Black Diamond Therapeutics, Inc. announced the presentation of three posters reporting new preclinical data on BDTX-1535 and BDTX-4933 at the 34thEuropean Organisation for Research and Treatment of Cancer—National Cancer Institute—American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics being held in Barcelona, Spain. The poster presentations highlight new preclinical data demonstrating robust anti-tumor activity of both programs in a broad range of preclinical models of oncogene driven cancers. Black Diamond presented two posters highlighting preclinical data showcasing BDTX-1535's preclinical exposure and anti-tumor activity across patient derived xenograft and allograft models of both non-small cell lung cancer and glioblastoma multiforme.

BDTX-1535 is a CNS penetrant 4th generation irreversible EGFR MasterKey inhibitor targeting the family of classical, intrinsic and acquired resistance mutations expressed in NSCLC, and amplification and extracellular domain alterations expressed in GBM, while sparing WT EGFR. BDTX-1535 was designed using Black Diamond's proprietary MAP Drug Discovery Engine and targets the common, activated conformations used by oncogenic EGFR to drive tumor cell growth in GBM and NSCLC. The family of EGFR alterations expressed in GBM forms constitutively active homodimers, which exhibit paradoxical activation by a range of reversible ATP competitive inhibitors, but which are demonstrated to be effectively inhibited in vitro and in vivo by the irreversible EGFR MasterKey inhibitor, BDTX-1535.

BDTX-1535 is shown to be highly CNS penetrant and demonstrates robust anti-tumor activity as evidenced by growth regression and survival benefit across PDX and intracranial models expressing EGFR alterations and amplification. Real world data based on tumor DNA sequencing provides direct evidence that oncogenic alterations in EGFR, commonly expressed in GBM, are retained throughout current standard of care treatment. In a poster titled, “BDTX-1535 is a Fourth Generation MasterKey Inhibitor of a Broad Spectrum of Intrinsic and Acquired Resistance Mutations of EGFR Expressed in NSCLC,” Black Diamond outlined the significant unmet clinical need in NSCLC patients with acquired and intrinsic resistance EGFR mutations against 3rd generation EGFR tyrosine kinase inhibitors which is potentially addressed by BDTX-1535 targeting activated conformations of EGFR caused by these alterations.

Black Diamond highlighted that BDTX-1535 is designed using Black Diamond's proprietary MAP Drug Discovery Engine to target common activated EGFR conformations in NSCLC which result from multiple classical, intrinsic, and acquired oncogenic alterations including C797S, L718Q, G724S, and S768I mutations. Additional highlights include: BDTX-1535 potently inhibits multiple classical, intrinsic and acquired EGFR alterations observed in NSCLC patients that are resistant or inadequately addressed by 3rd generation EGFR TKIs. BDTX-1535 demonstrated potent anti-tumor activity and tumor growth regression in multiple mouse models expressing oncogenic EGFR alterations including coexisting EGFR mutations such as EGFR Exon19del + C797S that render osimertinib ineffective.

Black Diamond is currently evaluating BDTX-1535 in a Phase 1 study in GBM patients with EGFR alterations and NSCLC patients with EGFR resistance mutations, including de novo resistance and acquired resistance to 3rd generation EGFR TKIs. The Company expects to provide a clinical update on BDTX-1535 in 2023. Preclinical Data Demonstrate BDTX-4933's Ability to Achieve On-Target Inhibition of Oncogenic BRAF Class I/II/III Mutations: Black Diamond presented a poster highlighting Black Diamond's approach to characterizing, de-orphaning potentially oncogenic BRAF and MAPK pathway alterations, and grouping them into druggable oncogene families.

BDTX-4933 was designed using Black Diamond's proprietary MAP Drug Discovery Engine to target the common activated conformations of oncogenic RAF which result from a broad family of oncogenic Class I/II/III BRAF mutations and RAS pathway alterations. In a poster titled, “Preclinical efficacy of BDTX-4933, a brain penetrant MasterKey inhibitor targeting oncogenic BRAF Class I/II/III mutations,” Black Diamond highlighted that based on preclinical studies, BDTX-4933 is shown to be a CNS penetrant BRAF inhibitor active against tumors that are driven by a Class I/II/III BRAF mutation, as well as by other oncogenic RAS pathway alterations that promote constitutive RAF dimer activation, including NRAS alterations. Additional highlights include: BDTX-4933 is an active-site inhibitor that binds to both monomeric and dimeric forms of a mutant BRAF, achieving on-target inhibition of cell proliferation driven by a large family of oncogenic BRAF and MAPK pathway alterations including NRAS mutations.

BDTX-4933 demonstrated potent, on-target inhibition of the RAF-MEK-ERK signaling pathway and anti-tumor activity in multiple preclinical tumor models, including intracranial tumor models. In mouse xenograft and allograft studies, BDTX-4933 showed regression of tumors carrying BRAF Class I, II and III mutations. BDTX-4933 retained potent activity against BRAF V600E PDX cell lines that are resistant to dabrafenib and trametinib combination.

Black Diamond expects to submit an Investigational New Drug application for BDTX-4933 with the U.S. Food and Drug Administration in the first half of 2023.