 53% tumor regression observed and treatment with BDTX-189 ongoing 13+ weeks). One patient with stable disease and one patient with progressive disease were observed…The Company will initiate the safety expansion cohort ahead of the Phase 2 portion of the MasterKey-01 study, which remains on track for initiation in the second half of 2021.”

EGFR exon 20 • P1 data • Trial status • Oncology • Solid Tumor

Black Diamond Therapeutics to Host Webcast Presentation of Data From Phase 1 Dose-Escalation Portion of MasterKey-01 Clinical Trial (GlobeNewswire) - “Black Diamond Therapeutics, Inc…announced that it will host a webcast presentation on Wednesday, May 19, 2021 at 6:00 PM ET to discuss pharmacokinetic, safety, and preliminary efficacy data from the Phase 1 dose-escalation portion of the MasterKey-01 trial of BDTX-189 in patients with advanced solid tumors, which will also be presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place June 4-8, 2021.”

P1 data • Oncology • Solid Tumor

Black Diamond Therapeutics Reports First Quarter 2021 Financial Results and Provides Corporate Update (GlobeNewswire) - "Black Diamond continued to enroll and dose patients in the MasterKey-01 study, a Phase 1/2 clinical trial of BDTX-189...The Company is on track to complete the dose-escalation portion of the Phase 1 clinical trial in the first half of 2021...Initial Phase 1 clinical PK, safety, and preliminary efficacy data will be presented at the ASCO Annual Meeting....The Company is working toward selection of the recommended Phase 2 dose for BDTX-189 and plans to initiate the safety expansion cohort in the second quarter of 2021. The Phase 2 portion of the MasterKey-01 study is on track to begin in the second half of 2021."

Enrollment status • P1 data • Trial status • Oncology

"At ~$1B MC are $BDTX bulls expecting BDTX-189 data in EGFR(ex20ins) pts to be better than $CGEM at #ASCO21? CGEM ORR was 40% (10/25) in dose escalation, 40% had prior EGFRi, low grade 3 diarrhea and skin rash." (@BayAreaBiotechI)

Clinical • EGFR exon 20 • Dermatology • EGFR

Black Diamond Therapeutics to Present Phase 1 BDTX-189 Data in Advanced Solid Tumors at American Society of Clinical Oncology (GlobeNewswire) - "Black Diamond Therapeutics, Inc...announced that initial PK, safety, and preliminary efficacy data from the Phase 1 dose-escalation portion of the MasterKey-01 trial of BDTX-189 in patients with advanced solid tumors will be presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place June 4-8, 2021."

P1/2 data • Oncology • Solid Tumor