On February 10, 2025 iBio, Inc. (NYSEA:IBIO), reported financial results for the second quarter ended Dec. 31, 2024, and provided a corporate update on its progress (Press release, iBioPharma, FEB 10, 2025, View Source [SID1234650132]).

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"In our second fiscal quarter we further strengthened our leadership with key Board appointments, reinforcing our commitment to innovation and execution as we work to develop next-generation therapeutics," said CEO and Chief Scientific Officer Dr. Martin Brenner, Ph.D. "Following more recent developments, we also want to highlight the significant strides we have made in advancing our preclinical pipeline with the in-licensing of potentially best-in-class IBIO-600, the notable discovery of a novel Activin E antibody, and the launch of a bispecific antibody program targeting myostatin/activin A. We are excited by the momentum we have built through these results and remain focused on leveraging our AI-driven platform as we aim to transform the treatment landscape for patients with cardiometabolic diseases and obesity, offering hope for more effective, targeted therapies addressing the underlying causes of these conditions while improving overall metabolic health and quality of life."

Fiscal Second Quarter 2025 & Recent Corporate Updates:

Discovered a novel antibody targeting activin E in collaboration with AstralBio, leveraging iBio’s Machine-Learning Antibody Engine to overcome significant technical challenges, demonstrating the platform’s ability to engineer innovative therapeutics potentially for cardiometabolic disease and obesity.

Expanded iBio’s cardiometabolic and obesity program with IBIO-600, the long-acting anti-myostatin antibody in-licensed from AstralBio in January. IBIO-600 was discovered by AstralBio through the use of iBio’s Machine-Learning Antibody Engine and was designed for subcutaneous administration with the potential for an extended half-life.

Initiated a bispecific antibody program targeting myostatin/activin A to promote weight loss, muscle preservation, and prevent weight regain with plans for clinical investigation in obesity and cardiometabolic disorders in 2026. The program leverages iBio’s Machine-Learning Antibody Engine as well as the technology of IBIO-600.
Strengthened the Board of Directors with the appointments of biotech industry veterans David Arkowitz and António Parada on November 25, 2024.
In January we further extended our cash runway with the closing of a private placement offering with members of our Board of Directors and Officers, underscoring their confidence and support in our strategy to advance as a clinical-stage biotech.

Fiscal Second Quarter 2025 Financial Results:

Revenue of $0.2 million was reported for services provided to a collaborative partner during the quarter ended Dec. 31, 2024.

R&D and G&A expenses for the second quarter of fiscal 2025 totaled approximately $4.6 million as compared to $4.5 million in the same period of fiscal year 2024, an increase of approximately 3%. This slight increase is a result of additional spending on consumables supplies and research related activities offset by lower G&A personnel related costs, consulting fees and outside services spending. Net loss from continuing operations for the second quarter ended Dec. 31, 2024, was approximately $4.4 million, or $0.48 per share, compared to a net loss of approximately $4.5 million, or $2.42 per share, in the same period of fiscal 2024.

Cash, cash equivalents and restricted cash as of Dec. 31, 2024, was approximately $7.2 million, inclusive of $0.2 million of restricted cash.

On February 10, 2025 Greenwich LifeSciences, Inc. (Nasdaq: GLSI) (the "Company"), a clinical-stage biopharmaceutical company focused on its Phase III clinical trial, FLAMINGO-01, which is evaluating GLSI-100, an immunotherapy to prevent breast cancer recurrences, reported the following update on FLAMINGO-01 open label HLA data (Press release, Greenwich LifeSciences, FEB 10, 2025, View Source [SID1234650131]).

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Analysis of the open label data from FLAMINGO-01 has commenced and has been conducted in a manner that maintains the study blind. A preliminary review of FLAMINGO-01 HLA data in both the HLA-A*02 treated and placebo arms and the third open label arm with all other HLA types, shows that approximately 46% of all screened patients have at least one HLA-A*02 allele from either parent.

The main purpose of the open label arm is to investigate the safety and efficacy of GLSI-100 vaccination in patients who do not have an HLA-A*02 allele. It is possible that the open label arm may be large enough to draw immune response and efficacy conclusions. As discussed below, the HLA type can be analyzed by race and ethnicity in those patients who self-reported such information.

CEO Snehal Patel commented, "The review of open label data and the ability to look at multiple patient populations in the Phase III trial will be much greater than was possible in the Phase IIb trial. The HLA-A*02 prevalence of 46% in all screened patients meets our expectations of 40-50% prevalence and supports our sample size estimates for the trial and the interim analysis. We are also interested in studying the 8% of patients who have received HLA-A*02 alleles from both parents, as the mechanism of action in these double HLA-A*02 patients could lead to greater immune response and efficacy."

Mr. Patel further added, "There may be other subgroups of HLA types that can be analyzed in addition to the main arms. Approximately 92% of the patients that are in the HLA-A*02 arms have a second HLA-A type from the other parent that is not HLA-A*02 and could be any of 6 or more other prevalent HLA-A types. We can compare these HLA combinations against each other for immune response and clinical outcome, which could allow for subgroup analysis of HLA-A combinations. The prevalence of various HLA-A types by race or ethnicity may also help to inform the Company in its initial commercial development strategy by suggesting those markets where the most efficacious HLA patient populations may reside."

Background on FLAMINGO-01 Trial Design and HLA Testing

The design of the Phase III trial can be seen here. The trial is a prospective, randomized, double-blinded, multi-center study. The patient population is defined by major screening criteria and is stratified to balance the patient population between the treated and placebo arms of the trial.

As currently designed, approximately 500 patients with the HLA-A*02 allele will be randomized to receive GLSI-100 (GP2 and GM-CSF) or placebo control in the first two pivotal arms of the trial with a planned interim analysis.

In addition, patients without the HLA-A*02 allele will be enrolled in the third open label arm where all patients will receive GLSI-100 and where all endpoints will be open label. This non-HLA-A*02 arm was recently expanded from 100 to 250 patients based on recommendation of the steering committee and review/approval by the FDA and EMA.

HLA-A*02 blinded arms: A patient has 2 HLA-A genes, one from each parent, thus a single HLA-A*02 patient has received the HLA-A*02 allele from one parent. A double HLA-A*02 patient has received the HLA-A*02 allele from both parents. Both single and double HLA-A*02 patients are enrolled in the HLA-A*02 treated and placebo arms, which are blinded. Those patients who have a single HLA-A*02 allele will also have a second HLA-A gene of any other type.
Double HLA-A*02 Potential Mechanism of Action: Theoretically, a double HLA-A*02 patient may have double the amount of HLA-A*02-GP2 complex presented to the immune system to create cancer killing T-cells during the GLSI-100 vaccinations, and as a cancer cell recurs, the HER2 positive recurring cancer cells may have double the amounts HLA-A*02-GP2 complex for the trained T-cells to target and kill. It may be interesting to investigate immune or clinical response differences between single and double HLA-A*02 patients.
Open Label non-HLA-A*02 Third Arm: If a patient has no HLA-A*02 alleles, they will have 2 different or identical non-HLA-A*02 alleles. These non-HLA-A*02 patients are enrolled in the open label arm, where the immune or clinical response can be assessed as a group or by each HLA-A type, including double HLA-A types, providing the number of patients is sufficiently high to draw conclusions or trends.
Additional Information: A central laboratory in the US is sequencing the DNA of patients to determine both HLA-A allele types. The technology is available to sequence the HLA-B and HLA-C alleles, in addition to the HLA-A allele, to further assess other HLA types that may associate with GP2 to create a positive therapeutic effect. GP2 prediction binding algorithms may suggest that some HLA-B or HLA-C alleles may associate similarly to or stronger than HLA-A*02.
Phase IIb Clinical Trial Results

A variety of HLA types are predicted to associate with GP2 based on binding algorithms, and such binding can be tested in preclinical experiments. However, HLA-A*02 is the most common HLA type, thus it was studied first, and all patients in the Phase IIb trial had at least one HLA-A*02 allele. The HLA data collected did not identify if a patient was double HLA-A*02, nor were any other non-HLA-A*02 alleles identified.

Preliminary Review of FLAMINGO-01 HLA Data

Estimates of HLA prevalence by race are available in literature. As there are many sources and population studies to reference, a general consensus is that HLA-A*02 is prevalent in about 40-50% of the Caucasian population, which is the majority of the population in the US and Europe where the study is being conducted. To assess the prevalence of various HLA-A alleles by race, we have been collecting race and ethnicity data on all patients screened. We have summarized the preliminary data available to date in a blinded manner and have observed the results below. It is important to note that this preliminary summary may not reflect results at the end of the study.

Across all screened patients, HLA-A*02 prevalence is about 46%. The double HLA-A*02 prevalence, in patients who have received HLA-A*02 alleles from both parents, is about 8%. Because there are 2 HLA-A genes, one from each parent, the total of all prevalence percentages exceeds 100% and is less than 200% because of double HLA-A types. The HLA-A*03, HLA-A*24, and HLA-A*01 prevalences are about 20-25% for each allele. The HLA-A*11, HLA-A*68, HLA-A*29, and HLA-A*30 prevalences are about 9-12% for each allele.
In those screened patients who self-report as White, at least single or double HLA-A*02 genes are prevalent in approximately 50% of the patients. The double HLA-A*02 alleles are prevalent in 10% of these patients screened. The next most prevalent HLA-A types in the White populations are HLA-A*01 (29%), HLA-A*03 (21%), HLA-A*24 (19%), HLA-A*68 (10%), HLA-A*29 (13%), and HLA-A*11 (9%).
In those screened patients who self-report as Hispanic or Latino, at least single or double HLA-A*02 alleles are prevalent in approximately 50% of the patients. The double HLA-A*02 genes are prevalent in 7% of these patients screened. The next most prevalent HLA-A types in the Hispanic or Latino populations are HLA-A*01 (20%), HLA-A*24 (22%), HLA-A*68 (22%), HLA-A*30 (18%), HLA-A*29 (13%), and HLA-A*11 (13%).
In those screened patients who self-report as Black or African-American, at least single or double HLA-A*02 alleles are prevalent in approximately 40% of the patients. The next most prevalent HLA-A types in the Black or African-American populations are HLA-A*68 (33%), HLA-A*03 (27%), HLA-A*30 (27%), HLA-A*24 (13%), HLA-A*29 (13%), and HLA-A*23 (13%).
In those screened patients who self-report as Asian, at least single or double HLA-A*02 alleles are prevalent in approximately 17% of the patients. The other prevalent HLA-A types are HLA-A*24 (42%), HLA-A*33 (42%), HLA-A*11 (25%), and HLA-A*03 (25%).
The above preliminary Flamingo-01 open label data on HLA-A alleles by race and ethnicity is similar to the data available in literature. If any of the non-HLA-A*02 alleles have a strong association to GP2, it may be interesting to study the immune response and efficacy of GLSI-100 in patients with one allele of that type and one allele that is HLA-A*02 in addition to in patients with the double HLA-A*02 alleles.

About FLAMINGO-01 and GLSI-100

FLAMINGO-01 (NCT05232916) is a Phase III clinical trial designed to evaluate the safety and efficacy of GLSI-100 (GP2 + GM-CSF) in HER2 positive breast cancer patients who had residual disease or high-risk pathologic complete response at surgery and who have completed both neoadjuvant and postoperative adjuvant trastuzumab based treatment. The trial is led by Baylor College of Medicine and currently includes US clinical sites from university-based hospitals and cooperative networks with plans to expand into Europe and to open up to 150 sites globally. In the double-blinded arms of the Phase III trial, approximately 500 HLA-A*02 patients will be randomized to GLSI-100 or placebo, and up to 250 patients of other HLA types will be treated with GLSI-100 in a third arm. The trial has been designed to detect a hazard ratio of 0.3 in invasive breast cancer-free survival, where 28 events will be required. An interim analysis for superiority and futility will be conducted when at least half of those events, 14, have occurred. This sample size provides 80% power if the annual rate of events in placebo-treated subjects is 2.4% or greater.

For more information on FLAMINGO-01, please visit the Company’s website here and clinicaltrials.gov here. Contact information and an interactive map of the majority of participating clinical sites can be viewed under the "Contacts and Locations" section. Please note that the interactive map is not viewable on mobile screens. Related questions and participation interest can be emailed to: [email protected]

About Breast Cancer and HER2/neu Positivity

One in eight U.S. women will develop invasive breast cancer over her lifetime, with approximately 300,000 new breast cancer patients and 4 million breast cancer survivors. HER2 (human epidermal growth factor receptor 2) protein is a cell surface receptor protein that is expressed in a variety of common cancers, including in 75% of breast cancers at low (1+), intermediate (2+), and high (3+ or over-expressor) levels.

On February 10, 2025 Clarity Pharmaceuticals (ASX: CU6) ("Clarity" or "Company"), a clinical-stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported the addition of a new asset, 64/67Cu-SAR-trastuzumab, into the Targeted Copper Theranostic (TCT) portfolio (Press release, Clarity Pharmaceuticals, FEB 10, 2025, View Source [SID1234650130]). Pre-clinical data on SAR-trastuzumab has recently been published and Clarity has signed a Supply Agreement with EirGenix, Inc. ("EirGenix") for the clinical development and future commercial supply of clinical-grade GMP trastuzumab biosimilar, EG12014. The supply enables the development of a radiolabelled product using Clarity’s SAR Technology.

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Trastuzumab is an antibody that targets HER2, which is expressed in many cancers, including some types of lung, gastric and breast cancers4. This novel theranostic asset will initially focus on breast cancer and, combined with SAR-Bombesin, SARTATE and SAR-bisPSMA, bolster Clarity’s renewed focus on this important indication.

Through pioneering work in collaboration with the University of Melbourne, the trastuzumab antibody was combined with Clarity’s proprietary SAR chelator and radiolabelled with copper-64 (Cu-64 or 64Cu) for diagnostic imaging and copper-67 (Cu-67 or 67Cu), forming an RIT3. 64Cu-SAR-trastuzumab was shown to target HER2-positive cancer cells to a very high level pre-clinically. 67Cu-SAR-trastuzumab was shown to significantly reduce the growth of HER2-expressing tumours in a dose-dependent manner, as well as to improve the survival of mice treated with the product.

Clarity intends to conduct a Phase 1/2a theranostic study with 64/67Cu-SAR-trastuzumab in HER2-positive breast cancer patients to address a significant unmet clinical need. This subtype of breast cancer is characterised as being aggressive and has a poor prognosis5. Despite recent advances in the treatment of patients with early HER2-positive breast cancer, relapse still occurs in up to 25% of patients within 10 years6.

Clarity’s Executive Chairperson, Dr Alan Taylor, commented, "The antibody revolution over the last few decades has transformed the treatment of many diseases and has also led to the development of the antibody-drug conjugate (ADC) market. However, the application of antibodies in radiopharmaceuticals, despite many potential benefits of radiation compared to the cytotoxic payloads used in ADCs, has been limited with the current strategies being sub-optimal, particularly in comparison with peptides. At Clarity, we continue to strive for excellence when it comes to science and treatment outcomes, working to firstly open up a broad range of targeting technologies for radiopharmaceuticals in a safe and effective manner, and secondly, broaden the use of radiopharmaceuticals outside of prostate cancer when looking at large cancer indications.

"We have been investigating a number of antibody strategies for many years, including the use of whole antibodies, antibody fragments and antibody pre-targeting in combination with our SAR Technology to develop a new class of treatments when combined with antibodies in RIT. The 64/67Cu-SAR-trastuzumab product is a result of this R&D process.

"The pre-clinical results we generated so far are very exciting and highlight the potential benefit of 64/67Cu-SAR-trastuzumab to image and treat patients with HER2-positive cancers. This is an area of high unmet need, as a considerable proportion of patients, most of whom are women, will relapse or develop resistance to standard treatments, and metastatic disease remains incurable. We are also committed to progressing our SAR-Bombesin, SARTATE and SAR-bisPSMA products in breast cancer, complementing the existing focus on prostate cancer, neuroblastoma and neuroendocrine tumours.

"We are uniquely placed at Clarity to address large markets, firstly with the proven background of using great science to make novel products, and secondly with the commercialisation of the "perfect pairing" of copper isotopes. Those factors combined have myriad advantages in relation to efficacy, supply and manufacturing. With regards to supply, particularly of copper-67, the simple manufacturing process on basic linear accelerators and plentiful precursor means that large markets can be served in a modular format, instead of the reliance on the small number of research reactors around the world and rare earth materials as feedstock in the case of lutetium-177 supply. The supply chains of chelatable alpha radioisotopes, that are yet to show safety and efficacy, are still in their infancy with many hurdles to overcome. Having abundant supply of diagnostic and therapeutic isotopes and finished products made under the one roof to treat large populations of patients in the same country the isotopes and products are made in is an ideal scenario quickly becoming reality and made possible with the perfect pairing of copper.

"We are excited to have entered into the Supply Agreement for trastuzumab with EirGenix, given their excellent capabilities to produce an approved biosimilar product, and progress to the next step in our RIT program. Having a reliable and secure supply of 67Cu-SAR-trastuzumab for future trials in breast cancer is essential as we continue to build a commanding pipeline of radiopharmaceuticals in order to reach our ultimate goal of better treating children and adults with cancer."

EirGenix’s Chairman & President, Dr. Liu, commented, "We are very pleased to be working with Clarity on this important program to develop a novel treatment option for breast cancer patients. At EirGenix we believe that RIT using copper-67 is a promising avenue for the next generation of antibody therapies, and we are thrilled to be contributing to the development of this unique product."

About SAR Technology
Clarity’s proprietary copper-chelating technology, called "sarcophagine" or SAR Technology, has enabled the Company to advance the TCT product pipeline into a range of theranostic clinical trials that use copper-64 for diagnostic imaging and copper-67 for therapy. Clarity is currently progressing three key product areas, SAR-bisPSMA, SAR-Bombesin and SARTATE, with three theranostic and four diagnostic clinical trials with a focus on prostate cancer indications.

64Cu-SAR-trastuzumab and 67Cu-SAR-trastuzumab are unregistered products. The data outlined in this announcement has not been assessed by health authorities such as the US Food and Drug Administration (FDA) or the Therapeutic Goods Administration (TGA). Outcomes from human clinical trials may differ from pre-clinical findings. A clinical development program is currently undergoing feasibility assessment. There is no guarantee that these products will become commercially available.

About Breast Cancer
Breast cancer is the most common cancer in women in the US, excluding skin cancers, although it can also affect some men. It accounts for about 30% of all new cancer diagnoses in women each year7. In 2025 in the US, an estimated 319,750 individuals are projected to be diagnosed with invasive breast cancer, with 316,950 of them being women1. Breast cancer remains the second leading cause of cancer death in women, after lung cancer. It is estimated that 42,170 women will die from breast cancer in 2025 in the US1. The lifetime risk of a woman developing breast cancer is about 13%, or 1 in 87. Incidence rates have increased slightly in recent years, especially in women under 507. Approximately up to 20% of breast cancers are HER2-positive, meaning they have higher levels of the HER2 protein, which promotes faster growth of the cancer.

On February 10, 2025 Bristol Myers Squibb (NYSE: BMY) reported the Phase 2 TRANSCEND FL trial evaluating Breyanzi (lisocabtagene maraleucel) in adult patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma met its primary endpoint in the marginal zone lymphoma (MZL) cohort (Press release, Bristol-Myers Squibb, FEB 10, 2025, View Source [SID1234650129]). Results showed Breyanzi demonstrated a statistically significant and clinically meaningful overall response rate (ORR) in these patients.

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The study also met the key secondary endpoint of complete response rate (CRR). In the topline analysis, Breyanzi continued to demonstrate durable responses and a consistent safety profile with no new safety signals observed. This study marks the fifth cancer type in which Breyanzi has demonstrated clinically meaningful benefit, representing the broadest array of B-cell malignancies of any CD19-directed CAR T cell therapy and furthering evidence of Breyanzi’s best-in-class and best-in-disease profile.

"Marginal zone lymphoma is a slow-growing cancer that, for many, has a favorable prognosis. But for those patients who relapse or become refractory, the disease can be quite aggressive, and there is a need for new effective and tolerable treatment options to address this unmet critical need," said Rosanna Ricafort, vice president, head of Late Development Program Leadership, Hematology and Cell Therapy, Bristol Myers Squibb. "We are pleased that the TRANSCEND FL study supports the potential of Breyanzi in marginal zone lymphoma and look forward to presenting detailed results from the study at an upcoming medical meeting."

Bristol Myers Squibb thanks the patients and investigators who are participating in the TRANSCEND FL clinical trial.

About TRANSCEND FL
TRANSCEND FL (NCT04245839) is an open-label, global, multicenter, Phase 2, single-arm study to determine the efficacy and safety of Breyanzi in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma, including follicular lymphoma and marginal zone lymphoma. The primary outcome measure is overall response rate. Secondary outcome measures include complete response rate, duration of response, and progression-free survival.

About MZL
Marginal zone lymphoma (MZL) is the second most common, slow-growing form of non-Hodgkin lymphoma (NHL), accounting for about 7% of all NHL cases. Most patients with MZL are at a median age of 67 when they are diagnosed. MZL develops when white blood cells cluster together to form lumps in a person’s lymph nodes or organs. MZL presents in three main forms: extranodal, which affects the gastrointestinal tract, skin, and lung, comprising 60% of cases; nodal, involving the lymph nodes, 30%; and splenic, involving the spleen, 10%. Initial therapy often leads to long remissions, but relapse is common, sometimes occurring several times over many years. A small portion of MZL cases transform into diffuse large-B-cell lymphoma, a more aggressive lymphoma.

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.

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, and for the treatment of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma after at least two prior lines of therapy, and for the treatment of relapsed or refractory follicular lymphoma in adult patients who have received two or more prior lines of systemic therapy, and for the treatment of relapsed or refractory mantle cell lymphoma in patients who have received at least two prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Breyanzi is also approved in Japan and Europe for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland and Canada for relapsed and refractory LBCL after two or more lines of systemic therapy, and in Japan for the treatment of relapsed or refractory patients with high-risk follicular lymphoma after one prior line of systemic therapy and in patients 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.

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.
Important Safety Information
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.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
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.

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
Certified healthcare facilities must have on-site, immediate access to tocilizumab.
Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Further information is available at www.BreyanziREMS.com, or contact Bristol Myers Squibb at 1-866-340-7332.

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.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.

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.

On February 10, 2025 Agenus reported that in January 2015 it has entered into a License, Development, and Commercialization Agreement (the "Agreement") with Incyte Corporation ("Incyte"), under which Incyte licensed exclusive rights to certain immuno-oncology programs, including antibodies targeting GITR, OX40, TIM-3, LAG-3, and additional undisclosed targets (Filing, 8-K, Agenus, FEB 10, 2025, View Source [SID1234650127]).

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Incyte previously terminated the OX40 program (effective October 2023) and the GITR and an undisclosed program (effective May 2024). In July 2024, Incyte announced that it would discontinue development of its LAG-3 and TIM-3 programs. On February 4, 2025, Agenus received formal notice from Incyte electing to terminate the Agreement effective February 4, 2026, in line with its strategic portfolio reprioritization. Upon termination, all rights to LAG-3 and TIM-3 revert to Agenus.

With this termination, Agenus will regain full control of these assets and will evaluate future opportunities for their advancement, including internal development and potential new partnerships.

The foregoing summary of the material terms of the Agreement is qualified in its entirety by the complete terms and conditions of the Agreement, filed with the Securities and Exchange Commission on March 16, 2015, as Exhibit 10.22 to the Company’s Annual Report on Form 10-K for the year ended December 31, 2014 and the First Amendment to the Agreement filed on May 4, 2017, as Exhibit 10.1 to the Company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2017.