On December 12, 2024 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) reported that the Center for Drug Evaluation of China’s National Medical Products Administration ("NMPA") has granted Breakthrough Therapy Designation ("BTD") to the combination of ORPATHYS (savolitinib) and TAGRISSO (osimertinib) for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor ("EGFR") mutation-positive non-small cell lung cancer ("NSCLC") with MET amplification after disease progression on EGFR inhibitor therapy (Press release, HUTCHMED, DEC 12, 2024, View Source [SID1234649073]). ORPATHYS is an oral, potent and highly selective MET tyrosine kinase inhibitor ("TKI"). TAGRISSO is a third-generation, irreversible EGFR TKI.

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This treatment combination is being evaluated in China in the ongoing multi-center, open-label, randomized, controlled, Phase III SACHI trial. The study is investigating the efficacy and safety of a combination of ORPATHYS and TAGRISSO compared to platinum-based doublet-chemotherapy (pemetrexed plus cisplatin or carboplatin), the standard-of-care treatment option, in patients with locally advanced or metastatic NSCLC with MET amplification after failure of EGFR inhibitor therapy. The primary endpoint of the study is progression-free survival ("PFS") as assessed by investigators. Other endpoints include PFS assessed by an independent review committee, overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), time to response (TTR), and safety (NCT05015608).

NMPA grants BTD to new drugs that treat life-threatening diseases or serious conditions for which there are no effective treatment options, and where clinical evidence demonstrates significant advantages over existing therapies. Drug candidates with BTD may be considered for conditional approval and priority review when submitting an NDA. This indicates that the development and review of the therapy for this disease indication may be expedited, to address patients’ unmet needs more quickly.

About NSCLC and MET aberrations

Lung cancer is the leading cause of cancer death, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.2 The majority of NSCLC patients (approximately 75%) are diagnosed with advanced disease, and approximately 10-15% of NSCLC patients in the US and Europe and 30-40% of patients in Asia have EGFR-mutated ("EGFRm") NSCLC.3,4,5,6

MET is a tyrosine kinase receptor that has an essential role in normal cell development.7 MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is one of the mechanisms of acquired resistance to EGFR TKI for metastatic EGFR-mutated NSCLC.7,8 Approximately 2-3% of NSCLC patients have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.9 MET aberration is a major mechanism for acquired resistance to both first/second-generation EGFR TKIs as well as third-generation EGFR TKIs like osimertinib. Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration.10,11,12,13,14 The prevalence of MET aberration depends on the sample type, detection method and assay thresholds used.15

About ORPATHYS and TAGRISSO Combination Development in EGFR mutation-positive NSCLC

The combination of ORPATHYS and TAGRISSO has been studied extensively in patients with EGFR mutation-positive NSCLC, including the TATTON (NCT02143466) and SAVANNAH (NCT03778229) studies. The encouraging results from these studies led to the initiation of three Phase III trials with this combination: SACHI (NCT05015608) and SANOVO (NCT05009836) were initiated in China in 2021, and the global, pivotal Phase III SAFFRON (NCT05261399) study started enrollment in 2022. In comparison to other treatment options, this combination treatment is chemotherapy-free, biomarker-specific and orally administered, aiming for a balanced efficacy, safety and quality-of-life profile for lung cancer patients.

SAVANNAH is a global Phase II study in patients who have progressed following osimertinib due to MET amplification or overexpression, and recruitment completed earlier in 2024. The evaluation of savolitinib in combination with osimertinib was designated as a Fast Track development program by the US Food and Drug Administration (FDA) in 2023.

SAFFRON is a multi-center, randomized, controlled, open-label, global Phase III trial in patients with EGFR mutation-positive NSCLC with MET overexpression and/or amplification after disease progression on osimertinib.

SACHI is a multi-center, randomized, controlled, open-label, China Phase III trial in patients with EGFR mutation-positive NSCLC with MET amplification after disease progression on any EGFR inhibitor therapy, including third-generation EGFR-TKIs such as osimertinib.

SANOVO is a multi-center, randomized, controlled, blinded, China Phase III trial in treatment-naïve patients with EGFR mutation-positive NSCLC with MET-positive tumors.

About ORPATHYS Approval in China

ORPATHYS was granted conditional approval in China for the treatment of patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. ORPATHYS is the first selective MET inhibitor approved in China. It has been included in the National Reimbursement Drug List of China (NRDL) since March 2023. A supplementary NDA is under review which, if approved, could expand this indication to include treatment-naïve adult patients in China. More than a third of the world’s lung cancer patients are in China and, among those with NSCLC globally, approximately 2-3% have tumors with MET exon 14 skipping alterations.

About ORPATHYS (savolitinib)

ORPATHYS is an oral, potent and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression.

ORPATHYS is marketed in China and is currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines.

In 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize ORPATHYS. Joint development of ORPATHYS in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of ORPATHYS in China. AstraZeneca is responsible for the commercialization of ORPATHYS in China and worldwide. Sales of ORPATHYS are recognized by AstraZeneca.

About TAGRISSO

TAGRISSO (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. TAGRISSO (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore TAGRISSO as a treatment for patients across multiple stages of EGFRm NSCLC.

There is an extensive body of evidence supporting the use of TAGRISSO as standard of care in EGFRm NSCLC. TAGRISSO improved patient outcomes in early-stage disease in the ADAURA Phase III trial, locally advanced disease in the LAURA Phase III trial, late-stage disease in the FLAURA Phase III trial, and with chemotherapy in the FLAURA2 Phase III trial.

On December 12, 2024 Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, reported the nomination of EO-1022 as its HER3 ADC development candidate (Press release, Elevation Oncology, DEC 12, 2024, View Source;utm_medium=rss&utm_campaign=elevation-oncology-expands-pipeline-with-nomination-of-eo-1022-a-her3-adc-for-the-treatment-of-her3-expressing-solid-tumors [SID1234649071]). EO-1022 is currently progressing through preclinical development, and Elevation Oncology expects to file an investigational new drug (IND) application in 2026.

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HER3 is a protein expressed across several types of solid tumors, including breast cancer, EGFR-mutant non-small cell lung cancer and pancreatic cancer, and often associated with poor clinical outcomes. EO-1022 is a differentiated ADC containing seribantumab, an anti-HER3 monoclonal antibody (mAb), and a monomethyl auristatin E (MMAE) payload, with site-specific conjugation to the glycan. EO-1022 is being developed for the treatment of patients living with solid tumors that express HER3.

"The nomination of our HER3-ADC development candidate marks a key milestone for Elevation Oncology in bolstering our ADC pipeline. EO-1022 combines the seribantumab antibody and state-of the-art ADC site-specific technology. We believe seribantumab is ideally-suited to be used in an ADC due to its selectivity in delivering cytotoxic payload to HER3-expressing cancer cells and its well-tolerated safety profile demonstrated in over 900 patients in multiple studies," said Joseph Ferra, President and Chief Executive Officer of Elevation Oncology. "This program is another step forward in leveraging our ADC and oncology drug development expertise to develop innovative, selective cancer therapies that address significant unmet needs. We look forward to sharing preclinical data for EO-1022 in the first half of 2025, as we continue to advance this asset toward the clinic."

Also today, Elevation Oncology announced that it has entered into a licensing agreement with Synaffix B.V. (Synaffix). This licensing agreement gives Elevation Oncology global access to Synaffix’s clinical stage, site-specific ADC technology platform, including GlycoConnect antibody conjugation technology, HydraSpace polar spacer technology, as well as the toxSYN linker-payload, SYNstatin E. The license granted to GlycoConnect and HydraSpace technologies is exclusive to HER3 as a single target in combination with SYNstatin E linker-payload.

"HER3 is broadly expressed in various cancer types, making it a compelling target for innovative therapeutic strategies. We believe an ADC approach is uniquely positioned to fully unlock the clinical potential of HER3," said David Dornan, Ph.D., Chief Scientific Officer of Elevation Oncology. "We are excited to nominate EO-1022, which leverages Synaffix’s state-of-the art site-specific conjugation and differentiated linker-payload for a potentially best-in-class profile. We look forward to advancing our pipeline, as we work towards transforming the care and treatment of patients living with solid tumors that overexpress HER3."

"As a dedicated partner in the ADC space, Synaffix is excited to collaborate with Elevation Oncology to push the boundary of ADC innovation," said Peter van de Sande, Head of Synaffix. "With our state-of-the-art ADC technology platform and established supply chain, Elevation is well-positioned to accelerate the development of its differentiated HER3 ADC."

On December 12, 2024 Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported the presentation of data showing the enhanced anti-tumor activity of zelenectide pevedotin monotherapy in breast cancer patients with NECTIN4 gene amplification at the 2024 San Antonio Breast Conference Symposium (SABCS) in San Antonio, Texas (Press release, Bicycle Therapeutics, DEC 12, 2024, View Source [SID1234649070]). The company also announced topline combination data for zelenectide pevedotin plus pembrolizumab in previously untreated (first-line) cisplatin-ineligible patients with metastatic urothelial cancer (mUC), provided an enrollment and timeline update for the company’s Phase 2/3 Duravelo-2 trial and shared topline monotherapy data for zelenectide pevedotin in non-small cell lung cancer (NSCLC) patients with NECTIN4 gene amplification. Bicycle Therapeutics will host a conference call and webcast tomorrow, Dec. 13, at 8 a.m. ET to review the data updates for zelenectide pevedotin and discuss its development strategy leveraging NECTIN4 gene amplification. Management will be joined by oncology experts Sherene Loi, M.D., Ph.D., from the Peter MacCallum Cancer Centre in Melbourne, Australia, and Niklas Klümper, M.D., from the University Hospital Bonn in Germany.

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"The totality of the data shared today builds on the breadth of previously reported data for zelenectide pevedotin that we believe, when combined with our ambitious development strategy leveraging NECTIN4 gene amplification, position Bicycle as a leader in addressing Nectin-4 associated cancers," said Bicycle Therapeutics CEO Kevin Lee, Ph.D. "We are encouraged by the topline zelenectide pevedotin data in combination with pembrolizumab in first-line mUC patients, which demonstrate zelenectide pevedotin’s response data are in line with other drug conjugates used to treat mUC while its safety and tolerability profile continues to be differentiated. Additionally, we are very pleased with our progress in enrolling our Duravelo-2 registrational trial for zelenectide pevedotin in mUC and look forward to providing dose selection and topline data in the second half of next year."

Dr. Lee continued: "While early, the zelenectide pevedotin monotherapy data in breast cancer and NSCLC patients with NECTIN4 gene amplification underscore its promising anti-tumor activity and solidify our next steps for the therapy’s development. By leveraging NECTIN4 gene amplification, we expect to be able to identify the patients who may most benefit from zelenectide pevedotin and accelerate development for solid tumor indications beyond bladder cancer. Over the course of 2025, we plan to initiate Phase 1/2 trials evaluating zelenectide pevedotin in NECTIN4 gene-amplified breast cancer, lung cancer and multiple other cancers."

Topline Zelenectide Pevedotin Plus Pembrolizumab Combination Data in First-line mUC Highlights
Zelenectide pevedotin is a Bicycle Toxin Conjugate (BTC) targeting Nectin-4, a well-validated tumor antigen. Topline results from the ongoing Phase 1/2 Duravelo-1 trial evaluating zelenectide pevedotin 5 mg/m2 weekly plus pembrolizumab 200 mg once every three weeks in 22 first-line cisplatin-ineligible patients with mUC showed:

60% overall response rate (ORR) (12/20) among efficacy-evaluable patients. Of the responses, 5 were confirmed and 7 were unconfirmed at the time of the data cut. Fifteen patients remained on treatment at the time of the data cut.
Safety and tolerability profile was broadly consistent with late-line Duravelo-1 monotherapy and combination cohorts.
Adverse events of clinical interest such as peripheral neuropathy, skin reactions and eye disorders were primarily low grade. There was one report of Grade 3 sensory peripheral neuropathy and one report of Grade 3 rash, both of which were transient and reverted to Grade 1 upon dose interruption.
More detailed data from this study will be presented at a future medical meeting.

Bicycle Therapeutics is currently conducting the Phase 2/3 Duravelo-2 trial evaluating zelenectide pevedotin plus pembrolizumab versus chemotherapy in first-line mUC (Cohort 1), and zelenectide pevedotin monotherapy and in combination with pembrolizumab in late-line mUC (Cohort 2). In each cohort, two doses of zelenectide pevedotin – 5 mg/m2 weekly and 6 mg/m2 two weeks on, one week off – are being initially assessed. Based on enrollment progress, the company plans to report dose selection and topline data for both cohorts in the second half of 2025.

Zelenectide Pevedotin Monotherapy Data in Breast Cancer Patients with NECTIN4 Gene Amplification Highlights (Presented at 2024 SABCS)
Gene amplification is a common mechanism by which cancer cells gain function. Bicycle Therapeutics identified that the NECTIN4 gene sits on a commonly amplified chromosomal site in cancer, creating more copies of the gene and often translating to more protein expression. Since zelenectide pevedotin binds to Nectin-4, it was hypothesized that NECTIN4 gene amplification may predict response and could serve as a biomarker for therapy stratification.

The company conducted a post-hoc analysis of 38 heavily pretreated breast cancer patients enrolled in Duravelo-1, of which 32 were confirmed to have triple-negative breast cancer (TNBC). The majority of patients were treated with zelenectide pevedotin 5 mg/m2 weekly.

Of the 38 breast cancer patients enrolled, 35 patients were efficacy evaluable. Additionally, 23 breast cancer patient samples were available for NECTIN4 testing, of which 8 demonstrated NECTIN4 gene amplification or harbored NECTIN4 polysomy. Results showed:

62.5% ORR (5/8) among breast cancer patients with NECTIN4 gene amplification or polysomy, compared to 14.3% ORR (5/35) among all efficacy-evaluable breast cancer patients.
Of the 5 partial responses, 4 were confirmed and 1 was unconfirmed.
No responses in non-amplified or non-polysomy patients.
Of the 32 TNBC patients enrolled, 30 patients were efficacy evaluable. Additionally, 19 TNBC patient samples were available for NECTIN4 testing, of which 7 demonstrated NECTIN4 gene amplification or harbored a NECTIN4 polysomy. Results showed:

57.1% ORR (4/7) among TNBC patients with NECTIN4 gene amplification or polysomy, compared to 13.3% ORR (4/30) among all efficacy-evaluable TNBC patients.
Of the 4 partial responses, 3 were confirmed and 1 was unconfirmed.
All 3 TNBC patients with NECTIN4 gene amplification who responded to zelenectide pevedotin had prior treatment with sacituzumab govitecan.
No responses in non-amplified or non-polysomy patients.
In this study of heavily pretreated breast cancer patients, zelenectide pevedotin was generally well tolerated, and its safety and tolerability profile was consistent with data from other Duravelo-1 cohorts. Low rates of Grade ≥3 treatment-related adverse events (TRAEs) (34.2%) and Grade ≥3 treatment-related serious adverse events (TRSAEs) (10.5%) occurred. The most common TRAEs were fever (pyrexia), nausea and diarrhea. TRAEs of clinical interest, including peripheral neuropathy (any kind) and skin reactions, were low grade.

"Although the sample size was limited, this post-hoc analysis highlights the encouraging anti-tumor activity of zelenectide pevedotin in breast cancer patients with NECTIN4 gene amplification, particularly among those with TNBC who urgently need new treatment options," said Professor Sherene Loi, M.D., Ph.D., consultant medical oncologist in the Breast Unit and group leader at the Peter MacCallum Cancer Centre in Melbourne, Australia. "As innovative and genomically targeted therapies for breast cancer continue to emerge, these findings position zelenectide pevedotin as a promising potential new therapy and NECTIN4 gene amplification as a novel target for breast cancer drug development."

The poster presentation, "Enhanced anti-tumor activity of zelenectide pevedotin in triple-negative breast cancer (TNBC) patients with NECTIN4 gene amplification" is available in the Publications section of the Bicycle Therapeutics website.

Topline Zelenectide Pevedotin Monotherapy Data in NSCLC Patients with NECTIN4 Gene Amplification Highlights
The company conducted a post-hoc analysis of 40 pretreated patients with NSCLC enrolled in Duravelo-1. The majority of patients received zelenectide pevedotin 5 mg/m2 weekly.

Of the 40 patients enrolled, 34 patients were efficacy evaluable. Additionally, 19 patient samples were available for NECTIN4 testing, of which 6 demonstrated NECTIN4 gene amplification. Five out of 6 patients with NECTIN4 gene amplification were efficacy evaluable. Results showed:

40.0% ORR (2/5) among patients with NECTIN4 gene amplification, compared to 8.8% ORR (3/34) among all efficacy-evaluable patients.
Of the 3 partial responses, 2 were confirmed and 1 was unconfirmed.
Out of 19 patients tested for NECTIN4 gene amplification, none of the non-amplified patients responded.
The safety and tolerability profile of zelenectide pevedotin was broadly consistent with data from other Duravelo-1 monotherapy cohorts.

More detailed data from this study will be presented at a future medical meeting.

Overview of Development Strategy Leveraging NECTIN4 Gene Amplification
Bicycle Therapeutics plans to advance development of zelenectide pevedotin in broader indications outside of mUC utilizing a NECTIN4 gene amplification strategy to target patients who have the potential for significantly deeper responses.

Over the course of 2025, Bicycle Therapeutics plans to initiate several additional Phase 1/2 trials to assess zelenectide pevedotin in NECTIN4 gene-amplified breast cancer, lung cancer and multiple other cancers. Through this strategy, the company believes it has the opportunity to become the leader in addressing Nectin-4 associated cancers and potentially transform the treatment landscape for thousands of patients in the United States.

Conference Call Details
Bicycle Therapeutics will host a conference call and webcast on Friday, Dec. 13, at 8 a.m. ET to review the data updates for zelenectide pevedotin. The company’s management team will be joined by Sherene Loi, M.D., Ph.D., Peter MacCallum Cancer Centre, and Niklas Klümper, M.D., University Hospital Bonn.

To access the call, please dial +1-833-816-1408 (U.S.) or +1-412-317-0501 (international) and ask to join the Bicycle Therapeutics call. A live webcast and replay of the conference call will be accessible in the Investor section of the Company’s website at www.bicycletherapeutics.com.

On December 12, 2024 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global oncology company that intends to change its name to BeOne Medicines Ltd., reported new data on its emerging breast cancer portfolio following its first-ever presentations at the San Antonio Breast Cancer Symposium (SABCS). Poster presentations included first-in-human data for BeiGene’s investigational cyclin-dependent kinase (CDK) 4 inhibitor BGB-43395 in hormone receptor- positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer (Press release, BeiGene, DEC 12, 2024, View Source [SID1234649069]). Two posters highlighting the designs of in-progress trials for BGB-43395 and CDK2 inhibitor BG-68501/EXT-197 and a poster detailing the preclinical characterization of BGB-43395 were also presented.

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"Despite treatment advances, breast cancer remains the fourth leading cause of cancer mortality worldwide and the number one cause of cancer death in women," said Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. "We are advancing a robust portfolio of investigational medicines for breast cancer and are pleased to share our first clinical data for our investigational CDK4 inhibitor BGB-43395 at SABCS. We’ve made tremendous progress with this program, having enrolled over 100 patients in the first year of clinical development, and the early results are encouraging. We look forward to continuing its development alongside other molecules in our breast cancer pipeline, including additional cell cycle dependent kinase inhibitors and ADCs."

BeiGene’s breast cancer pipeline features cell cycle dependent kinase inhibitors designed to potentially deliver better efficacy and reduced toxicity than currently available options, initially for HR+/HER2- disease. CDK inhibitors target checkpoint proteins that control cell division to stop the growth of cancer cells. Widely used CDK4/6 inhibitors have been shown to provide substantial clinical benefit for patients with certain breast cancers. However, dose-limiting toxicities, thought to be the result of CDK6 inhibition, and the development of resistance mutations, curb the utility of these medicines. BeiGene’s CDK4 inhibitor, BGB-43395, is highly potent and selective for CDK4 relative to CDK6, and it has the potential to reduce dose-limiting toxicities, improving tolerability while achieving comparable or better efficacy.

BGB-43395 is being investigated in an ongoing phase 1 study (NCT06120283). Early safety and tolerability data for 65 patients with metastatic HR+/HER2- breast cancer or other advanced solid tumors who received BGB-43395 either as monotherapy or in combination with fulvestrant or letrozole in escalating dose cohorts were presented in a poster at SABCS. To date, the results indicate that BGB-43395 has been generally well tolerated across different dose levels, with encouraging early signs of clinical activity emerging. The data support continued development; more than 100 patients have been enrolled to date across the program, and further results of ongoing studies will be presented at future scientific conferences.

Complementing BGB-43395, BeiGene’s CDK2 inhibitor, BG-68501/EXT-197, targets elevated CDK2 activity, which is a key resistance mechanism to CDK4/6 inhibition in HR+/HER2- breast cancer. BG-68501 is currently being evaluated in a first-in-human Phase 1 study (NCT06257264). In addition to small molecule cell cycle dependent kinase inhibitors, BeiGene’s pipeline in breast and gynecologic cancers includes novel antibody-drug conjugates (ADCs) and other molecularly targeted agents and modalities. BG-C9074, an ADC targeting the B7H4 protein, which is broadly expressed in breast and gynecologic cancers, is currently in Phase 1 development (NCT06233942). BeiGene also plans to evaluate the potential of BCL2 inhibition in breast cancer, with next-generation BCL2 inhibitor BGB-21447 expected to begin clinical testing in solid tumor indications soon. Multispecific antibodies and targeted protein degraders with potential applications in breast cancer are among the preclinical assets being developed.

BeiGene recently launched the Cancer Has No Borders podcast, featuring engaging discussions on the world of oncology and BeiGene. The first episode features Claire Saxton, Executive Vice President, Insights & Impact at Cancer Support Community (CSC), and BeiGene’s Dr. Lanasa discussing the unmet need in breast cancer, the realities of the current treatment landscape, and the need for innovation. CSC is a global nonprofit that uplifts and strengthens people impacted by cancer by providing support, fostering compassionate communities, and breaking down barriers to care. Listen on podcast platforms: Apple Podcasts, Spotify, iHeartRadio, Amazon, and YouTube.

BeiGene will host an investor conference call and webcast on Monday, December 16th, 2024, at 8:30 a.m. EST to discuss recent data presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2024 Annual Meeting and at SABCS. A live webcast of the conference call can be accessed from the investors section of BeiGene’s website at View Source, View Source, or View Source An archived replay will be available for 90 days following the event.

The Company recently announced its intent to change its name to BeOne, reaffirming its commitment to develop innovative medicines to eliminate cancer by partnering with the global community to serve as many patients as possible.

About Breast Cancer

Breast cancer accounts for close to one in four cancer cases and one in six cancer deaths in women worldwide.1 Globally, breast cancer is the second most common cancer and the fourth highest cause of cancer mortality as well as the leading cause of cancer death in women.1 More than 2.3 million patients were diagnosed with breast cancer in 2022, and over 666,000 deaths were reported globally.1 Approximately two-thirds of breast cancer cases are the HR+/HER2- subtype.

On December 12, 2024 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated targeted agents to treat hematologic malignancies, reported the publication of preclinical data for Aptose’s lead hematology compound tuspetinib (TUS) in Cancer Research Communications, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Aptose Biosciences, DEC 12, 2024, View Source [SID1234649068]).

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The publication, entitled "Preclinical development of tuspetinib for the treatment of acute myeloid leukemia," is the first preclinical profiling of tuspetinib, a well-tolerated, once daily, oral kinase inhibitor currently in clinical development for treatment of acute myeloid leukemia (AML). The publication defines TUS activities on select oncogenic signaling targets, demonstrates enhanced activity and safety of TUS when combined with other agents, and illustrates synthetic lethality when combined with venetoclax (VEN). Pharmacokinetic and toxicology studies revealed that TUS is readily absorbed and achieves plasma concentrations sufficient to inhibit the target kinases, it has a plasma half-life that supports once daily dosing, and it demonstrates a favorable safety profile.

Aptose is now enrolling newly diagnosed AML patients in a Phase 1/2 clinical study to receive the tuspetinib + venetoclax + azacitidine (TUS+VEN+AZA) triplet combination (NCT03850574). Clinical studies in patients with relapsed or refractory AML receiving TUS single agent or the TUS+VEN combination have been completed.

"The non-clinical findings presented in the publication suggest that TUS will demonstrate favorable safety and a breadth of antileukemic activity across AML patient populations with a diversity of adverse mutations, and the initial clinical data is bearing that out," said William G. Rice, Chairman, President and Chief Executive Officer. "We are eager for the next set of data in our triplet combination trial of TUS+VEN+AZA."

Key findings:

Tuspetinib inhibits a defined cluster of oncogenic signaling kinases operative in AML
TUS inhibits SYK, JAK1/2, RSK2, mutant KIT, and wild type and mutant forms of FLT3
TUS potently killed AML lines (GI50 = 1.3 to 5.2 nM) and Ba/F3 cells expressing wildtype (GI50 = 9.1 nM) or various mutant forms of FLT3 (GI50 = 2.5 – 56 nM)
TUS dampens stroma-induced activation of FLT3-ITD signaling in AML cells
TUS prolongs survival in multiple AML models
Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3 mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax or 5-azacytidine
TUS combines effectively with other classes of agents to kill AML cells with mutations in RAS and other difficult-to-treat adverse mutations
TUS was 2.1-15-fold and a 4.5-13-fold more potent than gilteritinib at blocking fibrinogen and immunoglobulin-mediated activation of SYK in KG-1a cells
The most notable observation was the marked and unexpected synthetic lethal vulnerability to venetoclax and two MCL1 inhibitors in the TUS-resistant cells