Carney Complex

iStock/ Jian Fan Having established success in cancer, biopharma is now looking to leverage CAR T therapies against a new target, autoimmune disorders, with several early- to mid-stage readouts expected this year. In September 2022, an intriguing report went up on Nature Medicine. Though the study was small, its impact on biopharma has been huge. The study enrolled five patients with systemic lupus erythematosus (SLE), a chronic autoimmune condition where the immune system targets the patient’s own body. SLE triggers inflammation in organs across the body and can manifest as a wide variety of symptoms, including fevers, blood clots, swollen extremities, fatigue and mouth sores. There is currently no cure for SLE, but the Nature Medicine paper sparked hope that one might be near. The study tested a relatively new technology called CAR T cell therapy, which often uses a patient’s own immune T cells, modifying them outside of the body to make them more potent against certain target cells and then injecting them back into the patient. This approach has already seen success in cancer, with several therapies having earned the FDA’s approval: Gilead’s Yescarta, Johnson & Johnson’s Carvykti and Novartis’ Kymriah, to name a few. The Nature Medicine study hinted at similar promise in autoimmune diseases—all five treated patients hit and maintained remission for an average of eight months and no longer needed other treatments to keep SLE at bay. Two years later, the New England Journal of Medicine published a slightly larger study —including 15 patients—that confirmed these findings and pointed to even broader benefits. CAR T therapy not only elicited remission in SLE patients but also resulted in encouraging response rates in those with idiopathic inflammatory myositis or systemic sclerosis. “Cell therapies are the only modality that appear to provide a prolonged period of drug-free remission, which can be transformative for [a] patient’s quality of life,” Sami Corwin, an analyst at William Blair, told BioSpace in an email. The CAR T approach, in particular, offers a one-time treatment option and is “not associated with chronic side-effects,” as compared with other modalities, Corwin added. Though T cell engagers and NK cells are also being eyed as autoimmune treatments, CAR T therapies are leading the charge—for good reason. “CAR T therapies have already demonstrated remarkable success in conditions like lupus and systemic sclerosis by selectively depleting autoreactive B cells, resulting in sustained immune reset,” Katy Rezvani, head of the Institute for Cell Therapy Discovery & Innovation at MD Anderson, told BioSpace in an email. The biopharma industry is now seeking to expand on this early success, with Bristol Myers Squibb, Kyverna, CRISPR Therapeutics and more progressing CAR T therapies in a wide range of indications, including SLE, multiple sclerosis and stiff person syndrome. Here, BioSpace reviews five of the most advanced players in this space and how they’re harnessing—and innovating on—CAR T technology to address autoimmune diseases. BMS Brings CAR T Cancer Expertise to SLE A leader in CAR T therapies for cancer, Bristol Myers Squibb is now leveraging its cell therapy expertise to address autoimmune diseases. The pharma is working on CD19 NEX-T , an investigational CAR T therapy designed to seek out the cell surface protein CD19, which is highly expressed in B cells. Once it binds to CD19, the CAR T construct activates, releasing a cocktail of inflammatory cytokines and other chemicals that destroy the target B cell. This approach is similar to how BMS’ CAR T therapy Breyanzi works—only this time, the pharma is using this mode of action not to kill cancerous B cells in lymphomas but to deplete defective immune cells that mistakenly attack healthy cells. In an email interview with BioSpace , Rosanna Ricafort, vice president and head of late development, hematology and cell therapy at BMS, called CD19 NEX-T a “top priority” for the pharma, with which it plans to “push the boundaries in immune-mediated diseases.” In service of this goal, the pharma is running the Phase I Breakfree-1 and Breakfree-2 studies of CD19 NEX-T in SLE. At the 66th Annual Meeting of the American Society of Hematology in December 2024, BMS presented early data from both trials showing that three patients followed for at least six months were able to stop all other therapies without showing new signs of disease activity. One patient hit the definition of disease remission at six months. Aside from SLE, BMS is also advancing CD19 NEX-T for multiple sclerosis (MS), for which it unveiled early data last month, pointing to encouraging safety and tolerability. The pharma expects to provide additional early-stage data from the Phase I CD19 NEX-T program this year, building up to pivotal trials as soon as the data allow. “Our ultimate goal is to target the root cause of disease and drive long-term, treatment-free disease control for patients with severe forms of these autoimmune diseases,” Ricafort said. Kyverna Targets First CAR T Therapy for Stiff Person Syndrome This year, Kyverna Therapeutics is anticipating several key milestones for its investigational CAR T therapy KYV-101. Like BMS, Kyverna’s approach targets CD19 to eliminate dysfunctional immune cells, leading to what the biotech calls an “ immune reset ” in patients with autoimmune diseases. KYV-101 is unique in that it is designed specifically to avoid cytokine release syndrome and improve tolerability. Kyverna is testing KYV-101 for three target conditions : Stiff person syndrome (SPS), myasthenia gravis and lupus nephritis. Of these, the most mature indication is SPS, for which Kyverna expects to complete enrollment of a Phase II trial by mid-2025, building up to a topline readout in early 2026, CEO Warner Biddle told BioSpace in an email. Typically afflicting women more than men—and more frequently diagnosed in people 20 to 60 years of age—SPS is a rare disorder that arises when the body makes antibodies that attack the enzyme glutamic acid decarboxylase, which plays a role in the production of a neurotransmitter involved in muscle control. Common symptoms include muscle stiffness and painful spasms. If all goes well for Kyverna this year, the biotech expects to file a Biologics License Application for KYV-101 for SPS next year. “We believe this focused approach in SPS will enable us to deliver the first CAR T cell therapy in autoimmune disease to the market,” Biddle said. Beyond SPS, Kyverna is also looking forward to several catalysts in myasthenia gravis this year, including aligning with the FDA on a registrational path for the CAR T therapy in the first half of 2025, followed by a topline mid-stage readout in the latter half of the year. Kyverna’s autoimmune CAR T program is comprehensive, with the company having treated the most patients with a CAR T cell therapy so far, according to Biddle. CRISPR Homes in on Off-the-Shelf CAR T Market Seeking to build on the momentum from its Vertex Pharmaceuticals–partnered gene therapy Casgevy, CRISPR Therapeutics is now moving its allogeneic next-generation CAR T therapy CTX112 through clinical trials in various autoimmune diseases. The key advantage for CTX112 is its off-the-shelf availability, CRISPR Therapeutics Chief Medical Officer Naimish Patel told BioSpace in an email. “The drawbacks of autologous CAR T cell therapies”—those that draw cells from the patients themselves—“are that they are very expensive, require patients to stop their immunomodulatory therapy to get T cells harvested, are not widely available … and are associated with potentially severe side effects.” CRISPR Therapeutics is evaluating the potential of CTX112 in various autoimmune diseases, supported by safety, pharmacokinetic and pharmacodynamic data from cancer studies. The asset is currently in Phase I development for SLE, but at the 43rd J.P. Morgan Healthcare Conference in January, CEO Samarth Kulkarni bared the company’s plans to expand testing to other autoimmune indications. In its fourth-quarter and full-year 2024 business report last month, CRISPR Therapeutics revealed it had expanded its basket trial for CTX112 to include systemic sclerosis and inflammatory myositis. Updates for study are expected mid-2025, as per the biotech. “We see incredible potential for our allogeneic CAR T program, and we are looking forward to sharing a broad program update on CTX112 mid-year 2025,” Patel said. Autolus Awaits Q1 SLE Readout for Obe-Cel The only therapy on this list with an FDA approval under its belt is Autolus Therapeutics’ obecabtagene autoleucel, also called obe-cel, which was cleared by the regulator in November 2024 for relapsed/refractory B cell acute lymphoblastic leukemia. In this indication, obe-cel is marketed as Aucatzyl. Like most of the other assets in this class, obe-cel targets the CD19 epitope. Autolus is seeking to set its candidate apart from the rest of the space through a unique CAR construct that has what it calls a “ fast-off ” kinetic mechanism, which, unlike the traditional approach, enables the controlled binding of the CAR molecule to its target, in turn activating T cells in a similarly controlled manner. According to Autolus, this fast-off scheme closely mirrors the physiological interactions of T cells with their corresponding receptors. Results from a Phase Ib/II study of obe-cel in B-cell acute lymphoblastic leukemia, published in the New England Journal of Medicine in November 2024, suggest that Autolus’ fast-off approach improves T cell persistence and lowers exhaustion, leading to better clinical outcomes. More than half of patients achieved complete remission after obe-cel treatment, with an estimated 12-month overall survival rate of 61.1% Autolus still doesn’t have such detailed data for obe-cel in autoimmune diseases. The biotech is currently running the Phase I CARLYSLE study in advanced SLE, for which initial data are expected in the first quarter of this year, as per a November 2024 company presentation . Cabaletta Anticipates Multiple Catalysts for Rese-Cel in 2025 Cabaletta Bio—which launched in November 2018 with a stated focus on autoimmune disease—was ahead of the curve in this space. It is also the only company on this list that is developing its investigational cell therapy exclusively for autoimmune diseases. CABA-201 , also called resecabtagene autoleucel or rese-cel, is an investigational CAR T therapy that also targets CD19. What makes rese-cel unique is that it contains a 4-1BB domain, which is a protein commonly expressed on activated T cells that helps enhance their activity . Recent preclinical evidence has pointed to the potential of targeting 4-1BB to address autoimmune diseases. Cabaletta is testing this approach in the clinic with its Phase I/II RESET program, which is assessing rese-cel in a wide variety of autoimmune disorders, including myositis, SLE, systemic sclerosis, myasthenia gravis, MS and pemphigus vulgaris. Of these indications, the biotech named as primary focuses myositis, SLE and systemic sclerosis, for which rese-cel’s mechanism has the potential to “achieve robust improvement in clinical disease activity within 3 months of treatment,” according to its website . In a corporate presentation last month, Cabaletta unveiled initial clinical data from the RESET program, touting “consistent and deep” depletion of B cells 22 days after infusion. Additionally, treatment with rese-cel resulted in strong treatment response, pointing to the potential to achieve drug-free remission in patients with refractory disease. Similarly, rese-cel showed the potential of a “drug-free clinical response” in systemic sclerosis, while early data for SLE pointed to promising rates of remission. Cabaletta has several other rese-cel milestones lined up for 2025 , including more clinical and translational readouts throughout the year and a meeting with the FDA to align on a registrational path for the asset.

PRINCETON, N.J.--( BUSINESS WIRE )-- Bristol Myers Squibb (NYSE: BMY) today announced 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. Results showed Breyanzi demonstrated a statistically significant and clinically meaningful overall response rate (ORR) in these patients. 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. Please see full Prescribing Information , including Boxed WARNINGS and Medication Guide . Bristol Myers Squibb: Unlocking the Full Potential of Cell Therapy A pioneer in harnessing the immune system to fight cancer and an established leader in cell therapy, Bristol Myers Squibb is uniquely positioned to unlock the full potential of this technology across blood cancers and within new frontiers, including autoimmune disease. Bristol Myers Squibb is currently the only company with two approved CAR T cell therapies with two distinct targets, available in major markets around the world. Our bold vision for the future is one in which hundreds of thousands of patients can be treated with cell therapy’s transformational potential. The building blocks to realize this ambition—a promising and differentiated pipeline, extensive translational and clinical data sets, a deep bench of talent, and robust manufacturing capabilities— are in our cells. We are laser-focused on advancing the field of cell therapy toward a true revolution for patients. Learn more about the science behind cell therapy and ongoing progress at Bristol Myers Squibb here . About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , X , YouTube , Facebook and Instagram . Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that Breyanzi (lisocabtagene maraleucel), may not receive regulatory approval for the additional indication, described in this release, in the currently anticipated timeline or at all, any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether Breyanzi for such indication will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- 2seventy bio, Inc. (Nasdaq: TSVT) today provided full-year Abecma® (idecabtagene vicleucel; ide-cel) sales results for 2024, in partnership with Bristol Myers Squibb (BMS). “ We are pleased to see Abecma expansion in the third line setting and recorded U.S. revenue of $242 million in 2024, within our previously issued guidance of $240 to $250 million. Fourth quarter revenue was impacted by higher deferrals of infusions into 2025. We expect the use of CAR-T in multiple myeloma will continue to grow, and while competition remains high, we believe Abecma will continue to make a meaningful difference in the lives of patients,” said Chip Baird, chief executive officer, 2seventy bio. “ Equally important is that our Abecma- focused strategy, which led to the monetization of our R&D assets and streamlining of our operations, has put us on track to achieve quarterly breakeven later this year based on our current expectations. We remain committed to maximizing value for stakeholders and look forward to sharing more detail during our earnings call next month.” Further details on fourth quarter and full year 2024 results will be provided on the Company’s earnings call and within its Form 10-K, which is expected to be filed with the SEC by no later than March 17, 2025. 2seventy bio and BMS share equally in all profits and losses related to development, manufacturing, and commercialization of Abecma in the U.S. *Fourth quarter and full-year 2024 financial results are preliminary, unaudited, and provided as an approximation in advance of 2seventy bio’s announcement of complete financial results in March 2025. This information is based on currently available information. Final results may therefore vary from these estimates. These preliminary estimates have not been audited by 2seventy bio’s independent registered public accounting firm. ABECMA U.S. INDICATION ABECMA is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. U.S. Important Safety Information BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED CYTOPENIA and SECONDARY HEMATOLOGICAL MALIGNANCIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed. Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities. Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including ABECMA ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Warnings and Precautions: Early Death: In KarMMa-3, a randomized (2:1), controlled trial, a higher proportion of patients experienced death within 9 months after randomization in the ABECMA arm (45/254; 18%) compared to the standard regimens arm (15/132; 11%). Early deaths occurred in 8% (20/254) and 0% prior to ABECMA infusion and standard regimen administration, respectively, and 10% (25/254) and 11% (15/132) after ABECMA infusion and standard regimen administration, respectively. Out of the 20 deaths that occurred prior to ABECMA infusion, 15 occurred from disease progression, 3 occurred from adverse events and 2 occurred from unknown causes. Out of the 25 deaths that occurred after ABECMA infusion, 10 occurred from disease progression, 11 occurred from adverse events, and 4 occurred from unknown causes. Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. Among patients receiving ABECMA for relapsed refractory multiple myeloma in the KarMMa and KarMMa-3 studies (N=349), CRS occurred in 89% (310/349), including ≥ Grade 3 CRS (Lee grading system) in 7% (23/349) of patients and Grade 5 CRS in 0.9% (3/349) of patients. The median time-to-onset of CRS, any grade, was 1 day (range: 1 to 27 days), and the median duration of CRS was 5 days (range: 1 to 63 days). In the pooled studies, the rate of ≥Grade 3 CRS was 10% (7/71) for patients treated in dose range of 460 to 510 x 10 6 CAR-positive T cells and 5.4% (13/241) for patients treated in dose range of 300 to 460 x 10 6 CAR-positive T cells. The most common manifestations of CRS (greater than or equal to 10%) included pyrexia (87%), hypotension (30%), tachycardia (26%), chills (19%), hypoxia (16%). Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, ARDS, atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, coagulopathy, renal failure, multiple organ dysfunction syndrome and HLH/MAS. Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Of the 349 patients who received ABECMA in clinical trials, 226 (65%) patients received tocilizumab; 39% (135/349) received a single dose, while 26% (91/349) received more than 1 dose of tocilizumab. Overall, 24% (82/349) of patients received at least 1 dose of corticosteroids for treatment of CRS. Almost all patients who received corticosteroids for CRS also received tocilizumab. For patients treated in dose range of 460 to 510 x 10 6 CAR-positive T cells, 76% (54/71) of patients received tocilizumab and 35% (25/71) received at least 1 dose of corticosteroids for treatment of CRS. For patients treated in dose range of 300 to 460 x 10 6 CAR-positive T cells, 63% (152/241) of patients received tocilizumab and 20% (49/241) received at least 1 dose of corticosteroid for treatment of CRS. Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. Neurologic Toxicities: Neurologic toxicities, including immune-effector cell-associated neurotoxicity (ICANS), which may be severe or life- threatening, occurred concurrently with CRS, after CRS resolution, or in the absence of CRS following treatment with ABECMA. In patients receiving ABECMA in the KarMMa and KarMMa-3 studies, CAR T cell-associated neurotoxicity occurred in 40% (139/349), including Grade 3 in 4% (14/349) and Grade 4 in 0.6% (2/349) of patients. The median time to onset of neurotoxicity was 2 days (range: 1 to 148 days). The median duration of CAR T cell-associated neurotoxicity was 8 days (range: 1 to 720 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. CAR T cell-associated neurotoxicity resolved in 123 of 139 (88%) patients and median time to resolution was 5 days (range: 1 to 245 days). One-hundred and thirty four out of 349 (38%) patients with neurotoxicity had CRS. The onset of neurotoxicity during CRS was observed in 93 patients, before the onset of CRS in 12 patients, and after the CRS event in 29 patients. The rate of Grade 3 or 4 CAR T cell-associated neurotoxicity was 5.6% (4/71) and 3.7% (9/241) for patients treated in dose range of 460 to 510 x 10 6 CAR-positive T cells and 300 to 460 x 10 6 CAR-positive T cells, respectively. The most frequent (greater than or equal to 5%) manifestations of CAR T cell-associated neurotoxicity include encephalopathy (21%), headache (15%), dizziness (8%), delirium (6%), and tremor (6%). At the safety update for KarMMa-3 study, one patient developed fatal neurotoxicity 43 days after ABECMA. In KarMMa, one patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. Cerebral edema has been associated with ABECMA in a patient in another study in multiple myeloma. Grade 3 myelitis and Grade 3 parkinsonism have occurred after treatment with ABECMA in another study in multiple myeloma. Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly. Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed. Counsel patients to seek immediate medical attention should signs or symptoms occur at any time. Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): In patients receiving ABECMA in the KarMMa and KarMMa-3 studies, HLH/MAS occurred in 2.9% (10/349) of patients. All events of HLH/MAS had onset within 10 days of receiving ABECMA, with a median onset of 6.5 days (range: 4 to 10 days) and occurred in the setting of ongoing or worsening CRS. Five patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction and cytopenia. In KarMMa-3, one patient had Grade 5, two patients had Grade 4 and two patients had Grade 3 HLH/MAS. The patient with Grade 5 HLH/MAS also had Grade 5 candida sepsis and Grade 5 CRS. In another patient who died due to stroke, the Grade 4 HLH/MAS had resolved prior to death. Two cases of Grade 3 and one case of Grade 4 HLH/MAS had resolved. In KarMMa, one patient treated in the 300 x 10 6 CAR-positive T cells dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines. ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at www.AbecmaREMS.com or contact Bristol-Myers Squibb at 1-866-340-7332. Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA. Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. In all patients receiving ABECMA in the KarMMa and KarMMa-3 studies, infections (all grades) occurred in 61% of patients. Grade 3 or 4 infections occurred in 21% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 7%, bacterial infections in 4.3%, and fungal infections in 1.4% of patients. Overall, 15 patients had Grade 5 infections (4.3%); 8 patients (2.3%) with infections of pathogen unspecified, 3 patients (0.9%) with fungal infections, 3 patients (0.9%) with viral infections, and 1 patient (0.3%) with bacterial infection. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines. Febrile neutropenia was observed in 38% (133/349) of patients after ABECMA infusion and 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. Viral Reactivation: Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. 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 plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice. Prolonged Cytopenias: In patients receiving ABECMA in the KarMMa and KarMMa-3 studies, 40% of patients (139/349) experienced prolonged Grade 3 or 4 neutropenia and 42% (145/349) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 89% (123/139) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 76% (110/145) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 1.9 months. Five patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. The rate of Grade 3 or 4 thrombocytopenia was 62% (44/71) and 56% (135/241) for patients treated in dose range of 460 to 510 x 10 6 CAR-positive T cells and 300 to 460 x 10 6 CAR-positive T cells, respectively. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to local institutional guidelines. Hypogammaglobulinemia: In all patients receiving ABECMA in the KarMMa and KarMMa-3 studies, hypogammaglobulinemia was reported as an adverse event in 13% (46/349) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 37% (130/349) of patients treated with ABECMA. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion occurred in 45% (158/349) of patients treated with ABECMA. Forty-one percent of patients received intravenous immunoglobulin (IVIG) post-ABECMA for serum IgG <400 mg/dL. Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis. Use of Live Vaccines: The safety of immunization with live viral vaccines during or after ABECMA 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 ABECMA treatment, and until immune recovery following treatment with ABECMA. Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. In KarMMa-3, myeloid neoplasms (four cases of myelodysplastic syndrome and one case of acute myeloid leukemia) occurred in 2.2% (5/222) of patients following treatment with ABECMA compared to none in the standard regimens arm at the time of the safety update. The median time to onset of myeloid neoplasm from ide-cel infusion was 338 days (Range: 277 to 794 days). Three of these five patients have died following the development of myeloid neoplasm. One out of the five cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including ABECMA. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor life-long 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 of secondary malignancy. Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, including altered mental status or seizures, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. Adverse Reactions: The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) include pyrexia, CRS, hypogammaglobulinemia, infections – pathogen unspecified, musculoskeletal pain, fatigue, febrile neutropenia, hypotension, tachycardia, diarrhea, nausea, headache, chills, upper respiratory tract infection, encephalopathy, edema, dyspnea and viral infections. Please see full Prescribing Information , including Boxed WARNINGS and Medication Guide . About Bristol Myers Squibb and 2seventy bio Abecma is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio. Bristol Myers Squibb assumes sole responsibility for Abecma drug product manufacturing and commercialization outside of the U.S. The companies’ clinical development program for Abecma includes ongoing clinical studies (KarMMa-2, KarMMa-3) in earlier lines of treatment for patients with multiple myeloma. For more information visit clinicaltrials.gov . About 2seventy bio Our name, 2seventy bio, reflects why we do what we do - TIME. Cancer rips time away, and our goal is to work at the maximum speed of translating human thought into action – 270 miles per hour – to give the people we serve more time. With a deep understanding of the human body’s immune response to tumor cells and how to translate cell therapies into practice, we’re applying this knowledge to deliver the first FDA-approved CAR T cell therapy for multiple myeloma to as many patients as possible. Importantly, we remain focused on accomplishing our mission by staying genuine and authentic to our “why” and keeping our people and culture top of mind every day. For more information, visit www.2seventybio.com . Follow 2seventy bio on social media: X (Twitter) and LinkedIn . 2seventy bio is a trademark of 2seventy bio, Inc. Cautionary Note Regarding Forward-Looking Statements This release contains “forward-looking statements” within the meaning of applicable laws and regulations. These statements include, but are not limited to: statements regarding preliminary selected financial results, the future use of CAR-T in multiple myeloma, the impact of Abecma , and timeline for quarterly breakeven in our financial results. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, our limited independent operating history and the risk that our accounting and other management systems may not be prepared to meet the financial reporting and other requirements of operating as an independent public company; the risk that Abecma will not be as commercially successful as we may anticipate; the risk that our strategic realignment to focus on the development and commercialization of Abecma may not be as successful as anticipated, may fail to achieve the anticipated cost savings, and may cause disruptions in our business that could make it difficult to achieve our strategic objectives; and the risk that we are unable to manage our operating expenses or cash use for operations. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in our Annual Report on Form 10-K filed March 7, 2024 and its other filings made with the Securities Exchange Commission from time to time. All information in this press release is as of the date of this release, and we undertake no duty to update this information unless required by law.