On November 24, 2025 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a development stage biopharmaceutical company pursuing life-changing therapies in oncology and rare diseases, reported its unaudited financial results for the quarter ended September 30, 2025, and provided a corporate update.

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"The clear highlight of the third quarter was our announcement in September that we established a joint venture with Hemispherian, expanding our development pipeline into additional high-need cancer indications, leading with glioblastoma, in addition to our ongoing PDAC program," stated Philip Serlin, Chief Executive Officer of BioLineRx. "Hemispherian’s lead asset, GLIX1, is a versatile molecule with a novel mechanism of action that targets the DNA repair mechanism in cancer cells and has demonstrated compelling efficacy in numerous pre-clinical models. Importantly, the development path is straightforward and efficient, and we are eager to initiate a Phase 1/2a first-in-human study in the first quarter of next year while also advancing pre-clinical activities in support of future potential trials of GLIX1 in other cancers."

"At the same time, the ongoing CheMo4METPANC Phase 2b clinical trial of motixafortide in metastatic pancreatic cancer, which is being led by Columbia University and supported by both Regeneron and BioLineRx, continues to progress, giving us a second opportunity to leverage our drug development expertise to bring true innovation to patients with difficult-to-treat cancers," Mr. Serlin concluded.

Corporate Updates

Announced formation of a joint venture to advance privately held Hemispherian’s small molecule cancer therapeutic, GLIX1
GLIX1, a Phase 1-ready candidate that is being developed as a potential treatment for glioblastoma, estimated to be a greater than $3.7 billion global addressable market by 2030 that has seen little innovation since the current standard of care was developed in 2005. The compound is also expected to be evaluated in other cancers, with preclinical work beginning in 2026.
Announced that it has received Notice of Allowance from the U.S. Patent and Trademark Office (USPTO) for a key patent covering GLIX1 for cancers in which cytidine deaminase (CDA) is not over-expressed beyond a specific threshold, estimated to be 90% of all cancers.
Patent preserves BioLineRx’s ability to evaluate GLIX1 in other cancers beyond glioblastoma, including both hematological and solid tumor cancer types.
Patent further broadens and strengthens GLIX1’s patent protection until 2040, with a possible patent-term extension of up to five years.

Financial Updates

With $25.2 million on its balance sheet as of September 30, 2025, BioLineRx is maintaining its cash runway guidance into the first half of 2027.
Clinical Updates

GLIX1

Continued to advance preparations for initiation of a Phase 1/2a clinical trial of GLIX1 in recurrent and newly diagnosed glioblastoma in the first quarter of 2026.
World leading investigators in the field of glioblastoma, Dr. Roger Stupp and Dr. Ditte Primdahl of the Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center at Northwestern University, will serve as principal investigators for the study.
The Phase 1 part of the trial aims to establish a maximum tolerated dose (MTD) and/or a recommended dose based on safety, PK/PD and preliminary efficacy.
The Phase 2a expansion part of the trial is planned to include three population cohorts: (1) GLIX1 as monotherapy in recurrent GBM, (2) GLIX1 on top of standard of care in newly diagnosed GBM patients (likely a "window of opportunity" study, with biopsies before and after treatment for PD assessment), and (3) GLIX1 in combination with PARP inhibitors in other solid tumors.
Pre-clinical activities in support of potential clinical trials of GLIX1 in additional cancers are ongoing.
Motixafortide

Pancreatic Ductal Adenocarcinoma (mPDAC)

Enrollment continues in the CheMo4METPANC Phase 2b clinical trial, which is being led by Columbia University, and supported by both Regeneron and BioLineRx. The CheMo4METPANC trial is evaluating motixafortide in combination with the PD-1 inhibitor cemiplimab and standard chemotherapy (gemcitabine and nab-paclitaxel).
A prespecified interim analysis is planned when 40% of progression-free survival (PFS) events are observed.
Sickle Cell Disease (SCD) & Gene Therapy

Announced that a poster featuring final results from a Phase 1 clinical trial (NCT05618301) evaluating motixafortide as monotherapy and in combination with natalizumab for CD34+ hematopoietic stem cell (HSC) mobilization for gene therapies in sickle cell disease (SCD) was accepted for presentation at the 67th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition taking place December 6-9, 2025, in Orlando, FL.
The 10-subject proof-of-concept study, which was conducted in collaboration with Washington University School of Medicine, demonstrated that motixafortide alone, and in combination with natalizumab, were found to be safe and well- tolerated. Common adverse events were transient and included Grade 1-2 injection site and systemic reactions. No Grade 4 adverse events, dose limiting toxicities or complicated vaso-occlusive events occurred. Motixafortide alone, and in combination with natalizumab resulted in robust CD34+ HSC mobilization.
Motixafortide alone mobilized a median of 189 CD34+ cells/μl (range 77-690) to the peripheral blood (PB), with a median yield of 4.22×106 CD34+ cells/kg following a single blood volume collection, projecting the collection of 16.9×106 cells/kg in a four-blood-volume apheresis collection session. Motixafortide in combination with natalizumab mobilized a median of 312 CD34+ cells/μl (range 117-447) to the PB, with a median yield of 4.89×106 CD34+ cells/kg following a single blood volume collection, projecting the collection of 19.6×106 CD34+ cells/kg in a four-blood-volume apheresis collection session. The collection yields of motixafortide alone and in combination with natalizumab are encouraging given that hematopoietic stem cell-based gene therapy for sickle cell disease requires sufficient HSCs (16.5-20×106 CD34+ cells/kg) to generate a product.
In two subjects with prior plerixafor mobilization, motixafortide alone, and in combination with natalizumab, led to 2.7-2.8 fold higher CD34+ cells/μl mobilization to PB and 2.8-3.2 fold higher CD34+ cells/kg collection yield, respectively, than plerixafor.
A second SCD study, sponsored by St. Jude Children’s Research Hospital, continues to enroll patients. The study is a multi-center Phase 1 clinical trial evaluating motixafortide for the mobilization of CD34+ HSCs used in the development of gene therapies for patients with SCD.
APHEXDA Performance Update

APHEXDA generated sales of $2.4 million in the third quarter of 2025, providing royalty revenue to the Company of $0.4 million.
Financial Results for the Quarter Ended September 30, 2025

Total revenues for the third quarter of 2025 were $0.4 million, reflecting the royalties paid by Ayrmid from the commercialization of APHEXDA in stem cell mobilization in the U.S. Total revenues in 2025 are not comparable to the same period in 2024, which included a portion of the upfront payment from Gloria Biosciences ($3.2 million) as well as direct commercial sales by BioLineRx ($1.7 million) prior to the Ayrmid transaction in November 2024.

Cost of revenues for the third quarter of 2025 was immaterial, compared to cost of revenues of $0.8 million for the third quarter of 2024. The cost of revenues in 2025 reflects sub-license fees on royalties paid by Ayrmid from the commercialization of APHEXDA in stem cell mobilization in the U.S. The cost of revenues in 2024 primarily reflects amortization of intangible assets, royalties on net product sales of APHEXDA in the U.S. and cost of goods sold on product sales.

Research and development expenses for the third quarter of 2025 were $1.7 million, a decrease of $0.8 million, or 33.0%, compared to $2.6 million for the third quarter of 2024. The decrease resulted primarily from lower expenses related to motixafortide due to the out-licensing of U.S. rights to Ayrmid, as well as a decrease in payroll and share-based compensation, primarily due to a decrease in headcount.

There were no sales and marketing expenses for the third quarter of 2025, compared to $5.5 million for the third quarter of 2024. The decrease resulted primarily from the shutdown of U.S. commercial operations in the fourth quarter of 2024 following the Ayrmid out-licensing transaction.

General and administrative expenses for the third quarter of 2025 were $0.8 million, a decrease of $0.6 million, or 40.2%, compared to $1.4 million for the third quarter of 2024. The decrease resulted primarily from lower payroll and share-based compensation, primarily due to a decrease in headcount, as well as small decreases in a number of general and administrative expenses.

Non-operating income (expenses) for the third quarters of 2025 and 2024 primarily relate to fair-value adjustments of warrant liabilities on the Company’s balance sheet, as a result of changes in its share price, offset by warrant offering expenses.

Net financial income for the third quarter of 2025 was $0.1 million, compared to net financial expenses of $1.2 million for the third quarter of 2024. Net financial income (expenses) for both periods primarily relate to loan interest paid, partially offset by investment income earned on bank deposits and gains on foreign currency (primarily NIS) cash balances due to the strengthening of the NIS against the US dollar during the period. The significant decrease in financial expenses in the 2025 period results from a substantial paydown of the BlackRock loan balance in November 2024, following the transaction with Ayrmid.

Net loss for the third quarter of 2025 was $1.0 million, compared to net loss of $5.8 million for the third quarter of 2024.

As of September 30, 2025, the Company had cash, cash equivalents, and short-term bank deposits of $25.2 million, sufficient to fund operations, as currently planned, into the first half of 2027.

Conference Call and Webcast Information

To access the conference call, please dial +1-888-281-1167 from the U.S. or +972-3-918-0685 internationally. A live webcast and a replay of the call can be accessed through the event page on the Company’s website. Please allow extra time prior to the call to visit the site and download any necessary software to listen to the live broadcast. The call replay will be available approximately two hours after completion of the live conference call. A dial-in replay of the call will be available until November 26, 2025; please dial +1-888-295-2634 from the US or +972-3-925-5904 internationally.

(Press release, BioLineRx, NOV 24, 2025, View Source [SID1234660889])

On November 24, 2025 PharmaMar (MSE:PHM) reported that the Swiss Agency for Therapeutic Products (Swissmedic) has granted approval for Zepzelca (lurbinectedin) in combination with atezolizumab (Tecentriq) as a maintenance treatment for adults with extensive-stage small cell lung cancer

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(ES-SCLC), with no central nervous system (CNS) metastases whose disease has not progressed after first-line induction therapy with atezolizumab, carboplatin and etoposide. The decision marks the first combination therapy approval in an European country for first-line maintenance treatment of ES-SCLC, a fast growing and aggressive cancer with limited treatment options.

The Swissmedic approval is based on results from the Phase 3 IMforte[i] trial, which showed that the lurbinectedin and atezolizumab combination reduced the risk of disease progression or death by 46% and the risk of death by 27%, compared to atezolizumab maintenance therapy alone. Following four cycles of induction therapy, from the point of randomization the median overall survival (OS) for the combination regimen was 13.2 months versus 10.6 months and median progression-free survival (PFS) by independent assessment was 5.4 months versus 2.1 months, respectively. Safety was consistent with the known safety profiles of both treatments

In 2023, Swissmedic granted Temporary Authorisation for the commercialization of lurbinectedin alone for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy without CNS metastases in second line.

Luis Mora, Managing Director of PharmaMar, said: "Switzerland has become the first European country to approve this combination for use as a first-line treatment, giving patients access to this new therapy. We will continue working to ensure that as many patients as possible have access to this new therapy across as many countries as possible."

In October, the U.S Food and Drug Administration (FDA) granted approval for Zepzelca (lurbinectedin) in combination with atezolizumab (Tecentriq) as a maintenance treatment for adults with extensive-stage small cell lung cancer (ES-SCLC). In addition, the National Comprehensive Cancer Network (NCCN) recently updated the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for SCLC to include the combination as a preferred regimen for maintenance.

PharmaMar has also submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA), which is currently under review.

SCLC represents about 15% of all lung cancer cases in Europe, each year, approximately 72,600 new cases of SCLC are reported in Europe. Most of these patients are diagnosed with extensive stage disease, which is aggressive and often difficult to treat, with poor prognosis.

(Press release, PharmaMar, NOV 24, 2025, View Source [SID1234660905])

On November 24, 2025 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. (the "Company", 6990.HK) reported that the Independent Data Monitoring Committee (IDMC) concluded that the Phase III clinical study (OptiTROP-Lung05) of the company’s TROP2 ADC sacituzumab tirumotecan (sac-TMT, also known as SKB264/MK-2870), in combination with MSD’s anti-PD-1 therapy KEYTRUDA[1] (pembrolizumab), as a first-line treatment for PD-L1-positive advanced non-small cell lung cancer (NSCLC), has demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), the study’s primary endpoint. A positive trend in overall survival was also observed. This is the first Phase III clinical trial of ADC combined with immune checkpoint inhibitor to achieve its primary endpoint in the first-line treatment of NSCLC.

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OptiTROP-Lung05 is a randomized, open-label, multicenter Phase III clinical study evaluating the efficacy and safety profile of sac-TMT in combination with pembrolizumab versus pembrolizumab monotherapy as first-line treatment of patients with PD-L1-positive locally advanced or metastatic NSCLC with PD-L1 TPS ≥ 1%. At a pre-specified interim analysis, the sac-TMT combination therapy demonstrated a statistically significant and clinically meaningful improvement in PFS. Based on the results from the interim analysis, the Company plans to communicate with the Center for Drug Evaluation (CDE) of the National Medical Products Administration of China regarding the submission of a supplemental new drug application (sNDA) of sac-TMT.

Sac-TMT is already approved in China for the treatment of EGFR-mutant NSCLC in the second-line and later settings and has achieved dual benefits in PFS and overall survival (OS) in the EGFR-TKI-resistant lung cancer population, making it the first ADC to show statistically significant and clinically meaningful improvements in both PFS and OS compared to platinum doublet chemotherapy. These research findings have been published in internationally renowned journals, The New England Journal of Medicine and The BMJ.

Sac-TMT is currently being evaluated in ten registrational studies in lung cancer, including five registrational studies in China and five global multicenter Phase III studies.

About sac-TMT

Sac-TMT, a core product of the Company, is a novel human TROP2 ADC in which the Company has proprietary intellectual property rights, targeting advanced solid tumors such as NSCLC, BC, GC, gynecological tumors, among others. Sac-TMT is developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor with a drug-to-antibody-ratio (DAR) of 7.4. Sac-TMT specifically recognizes TROP2 on the surface of tumor cells by recombinant anti-TROP2 humanized monoclonal antibodies, which is then endocytosed by tumor cells and releases the payload KL610023 intracellularly. KL610023, as a topoisomerase I inhibitor, induces DNA damage to tumor cells, which in turn leads to cell-cycle arrest and apoptosis. In addition, it also releases KL610023 in the tumor microenvironment. Given that KL610023 is membrane permeable, it can enable a bystander effect, or in other words kill adjacent tumor cells.

In May 2022, the Company licensed the exclusive rights to MSD (the tradename of Merck & Co., Inc, Rahway, NJ, USA) to develop, use, manufacture and commercialize sac-TMT in all territories outside of Greater China (which includes Mainland China, Hong Kong, Macao and Taiwan).

To date, three indications for sac-TMT have been approved and marketed in China for the treatment of adult patients with unresectable locally advanced or metastatic triple negative breast cancer (TNBC) who have received at least two prior systemic therapies (at least one of them for advanced or metastatic setting), EGFR mutation-positive locally advanced or metastatic non-squamous NSCLC following progression on EGFR-TKI therapy and platinum-based chemotherapy and EGFR mutant-positive locally advanced or metastatic non-squamous NSCLC who progressed after treatment with EGFR-TKI therapy. Sac-TMT is the first TROP2 ADC drug approved for marketing in lung cancer globally. In addition, the sNDA for sac-TMT for the treatment of adult patients with unresectable locally advanced, metastatic HR+/HER2- BC who have received prior endocrine therapy and other systemic treatments in the advanced or metastatic setting was accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA), and was included in the priority review and approval process.

As of today, the Company has initiated 9 registrational clinical studies in China. MSD has initiated 15 ongoing Phase 3 global clinical studies of sac-TMT as a monotherapy or with pembrolizumab or other anti-cancer agents for several types of cancer. These studies are sponsored and led by MSD.

(Press release, Kelun, NOV 24, 2025, View Source [SID1234660921])

On November 24, 2025 Bristol Myers Squibb (NYSE: BMY) reported that the European Commission (EC) has granted approval to Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor.

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"This approval for Breyanzi in relapsed or refractory mantle cell lymphoma marks another important step as we continue to deliver on the promise of cell therapy for more eligible patients across Europe – the fourth approval for Breyanzi in Europe," said Emma Charles, senior vice president, Europe Region, Bristol Myers Squibb. "While frontline therapies have advanced over the years for this rare but aggressive form of non-Hodgkin lymphoma, the vast majority of patients relapse or become resistant and face reduced survival outlook, leaving a critical need for new treatment options. Breyanzi has the opportunity to address a treatment gap for this patient population based on its demonstrated clinical benefit."

The decision is based on results from the MCL cohort of TRANSCEND NHL 001, which enrolled adult patients with relapsed or refractory MCL who had received at least two prior lines of therapy including a BTK inhibitor. Among patients treated in the third-line plus setting, Breyanzi demonstrated a high overall response rate of 82.7% (95% CI: 72.7–90.2) and complete response (CR) rate of 71.6% (95% CI: 60.5–81.1), the study’s primary and key secondary endpoints, respectively. Responses were rapid and demonstrated sustained efficacy, with a median time to first response (CR or partial response (PR)) of 0.95 months (range: 0.7 to 3.0 months) and 50.8% (95% CI: 29.2–52.9) of patients still in response at 24 months.

Safety results were consistent with the well-established safety profile of Breyanzi observed across clinical trials and approved indications, with a predictable safety profile observed in MCL with early resolution. The majority of cytokine release syndrome (CRS) and neurologic toxicities developed during the first 14 days post infusion, reinforcing recent adjustments to short term monitoring requirements. For patients who received Breyanzi for MCL in the TRANSCEND NHL 001 trial, CRS occurred in 61% of patients, with only 1% of patients experiencing grade three or four CRS. The median time to onset was four days (range: 1 to 10 days). Any grade neurologic toxicities occurred in 31% of patients, including grade three or four in 9% of patients. The median time to onset of the first event was eight days (range: 1 to 25 days).

This expanded approval is applicable to all European Union (EU) member states as well as the European Economic Area (EEA) countries Iceland, Norway and Liechtenstein.* Breyanzi is also approved in the EU for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who relapsed within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy, and for the treatment of adult patients with relapsed or refractory DLBCL, PMBCL, and FL3B after two or more lines of systemic therapy, and for adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

*Centralized Marketing Authorization does not include approval in the United Kingdom (UK).

About TRANSCEND NHL 001

TRANSCEND NHL 001 (NCT02631044) is an open-label, multicenter, pivotal, Phase 1, single-arm, seamless-design study to determine the safety, pharmacokinetics and antitumor activity of Breyanzi in adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B and mantle cell lymphoma. The primary outcome measures are treatment-related adverse events, dose-limiting toxicities and overall response rate. Secondary outcome measures include complete response rate, duration of response, and progression-free survival.

About MCL

Mantle cell lymphoma (MCL) is an aggressive, rare form of non-Hodgkin lymphoma (NHL), representing roughly 3% of all NHL cases. MCL originates from cells in the "mantle zone" of the lymph node. MCL occurs more frequently in older adults with an average age at diagnosis in the mid-60s, and it is more often found in males than in females. In MCL, relapse after initial treatment is common, and for most, the disease eventually progresses or returns.

About Breyanzi

Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is made from a patient’s own T cells, which are collected and genetically reengineered to become CAR T cells that are then delivered via infusion as a one-time treatment. The treatment process includes blood collection, CAR T-cell creation, potential bridging therapy, lymphodepletion, administration, and side-effect monitoring.

Breyanzi is approved in the U.S. for the treatment of relapsed or refractory large B-cell lymphoma (LBCL) after at least one prior line of therapy, has received accelerated approval for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior lines of therapy and relapsed or refractory follicular lymphoma (FL) after two or more prior lines of systemic therapy, and is approved for the treatment of relapsed or refractory mantle cell lymphoma (MCL) after at least two prior lines of systemic therapy. Breyanzi is also approved in Japan, the European Union (EU), Switzerland, Israel, the United Kingdom, and Canada for the treatment of relapsed or refractory LBCL after at least one prior line of therapy; in Japan for the treatment of patients with relapsed or refractory high-risk FL after one prior line of systemic therapy, and in patients with relapsed or refractory FL after two or more lines of systemic therapy; and in the EU, Switzerland and the UK for the treatment of relapsed or refractory FL after two or more lines of systemic therapy.

Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in other types of lymphoma. For more information, visit clinicaltrials.gov.

The European Summary of Product Characteristics for Breyanzi will be available from the European Commission and EMA websites at www.ema.europa.eu.

Breyanzi U.S. FDA-Approved Indications

BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
relapsed or refractory disease after two or more lines of systemic therapy.
Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma.

adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor.
U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, AND SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.
Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. In clinical trials of BREYANZI, which enrolled a total of 702 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 54% of patients, including ≥ Grade 3 CRS in 3.2% of patients. The median time to onset was 5 days (range: 1 to 63 days). CRS resolved in 98% of patients with a median duration of 5 days (range: 1 to 37 days). One patient had fatal CRS and 5 patients had ongoing CRS at the time of death. The most common manifestations of CRS (≥10%) were fever, hypotension, tachycardia, chills, hypoxia, and headache.

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.

In clinical trials of BREYANZI, CAR T cell-associated neurologic toxicities occurred in 31% of patients, including ≥ Grade 3 cases in 10% of patients. The median time to onset of neurotoxicity was 8 days (range: 1 to 63 days). Neurologic toxicities resolved in 88% of patients with a median duration of 7 days (range: 1 to 119 days). Of patients developing neurotoxicity, 82% also developed CRS.

The most common neurologic toxicities (≥5%) included encephalopathy, tremor, aphasia, headache, dizziness, and delirium.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In clinical trials of BREYANZI, infections of any grade occurred in 34% of patients, with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.7%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient who received 4 prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy 4 months after treatment with BREYANZI. One patient who received 3 prior lines of therapy developed a fatal case of cryptococcal meningoencephalitis 35 days after treatment with BREYANZI.

Febrile neutropenia developed after BREYANZI infusion in 8% of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In clinical trials of BREYANZI, 35 of 38 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. In clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 35% of patients, and included thrombocytopenia in 25%, neutropenia in 22%, and anemia in 6% of patients. Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 10% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 30% of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Three of 89 (3%) safety evaluable patients with R/R CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 18 days. Two of the 3 patients developed IEC-HS in the setting of ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS was fatal in 2 of 3 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death. IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines.

Adverse Reactions

The most common adverse reaction(s) (incidence ≥30%) in:

LBCL are fever, cytokine release syndrome, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.
CLL/SLL are cytokine release syndrome, encephalopathy, fatigue, musculoskeletal pain, nausea, edema, and diarrhea. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, hemoglobin decrease, platelet count decrease, and lymphocyte count decrease.
FL is cytokine release syndrome. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, and white blood cell decrease.
MCL are cytokine release syndrome, fatigue, musculoskeletal pain, and encephalopathy. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, and platelet count decrease.

(Press release, Bristol-Myers Squibb, NOV 24, 2025, View Source [SID1234660890])

On November 24, 2025 Rakovina Therapeutics Inc. ("Rakovina" or the "Company") (TSX-V: RKV)(FSE: 7JO0) a biopharmaceutical company advancing cancer therapies through AI-enabled drug discovery, reported impressive results from its AI-enabled ATR program at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting which took place November 19-23 in Honolulu, Hawaii.

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The poster, titled "Discovery and development of a novel CNS-penetrating ATR inhibitor: Dual inhibition of ATR and mTOR in PTEN-deficient tumors," highlights the discovery and early characterization of novel ATR/mTOR dual inhibitors designed using the Enki generative AI platform. The compounds are engineered to modulate two well-established cancer-driving pathways that, despite their importance, have never before been combined in a single therapeutic agent. Notably, Rakovina’s lead molecules were designed specifically to cross the blood–brain barrier and reach tumor cells within the central nervous system, supporting their potential relevance in primary brain cancers and cancers with a high risk of brain metastasis.

Rakovina’s senior management team presented the findings showing that the AI-discovered ATR+mTOR inhibitors achieve meaningful CNS penetration, addressing a key limitation of current clinical ATR inhibitors, which have poor CNS distribution. In direct comparisons, multiple Rakovina compounds showed >50% ATR inhibition at 1 µM and exhibited equal or greater enzymatic potency than leading ATR inhibitors ceralasertib, tuvusertib, and elimusertib, while maintaining similar PIKK-family selectivity.

Importantly, these compounds were engineered with a mechanistic rationale to co-target ATR and mTOR, two pathways on which PTEN-deficient tumors (including those prone to brain metastasis) are highly dependent. By simultaneously blocking ATR-mediated DNA damage response and mTOR-driven survival signaling, these CNS-penetrant inhibitors have the potential to overcome key resistance mechanisms in PTEN-deficient cancers and deliver therapeutic effects not achievable with ATR-only agents.

PTEN deficiency in cancer

PTEN is one of the most frequently lost tumor-suppressor genes in human cancer and serves as a key brake on the PI3K/AKT/mTOR signaling pathway that governs cell growth, metabolism, and survival. Its loss promotes unchecked proliferation, genomic instability, therapy resistance, and aggressive tumor progression.

PTEN deficiency is particularly prevalent in cancers with a high propensity for CNS spread, including ovarian, lung, breast, and melanoma – where tumor cells rely heavily on mTOR-driven growth and survival. In these settings, mTOR becomes an adaptive escape pathway, especially under ATR inhibition, allowing PTEN-deficient tumors to accelerate growth and diminish the effectiveness of ATR-only therapeutic strategies.

Prevalence of PTEN deficiency and CNS metastases in major cancers
Cancer type Approximate frequency of PTEN loss Est. CNS Metastases Prevalence
Lung cancer ~ 35-55 % ~55% in NSCLC
Breast cancer ~ 30-40 % ~40%
Prostate cancer ~ 25-50 % ~8%
Colorectal cancer ~ 10-40 % ~6%
Ovarian cancer ~ 30-50 % ~5%
Endometrial carcinoma ~ 50 % 1-2%
Glioblastoma (brain) ~ 80-85 % n/a (primary brain tumor
Using the ENKI generative AI platform, the Company designed a virtual library of 138 predicted compounds, from which, 43 priority molecules were synthesized for evaluation in biochemical and cellular assays. Multiple compounds demonstrated >50% inhibition of recombinant ATR at 1 µM and exhibited potency comparable to or exceeding ATR inhibitors currently in development including ceralasertib, tuvusertib, and elimusertib.

Pharmacokinetic profiling in mice following a single 5 mg/kg intraperitoneal dose revealed favorable tolerability, metabolic stability in human liver microsomes, and measurable CNS exposure, supporting further evaluation in brain tumor models.

"Sharing these data at SNO is an important milestone for our ATR/mTOR program," said Prof. Mads Daugaard, President and Chief Scientific Officer of Rakovina Therapeutics. "To our knowledge, no company has previously generated a single small-molecule therapeutic designed to combine ATR and mTOR inhibition with CNS penetration. Seeing generative AI propose compounds with this level of precision gives us a fundamentally new way to address these difficult-to-treat cancers with a high risk of brain involvement."

"The reception to our data at SNO has been very encouraging," added Jeffrey Bacha, executive chairman of Rakovina Therapeutics. "This program showcases how combining Variational AI’s Enki platform with the translational capabilities at the Vancouver Prostate Centre allows us to rapidly pursue differentiated DDR-targeted therapeutics with potential clinical relevance in areas of significant unmet need."

(Press release, Rakovina Therapeutics, NOV 24, 2025, View Source;utm_medium=rss&utm_campaign=rakovina-therapeutics-showcases-compelling-preclinical-data-on-ai-discovered-cns-penetrant-atr-mtor-inhibitors-at-the-2025-society-for-neuro-oncology-annual-meeting [SID1234660906])