On January 4, 2024 OnKure, Inc. reported that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application of OKI-219, a potential best-in-class, mutant selective PI3Ka H1047R inhibitor, for clinical evaluation (Press release, OnKure, JAN 4, 2024, View Source [SID1234638979]). H1047R is the most common mutation in PI3Ka, being found in 15% of breast cancer and 4% of cancers overall.

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There is a significant need for improved therapies targeting PI3Kα with safer and more effective drugs. OKI-219 is a highly selective inhibitor of PI3Ka H1047R, with over 100-fold selectivity for the wild-type enzyme, potentially sparing on-target toxicities that arise from inhibition of the wild-type form of the protein in normal tissues. OKI-219 shows strong, single-agent activity, including regressions at low doses in multiple PI3Ka H1047R xenograft models that are heterozygous for PI3Ka H1047R, the most common profile seen clinically for this mutation, and supporting the potential activity of highly mutant-selective inhibitors. Notably, in preclinical models, OKI-219 shows no evidence of toxicities related to PI3Ka wild-type inhibition as measured by markers of hyperglycemia, even at doses that are >15x higher than minimally active doses for antitumor activity.

Mutational activation of PI3Kα is associated with lower activity of both estrogen receptor (ER)-targeted and HER2-targeted agents in breast cancer. OKI-219 shows synergistic activity in combination with selective estrogen receptor degraders (SERDs), overcoming SERD resistance and driving strong regressions. Similarly, the combination of OKI-219 + tucatinib drives strong regressions in models of HER2+/ PI3Ka H1047R breast cancer that are resistant to HER2- inhibitors.

OnKure plans to initiate a first-in-human clinical trial, OKI-219-101 (PIKture-01), in the first quarter of 2024 that will include a dose escalation in patients with advanced solid tumors harboring the PI3Ka H1047R mutation. Subsequent evaluation of OKI-219 in combination with the SERD fulvestrant in ER+/ PI3Ka H1047R advanced breast cancer, and with the HER2-monoclonal antibody trastuzumab in HER2+/ PI3Ka H1047R advanced breast cancers will follow.

About PI3Ka and OKI-219

PI3Ka is the most frequently mutated oncogene in cancers, and PI3Ka H1047R is the most common mutation in this gene, being found in 15% of breast cancer and 4% of cancers overall. While novel drugs targeting PI3Ka have been approved, the lack of mutant selectivity of these therapeutics drives considerable on-target toxicity by inhibiting the normal version of this protein in various tissues. To address this challenge, OnKure is discovering and developing a platform of highly mutant-selective PI3Ka inhibitors with the goal of improving efficacy and safety with molecules that fully inhibit the mutant oncogene while sparing the wild-type enzyme in normal tissues. OKI-219 is a potential best-in-class, orally bioavailable, highly selective inhibitor of PI3Ka H1047R with over 100-fold selectivity for the mutated form of the enzyme compared to wild-type. OnKure believes that the wild-type sparing properties of OKI-219 should significantly improve the activity and safety relative to currently approved agents. OKI-219 is currently in Phase 1 of clinical development in solid tumor patients with PI3Ka H1047R mutations.

On January 4, 2024 Avistone Biotechnology Co., Ltd. (also referred to as Avistone Biotechnology or Avistone), an innovative biotechnology company focused on precision oncology therapeutics, reported that they had recently completed their Series B financing of 1 billion Chinese yuan (~$140 million USD) (Press release, Avistone Pharmaceuticals, JAN 4, 2024, View Source [SID1234638997]). The Series B financing was jointly led by SDIC CS Capital and IDG Capital, with participation from Yanchuang Capital and Cathay Capital. Existing shareholder Bain Capital continues to make additional investments.

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This round of financing will be used to support clinical research and development of the Avistone pipeline, including both drug monotherapy studies and internal combinations; to accelerate the screening of new molecules; to support clinical studies and expansion in the United States of America; and to support commercialization of PLB1001 (Vebreltinib) in China. In China, Avistone has established a commercial sales and marketing team covering 25 provinces, nearly 1,000 hospitals, and hundreds of commercial companies and retail outlets.

Dr. Hepeng Shi, founder, chairman and CEO of Avistone Biotechnology, said: "We thank our Series B investors for trusting and investing in Avistone. This very important financing will support the commercialization of our recently approved molecule, PLB1001 (Vebreltinib), in MET Exon 14 Skipping Non-Small Cell Lung Cancer (NSCLC) and will provide funding for our pipeline. We will continue to pursue our vision to become a leading biotechnology company with a deep pipeline and focus on innovation. We aspire to be highly trusted by the patients and families that we serve along with the physicians, practitioners, and scientists that we work with."

SDIC states: "We are pleased to lead the B-round financing for Avistone. The Company has demonstrated impressive execution capabilities and has led effective translational medical work. We firmly believe that the company will continue to produce more clinically advanced innovative products in the future. We are committed to collaborating closely with the Avistone team to foster the company’s growth, ultimately benefiting patients and contributing to the advancement of China’s innovative pharmaceutical industry."

IDG Capital noted that, "We believe that the demand for better products is a prevailing trend in the biopharmaceutical industry, and Avistone has consistently aimed for and practiced this goal. Dr. Shi’s team swiftly achieved breakthroughs from 0 to 1 in product development, showcasing strong execution and product layout capabilities. Additionally, we have high expectations for Avistone’s outstanding commercialization capabilities. We believe that in the future, Avistone can achieve more innovative breakthroughs, and IDG Capital is committed to ongoing support, contributing to the advancement of the innovative pharmaceutical industry alongside Avistone."

Jonathan Zhu, Partner and Co-Head of Asia Private Equity at Bain Capital, expressed that "We are delighted to witness Avistone’s breakthroughs in targeted oncology drug development, positioning itself as a leading domestic innovative pharmaceutical enterprise with successful ventures into Class 1 innovative drugs. We have observed the growth and development of Avistone and have strong confidence in the company’s research and development capabilities, execution efficiency, and pipeline layout strategy. Our continued investment in Avistone underscores our belief in Dr. Shi’s leadership and his team’s ability to efficiently develop groundbreaking innovative biopharmaceuticals. This establishes them as a pioneering platform for tumor-targeted drug innovation rooted in China and globally oriented."

On January 4, 2024 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with genetically defined cancers, reported a corporate update outlining clinical development plans and anticipated corporate milestones for 2024 (Press release, Black Diamond Therapeutics, JAN 4, 2024, View Source [SID1234638964]).

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"We made significant progress in 2023 and sharpened our focus on our clinical programs: BDTX-1535 in both EGFR mutant NSCLC and GBM, and BDTX-4933 in KRAS mutant NSCLC," said Mark Velleca, M.D., Ph.D., Chief Executive Officer of Black Diamond Therapeutics. "In 2024, we anticipate key readouts from each of these programs, including Phase 2 data from BDTX-1535 in NSCLC. Moreover, recent FDA feedback enables the enrollment of first-line NSCLC patients into the Phase 2 trial, reflecting the potential of BDTX-1535 to benefit patients in earlier lines of therapy. Due to disciplined spend, we expect our cash to be sufficient for this year’s milestones and to extend into the second quarter of 2025."

Clinical Program Updates/Anticipated 2024 Milestones

BDTX-1535 in patients with Epidermal Growth Factor Receptor (EGFR) mutant Non-Small Cell Lung Cancer (NSCLC)

Dose escalation results were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in October 2023. Phase 2 data in second/third-line patients with EGFR mutant NSCLC are expected in the third quarter of 2024. The Company intends to discuss Phase 2 results with the U.S. Food and Drug Administration (FDA) to finalize a pivotal clinical trial design.
BDTX-1535 received Fast Track Designation for the treatment of patients with EGFR mutant C797S-positive NSCLC whose disease has progressed on/after a third-generation EGFR tyrosine kinase inhibitor (TKI).
Following End of Phase 1 feedback received from the FDA in the fourth quarter of 2023, a Phase 2 cohort in first-line patients with non-classical EGFR mutant NSCLC is being initiated.
The Company is also exploring the potential development of BDTX-1535 in first-line patients who are post-osimertinib adjuvant treatment.
BDTX-1535 in patients with EGFR mutant Glioblastoma (GBM)

Following release of top-line Phase 1 data in December 2023, presentation of Phase 1 trial results is anticipated at a medical meeting in the second quarter of 2024.
Enrollment is ongoing in a "window of opportunity" trial sponsored by the Ivy Brain Tumor Center in patients with recurrent glioma who are undergoing a planned resection. Results from this trial are expected to be presented at a medical meeting in the second quarter of 2024.
The Company expects that results from the dose escalation and "window of opportunity" trials will inform the next steps in the GBM development program, including a potential randomized trial in the first-line setting.
BDTX-4933 in patients with KRAS mutant NSCLC

BDTX-4933 was designed as a "RAF/RAS clamp" to target the activated RAF conformation in the context of either RAF or RAS mutations, a mechanism distinct from earlier generation RAF inhibitors.
Enrollment in a Phase 1 trial began in September 2023 in patients with KRAS mutant NSCLC. Results from this trial are anticipated in the fourth quarter of 2024.
About BDTX-1535
BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), including classical driver mutations, families of non-classical driver mutations (e.g., L747P, L718Q), acquired resistance C797S mutation, and complex mutations. BDTX-1535 is a fourth-generation tyrosine kinase inhibitor (TKI) that potently inhibits, based on preclinical data, more than 50 oncogenic EGFR mutations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. A "window of opportunity" trial of BDTX-1535 in patients with GBM is ongoing (NCT06072586) and a Phase 2 trial is currently ongoing in patients with NSCLC (NCT05256290).

About BDTX-4933
BDTX-4933 is an oral, brain-penetrant RAF MasterKey inhibitor designed to target oncogenic alterations in KRAS, NRAS and BRAF, while also avoiding paradoxical activation. In preclinical studies, BDTX-4933 has demonstrated a potential best-in-class profile, showing potent target engagement, inhibition of MAPK signaling and strong anti-tumor activity/tumor regression across tumor models driven by either KRAS, NRAS or BRAF mutations. BDTX-4933 also exhibits high central nervous system (CNS) exposure leading to dose-dependent tumor growth inhibition and a survival benefit in an intracranial tumor model harboring oncogenic BRAF mutation. The ongoing BDTX-4933 Phase 1 clinical trial is currently in dose escalation with emphasis on KRAS mutant NSCLC patients (NCT05786924).

On January 4, 2024 Portage Biotech Inc. (NASDAQ: PRTG), a clinical-stage immuno-oncology company advancing novel multi-targeted therapies for use as monotherapy and in combination, reported the outcome from the company’s comprehensive review of its pipeline in the context of the current capital raising market conditions (Press release, Portage Biotech, JAN 4, 2024, View Source [SID1234638980]).

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The ADPORT-201 adaptive Phase 1a/1b clinical trial of PORT-6 (adenosine 2A inhibitor) and PORT-7 (adenosine 2B inhibitor) has been progressing well with strong interest from our eight academic centers in the US. The phase 1a dose escalation portion of the trial is enrolling quickly and there have been no safety signals of concern at the doses evaluated to date. The company looks forward to presenting data from this portion of the trial at a conference later this year. We are also excited about future development with these candidates including combining our potential best-in-class adenosine 2A and adenosine 2B inhibitors at the optimum biologic doses in a biomarker enriched population and collaborating with Merck to study combinations with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy.

After a review of Portage’s funding requirements, the Board of Directors has made the difficult decision to pause further drug development in the PORT-2 iNKT program. "This was a difficult decision considering the promising phase 1 safety and translational data from the non-small cell lung and melanoma trial," said Dr Ian B. Walters, chairman and CEO, "As a result, the company will evaluate a range of potential strategic options which may include among other things, finding a partner for our iNKT program or other corporate transactions." Portage does not intend to disclose developments with respect to this evaluation unless and until it determines that further disclosure is appropriate or necessary.

In connection with these developments and to extend its cash runway, Portage is implementing a cost-savings plan that includes a reduction in internal and contracted workforce, with remaining employees focusing primarily on pursuing the adenosine clinical programs.

"I want to express my sincere gratitude to our investigators and collaborators for their drug development efforts on our iNKT program, as well as the patients who participated in the trials. There is still much to learn about how to develop therapeutics for this target," remarked Dr. Walters.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

On January 4, 2024 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science to develop a new generation of small-molecule medicines and transform how disease is treated, reported the closing of the previously announced $25 million stock purchase agreement with a wholly-owned subsidiary of Betta Pharmaceuticals Co. Ltd (Betta) (300558.SZ), a leading pharmaceutical company focusing on the development of innovative oncology therapies in China (Press release, C4 Therapeutics, JAN 4, 2024, View Source [SID1234638965]). This investment was completed at $4.49 per share. The purchase price represents a 25% premium over the 60-trading-day volume weighted average through the date that was two business days prior to the entry into the stock purchase agreement on May 29, 2023.

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