On August 4, 2025 Intensity Therapeutics, Inc. (Nasdaq: INTS) ("Intensity" or "the Company"), a late-stage clinical biotechnology company focused on the discovery and development of novel intratumoral cancer therapies that are designed to kill tumors and increase immune system recognition of cancers using its proprietary non-covalent conjugation technology, reported that in July 2025 the Company added $6.6 million in gross proceeds ($6.3 million net) by selling 19,868,658 shares of its common stock via its At-the-Market offering (the "ATM") at an average price of $0.3323 per share (Press release, Intensity Therapeutics, AUG 4, 2025, View Source [SID1234654727]). Following such sales of common stock pursuant to the ATM, the Company has 46,035,081 shares of common stock issued and outstanding as of July 31, 2025.

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"We were able to take advantage of strong liquidity and favorable prices in our stock last month. The proceeds from these ATM sales strengthen our balance sheet considerably and allow us to continue to advance the clinical trials into the second half of 2026," said Lewis H. Bender, President and CEO of Intensity. "We are also pleased to announce that the average price per share for these ATM sales was more than 10% higher than our recently completed June 2025 public offering, and the costs to raise this incremental capital were much lower. We will continue to be selective and strategic in the deployment of the remainder of the ATM."

About At the Market Transactions

"At-the-Market" (ATM) offerings, also known as "ATM" programs, refer to a method where a public company sells its newly issued shares directly into the existing trading market at the prevailing market price, rather than through a traditional underwritten offering. This approach allows companies to raise capital opportunistically and incrementally, as needed, with minimal disruption to the market and typically lower costs.

About INT230-6

INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug consists of two proven, potent anti-cancer agents, cisplatin and vinblastine sulfate, and a diffusion and cell penetration enhancer molecule ("SHAO") that facilitates the dispersion of potent cytotoxic drugs throughout tumors, allowing the active agents to diffuse into cancer cells. These agents remain in the tumor, resulting in a favorable safety profile. In addition to local disease control and direct tumor killing, INT230-6 causes a release of a bolus of neoantigens specific to the malignancy, leading to immune system engagement and systemic anti-tumor effects. Importantly, these effects are mediated without immunosuppression, which often occurs with systemic chemotherapy.

On August 4, 2025 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported financial results for the second quarter ended June 30, 2025 (Press release, CRISPR Therapeutics, AUG 4, 2025, View Source [SID1234654716]).

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"We are entering the second half of the year with momentum across both our commercial and clinical programs," said Samarth Kulkarni, Ph.D., Chairman and Chief Executive Officer of CRISPR Therapeutics. "The activation of 75 authorized treatment centers for CASGEVY has been achieved, marking a meaningful step in expanding patient access, while clinical trials across multiple other programs continue to advance. Looking ahead, we expect several key milestones including the presentation of complete Phase 1 data for CTX310, as well as updates across our oncology and autoimmune portfolios. Our focus remains on delivering transformative therapies for patients with critical unmet needs."

Recent Highlights and Outlook

Hemoglobinopathies and CASGEVY (exagamglogene autotemcel [exa-cel])

CASGEVY is a non-viral, ex vivo, CRISPR/Cas9 gene-edited cell therapy for eligible patients with sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT), designed to eliminate both vaso-occlusive crises (VOCs) and transfusion requirements. CASGEVY is approved in the U.S., Great Britain, the EU, the Kingdom of Saudi Arabia (KSA), the Kingdom of Bahrain (Bahrain), Qatar, Canada, Switzerland and the United Arab Emirates (UAE) for the treatment of both SCD and TDT. Building on the foundational launch in 2024, significant progress is being made to bring this transformative therapy to patients worldwide.
The target of activating 75 authorized treatment centers (ATCs) globally has been achieved, marking an important milestone in the commercial rollout of CASGEVY. Since launch through June 30, approximately 115 patients have completed their first cell collection, and 29 patients have received infusions of CASGEVY, including 16 infused in the second quarter. The launch of CASGEVY is building strong momentum, positioning the program for significant growth and broader impact.
Through reimbursement agreements, Vertex has secured access for eligible SCD and TDT patients in 10 countries. Recent agreements include Northern Ireland, Scotland and Denmark. Efforts are ongoing with government and reimbursement authorities globally to secure access for eligible patients.
CRISPR Therapeutics continues to advance its next-generation approaches designed to significantly broaden the addressable patient population for SCD and TDT. The Company’s internally developed targeted conditioning program, an anti-CD117 (c-Kit) antibody-drug conjugate (ADC), remains on track in preclinical development. In parallel, the Company is making continued progress in its in vivo editing platform aimed at enabling direct editing of hematopoietic stem cells (HSC) without the need for conditioning. By potentially eliminating the need for conditioning, this approach could unlock access to transformative therapies for a significantly larger patient population.
Immuno-Oncology and Autoimmune Disease Programs

Clinical trials are ongoing for the Company’s next-generation allogeneic CAR T product candidates, CTX112 and CTX131, targeting CD19 and CD70, respectively, across multiple indications. Both candidates incorporate novel potency edits designed to significantly enhance CAR T cell expansion and cytotoxicity, positioning them as potential best-in-class therapies.
CTX112, targeting CD19, is in development for hematologic malignancies and autoimmune diseases. Preliminary clinical data support a differentiated profile with strong clinical benefit combined with the convenience of an "off-the-shelf" therapy.
In relapsed or refractory B-cell malignancies, encouraging results from the ongoing Phase 1/2 clinical trial led to the FDA granting Regenerative Medicine Advanced Therapy (RMAT) designation for CTX112 in relapsed or refractory follicular lymphoma and marginal zone lymphoma.
A Phase 1 trial of CTX112 is ongoing in autoimmune indications, including systemic lupus erythematosus (SLE), systemic sclerosis and inflammatory myositis. Preliminary safety, pharmacokinetic, and pharmacodynamic data from oncology trials support its potential in autoimmune indications.
The Company plans to provide a broad update for CTX112 in oncology and autoimmune disease in the second half of 2025.
CTX131, targeting CD70, is in development for both solid tumors and hematologic malignancies. Clinical trials for CTX131 are ongoing, with an update expected in 2025.
CRISPR Therapeutics’ immuno-oncology and autoimmune disease efforts are supported by a wholly-owned, U.S. manufacturing facility located in Framingham, MA. This investment enables the production of clinical and commercial-stage good manufacturing practice (GMP) materials across the Company’s allogeneic cell therapy programs.
In Vivo Liver Editing Programs

CRISPR Therapeutics is advancing a pipeline of in vivo gene editing candidates targeting major unmet needs in cardiovascular and metabolic diseases using its proprietary lipid nanoparticle (LNP) delivery platform.
CTX310 is in an ongoing Phase 1 clinical trial targeting ANGPTL3 in patients with homozygous familial hypercholesterolemia (HoFH), severe hypertriglyceridemia (SHTG), heterozygous familial hypercholesterolemia (HeFH), or mixed dyslipidemias. ANGPTL3 loss-of-function mutations are linked to reduced in low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and a lower risk of atherosclerotic cardiovascular disease (ASCVD), without adverse effects on overall health. In the U.S., more than 40 million patients have elevated LDL, severely elevated TGs or both. CTX310 is initially focused on a high-risk subset of this group with the greatest unmet medical need and limited effective treatment options.
In June, the Company reported data for CTX310, demonstrating dose-dependent reductions in ANGPTL3, TG, and LDL following a single administration. As dose-range finding continues, data to date demonstrate peak reductions of up to 82% in TG and LDL reductions of up to 86% at DL4 without any clinically significant changes in liver enzymes and a safety and tolerability profile consistent with previous findings.
These initial results represent a significant milestone in the advancement of CRISPR Therapeutics’ proprietary LNP delivery technologies for gene editing in the liver. The Company anticipates presenting the complete Phase 1 data for CTX310 at a medical meeting in the second half of 2025.
CTX320 is in an ongoing Phase 1 clinical trial targeting the LPA gene in patients with elevated lipoprotein(a) [Lp(a)], a genetically determined risk factor associated with an increased incidence of major adverse cardiovascular events (MACE). Elevated Lp(a) levels affect up to 20% of the global population and remain unaddressed by current therapies. The Company plans to provide an update in the first half of 2026.
CRISPR Therapeutics continues to advance two preclinical programs: CTX340, targeting angiotensinogen (AGT) for the treatment of refractory hypertension, and CTX450, targeting 5’ aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias (AHP). Both candidates are currently in IND/CTA-enabling studies.
SRSD107

In May, the Company entered a strategic collaboration with Sirius Therapeutics to jointly develop and commercialize small interfering RNA (siRNA) therapies, beginning with SRSD107, a long-acting Factor XI (FXI) siRNA. Under the partnership, development and commercialization will be shared, with CRISPR Therapeutics leading efforts in the U.S. and Sirius in Greater China. The agreement also grants CRISPR Therapeutics the option to nominate two additional siRNA targets for future development. This collaboration expands CRISPR Therapeutics’ capabilities, enabling the development of a broader range of transformative gene-based medicines beyond its current gene-editing programs in the clinic.
In July, the European Medicines Agency (EMA) authorized the initiation of a Phase 2 clinical trial of SRSD107 for thromboembolic disorders. The study is designed to evaluate the safety and efficacy of SRSD107 in preventing post-operative venous thromboembolism in patients undergoing total knee arthroplasty and aims to confirm its anticoagulant potential.
Regenerative Medicine Programs

CRISPR Therapeutics continues to advance its regenerative medicine efforts in Type 1 diabetes (T1D). In addition to CTX211, the Company is developing next-generation programs focusing on induced pluripotent stem cell (iPSC) derived, allogeneic, gene-edited, beta islet cell precursors. These approaches aim to enable insulin independence in T1D patients without the need for chronic immunosuppression. The Company expects to provide an update in 2025.
Second Quarter 2025 Financial Results

Cash Position: Cash, cash equivalents, and marketable securities were $1,721.2 million as of June 30, 2025, compared to $1,903.8 million as of December 31, 2024. The decrease in cash was primarily driven by operating expenses, as well as the $25.0 million upfront cash payment made as part of the Sirius Agreement, offset by proceeds from interest income and proceeds from the issuance of common shares and option exercise activity.
R&D Expenses: R&D expenses were $69.9 million for the second quarter of 2025, compared to $80.2 million for the second quarter of 2024. The decrease in R&D expense was primarily driven by a decrease in employee-related expenses, including stock-based compensation expenses.
Acquired In-Process R&D Expenses: Acquired in-process R&D expenses were $96.3 million for the second quarter of 2025 related to costs incurred upon entering the Sirius Agreement during the second quarter of 2025.
G&A Expenses: General and administrative expenses were $18.9 million for the second quarter of 2025, compared to $19.5 million for the second quarter of 2024.
Collaboration Expense: Collaboration expense, net, was $45.2 million for the second quarter of 2025, compared to $52.1 million for the second quarter of 2024. The decrease in collaboration expense, net, was primarily attributable to an increase in CASGEVY revenue, as well as a decrease in operating expenses for the program.
Net Loss: Net loss was $208.5 million for the second quarter of 2025, compared to a net loss of $126.4 million for the second quarter of 2024.
About CASGEVY (exagamglogene autotemcel [exa-cel])
CASGEVY is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. CASGEVY has been shown to reduce or eliminate recurrent vaso-occlusive crises (VOCs) for patients with SCD and transfusion requirements for patients with TDT. CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients.

About the CRISPR Therapeutics – Vertex Collaboration for CASGEVY
CRISPR Therapeutics and Vertex entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CASGEVY represents the first potential treatment to emerge from the joint research program. Under an amended collaboration agreement, Vertex now leads global development, manufacturing, and commercialization of CASGEVY and splits program costs and profits worldwide 60/40 with CRISPR Therapeutics. Vertex is the manufacturer and exclusive license holder of CASGEVY.

About CTX112
CTX112 is being developed for both oncology and autoimmune indications. CTX112 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 19, or CD19, which incorporates edits designed to evade the immune system, enhance CAR T potency, and reduce CAR T exhaustion. CTX112 is being investigated in an ongoing clinical trial designed to assess safety and efficacy of the product candidate in adult patients with relapsed or refractory B-cell malignancies who have received at least two prior lines of therapy. In addition, CTX112 is being investigated in an ongoing clinical trial designed to assess the safety and efficacy of the product candidate in adult patients with systemic lupus erythematosus, systemic sclerosis, and inflammatory myositis.

About CTX131
CTX131 is being developed for both solid tumors and hematologic malignancies, including T cell lymphomas (TCL). CTX131 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX131 incorporates edits designed to evade the immune system, prevent fratricide, enhance CAR T potency, and reduce CAR T exhaustion. CTX131 is being investigated in ongoing clinical trials designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory solid tumors and hematologic malignancies, including TCL.

About In Vivo Programs
CRISPR Therapeutics has established a proprietary lipid nanoparticle (LNP) platform for the delivery of CRISPR/Cas9 to the liver. The Company’s in vivo portfolio includes its lead investigational programs, CTX310 (directed towards angiopoietin-related protein 3 (ANGPTL3)) and CTX320 (directed towards LPA, the gene encoding apolipoprotein(a) (apo(a)), a major component of lipoprotein(a) [Lp(a)]). Both are validated therapeutic targets for cardiovascular disease. CTX310 and CTX320 are in ongoing clinical trials in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemias, or severe hypertriglyceridemia, and in patients with elevated lipoprotein(a), respectively. In addition, the Company’s research and preclinical development candidates include CTX340 and CTX450, targeting angiotensinogen (AGT) for refractory hypertension and 5’-aminolevulinate synthase 1 (ALAS1) for acute hepatic porphyria (AHP), respectively.

About SRSD107
SRSD107 is a novel double-stranded small interfering ribonucleic acid (siRNA). Developed initially by Sirius Therapeutics, SRSD107 specifically targets the human coagulation factor XI (FXI) mRNA and inhibits FXI protein expression, thereby blocking the intrinsic coagulation pathway and promoting anticoagulant/anti-thrombotic effects.

On August 4, 2025 Cellectis (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene editing platform to develop life-saving cell and gene therapies, reported financial results for the second quarter 2025 ending June 30, 2025 and business updates (Press release, Cellectis, AUG 4, 2025, View Source [SID1234654715]).

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"I am pleased to announce that Cellectis will host an Investor R&D Day in New York City on October 16, 2025. The Company’s leadership team and key opinion leaders will present the Phase 1 dataset and outline the late-stage development strategy for lasme-cel (UCART22) in r/r B-ALL and will share insights on the Company’s vision and differentiated capabilities," said André Choulika, Ph.D., Chief Executive Officer at Cellectis.

"Our teams have remained focused on advancing research and developing solutions for patients with unmet medical needs. In July 2025, we completed the end-of-Phase 1 multidisciplinary meetings with both the FDA and EMA for lasme-cel in r/r B-ALL. We are excited about a pivotal Phase 2 which we expect to initiate in the second half of this year."

Pipeline Highlights

UCART Clinical Programs

BALLI-01 study evaluating lasme-cel (UCART22) in relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL)

In July 2025, Cellectis completed the multidisciplinary end-of-Phase 1 regulatory interactions with both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Preparations are currently underway in anticipation for an amendment to initiate a pivotal Phase 2 of lasme-cel in r/r B-ALL, which is expected in H2 2025.
Cellectis will present the Phase 1 dataset and late-stage development strategy for lasme-cel in r/r B-ALL at an Investor R&D Day that will take place on October 16, 2025 in New York City.
NatHaLi-01 study evaluating eti-cel (UCART20x22) in relapsed or refractory B-cell non-Hodgkin lymphoma (r/r NHL)

Cellectis continues to focus on the enrollment of patients in the NatHaLi-01 study and expects to present a Phase 1 readout for eti-cel in r/r NHL in late 2025.
Partnerships

Servier – Anti-CD19 CAR-T

In May 2025, Allogene Therapeutics, Inc. ("Allogene"), Servier’ sublicensee, announced that, as part of the ALPHA3 clinical trial evaluating cemacabtagene ansegedleucel (cema-cel) in first-line consolidation for large B-cell lymphoma, the milestone for lymphodepletion regimen selection and futility analysis has been shifted by approximately two quarters and is now expected by Allogene in the first half of 2026.
On August 1, 2025, Allogene announced that it has selected standard fludarabine and cyclophosphamide (FC) as the lymphodepletion regimen to be used in its ALPHA3 study. The arm testing FC plus ALLO-647, an anti-CD52 mAb (FCA), is now closed to further enrollment. According to Allogene, this decision, made ahead of the scheduled futility analysis, was prompted by a Grade 5 adverse event in the FC plus ALLO-647 arm that has been attributed to the use of ALLO-647. According to Allogene, this event was deemed unrelated to cema-cel. Allogene further announced that the amended ALPHA3 trial now proceeds as a randomized study with two arms, comparing cema-cel after standard FC lymphodepletion to observation, the current standard of care. Statistical design of the trial and the prespecified study conduct remain the same. The next milestone will be the futility analysis comparing MRD conversion and is expected by Allogene to occur 1H 2026.
Allogene – Anti-CD70 CAR-T

In June 2025, Allogene presented updated data from the Phase 1 TRAVERSE study of ALLO-316 in renal cell carcinoma during an oral presentation at the 2025 ASCO (Free ASCO Whitepaper) Annual Meeting. The presentation focused on the Phase 1b expansion cohort from the Phase 1 TRAVERSE study in which patients were treated with a standard regimen of cyclophosphamide and fludarabine following by a single dose of 80 million CAR-T cells.
AstraZeneca – Joint Research and Collaboration Agreement

Research and development activities are continuing to advance for the three cell and gene therapy programs under our Joint Research and Collaboration Agreement with AstraZeneca in November 2023 (the "AZ JRCA"): one allogeneic CAR-T for hematological malignancies, one allogeneic CAR-T for solid tumors, and one in vivo gene therapy for a genetic disorder.
Servier arbitration

With respect to the ongoing arbitration proceeding through the Centre de Médiation et d’Arbitrage de Paris, the arbitral decision is expected to be rendered on or before December 15, 2025.
Corporate Updates

Annual Shareholders’ Meeting

On June 26, 2025, Cellectis held a Shareholders General Meeting at the Biopark auditorium in Paris, France. At the meeting, during which approximately 57% of voting rights were exercised, resolutions 1 through 23 and resolutions 25 and 26 were adopted, while resolution 24 was rejected, consistent with the recommendations of the Board of Directors. The detailed results of the vote and the resolutions are available on Cellectis’ website: View Source
The Cellectis Shareholders’ Meeting appointed Mr. André Muller as a director of the Company’s Board of Directors, with immediate effect. In addition, at the close of this meeting, the term of Mr. Axel-Sven Malkomes expired, and the previously announced resignation of Mr. Pierre Bastid became effective. In connection with these changes to the Board of Directors, the Board of Directors appointed André Muller, Donald Bergstrom, and Rainer Boehm as the members of the Company’s Audit Committee.
Financial Results

Cash, cash equivalent and fixed-term deposits: As of June 30, 2025, Cellectis had $230 million in consolidated cash, cash equivalents, restricted cash and fixed-term deposits classified as current and non-current financial assets. The Company believes its cash, cash equivalents and fixed-term deposits will be sufficient to fund its operations into H2 2027.

This compares to $264 million in consolidated cash, cash equivalents, restricted cash and fixed-term deposits classified as current financial assets as of December 31, 2024, with no fixed-term deposits classified as non-current financial assets as of such date. This $33.2 million change includes $13.4 million of cash-in from our revenue, $5.1 million of interest income from our financial and cash-equivalent investments, offset by cash payments from Cellectis to suppliers of $23.2 million, Cellectis’ wages, bonuses and social expenses paid of $23.6 million, the payments of lease debts of $5.4 million, the repayment of the "PGE" loan of $2.6 million and the payments of capital expenditures for $0.7 million.

We currently foresee focusing our cash spending in supporting the development of our pipeline of product candidates, including the manufacturing and clinical trial expenses of lasme-cel (UCART22), eti-cel (UCART20x22) and potential new product candidates, and operating our state-of-the-art manufacturing capabilities in Paris (France) and Raleigh (North Carolina).

Revenues and Other Income: Consolidated revenues and other income were $30.2 million for the six-month period ended June 30, 2025, compared to $16.0 million for the six-month period ended June 30, 2024. This $14.2 million increase between the six-month period ended June 30, 2024 and 2025 was mainly attributable to a $20.0 million increase in revenue recognized under AstraZeneca Joint Research Collaboration Agreement in the first half 2025 based on the progress of our performance obligation rendered under the three research programs, partly offset by a slight decrease in other income by $0.6 million and by a one-off development milestone revenue of $5.4 million recorded last year as of June 30, 2024 under the Servier License Agreement.

R&D Expenses: Consolidated R&D expenses were $45.0 million for the six-month period ended June 30, 2025, compared to $45.8 million for the six-month period ended June 30, 2024, down by $0.8 million mainly driven by a decrease in purchases & external expenses and other expenses of $1.7 million, offset by an increase of $0.7 million in depreciation & amortization expenses and by a slight increase of $0.2 million in R&D personnel expenses related to non-cash stock based compensation.

SG&A Expenses: Consolidated SG&A expenses were $9.8 million for the six-month period ended June 30, 2025, compared to $9.0 million for the six-month period ended June 30, 2024. The $0.8 million change is mainly due to a non-cash stock-based compensation increase of $0.3 million and an increase of $0.6 million in purchases and external expenses, partially offset for by a decrease in amortization expenses of $0.1 million.

Other operating income and expenses: Other operating income increased slightly by $0.1 million between the six-month periods ended June 30, 2024, and 2025.

Net financial gain (loss): We had a consolidated net financial loss of $18.1 million for the six-month period ended June 30, 2025, compared to an $18.0 million net financial gain for the six-month period ended June 30, 2024. This $36.1 million difference reflects mainly (i) a one-off $14.3 million gain in change in fair value of the derivative instrument component of the Subsequent Investment Agreement dated November 7, 2023 between us and AstraZeneca Holdings (the "SIA"), which was recognized in the six-month period ended June 30, 2024, (ii) a $3.5 million decrease in change in fair value of the warrants issued to the European Investment Bank ("EIB"), as required by our finance contract entered into with EIB in December 2022, (iii) a $22.5 million increase in foreign exchange loss and a $1.0 million decrease in foreign exchange gain over the period due to the USD devaluation and (iv) a $0.3 million increase in interests on financial and lease liabilities, partially offset by (v) a $0.4 million increase in income from our financial investments and cash-equivalents, (vi) a $4.5 million decrease in loss on fair value mainly due to our investment in shares of Cibus, Inc., which was entirely sold in the first quarter of 2025 and (vii) a $0.6 million gain in fair value of foreign exchange derivatives recorded during the period.

Net Income (loss) Attributable to Shareholders of Cellectis: Consolidated net loss attributable to shareholders of Cellectis was $41.9 million (or a $0.42 net loss per share) for the six-month period ended June 30, 2025, compared to a $19.6 million net loss (or a $0.24 net loss per share) for the six-month period ended June 30, 2024. The $22.2 million change in net loss was primarily driven by (i) an increase in revenues and other income of $14.2 million and (ii) a $0.1 million decrease in operating expenses and other operating income, offset by (iii) a $36.1 million change from a net financial gain of $18.0 million as of June 30, 2024 to a net financial loss of $18.1 million as of June 30, 2025 and (iv) a decrease in deferred tax asset income of $0.5 million.

Adjusted Net Income (Loss) Attributable to Shareholders of Cellectis: Consolidated adjusted net loss attributable to shareholders of Cellectis was $39.6 million (or a $0.40 loss per share) for the six-month period ended June 30, 2025, compared to a net loss of $17.9 million (or a $0.22 loss per share) for the six-month period ended June 30, 2024.

The interim condensed consolidated financial statements of Cellectis have been prepared in accordance with International Financial Reporting Standards, as issued by the International Accounting Standards Board ("IFRS").

Please see "Note Regarding Use of Non-IFRS Financial Measures" for reconciliation of GAAP net income (loss) attributable to shareholders of Cellectis to adjusted net income (loss) attributable to shareholders of Cellectis.

CELLECTIS S.A.
INTERIM CONDENSED STATEMENT OF CONSOLIDATED FINANCIAL POSITION (unaudited)
($ in thousands)

As of
December 31, 2024 June 30, 2025
ASSETS
Non-current assets
Intangible assets 1,116 1,153
Property, plant, and equipment 45,895 42,790
Right-of-use assets 29,968 27,383
Non-current financial assets 7,521 35,491
Other non-current assets 11,594 16,127
Deferred tax assets 382 382
Total non-current assets 96,476 123,326
Current assets
Trade receivables 6,714 8,776
Subsidies receivables 14,521 16,382
Other current assets 5,528 7,333
Cash and cash equivalent and Current financial assets 260,306 198,151
Total current assets 287,069 230,641
TOTAL ASSETS 383,544 353,966
LIABILITIES
Shareholders’ equity
Share capital 5,889 5,902
Premiums related to the share capital 494,288 433,549
Currency translation adjustment (39,537 ) (33,885 )
Retained earnings (292,846 ) (266,592 )
Net income (loss) (36,761 ) (41,863 )
Total shareholders’ equity – Group Share 131,033 97,111
Non-controlling interests - -
Total shareholders’ equity 131,033 97,111
Non-current liabilities
Non-current financial liabilities 50,882 55,856
Non-current lease debts 34,245 32,264
Non-current provisions 1,115 1,303
Total non-current liabilities 86,241 89,424
Current liabilities
Current financial liabilities 16,134 18,230
Current lease debts 8,385 7,477
Trade payables 18,664 17,522
Deferred revenues and deferred income 112,161 113,379
Current provisions 828 875
Other current liabilities 10,097 9,949
Total current liabilities 166,269 167,432
TOTAL LIABILITIES AND SHAREHOLDERS’ EQUITY 383,544 353,966

Cellectis S.A.
INTERIM CONDENSED STATEMENTS OF CONSOLIDATED OPERATIONS (unaudited)
For the six-month period ended June 30, 2025
($ in thousands, except per share amounts)

For the six-month period ended June 30,
2024 2025

Revenues and other income
Revenues 12,589 27,380
Other income 3,412 2,842
Total revenues and other income 16,002 30,222
Operating expenses
Research and development expenses (45,841 ) (45,012 )
Selling, general and administrative expenses (8,986 ) (9,780 )
Other operating income (expenses) 721 804
Total operating expenses (54,107 ) (53,988 )

Operating income (loss) (38,105 ) (23,766 )

Financial gain (loss) 18,023 (18,098 )

Income tax 455 -

Net income (loss) (19,627 ) (41,863 )
Attributable to shareholders of Cellectis (19,627 ) (41,863 )
Basic net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.24 ) (0.42 )
Diluted net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.24 ) (0.42 )

Number of shares used for computing
Basic 80,881,026 100,231,292
Diluted 80,881,026 100,231,292

UNAUDITED STATEMENTS OF CONSOLIDATED OPERATIONS
For the three-month period ended June 30, 2025
($ in thousands, except per share amounts)

For the three-month period ended June 30,
2024 2025

Revenues and other income
Revenues 8 061 16,725
Other income 1,442 1,469
Total revenues and other income 9,504 18,193
Operating expenses
Research and development expenses (23,518 ) (23,080 )
Selling, general and administrative expenses (3,882 ) (5,078 )
Other operating income (expenses) 686 378
Total operating expenses (26,714 ) (27,779 )

Operating income (loss) (17,211 ) (9,586 )

Financial gain (loss) (8,251 ) (14,150 )

Income tax 193 -

Net income (loss) (25,270 ) (23,736 )
Attributable to shareholders of Cellectis (25,270 ) (23,736 )
Attributable to non-controlling interests - -
Basic and diluted net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.28 ) (0.24 )
Diluted net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.28 ) (0.24 )

Number of shares used for computing
Basic 89,852,142 100,305,204
Diluted 89,852,142 100,305,204

On August 4, 2025 Castle Biosciences, Inc. (Nasdaq: CSTL), a company improving health through innovative tests that guide patient care, reported its financial results for the second quarter and six months ended June 30, 2025 (Press release, Castle Biosciences, AUG 4, 2025, View Source [SID1234654725]).

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"Following a strong first quarter, our team closed out a very successful second quarter that we believe continued to reflect the clinical value our tests provide to clinicians and their patients," said Derek Maetzold, president and chief executive officer of Castle Biosciences. "We saw very solid total year-over-year test volume growth in our core revenue drivers, with both DecisionDx-Melanoma and TissueCypher exceeding our volume expectations for the quarter, driving our top-line performance.

"In alignment with our capital allocation priorities and M&A strategy, we closed the Previse tuck-in acquisition and announced an exciting collaboration and license agreement with SciBase, both of which we believe will support our mid- to long-term value creation goals. At the same time, we remain deeply focused on execution across our current test portfolio, which we believe positions us well for continued near-term success. Our ability to invest in the future while advancing our core franchises reflects the strength of our growth initiatives and commitment to delivering sustainable value to our stakeholders."

Second Quarter Ended June 30, 2025, Financial and Operational Highlights
•Revenues were $86.2 million, compared to $87.0 million in the second quarter of 2024. Affecting second quarter 2025 revenue was the Novitas local coverage determination (LCD), Genetic Testing in Oncology: Specific Tests, that included DecisionDx-SCC as noncovered, which became effective April 24, 2025, as well as discontinuation of IDgenetix in May 2025.
•Adjusted Revenues, which exclude the effects of revenue adjustments related to tests delivered in prior periods, were $86.2 million, compared to $86.6 million for the same period in 2024.
•Delivered 26,574 total test reports in the second quarter of 2025, an increase of 6% compared to 25,102 in the same period of 2024. Affecting second quarter 2025 test report volume was the Novitas LCD, Genetic Testing in Oncology: Specific Tests, that included DecisionDx-SCC as noncovered, which became effective April 24, 2025, as well as discontinuation of IDgenetix in May 2025:
◦DecisionDx-Melanoma test reports delivered in the quarter were 9,981, compared to 9,585 in the second quarter of 2024.
◦TissueCypher Barrett’s Esophagus test reports delivered in the quarter were 9,170, compared to 4,782 in the second quarter of 2024.
◦DecisionDx-SCC test reports delivered in the quarter were 4,762, compared to 4,277 in the second quarter of 2024. Affecting second quarter test report volume was the

Novitas LCD, Genetic Testing in Oncology: Specific Tests, that included DecisionDx-SCC as noncovered, which became effective April 24, 2025.
◦MyPath Melanoma test reports delivered in the quarter were 1,166, compared to 1,099 in the second quarter of 2024.
◦IDgenetix test reports delivered in the quarter were 1,027, compared to 4,903 in the second quarter of 2024. The Company discontinued its IDgenetix test offering effective May 2025.
◦DecisionDx-UM test reports delivered in the quarter were 468, compared to 456 in the second quarter of 2024.
•Gross margin was 77%, and Adjusted Gross Margin was 80%, compared to 81% and 83%, respectively, for the same periods in 2024.
•Net cash provided by operations was $20.8 million, compared to net cash provided by operations of $24.0 million for the same period in 2024.
•Net income, which includes non-cash stock-based compensation expense of $11.2 million, was $4.5 million, compared to net income of $8.9 million for the same period in 2024.
•Net income per share and Adjusted Net Income per Share, Basic and Diluted, was $0.16 and $0.15, respectively, compared to $0.32 and $0.31, respectively, for the same period in 2024.
•Adjusted EBITDA was $10.4 million, compared to $21.5 million for the same period in 2024.

Six Months Ended June 30, 2025, Financial and Operational Highlights

•Revenues were $174.2 million, a 9% increase compared to $160.0 million during the same period in 2024. Affecting six months ended June 30, 2025 revenue was the Novitas LCD, Genetic Testing in Oncology: Specific Tests, that included DecisionDx-SCC as noncovered, which became effective April 24, 2025, as well as discontinuation of IDgenetix in May 2025.

•Adjusted Revenues, which exclude the effects of revenue adjustments related to tests delivered in prior periods, were $176.2 million, an 11% increase compared to $159.0 million for the same period in 2024.
•Delivered 50,976 total test reports in the six months ended June 30, 2025, an increase of 11% compared to 45,990 in the same period of 2024. Affecting six months ended June 30, 2025 test report volume was the Novitas LCD, Genetic Testing in Oncology: Specific Tests, that included DecisionDx-SCC as noncovered, which became effective April 24, 2025, as well as discontinuation of IDgenetix in May 2025:
◦DecisionDx-Melanoma test reports delivered in the six months ended June 30, 2025, were 18,602, compared to 17,969 for the same period in 2024.
◦TissueCypher Barrett’s Esophagus test reports delivered in the six months ended June 30, 2025, were 16,602, compared to 8,211 for the same period in 2024.
◦DecisionDx-SCC test reports delivered in the six months ended June 30, 2025, were 9,137, compared to 7,854 for the same period in 2024. Affecting six months ended June 30, 2025 volume was the Novitas LCD, Genetic Testing in Oncology: Specific Tests, that included DecisionDx-SCC as noncovered, which became effective April 24, 2025.
◦MyPath Melanoma test reports delivered in the six months ended June 30, 2025, were 2,092, compared to 2,097 for the same period in 2024.
◦IDgenetix test reports delivered in the six months ended June 30, 2025, were 3,605, compared to 8,981 for the same period in 2024. The Company discontinued its IDgenetix test offering effective May 2025.
◦DecisionDx-UM test reports delivered in the six months ended June 30, 2025, were 938, compared to 878 for the same period in 2024.
•Gross margin for the six months ended June 30, 2025, was 63%, and Adjusted Gross Margin was 81%.
•Net cash provided by operations was $14.8 million, compared to $17.2 million net cash provided by operations for the same period in 2024.
•Net loss, which includes non-cash stock-based compensation expense of $22.4 million, was $21.3 million, compared to net income of $6.4 million for the same period in 2024.
•Net loss per share, Basic and Diluted, was $0.74 and Adjusted Net Loss per Share, Basic and Diluted, was $0.04, compared to Net income per share and Adjusted Net Income per Share, Basic and Diluted, of $0.23 and $0.22, respectively, for the same period in 2024.
•Adjusted EBITDA was $23.4 million, compared to $32.1 million for the same period in 2024.
Cash, Cash Equivalents and Marketable Investment Securities
As of June 30, 2025, the Company’s cash, cash equivalents and marketable investment securities totaled $275.9 million.
2025 Outlook
Castle Biosciences is raising its guidance for anticipated total revenue in 2025. The Company now anticipates generating between $310-320 million in total revenue in 2025, compared to the previously provided guidance of between $287-297 million.

Second Quarter and Recent Accomplishments and Highlights

Dermatology
•DecisionDx-Melanoma: DecisionDx-Melanoma test has been granted Breakthrough Device designation from the U.S. Food and Drug Administration (FDA). The FDA grants Breakthrough Device designation to select qualifying devices that may offer improved treatment or diagnosis of life-threatening or irreversibly debilitating diseases when compared to currently available alternatives. The Breakthrough Devices Program is intended to provide patients and healthcare providers with timely access to medical devices by speeding up development, assessment and review. See the Company’s news release from July 23, 2025, for more information.
•DecisionDx-Melanoma: Prior studies have shown that clinicians use DecisionDx-Melanoma to inform both avoiding sentinel lymph node biopsy procedures in low-risk patients and initiation of surveillance imaging and referrals to medical oncology in high-risk patients, which enables early detection of recurrences and initiation of therapy. Early detection has been shown to improve outcomes to a greater extent when therapy is initiated with smaller metastatic burden, which can improve net health outcomes. The Company presented novel research as part of Castle’s ongoing collaboration with the NCI’s SEER Program Registries at the 2025 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The study presented an updated matching of patients who received DecisionDx-Melanoma as part of their clinical care to those who did not. In this large, real-world cohort of 13,560 patients with CM – the largest real-world study of gene expression profile testing to date – the DecisionDx-Melanoma was associated with a 32% reduction in mortality risk compared to untested patients, providing further evidence of the test’s association with improved patient survival. Additionally, test performance on independent risk stratification was re-confirmed. See the Company’s news release from May 29, 2025, for more information.
•DecisionDx-SCC: The Company submitted a DecisionDx-SCC reconsideration request for the Novitas LCD and received notification confirming acceptance of the reconsideration submission.
•DecisionDx-SCC: Two new studies were published in SKIN The Journal of Cutaneous Medicine supporting the clinical utility of DecisionDx-SCC in patients with high-risk cutaneous squamous cell carcinoma (SCC). The first study represents a new validation milestone, establishing DecisionDx-SCC as a significant predictor of local recurrence (LR) in patients classified as high-risk by National Comprehensive Cancer Network (NCCN) guidelines, thereby adding a third utility to the test’s existing capabilities. The test has now been validated to predict individual risk of metastasis, benefit from adjuvant radiation therapy (ART) and risk of LR, providing comprehensive results to support tailored post-surgical management and treatment pathway recommendations for patients with SCC. The second study shares results from a clinician survey, affirming the impact of the test’s results in guiding these recommendations, specifically the use of ART and surveillance imaging, by providing actionable decision points based on individual patient risk.
Gastroenterology
•The Company closed its acquisition of Capsulomics, Inc., d/b/a Previse. This acquisition has the potential to increase Castle’s GI offerings. There is the potential to create a multiomics approach for improved patient care in Barrett’s esophagus, as well as a nonendoscopic sample collection device for pipeline opportunities to potentially expand screening and diagnostic support for patients with Barrett’s esophagus and other GI diseases. See the Company’s news release from May 5, 2025, for more information.
Uveal Melanoma
•The Company announced new data from the first independent validation of the recently published Collaborative Ocular Oncology Group Study No. 2 (COOG2.) by Harbour et al. The data, from a real-world cohort of 1,297 patients with uveal melanoma (UM), was presented at the Association for Research in Vision and Ophthalmology (ARVO) 2025 Annual Meeting in Salt Lake City. The findings provided further support for adding Preferentially Expressed Antigen in Melanoma (PRAME) gene expression information to the DecisionDx-UM test result to further refine metastatic risk prediction for patients with UM, which is a rare but aggressive eye cancer. See the Company’s news release from May 9, 2025, for more information.
Pipeline Initiatives
•The Company announced that it entered into a collaboration and license agreement with SciBase Holding AB ("SciBase") utilizing SciBase’s Electrical Impedance Spectroscopy technology, which includes both desktop and point-of-care instruments. The initial goal of the collaboration is to advance the development of a diagnostic test that predicts flares in patients diagnosed with atopic dermatitis (AD), a U.S., market with an estimated up to 24 million patients.1, 2 See the Company’s news release from June 16, 2025, for more information.
Corporate
•The Company announced that its founder, president and chief executive officer Derek Maetzold was awarded a distinguished Lifetime Achievement Award in the Management: Business Products Industries category in the 23rd Annual American Business Awards. The American Business Awards recognizes outstanding business performances in the United States, with more than 3,600 nominations from organizations of all sizes submitted this year for consideration in a wide range of categories. See the Company’s news release from June 4, 2025, for more information.
•The Company announced that it earned multiple awards through the 2025 Top Workplaces program: a third consecutive national Healthcare Industry Top Workplaces award, with Castle ranking third among other recognized companies in its size bracket; a fourth consecutive regional Arizona Top Workplaces award from AZ Central; and consecutive national Top Workplaces Culture Excellence awards for Innovation, Work-Life Flexibility, Compensation & Benefits, Leadership and Purpose & Values. Top Workplaces award designations are garnered solely through anonymous employee feedback gathered through a third-party survey administered by Energage. The confidential survey measures the workplace experience and various culture themes that are indicative of successful organizations. See the Company’s news release from July 17, 2025, for more information.
•The Company announced that Maetzold was also named a 2025 Most Admired CEO by the Houston Business Journal. This prestigious honor celebrates leaders who have demonstrated outstanding financial stewardship, fostered inclusive and thriving workplace cultures, and made meaningful contributions to the greater Houston community. See the Company’s news release from July 25, 2025, for more information.

Conference Call and Webcast Details
Castle Biosciences will hold a conference call on Monday, August 4, 2025, at 4:30 p.m. Eastern time to discuss its second quarter 2025 results and provide a corporate update.

A live webcast of the conference call can be accessed here: View Source or via the webcast link on the Investor Relations page of the Company’s website, View Source Please access the webcast at least 10 minutes before the conference call start time. An archive of the webcast will be available on the Company’s website until August 25, 2025.

To access the live conference call via phone, please dial 833 470 1428 from the United States, or +1 404 975 4839 internationally, at least 10 minutes prior to the start of the call, using the conference ID 638217.

There will be a brief Question & Answer session following management commentary.

On August 4, 2025 Bristol Myers Squibb (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted the supplemental biologics license application (sBLA) for Breyanzi (lisocabtagene maraleucel; liso-cel) as a potential treatment for adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least two prior lines of systemic therapy (Press release, Bristol-Myers Squibb, AUG 4, 2025, View Source;Food-and-Drug-Administration-FDA-in-Fifth-Cancer-Type-for-Relapsed-or-Refractory-Marginal-Zone-Lymphoma-MZL/default.aspx [SID1234654724]). The FDA has granted the application Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) goal date of December 5, 2025.

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"While initial therapy for MZL can be effective, multiple relapses over the course of several years are common, leaving patients in need of a new treatment option that can provide high, lasting response rates," said Rosanna Ricafort, vice president, Senior Global Program Lead for Hematology and Cell Therapy, Bristol Myers Squibb. "This FDA acceptance brings us one step closer to potentially standardizing CAR T cell therapy as a treatment option for MZL, while building on our commitment to bring this personalized therapy to as many eligible patients as possible."

The application is based on results from the primary analysis of the MZL cohort in TRANSCEND FL, an open-label, multicenter, Phase 2, single-arm study, which was shared in an oral presentation during the 2025 International Conference on Malignant Lymphoma (ICML) in June 2025.

The development progress of Breyanzi reflects BMS’ continued efforts to collaborate across the healthcare ecosystem, with the ultimate goal of reaching more patients and democratizing access to cell therapy. Recently, the FDA approved streamlined patient monitoring requirements and the removal of the REMS program for Breyanzi, easing known barriers to treatment and administration while maintaining patient safety.

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 third most common lymphoma, accounting for about 7% of all non-Hodgkin lymphoma cases. Most patients with MZL are at a median age of 67 years when they are diagnosed. MZL develops when white blood cells cluster together to form lumps in a person’s lymph nodes or organs. Initial therapy often leads to remission, 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. The treatment process includes blood collection, CAR T-cell creation, potential bridging therapy, lymphodepletion, administration, and side-effect monitoring.

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

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

Breyanzi U.S. FDA-Approved Indications

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

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

adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor.
Breyanzi U.S. 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.
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 for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Continue to monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 2 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. Advise patients to avoid driving for at least 2 weeks following infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.

Hypersensitivity Reactions

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

Serious Infections

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

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

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

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

Prolonged Cytopenias

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

Hypogammaglobulinemia

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

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

Secondary Malignancies

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

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

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

Adverse Reactions

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

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