On July 11, 2024 MEKanistic Therapeutics Inc., a biotechnology company pioneering the development of next-generation kinase inhibitors for cancer treatment, reported the peer-reviewed publication of new preclinical research on its lead candidate, MTX-531, an investigational dual-targeting therapy, in Nature Cancer (Press release, Mekanistic Therapeutics, JUL 11, 2024, View Source [SID1234644798]). MTX-531 is a potential first-in-class therapy uniquely designed to inhibit both EGFR (Epidermal Growth Factor Receptor) and PI3K (Phosphoinositide 3-kinase), two critical proteins involved in cancer cell survival and proliferation.

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"We are excited to share the positive MTX-531 preclinical research published in Nature Cancer, which we believe show promising signals toward a novel solution to addressing the root cause of resistance to current cancer treatments," said Danny Cunagin, chief executive officer, MEKanistic Therapeutics. "By targeting critical adaptive resistance mechanisms with a dual inhibition strategy, we aim to significantly halt cancer progression compared to single-target treatments, and look forward to advancing this innovative therapy to patients in clinical trials."

Key Findings of MTX-531 Study

High Potency, Selectivity Leading to First of Its Kind Tolerability

Preclinical studies demonstrated that MTX-531 exhibits nanomolar potency against both EGFR and PI3K (14.7 nM for EGFR, 6.44 nM for PI3K), with a high degree of selectivity as determined by broad kinome testing. In addition, MTX-531 did not cause hyperglycemia in mice at therapeutic doses, unlike other known pan-PI3K inhibitors, which have been reported to significantly increase blood glucose and insulin levels both in preclinical and clinical settings.

Judith Sebolt-Leopold, PhD, chief scientific officer, MEKanistic Therapeutics, commented, "MTX-531 is the first PI3K inhibitor capable of selectively co-targeting EGFR and the first known pan-PI3K inhibitor that does not induce hyperglycemia, a known challenge with PI3K inhibitors that often leads to treatment discontinuation. This unique feature, achieved through precise targeting enabled by MTX-531’s computational design, confers a favorable therapeutic index and resilience to adaptive resistance mechanisms not observed in prior PI3K inhibitor clinical programs."

Robust Tumor Suppression as Monotherapy and in Combination Therapy

MTX-531 monotherapy led to significant tumor regression in preclinical models of head and neck squamous cell carcinoma (HNSCC). Oral therapy effectively inhibited PI3K and EGFR signaling in a balanced fashion, achieving objective responses in every HNSCC model evaluated. Complete tumor regressions were observed across a broad dose range, with survival improvement ranging from 62% to >500% across models.

In addition, when combined with a MEK inhibitor (trametinib) or a KRAS inhibitor (sotorasib), treatment with MTX-531 more than doubled the incidence of tumor regressions achieving a 100% objective response rate in multiple KRAS mutant colorectal (CRC) and pancreatic tumor models.

Dr. Sebolt-Leopold added, "Our collective preclinical data show that MTX-531 effectively inhibits tumor growth in cancers with PIK3CA and KRAS mutations, which often lead to aggressive behavior and resistance to standard therapies. MTX-531 was well tolerated and outperformed the combination of drugs that individually target EGFR and PI3K. These findings highlight the versatility and broader potential of MTX-531 in treating hard-to-treat cancers."

The scientific paper can be accessed at the following link: View Source

About MTX-531 Development

Investigational new drug-enabling toxicology studies sponsored by the National Cancer Institute’s Experimental Therapeutics (NExT) Program are currently underway. The NExT Program aims to advance clinical practice by supporting promising new drug discovery and development projects. Through this program, MEKanistic Therapeutics collaborates with NCI staff and contractors on a milestone-driven project team to conduct these studies and assess MTX-531’s safety and efficacy in patients with cancer.

"Our partnership with the NCI is a testament to the promising potential of MTX-531," said Christopher Whitehead, PhD, co-founder and chief operating officer, MEKanistic Therapeutics. "With their support and our focused efforts on GMP manufacturing and drug product development, we are poised to make significant strides in bringing this innovative therapy closer to clinical trials and ultimately to patients in need."

On July 11, 2024 Senhwa Biosciences, Inc. (TPEx: 6492), reported IND Submission to US FDA for the Phase I/II study of Silmitasertib (CX-4945) in combination with chemotherapy in children and young adults with relapsed refractory solid tumors (Press release, Senhwa Biosciences, JUL 11, 2024, View Source [SID1234644797]). This investigator-initiated trial (IIT) will be conducted by the Penn State Health Children’s Hospital and the prestigious Beat Childhood Cancer Research Consortium, a group of over 50 universities and children’s hospitals, based at Penn State College of Medicine in Hershey, Pa., that offers a worldwide network of pediatric cancer clinical trials. The funding is sponsored by the Four Diamonds Foundation, with Senhwa Biosciences providing the investigational drug, Silmitasertib (CX-4945).

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The clinical trial is conducted in two phases: the first phase focuses on establishing the safety and dosage of Silmitasertib (CX-4945) in pediatric patients with relapsed or refractory solid tumors, while the second phase evaluates its efficacy and potential as a novel treatment option.

As high CK2 activity is noted across several pediatric cancers, including neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, medulloblastoma, and liposarcoma. Recent study has shown that CK2 is one of the key kinases that is essential for maintaining the stabilization of MYCN protein, the oncogenic driver in neuroblastoma. In view of the anti-tumor activity of CK2 inhibitor, the Beat Childhood Cancer Research Consortium at The Pennsylvania State University regards Silmitasertib (CX-4945) high therapeutic potential of treating pediatric cancers.

Neuroblastoma is the most common type of solid malignant tumor in children, aside from brain tumors and lymphomas. Over 90% of cases are diagnosed before the age of 5. 70% of patients already have metastatic disease by the time symptoms appear, and the 20-year survival rate is only around 30%. In the US, there are 700-800 new cases each year, accounting for about 6% of childhood cancers, meeting the definition of a rare disease.

Senhwa Biosciences is planning to apply for Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation (RPD) for Silmitasertib (CX-4945) for the treatment of neuroblastoma. If these designations are granted and the drug is successfully commercialized, the company would obtain a Priority Review Voucher (PRV). The holder of a PRV can designate any future human drug application to receive priority review, potentially shortening the review time to 6 months, which could accelerate the timeline for the company (or its partners) to bring other products to market.

The clinical trial design also includes Ewing’s sarcoma and osteosarcoma, which are common pediatric bone cancers with poor prognoses, representing unmet medical needs.

On July 11, 2024 Dynamic Cell Therapies (DCT) reported an investment of $1M from the Myeloma Investment Fund (MIF), the venture philanthropy subsidiary of the Multiple Myeloma Research Foundation (MMRF), to accelerate the development of novel CAR-T cell technologies for patients with multiple myeloma (Press release, Dynamic Cell Therapies, JUL 11, 2024, View Source [SID1234644796]). DCT is developing technology platforms that will allow CAR-T cells to attack unique and differentiated tumor targets that will allow for durable responses to treatment, and DCT’s proprietary CAR-T cells have demonstrated superiority to FDA-approved CAR-T cells in animal models. These technology platforms will improve the safety and efficacy of CAR-T cell therapies and have immediate application for patients with hematological cancers, including multiple myeloma. Supported by this recent investment, DCT is on track to advance a product into patients within the next two years.

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"Despite current successes in treating patients with CAR-T cells, many patients with multiple myeloma still relapse after therapy," said Fred Mermelstein, Ph.D., Chief Executive Officer of DCT. "The support of the MMRF & the Myeloma Investment Fund provides key expertise that will enable us to hasten the development of novel and best-in-class CAR-T cell therapies for patients with relapsed and refractory multiple myeloma."

"At the MMRF, we are deeply committed to advancing novel treatments intended to improve patient outcomes and get us closer to cures. We are energized by DCT’s cutting-edge cell therapy approach as a potentially transformative answer to patients with relapsed or refractory myeloma," said Michael Andreini, President and CEO of the Multiple Myeloma Research Foundation (MMRF).

On July 11, 2024 IDEAYA Biosciences, Inc. (Nasdaq: IDYA) reported the closing of its underwritten public offering of 8,355,714 shares of its common stock at a public offering price of $35.00 per share, before underwriting discounts and commissions, and pre-funded warrants to purchase 285,715 shares of common stock at a public offering price of $34.9999 per pre-funded warrant, before underwriting discounts and commissions (Press release, Ideaya Biosciences, JUL 11, 2024, View Source [SID1234644795]). This includes the exercise in full by the underwriters of their option to purchase up to an additional 1,127,142 shares of common stock in the offering. The gross proceeds from the offering, before deducting underwriting discounts and commissions and other offering expenses payable by IDEAYA, were approximately $302.4 million.

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J.P. Morgan, Goldman Sachs & Co. LLC, Jefferies and RBC Capital Markets acted as joint book-running managers for the offering.

The public offering was made by IDEAYA pursuant to an automatically effective shelf registration statement on Form S-3 that was previously filed with the U.S. Securities and Exchange Commission, or the SEC. The offering was made only by means of a written prospectus and prospectus supplement that form a part of the registration statement. A final prospectus supplement and accompanying prospectus relating to the offering has been filed with the SEC and is available on the SEC’s website at View Source Copies of the final prospectus supplement and the accompanying prospectus relating to the offering may also be obtained by request from: J.P. Morgan, by mail at J.P. Morgan Securities LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at 866-803-9204, or by email at [email protected]; Goldman Sachs & Co. LLC by mail at Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, or by telephone at 866-471-2526, or by email at [email protected]; Jefferies, by mail at Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, New York, NY 10022, or by telephone at 877-547-6340 or 877-821-7388, or by email at [email protected]; or RBC Capital Markets, by mail at RBC Capital Markets, LLC, Attention: Equity Capital Markets, 200 Vesey Street, 8th Floor, New York, NY 10281, or by telephone at 877-822-4089, or by email at [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

On July 11, 2024 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, reported the publication of a peer-reviewed research paper in Cancer Discovery (Press release, Revolution Medicines, JUL 11, 2024, View Source [SID1234644794]). The scientific paper demonstrates that the RAS(ON) multi-selective inhibitor RMC-7977 (a preclinical tool compound representative of the investigational drug candidate RMC-6236) exhibited robust and durable anti-tumor activity in multiple preclinical models of KRAS-mutated NSCLC. The data show this activity was further enhanced in the doublet combination with a RAS(ON) G12C-selective inhibitor RMC-4998 (a preclinical tool compound representative of the investigational drug RMC-6291), in preclinical models of KRAS G12C-mutated NSCLC. These findings are the result of original, collaborative research between scientists at Revolution Medicines and The University of Texas MD Anderson Cancer Center.

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Oncogenic RAS proteins drive up to 30 percent of all human cancers, most notably NSCLC, pancreatic ductal adenocarcinoma and colorectal cancer. RAS G12 mutations, such as G12D, G12V and G12C, predominate in these RAS-addicted cancers. Approved RAS-targeted cancer therapies target only one RAS mutation, KRAS G12C, which is present in approximately 13 percent of NSCLC. There remains a large unmet medical need for improved clinical outcomes with KRAS G12C-selective inhibitors and for extending therapy options to patients harboring KRAS non-G12C-driven tumors.

The paper highlights that direct RAS inhibition with a RAS(ON) multi-selective inhibitor monotherapy, alone or in combination with a RAS(ON) G12C-selective inhibitor, elicited rapid, deep and sustained tumor regressions and significantly prolonged time to tumor doubling in preclinical models of refractory KRAS G12C-mutated NSCLC. The combination dramatically improved anti-tumor activity as compared to RAS(ON) multi-selective inhibitor monotherapy and elicited cures (defined as recurrence free survival following treatment withdrawal) in all of the preclinical models bearing alterations in genes associated with the subsets of KRAS G12C-mutated NSCLC (e.g. KEAP1 and SMARCA4). The RAS(ON) multi-selective inhibitor overcame acquired resistance to RAS(OFF) and RAS(ON) G12C-selective inhibitors in these models of advanced KRAS G12C-mutated NSCLC, further underscoring the robust activity of this inhibitor.

The paper also unveils a conserved mucinous regenerative program, apparent upon treatment cessation, that may support long-term tumor cell persistence in the context of sustained RAS pathway inhibition. Characterization of this emergent population of persister cells, a rare slow cycling group of cancer cells that may endure despite ongoing inhibitor treatment, provides insights into potential therapeutic strategies that could prevent them from driving recurrent tumor growth.

"RAS-addicted cancers are widely known for being resistant to current cancer therapies and recent studies have highlighted mechanisms of clinical resistance to RAS(OFF) G12C-inhibitors. We evaluated the anti-tumor activity of a broad spectrum RAS(ON) multi-selective inhibitor alone and in combination with a RAS(ON) G12C mutant-selective inhibitor in models of clinically challenging subsets of KRAS G12C-mutated NSCLC. Given the novel mechanism of action of these inhibitors, directly targeting oncogenic RAS, a key question was whether primary, adaptive or acquired resistance mechanisms would emerge following treatment," said Jan Smith, Ph.D., Chief Scientific Officer of Revolution Medicines. "These encouraging preclinical data provide a strong rationale for our ongoing combination study of RMC-6236 as a doublet with RMC-6291 in patients with advanced KRAS G12C-mutated cancers."

The investigational oral drug RMC-6236 is a RAS(ON) multi-selective inhibitor designed to treat patients with cancers driven by a wide range of common RAS mutations. Revolution Medicines is currently evaluating RMC-6236 as monotherapy in a Phase 1/1b trial in patients with advanced solid tumors harboring G12X, G13X and Q61X mutations (NCT05379985). Following promising preliminary data in this Phase 1/1b study, planning is underway to initiate pivotal studies of RMC-6236 as monotherapy in PDAC and NSCLC. RMC-6236 is also being evaluated in combination with pembrolizumab with or without chemotherapy in patients with advanced RAS-mutated solid tumors (NCT06162221) and in combination with RMC-6291, the company’s investigational RAS(ON) G12C-selective inhibitor, for patients with advanced KRAS G12C-mutated solid tumors (NCT06128551).

The publication, entitled, "Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant NSCLC," is available online at:
View Source