On November 20, 2024 the National Medical Products Administration (NMPA) reported on its official website that the NMPA approved the listing of Zorifertinib Hydrochloride Tablets (trade name: Zorifer), a Class 1 innovative drug, developed by Alpha Biopharma (Press release, Alpha Biopharma, NOV 20, 2024, View Source [SID1234648530]). This product is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) accompanied with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation and central nervous system (CNS) metastases.

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Zorifertinib is the first drug in the world to launch a registration clinical trial specifically for advanced NSCLC with CNS metastases and achieve remarkable results. It is also the only* EGFR tyrosine kinase inhibitor (EGFR-TKI) currently available that was explicitly designed as non-blood-brain barrier efflux protein substrates and can penetrate the blood-brain barrier 100%.

The EVEREST trial, an international multi-center randomized controlled phase III trial of Zorifertinib, demonstrated its superior ability to control intracranial lesions. The trial enrolled patients with more severe disease, most of whom had EGFR L858R mutations or had more than 3 intracranial lesions. Zorifertinib showed a significant benefit in overall progression-free survival (PFS), with intracranial PFS reaching 17.9 months, and it significantly reduced the risk of intracranial progression/death by 37% (P = 0.0018). Furthermore, Zorifertinib demonstrated consistent and significant benefits in subgroups of patients with intracranial symptoms, EGFR L858R mutations, and more than 3 intracranial lesions.

As the global lead Principal Investigator (PI) for the EVEREST study, Professor Wu Yilong from Guangdong Provincial People’s Hospital mentioned that while several drugs have been approved for EGFR mutated NSCLC, there is still a lack of clinical head-to-head randomized controlled studies specifically targeting drug therapy for lung cancer with CNS metastases. The EVEREST study is the world’s first large-scale registered international multi-center clinical trial for the treatment of lung cancer with CNS metastases, and it has achieved statistically significant positive results. In the study, the therapeutic advantages of Zorifertinib in various subgroups were observed, and it was verified that all people with EGFR mutated NSCLC and brain metastases could benefit from Zorifertinib therapy. Among patients who were treated with third-generation TKI after progression, a trend of benefit in overall survival was also observed, suggesting that the combination or sequential therapy with third-generation TKI is expected to bring a better prognosis.

Zhang Yong, CEO of Alpha Biopharma, stated that the company is dedicated to developing innovative drugs that are urgently needed in clinical practice. We have collaborated with AstraZeneca to develop Zorifertinib, aiming to address the unmet clinical needs of patients with lung cancer and CNS metastases. Zorifertinib has demonstrated its therapeutic value during the clinical stage and has received support from clinical experts and regulatory authorities. It has become the world’s first approved new generation EGFR-TKI specifically targeting lung cancer with CNS metastases. The company anticipates that Zorifertinib will significantly enhance patient care in the future, offering more effective treatments for individuals with lung cancer and brain metastases.

About Lung Cancer and Central Nervous System Metastasis

In China, lung cancer is the most common and deadliest malignant tumor. In 2022, there were about 1.06 million new cases of lung cancer diagnosed, leading to approximately 730,000 deaths, with non-small cell lung cancer (NSCLC) accounting for around 85% of all cases. In the Chinese NSCLC population, about 38.4% of patients have been found to have EGFR mutation-positive, which is identified as one of the driving genes for NSCLC formation.

Central nervous system metastasis is a common occurrence in NSCLC patients, with approximately 25% of EGFR mutation-positive NSCLC patients having CNS metastases at the time of initial diagnosis. Additionally, 20% to 65% of lung cancer patients will develop CNS metastases during the course of their disease. Poor blood-brain barrier permeability of therapeutic drugs is one of the reasons why patients experience CNS progression during treatment.

About Blood-Brain Barrier and Efflux Proteins

The blood-brain barrier is a protective shield that prevents drugs from entering the brain. It is made up of tightly packed brain capillary endothelial cells, surrounded by pericellular, astrocyte terminal, and basement membrane structures. This barrier has high resistance and low permeability, making it challenging for drugs to reach the brain. As a result, the brain can act as a safe haven for tumor cells, contributing to the progression of central nervous system (CNS) diseases.

The blood-brain barrier contains a large number of efflux proteins, such as P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP), which are crucial for drug resistance in the development of brain lesions and the survival of tumor stem cells.

Remarks:

The "only … currently available" in this article is valid as of the deadline of Oct. 10, 2024.

References

Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol. 2018 Jan;19(1):e43-e55.
Zhou Q, Yu Y, Xing L, et al. First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial. Med. Published online October 3, 2024.
Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022[J]. Journal of the National Cancer Center, 2024.
Duma N, Santana-Davila R, Molina JR. Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clin Proc. 2019, 94(8):1623-1640.
Zhang YL, Yuan JQ, Wang KF, et al. Threapleton D, Yang ZY, Mao C, Tang JL. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016 Nov 29;7(48):78985-78993.
Preusser M, Winkler F, Valiente M, Manegold C, Moyal E, Widhalm G, Tonn JC, Zielinski C. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. ESMO (Free ESMO Whitepaper) Open. 2018 Jan 26;3(1):e000262.
Oncology Physician Branch of Chinese Medical Doctor Association, Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care. Chinese Treatment Guidelines for Brain Metastases from Lung Cancer (2021 Edition). Chinese Journal of Oncology, 2021, 43(03): 269-281.
Shetty V, Babu S. Management of CNS metastases in patients with EGFR mutation-positive NSCLC. Indian J Cancer. 2019 Nov;56(Supplement):S31-S37.

On November 20, 2024 Alloy Therapeutics Inc. ( "Alloy"), a biotechnology ecosystem company dedicated to democratizing access to cutting edge drug discovery technologies reported a strategic collaboration and license agreement with Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK "Takeda") to develop Takeda’s proprietary induced pluripotent stem cell (iPSC) derived CAR-T cell platform (iCAR-T) and iPSC-derived CAR-NK platform (iCAR-NK) (Press release, Alloy Therapeutics, NOV 20, 2024, View Source [SID1234648512]). Alloy will focus on accelerating the development of key therapies to overcome solid and hematological malignancies.

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iCAR-T technology was developed as part of the T-CiRA joint research program between Takeda and the Center for iPS Research and Application (CiRA) at Kyoto University. The core technology to differentiate iPSC into immune cells originates from CiRA’s Shin Kaneko’s laboratory. iCAR-T has potential to develop ‘off-the-shelf’ cell therapies, offering the potential for best-in-class performance with enhanced potency, and significantly lower manufacturing costs compared to autologous cell therapy.

"iCAR-T is one of our flagship projects graduating from T-CiRA, our decade-long joint research program between Takeda and CiRA. This agreement between Takeda and Alloy aims to advance iCAR-T from discovery to clinical development," said Yasushi Kajii, Head of R&D Japan Region at Takeda. "We are impressed with Alloy’s corporate culture of valuing platform technologies, flexibility in collaboration, patient-centric mindset, and company creation abilities, all of which were key elements to our decision to work with Alloy. We look forward to seeing iCAR-T and iCAR-NK blossom as the technology advances to its next phase."

Under the agreement, Alloy gains co-exclusive rights to commercialize iCAR-T and iCAR-NK products for oncology indications. Alloy will leverage synergies across its unique business model to further advance the iCAR-T/NK platform while enabling broader access to the technology for biotech and pharma partners to develop therapies for cancers including solid tumors. Future clinical validation and platform enhancements will further strengthen the platform.

"We are honored and excited to be chosen by Takeda to collaborate in fulfilling the promise of iPSC," said Errik Anderson, Founder, Chairman & CEO of Alloy. "This is another instance of how Alloy’s flexible approach allows us to enable the global scientific community with cutting edge technologies designed for rapid, successful drug development. We believe a robust engagement with the ecosystem will play a critical role in unlocking the vast potential of iPSC and enabling the next generation of cancer therapeutics."

To support these efforts, Alloy is establishing a Japanese subsidiary at Shonan Health Innovation Park in Kanagawa Prefecture, to be led by Victor Stone (Yoshihide Ishii) as the Head of Alloy Cell Therapies and Alloy Therapeutics Japan.

On November 20, 2024 Remix Therapeutics (Remix), a clinical-stage biotechnology company developing small molecule therapies to modulate RNA processing and address the underlying drivers of disease, reported an upcoming oral presentation at the 66th ASH (Free ASH Whitepaper) Annual Meeting taking place from December 7-10, 2024, in San Diego, CA (Press release, Remix Therapeutics, NOV 20, 2024, View Source [SID1234648531]). Results demonstrate oral dosing of REM-422, a selective mRNA degrader of the MYB oncogene, leads to robust anti-leukemic activity observed both as a monotherapy and in combination across a genetically diverse set of preclinical models of acute myeloid leukemia (AML), including eradication of AML blasts in engrafted patient-derived xenograft (PDX) models of AML. The presentation also highlights the differentiated mechanism of action of REM-422 as it can be combined effectively with other agents used in the treatment of AML/MDS and retains activity in cell models engineered with mutations known to confer resistance to other targeted agents.

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"The preclinical data for REM-422 provide strong therapeutic rationale for our ongoing Phase I study in AML and High-Risk MDS," said Peter Smith, Ph.D., President and Chief Executive Officer of Remix Therapeutics. "REM-422 is the first compound from our REMaster platform to enter clinical development. Its unique mechanism of action, coupled with the robust anti-leukemic activity observed both as a monotherapy and in combination, positions REM-422 as a promising candidate to address the unmet needs in these patient populations."

The MYB oncogenic transcription factor plays a crucial role in hematopoietic cell differentiation and proliferation. Its dysregulation and aberrant activity have been identified in various cancers, including adenoid cystic carcinoma (ACC), AML, acute lymphoblastic leukemia (ALL), and lymphoma. In AML, functional genomics studies have demonstrated a lineage-wide dependency on MYB, consistent with its involvement in disease driven by multiple oncogenic abnormalities (e.g. MLLr, NPM1, FLT3, p53, etc.).

REM-422 is a first-in-class, potent, selective, oral small molecule degrader of MYB mRNA currently in clinical development for AML/HR-MDS (NCT06297941) and ACC (NCT06118086). It functions by inducing the inclusion of a normally unused ‘poison exon’ (PE) in the MYB pre-mRNA transcript, activating the nonsense-mediated decay pathway and preventing MYB protein expression.

Details for the oral presentation are as follows:

Title: REM-422, a Small Molecule MYB mRNA Degrader, Demonstrates Anti-Leukemic Activity As Monotherapy and in Combination with Standards of Care in Preclinical Models of AML
Speaker: Samantha Levin-Furtney, Scientist, Remix Therapeutics
Session: 604- Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: New Targets and Drugs
Date: Monday, December 9, 2024
Time: 3:30 PM (Session time: 2:45-4:15 PM)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom ABCD

About REM-422
REM-422 is a first-in-class, potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and subsequent protein expression. REM-422 functions by facilitating the incorporation of poison exons within the mRNA transcript, leading to nonsense-mediated decay (NMD) of the transcript. REM-422 addresses MYB dysregulation, a driver of oncogenesis, upstream of protein expression.

About AML/HR-MDS
Acute myeloid leukemia (AML), a rare cancer of the blood and bone marrow, is the most common type of acute leukemia in adults. AML is caused by genetic mutations within bone marrow cells, which in turn causes the production of leukemic white blood cells that crowd out healthy blood cells. This may cause problems with bleeding, infection, and anemia. Myelodysplastic Syndromes (MDS) are disorders of blood-forming units in the bone marrow. High-risk (HR)-MDS patients have a higher percentage of blast cells in the bone marrow and that, in many cases, progresses to AML. There are several approved agents to treat AML, however, many patients relapse after achieving a response, underscoring the need for new therapies.

On November 20, 2024 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral targeted agents to treat hematologic malignancies, reported initiation of the TUSCANY study, tuspetinib (TUS) in combination therapy with azacitidine (AZA) and venetoclax (VEN) as a frontline triplet combination therapy for patients newly diagnosed with acute myeloid leukemia, or AML (Press release, Aptose Biosciences, NOV 20, 2024, View Source [SID1234648513]). The trial is being conducted at multiple U.S. clinical sites.

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Tuspetinib is being developed for frontline AML therapy as part of the TUS+VEN+AZA triplet for newly diagnosed AML patients ineligible to receive intensive chemotherapy. Tuspetinib, a convenient once daily oral agent that potently targets SYK, FLT3, mutated KIT, JAK1/2, and RSK2 kinases, avoids many typical toxicity concerns observed with other agents and has the potential to treat the larger AML populations, not just narrow subpopulations. In the recently conducted Phase 1/2 APTIVATE trial in a very ill and heavily pre-treated relapsed or refractory (R/R) AML population, tuspetinib as a single agent (TUS) and in combination with venetoclax (TUS+VEN) safely achieved broad activity across various difficult-to-treat AML subpopulations. This included patients with prior-VEN, prior-FLT3 inhibitor (FLT3i) and prior-hematopoietic stem cell transplantation (HSCT) therapies, those with highly adverse genetics – including mutations in TP53 and RAS genes, and those with mutated or unmutated (wildtype) FLT3 genes.

"Initiation of the trial is a key milestone for Aptose. AML treatment has rapidly shifted to combination therapies, and we are pleased to include tuspetinib as part of TUS+VEN+AZA triplet combination therapy in patients with newly-diagnosed AML – representing a new patient population for TUS," said William G. Rice, Chairman, President and Chief Executive Officer. "We thank our investigators for their enthusiasm and our clinical team for activating the TUSCANY triplet study. As one of our investigators noted, if TUS brings added efficacy to frontline treatment of a broad array of AML patients without the added toxicities that are plaguing some other agents, we may have a game changer in TUS."

TUSCANY: TUS+VEN+AZA Triplet Phase 1/2 Study
The triplet Phase 1/2 study is designed to test various doses and schedules of TUS in combination with standard of care dosing of azacitidine and venetoclax. TUS will be administered in 28-day cycles, beginning with 40mg, with dose escalations planned after safety review of each dose level. A planned 12 sites in the US will enroll in the TUSCANY trial with anticipated enrollment of 18-24 patients by mid-late 2025.

On November 20, 2024 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported the initiation of its ALISertib in CAncer (ALISCA-Breast1) Phase II trial (PUMA-ALI-1201; NCT06369285) of alisertib in combination with endocrine therapy for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-negative) recurrent or metastatic breast cancer who have been previously treated with CDK 4/6 inhibitors and received at least two prior lines of endocrine therapy in the recurrent or metastatic setting (Press release, Puma Biotechnology, NOV 20, 2024, View Source [SID1234648532]). The ALISCA-Breast1 trial will enroll up to 150 patients who will be randomized (1:1:1) to receive alisertib dosed at either 30 mg, 40 mg or 50 mg twice daily on days 1-3, 8-10 and 15-17 in a 28-day cycle in combination with the endocrine therapy of the investigator’s choice. Patients must provide blood and tissue specimens so that biomarkers can be analyzed.

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"Additional therapies are needed for patients with HER2-negative, HR+ metastatic breast cancer whose disease progresses on CDK4/6 inhibitors in the first-line setting"

The primary objective of the trial is to determine the optimal alisertib dose in combination with selected endocrine therapy. The primary endpoints of the trial include objective response rate, duration of response, disease control rate, progression-free survival, and overall survival. As a secondary endpoint, Puma will evaluate each of these efficacy endpoints within biomarker subgroups in order to determine whether any biomarker subgroup correlates with response. Puma will perform its biomarker analysis of the ALISCA-Breast1 trial in parallel with the execution of the clinical trial. Puma plans to perform an initial interim analysis for the evaluation of safety and efficacy.

Based upon the outcomes of the trial, Puma anticipates meeting with the U.S. Food and Drug Administration to explore the potential for an approval pathway for alisertib in HER2-negative, HR+ metastatic breast cancer. Once the optimal alisertib dose is identified, Puma plans to engage with global regulatory agencies regarding the design of a pivotal (Phase III) trial, which it anticipates will be a randomized trial of alisertib plus investigator’s choice endocrine therapy versus placebo plus investigator’s choice endocrine therapy in patients with HER2-negative, HR+ metastatic breast cancer.

"Additional therapies are needed for patients with HER2-negative, HR+ metastatic breast cancer whose disease progresses on CDK4/6 inhibitors in the first-line setting," said Joyce A. O’Shaughnessy, M.D., the Celebrating Women Chair in Breast Cancer Research at Baylor University Medical Center, Texas Oncology, Sarah Cannon Research Institute in Dallas, Texas. "The results from the TBCRC 041 trial indicated that alisertib has impressive clinical activity in the setting of endocrine therapy and CDK4/6 inhibitor-resistant metastatic breast cancer, with good tolerability. I look forward to the further evaluation of alisertib in the ALISCA-Breast1 trial to definitively determine the clinical impact of this treatment."

Alan H. Auerbach, Chief Executive Officer, President and Founder of Puma, stated, "We are excited to initiate this Phase II trial and to move forward with the development of alisertib in HER2-negative HR+ metastatic breast cancer. We believe that the data from the previous trial of alisertib monotherapy (published in Lancet Oncology) as well as the TBCRC 041 trial (published in JAMA Oncology), which tested alisertib alone and with fulvestrant, and the randomized trial of alisertib plus paclitaxel versus paclitaxel alone (published in JAMA Network Open) have demonstrated that alisertib is active in patients with HER2-negative, HR+ metastatic breast cancer and in biomarker focused subgroups. We look forward to enrollment in the ALISCA-Breast1 trial and anticipate that we should have initial data from this trial in 2025."