dcaf7
1 month ago
The prevalence of non-classical EGFR mutations is approximately four times higher than that of EGFR Exon 20 insertions.
On Monday, Wedbush, a financial services firm, increased its price target for Black Diamond Therapeutics (NASDAQ:BDTX) shares to $16.00, rising from the previous target of $10.00. The firm has maintained an Outperform rating on the stock.
This adjustment follows Black Diamond's presentation at the American Association for Cancer Research (AACR) which highlighted the potential market for its drug candidate BDTX-1535 in the treatment of non-classical EGFR mutations and osimertinib-resistance mutations in non-small cell lung cancer (NSCLC).
According to the analysis presented by Black Diamond, non-classical EGFR mutations are highly prevalent, found in 22-30% of first-line treatment-naรฏve EGFR-mutated NSCLC cases. This prevalence is approximately four times higher than that of EGFR Exon 20 insertions. The firm noted that patients with these non-classical mutations often have a poor response to existing EGFR inhibitors.
Additionally, the mutations, along with C797S, represent a significant mechanism of resistance to current EGFR inhibitors. Wedbush believes that BDTX-1535 could be a leading therapy for patients with non-classical and C797S mutations. The firm sees promising development opportunities for the drug in various treatment settings, including post-adjuvant, first-line (1L), and second-line (2L) post-osimertinib.
Black Diamond Therapeutics has recently begun a Phase 2 cohort study of BDTX-1535 in a first-line treatment setting following feedback from the FDA, with initial data expected in 2025.
The company is also anticipating Phase 2 data from second and third-line (2L/3L) cohorts for patients with C797S and/or non-classical mutations, and non-classical mutations alone, which are expected to be released in the third quarter of 2024.
https://www.investing.com/news/company-news/wedbush-raises-black-diamond-stock-target-on-drug-potential-93CH-3369858
dcaf7
2 months ago
So far, I like what I see. 1535 has a nice PK profile and it definitely has activity for non-classical mutations and C797S. Therefore, it potentially has a place in the market for post Osimertinib patients. First line non-classical also looks reasonably promising. I am not sure about GBM. Their โWindow of Opportunityโ trial is unusual by design. I've never heard of other drugs being tested that way, but I guess it is the only way to get a clear answer. Weโll see the data at ASCO. If positive, the company will be in a unique position to address unmet medical needs of patients with EGFR mutated GBM. Cannot say much about their second drug, BDTX-4933. Pre-clinical data looks good, but I wonโt speculate on drug activity until I see at least early clinical data.
FACT-MASTER
7 months ago
Thanks dc,
I'm not sure if David resigned though, it sounded more to me that he was removed by the BOD.
Could it be possible that the BOD ousted Epstein on account of finding out about his relationship with PairX?.. and to the extent of licensing ip!!
https://www.pairxbio.com/post/duke-nus-spinout-pairx-bio-launches-with-strong-biotech-credentials-venture-capital-backing
"โI am delighted that Duke-NUS, Esco Ventures, Avendesora and the PairX founding team are partnering to commercialise our platform and pipeline of novel cancer antigenโT cell pairs. This seed financing uniquely positions PairX to advance precision immunotherapies designed to treat cancer patients defined by shared mRNA splicing defects,โ
- Adj Assoc Prof Epstein
Theory: BOD saw this
https://www.biospectrumasia.com/news/54/16545/pairx-bio-launches-venture-capital-backing-targeting-cancer-immunotherapies.html
contacted David - "your fired".
(imo though, PairX is cutting edge in the TCR-T category and Epstein sees the future of this)
dcaf7
8 months ago
Titles of BDTX presentations at triple meeting:
1. Oral presentation, Oct 8, 2023, "BDTX-1535, a CNS penetrant MasterKey inhibitor of common, uncommon and resistant EGFR mutations, demonstrates in vivo efficacy and has potential to treat osimertinib-resistant NSCLC with or without brain metastases".
2. Poster, "Pre-clinical evaluation of next-generation inhibitor targeting a wide spectrum of oncogenic BRAF dimers".
3. Poster, "Discovery and characterization of selective, FGFR1 sparing, inhibitors of FGFR2/3 oncogenic mutations for the treatment of cancers".
FACT-MASTER
8 months ago
Thank you for explaining that very well.
Today's BDTX news appears to confirm what you outlined .
https://www.stocktitan.net/news/BDTX/black-diamond-therapeutics-announces-first-patients-dosed-in-phase-1-is334cticxtl.html
September 11, 2023 - 8:00 am
Company to present BDTX-1535 dose escalation data in NSCLC at the AACR-NCI-EORTC Conference in October 2023
CAMBRIDGE, Mass. and NEW YORK, Sept. 11, 2023 (GLOBE NEWSWIRE) -- Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage precision oncology company developing therapies that target families of oncogenic mutations in patients with genetically defined cancers, today announced the first patients dosed in mutation matched expansion cohorts of non-small cell lung cancer (NSCLC) in the ongoing Phase 1 clinical study evaluating BDTX-1535.
BDTX-1535, a fourth-generation, brain-penetrant epidermal growth factor receptor (EGFR) MasterKey tyrosine kinase inhibitor (TKI), is under investigation for the treatment of NSCLC harboring intrinsic driver and/or acquired resistance (post-osimertinib) EGFR mutations and glioblastoma multiforme (GBM) with multiple EGFR alterations. The BDTX-1535 expansion cohort portion of the study will assess single-agent objective response rate (ORR) in a second- or third-line setting in NSCLC patients with EGFR intrinsic driver and/or acquired resistance mutations, who have received prior treatment with approved EGFR TKI.
The dosing of the first patients in the expansion cohorts follows the Companyโs initial data readout from the dose escalation portion of the BDTX-1535 Phase 1 clinical study, which demonstrated clinical proof of activity through radiographic responses in NSCLC patients harboring diverse types of EGFR mutations including intrinsic driver and post-osimertinib acquired resistance EGFR mutations.
โThe Phase 1 expansion cohorts will assess objective response rate and durability of response in NSCLC patients whose disease has progressed after prior EGFR inhibitor therapy, including prior osimertinib, and who have evidence of a variety of EGFR driver or resistance mutations that are targeted by BDTX-1535,โ said Sergey Yurasov, M.D., Ph.D., Chief Medical Officer of Black Diamond Therapeutics. โIn conjunction with establishing an optimal dose for a future pivotal study, these efficacy data will be essential for establishing a regulatory pathway for BDTX-1535. Despite significant recent advances in treating lung cancer, there is a large unmet medical need for a targeted therapy for these EGFR mutation-positive NSCLC patients, for whom chemotherapy is still the most common treatment option.โ
โDosing of the first patients in the BDTX-1535 dose expansion cohorts represents an important step towards offering an oral therapeutic with manageable side effects as a potential alternative to chemotherapy-based regimens following progression on osimertinib for patients with treatment-resistant lung cancer,โ said David Epstein, Ph.D., President and Chief Executive Officer of Black Diamond Therapeutics. โThe population of EGFR mutation-positive NSCLC is genetically heterogeneous โ which has presented challenges in the development of effective therapies. BDTX-1535 was designed to disrupt the limited existing treatment paradigm by addressing real-world patterns of patient-specific EGFR mutations, and we remain focused on the rapid advancement of this novel MasterKey inhibitor.โ
The discovery and development of BDTX-1535 was informed by the Companyโs powerful Mutation-Allostery-Pharmacology (MAP) drug discovery engine, which leverages critical genomic profiling to expand the addressable patient population by targeting families of mutations with a single drug. Emergence of intrinsic driver and acquired resistance EGFR mutations to osimertinib represents a significant unmet need for patients with EGFR-mutant lung cancer. Thirteen percent of patients in the U.S. with EGFR mutation-positive NSCLC show presence of intrinsic driver mutations, which are associated with worse clinical outcomes when treated with currently approved EGFR TKIs. Fifteen percent of patients in the U.S. whose disease has progressed after osimertinib therapy show evidence of acquired resistance EGFR mutations (e.g., C797S) for which currently there is no approved EGFR TKI.
The Company is advancing BDTX-1535 as a potential targeted therapy option for patients with this broad spectrum of EGFR mutations in second-line NSCLC, and plans to investigate safety and efficacy in a first-line setting in NSCLC patients with intrinsic driver EGFR mutations after discussion with the U.S. Food and Drug Administration (FDA).
BDTX-1535 Phase 1 Clinical Study Design
The Phase 1 first-in-human, open-label clinical trial of BDTX-1535 (NCT05256290) consists of a dose escalation portion that evaluated the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of BDTX-1535 followed by dose expansion cohorts. The trial is evaluating BDTX-1535 in patients with advanced/metastatic NSCLC harboring EGFR mutations with or without central nervous system (CNS) disease, or with recurrent GBM expressing EGFR alterations. The Phase 1 dose escalation portion of the study in NSCLC and GBM patients has been completed and the study is now progressing to evaluate BDTX-1535 as a single agent, second-line or third-line therapy in two cohorts of EGFR mutation-positive NSCLC patients with progressive disease after prior therapy with EGFR TKI (e.g., osimertinib) to assess ORR, CNS ORR, duration of response, and progression-free survival and further evaluate safety, tolerability and PK:
Second- or third-line NSCLC patients with acquired EGFR resistance mutations +/- CNS metastasis; and
Second- or third-line NSCLC patients with EGFR intrinsic driver mutations +/- CNS metastasis.
About Black Diamond Therapeutics
Black Diamond Therapeutics is a clinical-stage precision oncology medicine company focused on the development of therapies that target families of oncogenic mutations in clinically validated targets. Black Diamond leverages a deep understanding of cancer genetics and onco-protein structure and function, to discover and develop innovative therapies. The Companyโs MasterKey therapies are designed to overcome resistance, minimize on-target, wild-type mediated toxicities, and be brain-penetrant to address significant unmet medical needs of patients with genetically defined cancers. The Company is advancing a robust pipeline with lead clinical-stage program BDTX-1535, targeting MasterKey mutations in both EGFR mutant-positive NSCLC and in GBM, and BDTX-4933, a program targeting RAF MasterKey mutations in solid tumors. For more information, please visit www.blackdiamondtherapeutics.com.
dcaf7
10 months ago
It is not easy to follow an evolving story of EGFR mutations in NSCLC and other cancers. Most common are mutations called the exon 19 deletions and exon 21 L858R mutation. Other mutations including exon 20 insertion mutations are less common. To treat patients with most common mutations, two drugs, Iressa and Tarceva were developed. BTW, David Epstein and Elizabeth Buck, were involved in the development of Tarceva. They know this field. Patients treated with Iressa or Tarceva sooner or later progress. One of the reasons for disease progression is the emergence of an additional mutation, called a resistant mutation, T790M. Tarceva or Iressa are ineffective against T790M. AstraZeneca found the way to overcome this resistance by inventing Osimertinib (Tagrisso). It turned out to be such a great drug that oncologists started using it as a first line treatment instead of chemotherapy, Iressa or Tarceva. Osimertinib is less toxic and more effective. And as David Epstein mentioned, patients treated with Osimertinib never develop T790M mutation. However, after some years on Osimertinib, patients become resistant to this drug as well. Why? Because new mutations emerge. Some of them are in EGFR again, some are in other proteins. Most common mutation in EGFR causing resistance to Osmertinib, is C797S. In addition, several less common Osimertinib resistance mutations were identified. To make EGFR mutation landscape more complicated, these Osimertinib resistance mutations can co-exist with other so-called intrinsic mutations. Now, how BDTX-1535 can help? It can block activation of EGFR caused by Osimertinib-resistant mutations and EGFR intrinsic mutations. Possibly it doesnโt work so good against T780M, but after Osimertinib you donโt have it. In GBM, EGFR mutations are different and one of the reasons why Osimertinib doesnโt work in GBM could be low brain penetrance.