On June 6, 2024 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers (mBC), reported that China’s National Medical Products Administration (NMPA) approved the investigational new drug application (IND) for oral lasofoxifene (HLX78 in China) submitted with the assistance of Chinese development partner Shanghai Henlius Biotech, Inc. (2696.HK) (Press release, Sermonix Pharmaceuticals, JUN 6, 2024, View Source [SID1234644226]).

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The IND approval allows Henlius to join the ongoing global registrational ELAINE-3 trial with responsibility in China. ELAINE-3 (NCT05696626), the third Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) trial, is assessing the efficacy of oral lasofoxifene and Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib (Verzenio) compared to fulvestrant and abemaciclib in 400 pre- and post-menopausal subjects with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation.

This month, Henlius expanded its license from Sermonix to add additional Asia territories for upfront, milestone and royalty payments. The agreement also allows Henlius to share with Sermonix expedited co-development of oral lasofoxifene in Japan. Sermonix has completed a Phase 1 Japanese PK study and, together with Henlius, will begin engagement with the Pharmaceuticals and Medical Devices Agency (PMDA) to address a regulatory path to study lasofoxifene in Japan, which is an important region for expanded global access to lasofoxifene investigation.

"With active ELAINE-3 enrollment already underway in the U.S., Canada, EU and Israel, we are pleased to announce that Henlius, our Chinese development partner for oral lasofoxifene, received approval for its investigational new drug application," said Dr. David Portman, Sermonix founder and chief executive officer. "This milestone clears Henlius to enroll patients in ELAINE-3 in China, therefore further diversifying our patient population and potentially helping more people to better confront this terrible disease."

"The collaboration between Henlius and Sermonix started in January 2024," said Ms. Ping Cao, Henlius chief business development officer and SVP of business development. "In mere months from agreement to amendment, our unified dedication shines, turning swift collaboration and full-hearted implementation into tangible success – as underscored by our product’s IND approval in China."

Oral lasofoxifene is an investigational novel targeted endocrine therapy in clinical development that has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations.

In two completed Phase 2 clinical studies (ELAINE-1 and ELAINE-2), lasofoxifene demonstrated anti-tumor activity against tumors with ESR1 mutations as a monotherapy and in combination with abemaciclib, a CDK4/6 inhibitor. Lasofoxifene’s bioavailability and potent activity in mutations of the estrogen receptor, in addition to its potential to improve sexual and urogenital health with a well-tolerated profile, could hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, and, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

Breast cancer is the second most diagnosed cancer in the world, according to GLOBOCAN 2022. There were around 2.3 million new cases of breast cancer in 2022 globally, including more than 357,000 in China.1 ER+ breast cancer comprises 60-70% of all breast cancers.2 Endocrine therapy remains the mainstay treatment for ER+ breast cancer and the most widely used class of aromatase inhibitor (AI) has been recommended by the National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines to be the adjuvant and first-line standard of care for patients with ER+/HER2- breast cancer.3,4 However, almost all patients treated with AIs in the advanced setting develop resistance,5 with ESR1 mutations being one of the most prevalent alterations, present in up to 40% of patients and a significant mechanism of resistance to endocrine therapy.6 Currently, there are limited treatment options for ER+/HER2- breast cancer with ESR1 mutations, and thus a large clinical need exists.

On June 6, 2024 SpringWorks Therapeutics, Inc. ("SpringWorks") reported to have received notice of termination of the Amended and Restated Collaboration and License Agreement, dated September 6, 2022, between SpringWorks and GlaxoSmithKline Intellectual Property Development Ltd ("GSK") (the "License Agreement"), effective 180 days following the receipt of notice of termination (Filing, 8-K, SpringWorks Therapeutics, JUN 6, 2024, View Source [SID1234644195]).

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In connection with such termination, SpringWorks expects that GSK will continue the ongoing clinical trials under the License Agreement that include nirogacestat in combination with low-dose belamaf, an antibody-drug conjugate targeting BCMA B-cell maturation antigen in multiple myeloma until completed with respect to the 27 patients currently enrolled in such trials. SpringWorks will continue to support the completion of such trials with drug product supply and future publication efforts with respect to the data developed.

Once the termination becomes effective, the non-exclusive licenses granted by SpringWorks to GSK under the License Agreement will terminate. Termination of the License Agreement does not trigger any payment obligations on the part of SpringWorks or any other material wind-down costs. This termination does not affect SpringWorks’ rights to continue developing or commercializing its products or product candidates.

On June 6, 2024 TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics ("BBOT" or the "Company"), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, reported that the first patient has been dosed in the ONKORAS-101 trial for its lead program, BBO-8520 (Press release, BridgeBio, JUN 6, 2024, View Source [SID1234644189]). BBO-8520 is a first-in-class orally bioavailable and highly potent small molecule direct inhibitor of KRASG12C (ON) state. BBO-8520 binds covalently to the Switch II pocket in both the GTP-bound (ON) and GDP-bound (OFF) state conformations of KRASG12C, leading to rapid and sustained inhibition of KRASG12C activity.

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On dosing the first patient, Professor Benjamin Solomon, head of lung medical oncology at the Peter MacCallum Cancer Center, said, "We are excited to partner with BridgeBio Oncology Therapeutics to bring a transformative new therapy to patients. Non-small cell lung cancer is among the most prevalent malignancies globally and there is a significant need for new precision oncology medicines to improve outcomes for patients in the metastatic setting. BBO-8520 promises to have a substantial impact in improving outcomes and prognosis for this group of patients."

BBO-8520 was designed to inhibit the (ON) state to provide optimal target coverage and to address KRASG12C amplification and receptor tyrosine kinase activation – the two key mechanisms of adaptive resistance to current (OFF) state inhibitors. BBO-8520 drives substantial tumor growth inhibition in multiple preclinical models, even after emergence of resistance to sotorasib, an FDA approved (OFF) state inhibitor of KRASG12C. BBO-8520’s discovery was the result of a collaboration between the National Cancer Institute RAS Initiative at Frederick National Laboratory for Cancer Research, Lawrence Livermore National Laboratory, and BridgeBio Oncology Therapeutics.

The ONKORAS-101 study will enroll patients pre-treated with first generation KRASG12C (OFF) inhibitors as well as patients with no prior KRASG12C targeted therapy experience. The trial will enroll across the US, Australia, Canada, and the EU.

BridgeBio Oncology Therapeutics’ CEO, Eli Wallace, PhD, added, "The initiation of the Phase 1 clinical trial of BBO-8520 represents an important advancement for BBOT, as we are now a clinical-stage organization. We are grateful for the opportunity to offer patients with KRASG12C-driven lung cancer a targeted therapy that is expected to provide a significant improvement over current standards of care."

On June 6, 2024 Twist Bioscience Corporation (NASDAQ: TWST), a company enabling customers to succeed through its offering of high-quality synthetic DNA using its silicon platform, reported the publication of a study detailing the discovery of TB206-001, a first-in-class antibody targeting adenosine A2A receptor (A2AR), a promising molecular target that could enhance cancer immunotherapy (Press release, Twist Bioscience, JUN 6, 2024, View Source [SID1234644188]). The study titled, "Discovery of a potent, selective, and tumor-suppressing antibody antagonist of adenosine A2A receptor", was published in the journal PLOS ONE.

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A2AR is an emerging immune checkpoint that plays a role in the immunosuppression of the tumor microenvironment. It is part of an important class of therapeutic targets, called G protein-coupled receptors (GPCRs), which are found on most immune cells and highly expressed in certain cancers. Tumors commonly produce excess adenosine, which activates A2A receptors and suppresses immune cells. Blocking A2AR could alleviate the suppressive environment and restore tumor immunity. A2AR has been shown to play a role in various cancers including colorectal cancer, gastric cancer, lymph node metastasis, breast cancer and melanoma as well as in autoimmune diseases and Parkinson’s.

"The majority of current therapies in clinical trials targeting A2AR are small molecules, as it has been traditionally difficult to discover antibodies that block GPCRs; however, antibodies have greater affinity for target molecules, do not cross into the central nervous system and could be dosed less frequently," said Emily M. Leproust, Ph.D., CEO and co-founder of Twist Bioscience. "With the right partner to take it forward, TB206-001, our Twist-discovered first-in-class antibody antagonist of A2AR, could be developed as a powerful inhibitor to restore immune responses in immunosuppressive environments that allow cancer to grow."

In the study, the researchers immunized two different sets of animals with DNA encoding wildtype or mutant hA2AR (C144S, S334A, S338A) modified to minimize the impact of the receptor’s natural signaling on its expression. Once the animals generated antibodies to the receptor, the researchers built immune and synthetic single-chain variable fragment (scFvs) phage display libraries from the immune repertoire. The libraries were subsequently screened against detergent solubilized A2AR, and positive hits were reformatted into monoclonal antibodies for further testing. The result was TB206-001, which directly targets A2AR and activates immune cells. In preclinical studies, the antibody has shown high affinity and specific activity for A2AR over other adenosine receptors and shows tumor-suppressing activity in colon tumor-bearing HuCD34-NCG mice. Additional studies in animal models found that TB206-001 reduced tumor volume better than PD-1 inhibitors.

"There is still tremendous potential for immunotherapies either in combination with or in addition to those targeting PD-1 and CLTA-4," said Gregory Carven, Ph.D., one of the original inventors of Keytruda. "Using the ability to create large antibody libraries enabling discovery of novel and highly specific therapeutics, Twist has discovered an antibody that blocks A2AR, a promising checkpoint target and demonstrated its activity in preclinical models. The antibody could be further developed as a standalone therapy, bispecific or combination therapy to bring potential therapeutic benefit to patients."

On June 6, 2024 MAIA Biotechnology, Inc., (NYSE American: MAIA) ("MAIA", the "Company"), a clinical-stage biopharmaceutical company developing targeted immunotherapies for cancer, reported Company highlights and key achievements year-to-date, including recent clinical progress for lead candidate THIO, a potential first-in-class cancer telomere targeting agent in clinical development to evaluate its activity in non-small cell lung cancer (NSCLC) (Press release, MAIA Biotechnology, JUN 6, 2024, View Source [SID1234644187]).

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"MAIA’s new science for cancer therapy is driving a powerful value proposition for our portfolio of novel anticancer compounds," said Vlad Vitoc, M.D., MAIA’s Chairman and Chief Executive Officer. "Our most recent clinical data points to THIO’s promising disease control, response rates, and post-therapy patient benefits. Third-line treatment with THIO has significantly outperformed reported standard-of-care data in NSCLC.

"Our confidence in the science and clinical pathways for our immuno-oncology therapies continues to grow," Dr. Vitoc added. "This week at ASCO (Free ASCO Whitepaper) 2024, our poster presentation and prospects for conducting studies in various geographies has generated a wealth of positive response and excitement from U.S. and foreign oncologists and investigators about our growing cancer treatment business."

THIO’s dual mechanism of action is designed to induce telomeric DNA damage and boost cancer-specific immune responses. The Phase 2 THIO-101 clinical trial evaluates THIO sequenced with an immune checkpoint inhibitor (CPI), cemiplimab, in patients with advanced non-small cell lung cancer (NSCLC) who failed two or more standard-of-care therapy regimens prior to THIO dosing. MAIA successfully secured a high value clinical supply agreement for the cemiplimab used throughout the THIO-101 trial.

As of April 30, 2024, THIO-101 data from THIO 180mg + CPI in third-line treatment showed, in part:

– overall response rate (ORR) of 38%
– disease control rate (DCR) of 85%
– median progression-free survival (PFS) of 5.5 months
– median survival follow-up time of 9.1 months

"THIO works well in all doses and has an excellent safety profile, but 180mg has shown the greatest efficacy and is well tolerated compared to existing therapies. Hence, we selected 180mg per cycle as the dose going forward," noted Dr. Vitoc. "For this heavily pre-treated population, comparative third-line data is limited. Checkpoint inhibitor resistant and platinum resistant patients are by far the largest populations with unmet medical needs in NSCLC and are also a substantial part of NSCLC cancer therapy market. We believe that our trial is providing the first real dataset in CPI-resistant patients like this. We are confident about THIO’s prospects for substantially extending patient survival and establishing a new standard of care for cancer.

"We remain steadfast in our goals for responsible access to capital. We have increased our access to cash while keeping dilution to a minimum. We plan to continue this strategy, which has shown desired outcomes so far this year while our share price has more than tripled," added Dr. Vitoc.

MAIA reported cash and current assets of $8.7 million as of March 31, 2024. The Company’s cash position has significantly improved due to approximately $12.4 million in funds raised since February 2024 pursuant to a combination of private placements of our equity securities and sales under our at-the-market offering facility, of which approximately $7.4 million has been raised since April 1, 2024 with $6.4 million of this amount due to sales under the ATM facility to fund continuing clinical development. Our independent directors have shown continued support by investing almost $900,000 in our March and April 2024 private placements with other accredited investors.

MAIA’s Phase 2 THIO-101 clinical trial is expected to near completion in 2024. The Company is also engaged in research and development for a portfolio of second-generation THIO-like compounds.

About THIO

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) is a first-in-class investigational telomere-targeting agent currently in clinical development to evaluate its activity in Non-Small Cell Lung Cancer (NSCLC). Telomeres, along with the enzyme telomerase, play a fundamental role in the survival of cancer cells and their resistance to current therapies. The modified nucleotide 6-thio-2’-deoxyguanosine (THIO) induces telomerase-dependent telomeric DNA modification, DNA damage responses, and selective cancer cell death. THIO-damaged telomeric fragments accumulate in cytosolic micronuclei and activates both innate (cGAS/STING) and adaptive (T-cell) immune responses. The sequential treatment with THIO followed by PD-(L)1 inhibitors resulted in profound and persistent tumor regression in advanced, in vivo cancer models by induction of cancer type–specific immune memory. THIO is presently developed as a second or later line of treatment for NSCLC for patients that have progressed beyond the standard-of-care regimen of existing checkpoint inhibitors.

About THIO-101, a Phase 2 Clinical Trial

THIO-101 is a multicenter, open-label, dose finding Phase 2 clinical trial. It is the first trial designed to evaluate THIO’s anti-tumor activity when followed by PD-(L)1 inhibition. The trial is testing the hypothesis that low doses of THIO administered prior to cemiplimab (Libtayo) will enhance and prolong immune response in patients with advanced NSCLC who previously did not respond or developed resistance and progressed after first-line treatment regimen containing another checkpoint inhibitor. The trial design has two primary objectives: (1) to evaluate the safety and tolerability of THIO administered as an anticancer compound and a priming immune activator (2) to assess the clinical efficacy of THIO using Overall Response Rate (ORR) as the primary clinical endpoint. Treatment with cemiplimab (Libtayo) followed by THIO has been generally well-tolerated to date in a heavily pre-treated population. For more information on this Phase II trial, please visit ClinicalTrials.gov using the identifier NCT05208944.