Category: 3. Business

• In late November and early December 2025, Deutsche Bank Aktiengesellschaft issued and announced multiple fixed‑coupon, senior unsecured, callable notes across maturities from 2029 to 2050, including several Eurobond and Eurodollar formats priced at par with discounts of 0.4% to 5% per security.

• This burst of fixed‑income issuance highlights Deutsche Bank’s active use of debt markets to refine its funding profile and support its broader banking activities, coinciding with a senior hire to lead global private bank investment solutions.

• We will now examine how this wave of senior unsecured bond issuance might influence Deutsche Bank’s investment narrative and future earnings mix.

These 13 companies survived and thrived after COVID and have the right ingredients to survive Trump’s tariffs. Discover why before your portfolio feels the trade war pinch.

To own Deutsche Bank, you need to believe it can convert improving profitability and disciplined capital returns into durable earnings, despite low forecast growth and lingering asset quality and litigation risks. The recent wave of fixed coupon senior unsecured issuance modestly tightens the funding story but does not materially change the near term focus on credit costs, especially in U.S. CRE, or on managing large one off items that still cloud earnings quality.

Among recent announcements, the appointment of Vivienne Chia as global head of private bank investment solutions stands out as most connected to this funding activity, because it speaks to the mix of fee based and interest driven earnings these bonds may support over time. As the private bank builds out higher margin investment solutions on top of a still credit heavy balance sheet, the key question is how quickly that mix can offset pressures from regulation, competition and capital requirements.

Yet investors should be aware that rising regulatory complexity and capital requirements could still…

Read the full narrative on Deutsche Bank (it’s free!)

Deutsche Bank’s narrative projects €33.8 billion revenue and €6.8 billion earnings by 2028. This requires 4.0% yearly revenue growth and about a €1.3 billion earnings increase from €5.5 billion today.

Uncover how Deutsche Bank’s forecasts yield a €31.30 fair value, in line with its current price.

Seven fair value estimates from the Simply Wall St Community span roughly €17 to about €35.89 per share, underlining how far apart views on Deutsche Bank’s upside can sit. When you weigh those opinions against the risk of persistently elevated credit losses and high bad loans, it becomes even more important to compare several viewpoints before deciding how this bank might fit into your portfolio.

Explore 7 other fair value estimates on Deutsche Bank – why the stock might be worth as much as 15% more than the current price!

Disagree with existing narratives? Create your own in under 3 minutes – extraordinary investment returns rarely come from following the herd.

Our daily scans reveal stocks with breakout potential. Don’t miss this chance:

This article by Simply Wall St is general in nature. We provide commentary based on historical data and analyst forecasts only using an unbiased methodology and our articles are not intended to be financial advice. It does not constitute a recommendation to buy or sell any stock, and does not take account of your objectives, or your financial situation. We aim to bring you long-term focused analysis driven by fundamental data. Note that our analysis may not factor in the latest price-sensitive company announcements or qualitative material. Simply Wall St has no position in any stocks mentioned.

Companies discussed in this article include DBK.DE.

Have feedback on this article? Concerned about the content? Get in touch with us directly. Alternatively, email editorial-team@simplywallst.com

Story Continues

Introduction

Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease that primarily affects the upper and lower motor neurons.¹ Patients often initially present with progressively worsening muscle weakness and atrophy. As the disease advances, it gradually involves the muscles responsible for swallowing, speech, and respiration. In the late stages, widespread muscle atrophy becomes pronounced, leading to dysphagia and respiratory muscle paralysis, with the majority of patients ultimately succumbing to respiratory failure.² Research suggests that multiple mechanisms collectively contribute to the pathogenesis of ALS, including oxidative stress, excitotoxicity, mitochondrial and proteasomal dysfunction, abnormal RNA metabolism, impaired axonal transport, and neuroinflammation.³ Currently, Riluzole and Edaravone are the only drugs approved by the FDA for ALS treatment; however, they can only partially alleviate symptoms and marginally extend patient survival, without halting or reversing disease progression.⁴ Although emerging strategies like gene therapy offer new directions for ALS treatment,⁵ they remain largely exploratory, and effective therapeutic targets and interventions for the disease are still scarce.

The TAR DNA-binding Protein of 43 kDa (TDP-43) is a key pathological hallmark in various neurodegenerative diseases, including ALS.^6,7 Abnormal, ubiquitinated, and phosphorylated TDP-43 inclusions are found in the affected neurons of approximately 97% of ALS patients and a significant subset of patients with Frontotemporal Lobar Degeneration (FTLD).^8,9 The core pathogenic mechanisms of TDP-43 involve a loss of its nuclear function, leading to dysregulation of RNA metabolism,¹⁰ and the abnormal aggregation of its C-terminal domain in the cytoplasm, forming neurotoxic amyloid aggregates. In familial ALS, various C-terminal mutations disrupt protein homeostasis,¹¹ causing multiple cellular functional defects and activating degradation pathways, thereby creating a vicious cycle.¹²

ALDOA, a member of the aldolase family, plays a crucial role in glycolysis and gluconeogenesis by reversibly catalyzing the conversion of fructose-1,6-bisphosphate to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate.¹³ Dysregulation of its expression can mediate glycolytic dysfunction. Previous studies have indicated that enhanced glycolysis promotes the progression of neurodegenerative diseases such as Parkinson’s disease (PD).^14,15 A proteomic analysis of cerebrospinal fluid from AD patients revealed a significant increase in ALDOA expression levels.¹⁶ However, the interaction between TDP-43 and ALDOA remains to be elucidated. Meanwhile, the impact of TDP-43 gene mutations on ALDOA function in the context of ALS requires further investigated.

Proteomics is a discipline focused on the study of the proteome, dedicated to the systematic analysis of protein expression levels, post-translational modification states, and protein-protein interaction networks, thereby comprehensively revealing the overall molecular mechanisms of disease pathogenesis and cellular metabolic regulation.¹⁷ This technology has been widely applied in the field of neurodegenerative disease research, playing a significant role in screening disease-related biomarkers and providing in-depth insights into pathogenic molecular mechanisms.^18,19 This study comprehensively utilizes proteomic analysis and molecular biology experiments to screen proteins interacting with TDP-43 and construct their interaction network. It further validates changes in ALDOA expression levels to deeply explore the interaction between TDP-43 and ALDOA and its potential mechanism in ALS. The aim is to provide new theoretical foundations and potential therapeutic targets for ALS pathological mechanism research and clinical treatment.

Materials and Methods

Materials

The HEK-293T cell line was purchased from Procell Life Science & Technology Co., Ltd. Fetal bovine serum (FBS) was obtained from Lonsera (S711-001S, China). Lipofectamine™ 3000 Transfection Reagent was provided by Thermo Fisher Scientific (L3000015, USA). Opti-MEM™ I Reduced Serum Medium was purchased from Thermo Fisher Scientific (31985070, USA). The BCA Protein Assay Kit was acquired from Solarbio (PC0020, China).

Cell Culture

All cells were cultured and preserved at the Fifth Affiliated Hospital of Sun Yat-sen University. HEK-293T cells were maintained in DMEM medium (GIBCO, USA) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. For cell resuscitation, cryovials were retrieved from liquid nitrogen and quickly placed in a 37°C water bath with gentle shaking until thawed. After complete thawing, the cell suspension was transferred to a centrifuge tube, mixed with an appropriate amount of complete medium, and subjected to low-speed centrifugation followed by supernatant removal. The cells were then seeded in DMEM medium (GIBCO, USA) containing 10% fetal bovine serum and 1% penicillin/streptomycin, and incubated at 37°C in a 5% CO₂ incubator. Cells beyond the 20th passage were excluded from the experiments.

Cell Transfection

HEK293T cells at 60% confluence were transfected with the following plasmids: Vector (GL107 pSLenti-EF1-EGFP-P2A-Puro-CMV-MCS-3×FLAG-WPRE), Flag-TDP-43 (pSLenti-EF1-EGFP-P2A-Puro-CMV-Tardbp(Tdp43)-3×FLAG-WPRE), and Flag-TDP-43 M337V (pSLenti-EF1-EGFP-P2A-Puro-CMV-Tardbp(p.M337V)-3×FLAG-WPRE). For each transfection, 3 μg of plasmid was diluted in 200 μL of Opti-MEM™ I Reduced Serum Medium and incubated for 5 minutes. Separately, 6 μL of Lipofectamine™ 3000 transfection reagent was mixed with 200 μL of Opti-MEM™ I Reduced Serum Medium and also incubated for 5 minutes. The two solutions were then combined, mixed gently, and further incubated for 5 minutes. The resulting mixture was added to the respective cell groups, and cells were harvested 48 hours post-transfection.

Sample Preparation

Proteins were extracted from the cells using a mixture of protein lysis buffer and protease inhibitors. After lysis and centrifugation, the supernatant was collected. Protein concentration was determined using the BCA Protein Assay Kit to ensure consistency across groups in subsequent experiments. Input samples were prepared as controls, and co-immunoprecipitation (IP) samples were prepared to enrich proteins interacting with TDP-43.

Mass Spectrometry Analysis and Screening

Peptides were dissolved in mobile phase A and separated using an EASY-nLC 1200 ultra-high-performance liquid chromatography (UHPLC) system. Mobile phase A consisted of aqueous solution containing 0.1% formic acid and 2% acetonitrile; mobile phase B consisted of aqueous solution containing 0.1% formic acid and 90% acetonitrile. The liquid chromatography gradient was set as follows: 0–14.5 min, 6%–22% B; 14.5–17.5 min, 22%–34% B; 17.5–19 min, 34%–80% B; 19–20 min, 80% B, with a flow rate maintained at 700 nl/min.

After separation by the UHPLC system, the peptides were ionized via an NSI ion source and then analyzed using an Orbitrap Exploris 480 mass spectrometer. The ion source voltage was set to 2300 V, and the FAIMS compensation voltage (CV) was set to −45 V. Both the precursor ions and their secondary fragments were detected and analyzed using the high-resolution Orbitrap. The primary mass spectrometry scanning range was set to 350–1400 m/z with a resolution of 60,000; the secondary mass spectrometry scanning range started fixed at 120 m/z with a resolution of 15,000.

Data acquisition was performed using data-independent acquisition (DIA), where after full MS¹ scanning, peptide ions within multiple consecutive m/z windows were fragmented in the HCD collision cell with 27% fragmentation energy, followed by sequential MS² analysis. To improve mass spectrometry efficiency, the automatic gain control (AGC) was set to 1E6 and the maximum injection time was set to 22 ms.

Bioinformatics Analysis

The database accession numbers or protein sequences of differentially expressed proteins identified from comparative groups were compared against the STRING protein-protein interaction database. Interactions with a confidence score > 0.7 (high confidence) were extracted to construct the protein interaction network of differentially expressed proteins. The network was then visualized using the R package “visNetwork”.

Co-Immunoprecipitation Assay

First, collect the cells to be analyzed and lyse them on ice using a pre-cooled RIPA lysis buffer for 30 minutes. Then, centrifuge the lysate at 4°C and 12,000 × g for 15 minutes to remove cell debris. The resulting supernatant, referred to as Supernatant A, contains the total protein extract, and its concentration should be determined.

Next, divide Supernatant A equally into two portions: one for the experimental group, to which a specific antibody against the target protein is added, and the other for the negative control group, to which the same amount of a non-specific immunoglobulin from the same species or IgG is added. Incubate the mixtures overnight at 4°C with slow agitation to allow sufficient formation of immune complexes between the antibodies and the target protein.

The following day, add an appropriate amount of Protein A/G magnetic beads, pre-washed with lysis buffer, to each reaction system. Continue incubation at 4°C with slow agitation for 2–4 hours to efficiently capture the antibody-target protein complexes by the magnetic beads.

After incubation, place the samples on a magnetic stand and discard the supernatant. Wash the precipitated magnetic beads 3–4 times with pre-cooled lysis buffer to thoroughly remove non-specifically bound proteins.

Finally, add an appropriate volume of 1× SDS-PAGE loading buffer to the magnetic bead pellet, heat the mixture at boiling temperature for 5–10 minutes, and then collect the supernatant by centrifugation for subsequent Western Blotting analysis.

Western Blot

SDS-PAGE gels with concentrations ranging from 6% to 12% were prepared. Samples were loaded at 30 μg of protein per well. Electrophoresis was performed at a constant voltage of 100 V to separate the proteins, which were then transferred to a PVDF membrane under a constant current of 400 mA. The membrane was subsequently blocked with TBST containing 5% skim milk at room temperature for 1 hour.

After blocking, the membrane was incubated overnight at 4 °C with the following primary antibodies: anti-ALDOA (1:1000, 11,217-1-AP, Proteintech, China), anti-TDP-43 (1:1000, 10,782-2-AP, Proteintech, China), and anti-Tubulin (1:5000, 11,224-1-AP, Proteintech, China). The membrane was then washed three times with TBST to remove unbound primary antibodies.

Next, corresponding species-specific HRP-conjugated secondary antibodies (1:5000) were applied and incubated at room temperature for 1 hour. After incubation, the membrane was washed again with TBST. Finally, specific protein bands were detected using a chemiluminescence imaging system, and band intensity was quantified to compare the expression levels of target proteins across different samples.

Immunofluorescence

After removing the culture medium, HEK293T cells were gently washed twice with room temperature PBS buffer for 5 seconds each. Then, 4% neutral formaldehyde fixative was added to cover the cells and incubated at room temperature for 15 minutes. After fixation, the fixative was discarded, and the cells were washed three times with pre-chilled PBS buffer (4°C) for 5 minutes each. Subsequently, the cells were permeabilized with Triton X-100 on ice for 10 minutes.

After permeabilization, the samples were covered with 5% goat serum and blocked at room temperature for 1 hour. The blocking solution was then removed, and the samples were incubated overnight at 4°C with the following primary antibodies: anti-ALDOA (1:200 dilution, Cat# ab252953, Abcam, USA) and anti-TDP-43 (1:200 dilution, Cat# 10782-2-AP, Proteintech, Wuhan, China).

The next day, the primary antibodies were discarded, and species-specific HRP-conjugated secondary antibodies were applied to cover the samples. Incubation was carried out at room temperature for 2 hours in the dark. The samples were then washed three times with PBS buffer. Finally, an anti-fade mounting medium was applied, and the images were observed and captured under a fluorescence microscope.

Statistical Analysis

Data from in vivo experiments were analyzed using GraphPad Prism 10.3.1 and the statsmodels Python package (v0.13.0). An unpaired t-test was employed for comparisons. All data presented as mean ± SD. Statistical significance was set at P < 0.05.

Results

Construction of TDP-43 Wild-Type and TDP-43 Mutant Cell Models

Forty-eight hours after plasmid transfection into HEK293T cells from each group, transfection efficiency was observed under a fluorescence microscope. The results showed a high fluorescence expression rate in each group, indicating successful plasmid transfection (Figure 1A). Silver staining results revealed clear protein bands in the silver-stained profiles of all samples, demonstrating good integrity and effective separation of the protein samples. Under equal protein concentrations, differences in protein expression patterns were observed among the groups, suggesting that plasmid transfection led to alterations in the protein expression profiles (Figure 1B).

Proteomic Analysis Reveals an Interaction Between ALDOA and TDP-43

Based on the mass spectrometry results, we successfully identified a specific peptide sequence of the ALDOA protein using affinity purification coupled with mass spectrometry. In the MS/MS spectrum of this peptide, we observed continuously distributed b-ions (b2–b4, b8–b11) and y-ions (y3, y7–y12) fragment signals. The most abundant fragment ions included y10⁺ (m/z 1049.51), y11⁺ (m/z 907.44), and y12⁺ (m/z 1162.6), while characteristic ions such as b3⁺ (m/z 284.2) and b4⁺ (m/z 355.23) were also detected in the low-mass region. These complementary ion series provided comprehensive fragment coverage, confirming that the peptide sequence is GAA DESGSK, corresponding to residues 120–128 of the ALDOA protein, which confirms the definite expression of ALDOA in the sample (Figure 2A).

Figure 2 Proteomic analysis reveals an interaction between ALDOA and TDP-43. (A) Mass spectrometry identification of a specific peptide derived from ALDOA; (B) Protein-protein interaction (PPI) network. TARDBP (TDP-43) and its interaction partner ALDOA are highlighted by red circles.

By comparing results with the STRING protein-protein interaction database and extracting interactions with a confidence score > 0.7 (high confidence), differential protein interaction relationships were obtained. Using Cytoscape software, a differential protein interaction network including ALDOA was constructed. The network analysis revealed that ALDOA occupies a central position and exhibits an interaction with TDP-43 (Figure 2B).

Validation of the Interaction and Co-Localization Between TDP-43 and ALDOA in HEK293T Cells

In this study, the expression and localization of TDP-43 and ALDOA within cells were detected by immunofluorescence assays. Following plasmid transfection, TDP-43 was localized to both the nucleus and cytoplasm, whereas ALDOA was predominantly nuclear. Consequently, the co-localization of the two proteins was primarily observed in the nucleus (Figure 3A and B). Furthermore, to further validate the interaction between the two proteins, we performed co-immunoprecipitation experiments. The results indicated that no ALDOA signal was detected in the Vector control group, whereas distinct ALDOA bands were observed in both the wild-type and mutant TDP-43 groups (Figure 3C), suggesting that ALDOA interacts directly or indirectly with both wild-type and mutant TDP-43.

Figure 3 Interaction between ALDOA and TDP-43 validated by immunofluorescence and co-immunoprecipitation. (A) Immunofluorescence images showing co-localization of ALDOA (green) and TDP-43 (red) in each group of cells; Bar = 50 μm. (B) Visual representation of fluorescence co-localization from (A). (C) Western blot results of co-immunoprecipitation assays.

TDP-43 Gene Mutation Leads to Upregulation of ALDOA Expression in HEK293T Cells

Western blot results further confirmed that TDP-43 protein bands were effectively detected in both the Vector control group and the mutant TDP-43 transfection group, with the TDP-43 protein expression level in the mutant TDP-43 transfection group being significantly higher than that in the Vector control group, indicating successful plasmid transfection (Figure 4A and B, P < 0.0001). Concurrently, at the protein level, ALDOA expression was significantly upregulated in the mutant TDP-43 transfection group compared to the Vector group (Figure 4A and C, P = 0.0157). Quantitative real-time PCR results showed that ALDOA mRNA expression was significantly higher in the mutant TDP-43 transfection group than in the Vector group (Figure 4A and D, P = 0.0117).

Figure 4 Expression of ALDOA is up-regulated in the TDP-43M337V group. (A) Representative Western blot images of TDP-43 and ALDOA protein bands in each group. (B and C) Quantitative analysis of band intensities shown in (A). (D) mRNA expression levels of ALDOA in each group. Data were analyzed by unpaired t‑test (n=3). *P < 0.05, ***P < 0.001 compared to the control group.

Discussion

Amyotrophic lateral sclerosis (ALS) is a highly debilitating motor neuron disease for which no effective treatment is currently available.⁴ The pathogenesis of ALS involves multiple mechanisms, including oxidative stress, mitochondrial and proteasomal dysfunction, abnormal RNA metabolism, altered synaptic function, disrupted axonal transport, and neuroinflammation.²⁰ Previous studies have identified the pathological roles of certain brain proteins in ALS progression, such as TDP-43²¹ and FUS,²² whose mutations or dysfunctions can trigger various neurodegenerative diseases.^23,24

TDP-43, encoded by the TARDBP gene, is a highly conserved nuclear protein primarily localized in the nucleus. It plays a critical role in regulating RNA transcription, alternative splicing, and the processing of miRNAs and lncRNAs, thereby maintaining cellular RNA homeostasis.²⁵ Its central role in neurodegenerative diseases was first established in 2006, when two independent research groups simultaneously identified TDP-43 as the primary component of neuronal inclusions in patients with sporadic amyotrophic lateral sclerosis (sALS) and frontotemporal lobar degeneration (FTLD).²⁶ Subsequent studies confirmed that the pathological aggregation of TDP-43 serves as a key biochemical hallmark of ALS.²⁷ In specific ALS subtypes, neuronal cytoplasmic inclusions formed by ubiquitinated and phosphorylated C-terminal TDP-43 fragments represent a characteristic neuropathological feature.^28,29 Notably, approximately 4% of familial ALS cases are directly linked to mutations in the TARDBP gene itself.³⁰ These pathogenic mutations (including M337V,³¹ A382T,³² G298S³³ and Q331K³⁴) are predominantly clustered within the C-terminal glycine-rich domain of the TDP-43 protein. Among them, M337V, as one of the most frequent pathogenic mutations, plays a critical role in ALS pathogenesis: this mutation significantly enhances the abnormal aggregation propensity of TDP-43, disrupts its normal nucleocytoplasmic localization, impairs liquid-liquid phase separation equilibrium, and induces a cytotoxic gain-of-function in the cytoplasm. Consequently, these alterations compromise TDP-43’s ability to regulate RNA metabolism, ultimately leading to motor neuron degeneration and driving the progression of ALS.³⁵

ALDOA is a key enzyme in the glycolytic pathway. Its high expression enhances glycolytic flux primarily by elevating its catalytic efficiency, accelerating the conversion of glucose to pyruvate, thereby increasing lactate production and facilitating rapid ATP generation. Studies have demonstrated that ALDOA promotes disease progression in malignancies such as hepatocellular carcinoma (HCC) by enhancing glycolysis.³⁶ Furthermore, ALDOA has been implicated in neurodegenerative diseases. Research indicates that ALDOA and pyruvate kinase (PKM) are specifically upregulated in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients.¹⁶ In sporadic Creutzfeldt-Jakob disease (sCJD), ALDOA expression is also specifically elevated and closely associated with prion protein (PrPSc) deposition and disease progression. The underlying mechanism may involve abnormal prion proteins interfering with the activity of ALDOA and other glycolytic enzymes, disrupting energy metabolism homeostasis in the brain.³⁷ Studies utilizing TDP-43 cellular models carrying familial ALS mutations (A315T, M337V and S379P), specifically a triple mutant (3×-TDP-43) model, revealed that phosphorylated TDP-43 aggregates cause autophagy dysfunction and subsequently disrupt the expression of key glycolytic molecules, including ALDOA. This suggests that TDP-43 pathology may contribute to ALS pathogenesis by perturbing energy metabolism homeostasis.³⁸ However, the specific biological functions and molecular mechanisms of ALDOA in ALS remain incompletely elucidated. This study identified and experimentally validated an interaction between ALS biomarker protein TDP-43 and ALDOA, providing new directions for further exploration of ALDOA’s role in ALS pathogenesis.

When ALDOA is highly expressed, it enhances glycolytic flux. The primary mechanism lies in the increased expression level of ALDOA directly elevating its catalytic efficiency, accelerating the conversion of glucose to pyruvate, which consequently leads to increased lactate production and rapid ATP generation. Under certain pathological conditions, the glycolytic process can be aberrantly activated and contribute to disease progression, as seen in cancers,³⁹ Alzheimer’s disease,⁴⁰ and Parkinson’s disease.⁴¹ Notably, disrupted glycolysis has been demonstrated to participate in various pathological processes such as cellular apoptosis⁴² and inflammatory responses,⁴³ suggesting that abnormalities in this pathway may represent a common mechanism underlying multiple neurological disorders.⁴⁴ In the pathogenesis of ALS, such coordinated metabolic mechanisms are disrupted, and metabolic dysregulation becomes a key factor driving disease progression. The interaction between TDP-43 and ALDOA and its alterations observed in this study may precisely represent one manifestation of glycolytic metabolic disruption in ALS.

This study integrated proteomics and molecular experiments by transfecting HEK293T cells with Flag-Vector, Flag-TDP-43, and Flag-TDP-43 ^M337V plasmids, respectively, to further investigate cellular mechanisms and related molecular targets. Based on the proteomics findings, we performed co-immunoprecipitation (co-IP) validation, which demonstrated that both wild-type TDP-43 and mutant TDP-43 ^M337V interact with the ALDOA protein. Furthermore, immunofluorescence assays confirmed the co-localization of ALDOA with both wild-type and mutant TDP-43 ^M337V in HEK293T cells. Subsequently, we examined ALDOA expression in the Vector group and the mutant TDP-43 M337V group. Both RT-qPCR and Western blot analyses revealed that compared to the Vector group, ALDOA mRNA and protein levels were elevated in the mutant TDP-43 ^M337V group, suggesting that TDP-43 mutation may upregulate ALDOA expression, thereby influencing the glycolytic pathway and contributing to the pathological process of ALS.

In summary, this study conducted an in-depth investigation of the proteome in cells transfected with ALS-associated wild-type and mutant TDP-43 plasmids, leading to the identification of ALDOA as an interacting partner. Differential expression levels of ALDOA were observed across various TDP-43 experimental groups. These findings establish a foundation for further exploration of the molecular mechanisms through which TDP-43-interacting protein ALDOA contributes to ALS pathogenesis. ALDOA and key proteins within its interactome may emerge as potential therapeutic targets for neurodegenerative diseases, suggesting that modulating the functions of these interacting proteins could offer novel strategic approaches for treatment.

Limitations of the Study

This study, through an in-depth investigation of the interaction between TDP-43 and ALDOA, reveals its potential role in the pathogenesis of ALS. The findings not only enhance the understanding of the pathophysiological processes of ALS but also provide a theoretical foundation for developing novel therapeutic strategies targeting this disease. However, this study has certain limitations, such as a relatively small sample size and the need for further optimization of experimental conditions. Future research should expand the sample size, delve deeper into the specific molecular mechanisms of the TDP-43-ALDOA interaction, and evaluate its feasibility and effectiveness as a therapeutic target. Moreover, utilizing preclinical models to further validate the translational potential of these findings could offer new hope for ALS patients.

Conclusion

This study confirms an interaction between TDP-43 and ALDOA, and demonstrates that the TDP-43 ^M337V mutation significantly promotes the upregulation of ALDOA expression. These results suggest that ALDOA, as a key glycolytic enzyme, may participate in TDP-43-mediated ALS pathogenesis by influencing cellular energy metabolism processes. The findings provide new experimental evidence for a deeper understanding of the molecular pathological mechanisms of ALS and also identify a potential target for therapeutic strategies aimed at intervening in metabolic pathways.

Funding

This study was supported by the Central Government Guidance Funds for Local Science and Technology Development (ZYYD2024ZY05) and the Xinjiang Medical University Young Top Talent Training Program (XYD2024Q08), National Natural Science Foundation of China (Grant No. 82171433), and Natural Science Foundation of Hunan Province of China (Grant No.2022JJ30918).

Disclosure

The authors report no conflicts of interest for this work.

References

1. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942–955. PMID: 21296405. doi:10.1016/S0140-6736(10)61156-7

2. Verma A. Clinical manifestation and management of amyotrophic lateral sclerosis. In: Araki T, editor. Amyotrophic Lateral Sclerosis. Brisbane (AU): Exon Publications; 2021. Chapter 1. PMID: 34473441.

3. Mejzini R, Flynn LL, Pitout IL, et al. ALS genetics, mechanisms, and therapeutics: where are we now? Front Neurosci. 2019;13:1310. PMID: 31866818; PMCID: PMC6909825. doi:10.3389/fnins.2019.01310

4. Tzeplaeff L, Wilfling S, Requardt MV, et al. Current state and future directions in the therapy of ALS. Cells. 2023;12(11):1523. PMID: 37296644; PMCID: PMC10252394. doi:10.3390/cells12111523

5. Yang X, Ji Y, Wang W, et al. Amyotrophic lateral sclerosis: molecular mechanisms, biomarkers, and therapeutic strategies. Antioxidants. 2021;10(7):1012. PMID: 34202494; PMCID: PMC8300638. doi:10.3390/antiox10071012

6. Zhou C, Hardin EJ, Zimmer TS, et al. Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology. Neurobiol Dis. 2025;211:106939. PMID: 40339618; PMCID: PMC12240875. doi:10.1016/j.nbd.2025.106939

7. Zeng J, Luo C, Jiang Y, et al. Decoding TDP-43: the molecular chameleon of neurodegenerative diseases. Acta Neuropathol Commun. 2024;12(1):205. PMID: 39736783; PMCID: PMC11687198. doi:10.1186/s40478-024-01914-9

8. Kurashige T, Murao T, Kanaya Y, et al. Intramuscular nerve bundles reflect TDP-43 pathology in the medulla and spinal cord of ALS patients. Neuropathol Appl Neurobiol. 2025;51(2):e70016. PMID: 40192272; PMCID: PMC11974360. doi:10.1111/nan.70016

9. Chauhan S, Maan P, Panghal A. TDP-43 proteinopathies in ALS and FTLD: mechanistic insights and therapeutic approaches. CNS Neurol Disord Drug Targets. 2025;24. PMID: 40619651. doi:10.2174/0118715273374466250617085832

10. Horiuchi M, Watanabe S, Komine O, et al. ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice. Acta Neuropathol Commun. 2024;12(1):184. PMID: 39605053; PMCID: PMC11603663. doi:10.1186/s40478-024-01893-x

11. Romano R, Del Fiore VS, Ruotolo G, et al. Lysosomal dysfunction in amyotrophic lateral sclerosis: a familial case linked to the p.G376D TARDBP mutation. Int J Mol Sci. 2025;26(7):2867. PMID: 40243477; PMCID: PMC11988578. doi:10.3390/ijms26072867

12. Verde EM, Secco V, Ghezzi A, et al. Molecular mechanisms of protein aggregation in ALS-FTD: focus on TDP-43 and cellular protective responses. Cells. 2025;14(10):680. PMID: 40422183; PMCID: PMC12109844. doi:10.3390/cells14100680

13. Sobanski T, Suraweera A, Burgess JT, et al. The fructose-bisphosphate, aldolase A (ALDOA), facilitates DNA-PKcs and ATM kinase activity to regulate DNA double-strand break repair. Sci Rep. 2023;13(1):15171. PMID: 37704669; PMCID: PMC10499815. doi:10.1038/s41598-023-41133-1

14. Zhao Y, Wang Y, Wu Y, et al. PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson’s disease in diabetic rats. J Pharm Anal. 2023;13(2):187–200. PMID: 36908857; PMCID: PMC9999299. doi:10.1016/j.jpha.2022.11.006

15. Li J, Chen L, Qin Q, et al. Upregulated hexokinase 2 expression induces the apoptosis of dopaminergic neurons by promoting lactate production in Parkinson’s disease. Neurobiol Dis. 2022;163:105605. PMID: 34973450. doi:10.1016/j.nbd.2021.105605

16. de Geus MB, Leslie SN, Lam T, et al. Mass spectrometry in cerebrospinal fluid uncovers association of glycolysis biomarkers with Alzheimer’s disease in a large clinical sample. Sci Rep. 2023;13(1):22406. PMID: 38104170; PMCID: PMC10725469. doi:10.1038/s41598-023-49440-3

17. Rozanova S, Barkovits K, Nikolov M, et al. Quantitative mass spectrometry-based proteomics: an overview. Methods Mol Biol. 2021;2228:85–116. PMID: 33950486. doi:10.1007/978-1-0716-1024-4_8

18. Karayel O, Virreira Winter S, Padmanabhan S, et al. Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease. Cell Rep Med. 2022;3(6):100661. PMID: 35732154; PMCID: PMC9245058. doi:10.1016/j.xcrm.2022.100661

19. Di Domenico F, Zuliani I, Tramutola A. Shining a light on defective autophagy by proteomics approaches: implications for neurodegenerative illnesses. Expert Rev Proteomics. 2019;16(11–12):951–964. PMID: 31709850. doi:10.1080/14789450.2019.1691919

20. Goutman SA, Hardiman O, Al-Chalabi A, et al. Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol. 2022;21(5):465–479. doi:10.1016/S1474-4422(21)00414-2

21. Ho PC, Hsieh TC, Tsai KJ. TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: from pathomechanisms to therapeutic strategies. Ageing Res Rev. 2024;100:102441. doi:10.1016/j.arr.2024.102441

22. Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, Jafar-Nejad P, Shneider NA. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med. 2022;28(1):104–116. doi:10.1038/s41591-021-01615-z

23. Modafferi S, Farina S, Esposito F, et al. DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue. Cell Death Differ. 2025. doi:10.1038/s41418-025-01530-7

24. Piol D, Robberechts T, Da Cruz S. Lost in local translation: TDP-43 and FUS in axonal/neuromuscular junction maintenance and dysregulation in amyotrophic lateral sclerosis. Neuron. 2023;111(9):1355–1380. doi:10.1016/j.neuron.2023.02.028

25. Cheng F, Chapman T, Zhang S, et al. Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease[J]. Ageing Res Rev. 2024;96:102246. doi:10.1016/j.arr.2024.102246

26. Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602–611. PMID: 17084815. doi:10.1016/j.bbrc.2006.10.093

27. San Gil R, Pascovici D, Venturato J, et al. A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration. Nat Commun. 2024;15(1):1508. doi:10.1038/s41467-024-45646-9

28. Lee YC, Huang WC, Lin JH, et al. Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology. J Biomed Sci. 2018;25(1):76. doi:10.1186/s12929-018-0479-4

29. Ko VI, Ong K, Kwon DY, et al. CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2024;12(1):187. doi:10.1186/s40478-024-01902-z

30. Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010;9(10):995–1007. PMID: 20864052. doi:10.1016/S1474-4422(10)70195-2

31. Gordon D, Dafinca R, Scaber J, et al. Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction. Neurobiol Dis. 2019;121:148–162. doi:10.1016/j.nbd.2018.09.024

32. Zanini G, Selleri V, Nasi M, et al. Mitochondrial and endoplasmic Reticulum alterations in a case of amyotrophic lateral sclerosis caused by TDP-43 A382T mutation. Int J Mol Sci. 2022;23(19):11881. doi:10.3390/ijms231911881

33. Buck E, Oeckl P, Grozdanov V, et al. Increased NF-L levels in the TDP-43G298S ALS mouse model resemble NF-L levels in ALS patients. Acta Neuropathol. 2022;144(1):161–164. doi:10.1007/s00401-022-02436-1

34. Lee JD, Levin SC, Willis EF, Li R, Woodruff TM, Noakes PG. Complement components are upregulated and correlate with disease progression in the TDP-43Q331K mouse model of amyotrophic lateral sclerosis. J Neuroinflammation. 2018;15(1):171. doi:10.1186/s12974-018-1217-2

35. Zeng J, Tang Y, Dong X, Li F, Wei G Influence of ALS-linked M337V mutation on the conformational ensembles of TDP-43321-340 peptide monomer and dimer. Proteins. 2024;92(9):1059–1069. doi:10.1002/prot.26482

36. Meng W, Lu X, Wang G, et al. ZNF692 drives malignant development of hepatocellular carcinoma cells by promoting ALDOA-dependent glycolysis[J]. Funct Integr Genomics. 2024;24(2):53. doi:10.1007/s10142-024-01326-x

37. Gawinecka J, Dieks J, Asif AR, et al. Codon 129 polymorphism specific cerebrospinal fluid proteome pattern in sporadic Creutzfeldt-Jakob disease and the implication of glycolytic enzymes in prion-induced pathology. J Proteome Res. 2010;9(11):5646–5657. doi:10.1021/pr1004604

38. Dopler MB, Abeer MI, Arezoumandan S, et al. A cellular model of TDP −43 induces phosphorylated TDP −43 aggregation with distinct changes in solubility and autophagy dysregulation. FEBS J. 2025;292(18):4870–4897. PMID: 39887552; PMCID: PMC12310990. doi:10.1111/febs.17413

39. Paul S, Ghosh S, Kumar S. Tumor glycolysis, an essential sweet tooth of tumor cells[J]. Semin Cancer Biol. 2022;86(Pt 3).

40. Zhang Y, Yang X, Zhuang J, et al. β-Amyloid activates reactive astrocytes by enhancing glycolysis of astrocytes[J]. Mol Biol Rep. 2022;49(6):4699–4707. doi:10.1007/s11033-022-07319-y

41. Zhao Y, Wang Y, Wu Y, et al. PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson’s disease in diabetic rats[J]. J Pharm Anal. 2023;13(2):187–200.

42. Gunasangkaran G, Muthukrishnan S, Ravi AK, et al. Targeting the lncRNA RBM5-AS1/GCN5 axis under fasting conditions reprograms Glycolysis and induces apoptosis in ovarian cancer cells. Mol Biol Rep. 2025;52(1):691. doi:10.1007/s11033-025-10800-z. PMID: 40632300..

43. Liu Y, Han C, Guo L, et al. Deer antler uridine regulates glycolysis in microglia via HSP90/HIF-1α to improve cognitive impairment in Alzheimer’s disease mice. CNS Neurosci Ther. 2025;31(5). doi:10.1111/cns.70416

44. Gao R, Gao Y, Su W, Wang R. Decoding microglial polarization and metabolic reprogramming in neurodegenerative diseases: implications for disease progression and therapy. Aging Dis. 2025. PMID: 40072374. doi:10.14336/AD.2024.1629

The trial, which enrolled 22 patients, studied safety and preliminary efficacy of the company’s therapy, odronextamab, in combination with chemotherapy in patients with Diffuse Large B-Cell Lymphoma or DLBCL.

Sign up here.

Odronextamab belongs to a class of treatments called bispecific antibodies that are designed to attach to a cancer cell and an immune cell, bringing them together so that the body’s immune system can kill the cancer.

At the 160 mg dose of the combination, patients showed 100% complete response rate, the company said.

DLBCL is a fast-growing blood cancer that affects the lymphatic system, which is a network of tissues, vessels and organs that help fight infection in the body. It involves changes in the B cells, a particular type of white blood cell.

B-cell counts were cleared completely after the first dose of the therapy, the company said in a presentation at the American Society of Hematology Annual Meeting.

Most patients completed six cycles of the combination at both 80 mg and 160 mg dose levels. The higher dose has been selected for further studies.

Data also suggested that when combining odronextamab with the chemotherapy regimen known as CHOP, deep and lasting responses were achieved without the need for rituximab.

“Part of our focus here at Regeneron is to develop bispecifics which are extremely potent and which don’t require a very heavy burdensome additional cocktail of drugs to be combined with because their activity in itself is very potent,” said Aafia Chaudhry, global program head.

The company will be initiating enrollment of patients for the second part of the study to see how effective the combination is in comparison with the combination of rituximab and chemotherapy, the current standard of care treatment approved for DLBCL.

“Our strategy is to replace rituximab rather than to add on to rituximab,” Chaudhry added.

Our Standards: The Thomson Reuters Trust Principles., opens new tab

Follow-up data from CARTITUDE-4 show at least 80 percent of as-treated standard-risk patients remained progression and treatment-free following a single infusion as early as second line

Data suggest stronger immune fitness in earlier lines may be associated with longer progression free survival

ORLANDO, Fla., Dec. 6, 2025 /PRNewswire/ — Johnson & Johnson (NYSE: JNJ) announced today updated results from the Phase 3 CARTITUDE-4 study supporting durable treatment-free remissions as early as second line treatment with CARVYKTI^® (ciltacabtagene autoleucel; cilta-cel). In 80 percent of as-treated patients with relapsed or refractory multiple myeloma (RRMM) and standard-risk cytogenetics who were treated with CARVYKTI^® as early as first relapse, the disease did not progress and no further treatment was required at 2.5 years (30 months).¹ These results add to the body of clinical and real-world experience established across more than 9,000 patients treated with CARVYKTI^® globally.¹

Additional translational analyses demonstrated that patients receiving CARVYKTI^® in earlier lines had improved immune fitness, which suggests a correlation with longer progression-free survival (PFS).¹ These data (Abstracts #92, #94) were featured in oral presentations at the 2025 American Society of Hematology (ASH) Annual Meeting.

“These data suggest that a single infusion of CARVYKTI for standard-risk patients may provide additional benefit to patients as early as second line of therapy,” said Luciano J. Costa, M.D., Ph.D.,* Professor of Medicine at the University of Alabama and principal investigator of the CARTITUDE-4 study. “Treating patients with multiple myeloma after first relapse offers the opportunity to achieve deeper and more durable responses, shifting the treatment paradigm closer to the possibility of long-term remission and, ultimately, cure.”

“Our goal is to treat patients as early as possible, when they have the best chance for lasting remission,” said Jordan Schecter, M.D., Vice President, Research & Development, Multiple Myeloma, Johnson & Johnson Innovative Medicine. “With more than 9,000 patients treated globally, CARVYKTI has demonstrated robust efficacy as soon as first relapse and is the first and only CAR-T to significantly extend overall survival versus standard therapies.”

In the analysis of CARTITUDE-4 data, 176 patients received CARVYKTI^® as early as second line and 59 of those patients had standard-risk cytogenetics.¹ At a median follow-up of 33.6 months, the 30-month PFS rate among the standard-risk patients in the as-treated population appeared to plateau at 80.5 percent (95 percent CI, 67.2–88.8) following a single infusion of CARVYKTI^®.¹ Notably, all 26 patients (100%) from this group who achieved minimal residual disease (MRD)-negative complete response at 12 months following CARVYKTI^® infusion remained progression-free at 30 months.¹

Additionally, a translational analysis evaluated the relationship between immune biomarkers and PFS in patients treated with CARVYKTI^® in CARTITUDE-1 and CARTITUDE-4.² Using CARVYKTI^® after one or two prior lines of therapy demonstrated stronger immune fitness versus patients with three or more prior lines of therapy, characterized by increased baseline CD4⁺ naïve T cells (a type of immune cell that has not encountered an antigen) in peripheral blood.² Bone marrow tumor analyses from patients treated with CARVYKTI^® in CARTITUDE-4 also demonstrated a more immune-activated profile in patients treated after one prior line of therapy versus three.² These biomarker data identify potential immunologic factors associated with longer PFS and support the improved survival outcomes exhibited with CARVYKTI^® for patients treated as early as second line.² 

As CARVYKTI^® use has broadened across academic centers and community practices, Johnson & Johnson continues to collect and analyze clinical and real-world data to further characterize long-term remission outcomes and safety trends. This comprehensive experience across diverse patient populations provides an important foundation for expanding use into earlier treatment settings.

About the CARTITUDE-1 Study 

CARTITUDE-1 (NCT03548207) is a Phase 1b/2, open-label, multicenter study that evaluated the efficacy and safety of cilta-cel in adults with relapsed and/or refractory multiple myeloma (RRMM), 99 percent of whom were refractory to the last line of treatment; 88 percent of whom were triple-class refractory, meaning their cancer did not or no longer responds to an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.³ 

The primary objective of the Phase 1b portion of the study, involving 29 patients, was to characterize the safety and confirm the dose of cilta-cel, informed by the first-in-human study with LCAR-B38M CAR-T cells (LEGEND-2). Based on the safety profile observed in this portion of the study, outpatient dosing is being evaluated in additional CARTITUDE studies. The Phase 2 portion of the study is evaluating the efficacy of cilta-cel with overall response as the primary endpoint. The study involved patients with heavily pretreated RRMM who historically have an expected median PFS of <6 months and median overall survival of ~1 year.

About the CARTITUDE-4 Study

CARTITUDE-4 (NCT04181827) is the first randomized Phase 3 study evaluating the efficacy and safety of CARVYKTI^®. The study compares CARVYKTI^® with standard of care treatments PVd or DPd in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy. The primary endpoint of the study is PFS; safety, OS, minimal residual disease negative rate and overall response rate are secondary endpoints. 

About CARVYKTI^® (ciltacabtagene autoleucel; cilta-cel)

CARVYKTI^® (cilta-cel) received U.S. Food and Drug Administration approval in February 2022 for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.⁴ In April 2024, CARVYKTI^® was approved as the first and only cell therapy in the U.S. for treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor, an immunomodulatory agent, and who are refractory to lenalidomide. In April 2024, the European Medicines Agency (EMA) approved a Type II variation for CARVYKTI^® for the treatment of adults with relapsed and refractory multiple myeloma who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide.

CARVYKTI^® is a BCMA-directed, genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s own T-cells with a transgene encoding chimeric antigen receptor (CAR) that directs the CAR-positive T cells to eliminate cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The CARVYKTI^® CAR protein features two BCMA-targeting single domains designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.

In December 2017, Janssen Biotech, Inc., a Johnson & Johnson company, entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize CARVYKTI^®.

For more information, visit www.CARVYKTI.com.

About Multiple Myeloma 

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.⁵ In multiple myeloma, these plasma cells proliferate and spread rapidly and replace normal cells in the bone marrow with tumors.⁶ Multiple myeloma is the third most common blood cancer worldwide and remains an incurable disease.⁷ In 2024, it was estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 people would die from the disease.⁸ People living with multiple myeloma have a 5-year survival rate of 59.8 percent.⁹ While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels and kidney problems or infections.^10,11

CARVYKTI^® IMPORTANT SAFETY INFORMATION  

INDICATIONS AND USAGE 

CARVYKTI^® (ciltacabtagene autoleucel) 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, who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Increased early mortality. In CARTITUDE-4, a (1:1) randomized controlled trial, there was a numerically higher percentage of early deaths in patients randomized to the CARVYKTI^® treatment arm compared to the control arm. Among patients with deaths occurring within the first 10 months from randomization, a greater proportion (29/208; 14%) occurred in the CARVYKTI^® arm compared to (25/211; 12%) in the control arm. Of the 29 deaths that occurred in the CARVYKTI^® arm within the first 10 months of randomization, 10 deaths occurred prior to CARVYKTI^® infusion, and 19 deaths occurred after CARVYKTI^® infusion. Of the 10 deaths that occurred prior to CARVYKTI^® infusion, all occurred due to disease progression, and none occurred due to adverse events. Of the 19 deaths that occurred after CARVYKTI^® infusion, 3 occurred due to disease progression, and 16 occurred due to adverse events. The most common adverse events were due to infection (n=12).

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI^®. Among patients receiving CARVYKTI^® for RRMM in the CARTITUDE-1 & -4 studies (N=285), CRS occurred in 84% (238/285), including ≥ Grade 3 CRS (ASTCT 2019) in 4% (11/285) of patients. Median time to onset of CRS, any grade, was 7 days (range: 1 to 23 days). CRS resolved in 82% with a median duration of 4 days (range: 1 to 97 days). The most common manifestations of CRS in all patients combined (≥10%) included fever (84%), hypotension (29%) and aspartate aminotransferase increased (11%). Serious events that may be associated with CRS include pyrexia, hemophagocytic lymphohistiocytosis, respiratory failure, disseminated intravascular coagulation, capillary leak syndrome, and supraventricular and ventricular tachycardia. CRS occurred in 78% of patients in CARTITUDE-4 (3% Grade 3 to 4) and in 95% of patients in CARTITUDE-1 (4% Grade 3 to 4).

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.

Confirm that a minimum of 2 doses of tocilizumab are available prior to infusion of CARVYKTI^®.

Of the 285 patients who received CARVYKTI^® in clinical trials, 53% (150/285) patients received tocilizumab; 35% (100/285) received a single dose, while 18% (50/285) received more than 1 dose of tocilizumab. Overall, 14% (39/285) of patients received at least 1 dose of corticosteroids for treatment of CRS.

Monitor patients at least daily for 7 days following CARVYKTI^® infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 2 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic toxicities, which may be severe, life-threatening, or fatal, occurred following treatment with CARVYKTI^®. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of Parkinsonism, GBS, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Among patients receiving CARVYKTI^® in the CARTITUDE-1 & 4 studies for RRMM, one or more neurologic toxicities occurred in 24% (69/285), including ≥ Grade 3 cases in 7% (19/285) of patients. Median time to onset was 10 days (range: 1 to 101) with 63/69 (91%) of cases developing by 30 days. Neurologic toxicities resolved in 72% (50/69) of patients with a median duration to resolution of 23 days (range: 1 to 544). Of patients developing neurotoxicity, 96% (66/69) also developed CRS. Subtypes of neurologic toxicities included ICANS in 13%, peripheral neuropathy in 7%, cranial nerve palsy in 7%, parkinsonism in 3%, and immune mediated myelitis in 0.4% of the patients.

Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS): Patients receiving CARVYKTI^® may experience fatal or life-threatening ICANS following treatment with CARVYKTI^®, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS.

Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, ICANS occurred in 13% (36/285), including Grade ≥3 in 2% (6/285) of the patients. Median time to onset of ICANS was 8 days (range: 1 to 28 days). ICANS resolved in 30 of 36 (83%) of patients, with a median time to resolution of 3 days (range: 1 to 143 days). Median duration of ICANS was 6 days (range: 1 to 1229 days) in all patients, including those with ongoing neurologic events at the time of death or data cutoff. Of patients with ICANS, 97% (35/36) had CRS. The onset of ICANS occurred during CRS in 69% of patients, before and after the onset of CRS in 14% of patients, respectively.

Immune Effector Cell-associated Neurotoxicity Syndrome occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3) and in 23% of patients in CARTITUDE-1 (3% Grade 3). The most frequent (≥2%) manifestations of ICANS included encephalopathy (12%), aphasia (4%), headache (3%), motor dysfunction (3%), ataxia (2%), and sleep disorder (2%).

Monitor patients at least daily for 7 days following CARVYKTI^® infusion for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 2 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed. Advise patients to avoid driving for at least 2 weeks following infusion.

Parkinsonism: Neurologic toxicity with parkinsonism has been reported in clinical trials of CARVYKTI^®. Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, parkinsonism occurred in 3% (8/285), including Grade ≥3 in 2% (5/285) of the patients. Median time to onset of parkinsonism was 56 days (range: 14 to 914 days). Parkinsonism resolved in 1 of 8 (13%) of patients with a median time to resolution of 523 days. Median duration of parkinsonism was 243.5 days (range: 62 to 720 days) in all patients, including those with ongoing neurologic events at the time of death or data cutoff. The onset of parkinsonism occurred after CRS for all patients and after ICANS for 6 patients.

Parkinsonism occurred in 1% of patients in CARTITUDE-4 (no Grade 3 to 4) and in 6% of patients in CARTITUDE-1 (4% Grade 3 to 4).

Manifestations of parkinsonism included movement disorders, cognitive impairment, and personality changes. Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease for the improvement or resolution of parkinsonism symptoms following CARVYKTI^® treatment.

Guillain-Barré syndrome: A fatal outcome following GBS occurred following treatment with CARVYKTI^® despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Immune mediated myelitis: Grade 3 myelitis occurred 25 days following treatment with CARVYKTI^® in CARTITUDE-4 in a patient who received CARVYKTI^® as subsequent therapy. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause.

Peripheral neuropathy occurred following treatment with CARVYKTI^®. Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, peripheral neuropathy occurred in 7% (21/285), including Grade ≥3 in 1% (3/285) of the patients. Median time to onset of peripheral neuropathy was 57 days (range: 1 to 914 days). Peripheral neuropathy resolved in 11 of 21 (52%) of patients with a median time to resolution of 58 days (range: 1 to 215 days). Median duration of peripheral neuropathy was 149.5 days (range: 1 to 692 days) in all patients including those with ongoing neurologic events at the time of death or data
cutoff.

Peripheral neuropathies occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3 to 4) and in 7% of patients in CARTITUDE-1 (2% Grade 3 to 4). Monitor patients for signs and symptoms of peripheral neuropathies. Patients who experience peripheral neuropathy may also experience cranial nerve palsies or GBS.

Cranial nerve palsies occurred following treatment with CARVYKTI^®. Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, cranial nerve palsies occurred in 7% (19/285), including Grade ≥3 in 1% (1/285) of the patients. Median time to onset of cranial nerve palsies was 21 days (range: 17 to 101 days). Cranial nerve palsies resolved in 17 of 19 (89%) of patients with a median time to resolution of 66 days (range: 1 to 209 days). Median duration of cranial nerve palsies was 70 days (range: 1 to 262 days) in all patients, including those with ongoing neurologic events at the time of death or data cutoff. Cranial nerve palsies occurred in 9% of patients in CARTITUDE-4 (1% Grade 3 to 4) and in 3% of patients in CARTITUDE-1 (1% Grade 3 to 4).

The most frequent cranial nerve affected was the 7^th cranial nerve. Additionally, cranial nerves III, V, and VI have been reported to be affected.

Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, HLH/MAS occurred in 1% (3/285) of patients. All events of HLH/MAS had onset within 99 days of receiving CARVYKTI^®, with a median onset of 10 days (range: 8 to 99 days), and all occurred in the setting of ongoing or worsening CRS. The manifestations of HLH/MAS included hyperferritinemia, hypotension, hypoxia with diffuse alveolar damage, coagulopathy and hemorrhage, cytopenia, and multi-organ dysfunction, including renal dysfunction and respiratory failure.

Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematologic parameters in patients with HLH/MAS and transfuse per institutional guidelines. Fatal cases of HLH/MAS occurred following treatment with CARVYKTI^®.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

Prolonged and Recurrent Cytopenias: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI^® infusion.

Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, Grade 3 or higher cytopenias not resolved by Day 30 following CARVYKTI^® infusion occurred in 62% (176/285) of the patients and included thrombocytopenia 33% (94/285), neutropenia 27% (76/285), lymphopenia 24% (67/285), and anemia 2% (6/285). After Day 60 following CARVYKTI^® infusion, 22%, 20%, 5%, and 6% of patients had a recurrence of Grade 3 or 4 lymphopenia, neutropenia, thrombocytopenia, and anemia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Seventy-seven percent (219/285) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Sixteen and 25 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI^® infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

Infections: CARVYKTI^® should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after CARVYKTI^® infusion.

Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, infections occurred in 57% (163/285), including Grade ≥3 in 24% (69/285) of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 6%, bacterial infections in 5%, and fungal infections in 1% of patients. Overall, 5% (13/285) of patients had Grade 5 infections, 2.5% of which were due to COVID-19. Patients treated with CARVYKTI^® had an increased rate of fatal COVID-19 infections compared to the standard therapy arm.

Monitor patients for signs and symptoms of infection before and after CARVYKTI^® infusion and treat patients appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 5% of patients after CARVYKTI^® 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. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Reactivation of John Cunningham (JC) virus, leading to progressive multifocal leukoencephalopathy (PML), including cases with fatal outcomes, have been reported following treatment. Perform appropriate diagnostic evaluations in patients with neurological adverse events.

Hypogammaglobulinemia can occur in patients receiving treatment with CARVYKTI^®. Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, hypogammaglobulinemia adverse event was reported in 36% (102/285) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 93% (265/285) of patients. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion occurred in 94% (267/285) of patients treated. Fifty-six percent (161/285) of patients received intravenous immunoglobulin (IVIG) post CARVYKTI^® for either an adverse reaction or prophylaxis.

Monitor immunoglobulin levels after treatment with CARVYKTI^® and administer IVIG for IgG <400 mg/dL. Manage 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 following CARVYKTI^® 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 CARVYKTI^® treatment, and until immune recovery following treatment with CARVYKTI^®.

Hypersensitivity Reactions occurred following treatment with CARVYKTI^®. Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, hypersensitivity reactions occurred in 5% (13/285), all of which were ≤2 Grade. Manifestations of hypersensitivity reactions included flushing, chest discomfort, tachycardia, wheezing, tremor, burning sensation, non-cardiac chest pain, and pyrexia.

Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI^®. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction.

Immune effector cell-associated enterocolitis (IEC-EC) has occurred in patients treated with CARVYKTI^®. Manifestations include severe or prolonged diarrhea, abdominal pain, and weight loss requiring parenteral nutrition. IEC-EC has been associated with fatal outcome from perforation or sepsis. Manage according to institutional guidelines, including referral to gastroenterology and infectious disease specialists.

In cases of refractory IEC-EC, consider additional workup to exclude alternative etiologies, including T-cell lymphoma of the GI tract, which has been reported in the post marketing setting.

Secondary Malignancies: Patients treated with CARVYKTI^® may develop secondary malignancies. Among patients receiving CARVYKTI^® in the CARTITUDE-1 & -4 studies, myeloid neoplasms occurred in 5% (13/285) of patients (9 cases of myelodysplastic syndrome, 3 cases of acute myeloid leukemia, and 1 case of myelodysplastic syndrome followed by acute myeloid leukemia). The median time to onset of myeloid neoplasms was 447 days (range: 56 to 870 days) after treatment with CARVYKTI^®. Ten of these 13 patients died following the development of myeloid neoplasms; 2 of the 13 cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. Cases of myelodysplastic syndrome and acute myeloid leukemia have also been reported in the post marketing setting. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI^®. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusions, and may include fatal outcomes.

Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples.

ADVERSE REACTIONS

The most common nonlaboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common Grade 3 or 4 laboratory adverse reactions (incidence greater than or equal to 50%) include lymphopenia, neutropenia, white blood cell decreased, thrombocytopenia, and anemia.

Please read full Prescribing Information, including Boxed Warning, for CARVYKTI^®. 

About Johnson & Johnson

At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at https://www.jnj.com/ or at https://www.innovativemedicine.jnj.com. Follow us at @JNJInnovMed.

Cautions Concerning Forward-Looking Statements 
This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of CARVYKTI^®. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s most recent Annual Report on Form 10-K, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Johnson & Johnson does not undertake to update any forward-looking statement as a result of new information or future events or developments.

Footnotes:

^* Luciano J. Costa, M.D., Ph.D., Professor of Medicine at the University of Alabama, has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work.

¹ Dr. Parekh S, et al. Earlier use of ciltacabtagene autoleucel (cilta-cel) is associated with better immune fitness and stronger immune effects as shown by correlative analysis of peripheral blood and the bone marrow tumor microenvironment (TME) from the CARTITUDE-4 study. American Society of Hematology 2025 Annual Meeting. Accessed December 2025.
² Dr. Costa L, et al. Long-term progression-free survival benefit with ciltacabtagene autoleucel in standard-risk relapsed/refractory multiple myeloma. American Society of Hematology 2025 Annual Meeting. Accessed December 2025.
³ Usmani S. Phase 1b/2 study of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CARTITUDE-1): Two years post-LPI. Abstract #8028 [Poster]. Presented at the 2022 American Society of Clinical Oncology Annual Meeting.
⁴ CARVYKTI^® U.S. Prescribing Information. 
⁵ Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-5672020;95(5):548-567. http://www.ncbi.nlm.nih.gov/pubmed/32212178
⁶ National Cancer Institute. Plasma Cell Neoplasms. https://www.cancer.gov/types/myeloma/patient/myeloma-treatment-pdq. Accessed December 2025.
⁷ City of Hope. Multiple Myeloma: Causes, Symptoms & Treatments. https://www.cancercenter.com/cancer-types/multiple-myeloma. Accessed December 2025.
⁸ American Cancer Society. Key Statistics About Multiple Myeloma. https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html#:~:text=Multiple%20myeloma%20is%20a%20relatively,men%20and%2015%2C370%20in%20women. Accessed December 2025.
⁹ SEER Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute. https://seer.cancer.gov/explorer/. Accessed December 2025.
¹⁰ American Cancer Society. What is Multiple Myeloma? https://www.cancer.org/cancer/multiple-myeloma/about/what-is-multiple-myeloma.html. Accessed December 2025.
¹¹ American Cancer Society. Multiple Myeloma Early Detection, Diagnosis, and Staging https://www.cancer.org/cancer/types/multiple-myeloma/detection-diagnosis-staging/detection.html. Accessed December 2025.

SOURCE Johnson & Johnson

New catalytic funding will expand access to health, climate-resilient agriculture, and access to education across Africa and South Asia

DOHA, QATAR (December 6, 2025) – On the sidelines of the Doha Forum, the Gates Foundation and the Qatar Fund for Development (QFFD) announced a five-year strategic partnership, committing US$500 million to drive accelerated progress in global health, climate-resilient agriculture, and education. The goal of the partnership is to help improve outcomes for mothers, children, and young people across Africa, South Asia, and Southeast Asia. The signing ceremony was held in the presence of H.E. Sheikh Thani bin Hamad Al-Thani, Chairperson of Qatar Fund for Development, and Bill Gates, chair of the Gates Foundation, who witnessed the formalization of the agreement.”

“Solving big global health and development challenges takes more than good intentions. It requires practical innovation and partners committed to making sure those breakthroughs reach the people who need them most,” said Bill Gates. “Our partnership with the Qatar Fund for Development will help expand access to the tools that let families build healthier, more productive lives.”

Strengthening Multilateral Health Platforms

Both parties have agreed to strengthen multilateral platforms such as Gavi, the Vaccine Alliance; the Global Fund to Fight Aids, Tuberculosis and Malaria; and the Lives and Livelihoods Fund.

Fahad Hamad Al- Sulaiti, Director General of the Qatar Fund for Development, stated:

“This partnership reinforces Qatar’s commitment to tackling global development challenges through innovative and scalable financing. By deploying QFFD’s non-grant instruments, concessional loans, equity, guarantees, and transaction structuring, we are setting a new standard for sustainable, impact-driven cooperation. Together, we aim to mobilize US$500 million over five years to unlock transformative solutions for health, food security, climate resilience, and beyond.”

A History of Collaboration

The partnership follows the longstanding collaboration between the Gates Foundation and QFFD, including Nanmo, an initiative investing in climate-adaptive agricultural tools and technologies launched in 2022 to support smallholder farmers in sub-Saharan Africa, and the Doha Global South Health Policy Initiative, a South-South community of practice convening senior public health civil servants to address the unmet needs of low- and middle-income countries on policy implementation and solutions. Through the Nanmo partnership, the new funding announced today will expand climate-resilient catalytic projects, such as the aquaculture and nutrition work led by Worldfish, the development of aquaculture in Kenya, and the creation of jobs and improving food security for thousands of smallholder farmers.

About the Gates Foundation 

Guided by the belief that every life has equal value, the Gates Foundation works to help all people lead healthy, productive lives. In developing countries, we work with partners to create impactful solutions so that people can take charge of their futures and achieve their full potential. In the United States, we aim to ensure that everyone—especially those with the fewest resources—has access to the opportunities needed to succeed in school and life. Based in Seattle, Washington, the foundation is led by CEO Mark Suzman, under the direction of Bill Gates and our governing board. 

About the Qatar Fund for Development

The Qatar Fund for Development (QFFD) is the State of Qatar’s official institution for international development and humanitarian assistance. Guided by Qatar’s National Vision 2030 and the State’s International Cooperation Strategy, QFFD works to empower communities and improve lives by investing in education, health, economic opportunity, and resilience across more than 100 countries. Leveraging a diversified financing toolkit including concessional loans, guarantees, grants, and blended finance QFFD delivers scalable, sustainable solutions that promote inclusive growth and long-term stability.

Viatris to Receive $400 Million in Cash and $415 Million in Equity Shares of Biocon Limited

Transaction Accelerates the Expiration of Biosimilars Non-Compete Restrictions

PITTSBURGH, Dec. 6, 2025 /PRNewswire/ — Viatris Inc. (Nasdaq: VTRS) today announced that it has entered into definitive agreements with Biocon Limited (“Biocon”) for the sale of Viatris’ equity stake in Biocon Biologics Limited (“Biocon Biologics”). Under the definitive agreements, Biocon will acquire all of Viatris’ convertible preferred equity in Biocon Biologics for total consideration of $815 million, consisting of $400 million in cash and $415 million in newly issued equity shares of Biocon.

“This agreement is another important step in Viatris’ evolution,” said Scott A. Smith, Chief Executive Officer, Viatris. “Monetizing the value of our equity stake in Biocon Biologics and regaining access to the biosimilars market globally provides significant additional optionality as we continue to build a portfolio of generics, established brands and innovative brands that can contribute to our future growth.”

Key Terms of Transaction
Under the terms of the agreements, Viatris will sell its equity stake in Biocon Biologics to Biocon for $400 million in cash and $415 million in equity shares of Biocon Limited, which will be listed and traded on the National Stock Exchange of India. The shares are subject to a six-month lock up period. Transaction value will be subject to related taxes. In addition, the terms of the definitive agreements accelerate the expiration of biosimilars non-compete restrictions previously placed on Viatris in 2022 in connection with Viatris’ sale of its biosimilars portfolio and related commercial and other capabilities to Biocon Biologics. These restrictions will expire immediately at the time of close for all ex-U.S. markets and in November 2026 for U.S. markets. The transaction is expected to close in Q1 2026, subject to satisfaction of closing conditions.

Citi is acting as financial advisor to Viatris. Cravath, Swaine & Moore LLP and Indian law firm Khaitan & Co. are acting as legal advisors to Viatris.

About Viatris
Viatris Inc. (Nasdaq: VTRS) is a global healthcare company uniquely positioned to bridge the traditional divide between generics and brands, combining the best of both to more holistically address healthcare needs globally. With a mission to empower people worldwide to live healthier at every stage of life, we provide access at scale, currently supplying high-quality medicines to approximately 1 billion patients around the world annually and touching all of life’s moments, from birth to the end of life, acute conditions to chronic diseases. With our exceptionally extensive and diverse portfolio of medicines, a one-of-a-kind global supply chain designed to reach more people when and where they need them, and the scientific expertise to address some of the world’s most enduring health challenges, access takes on deep meaning at Viatris. We are headquartered in the U.S., with global centers in Pittsburgh, Shanghai and Hyderabad, India. Learn more at viatris.com and investor.viatris.com, and connect with us on LinkedIn, Instagram, YouTube and X.

Forward-Looking Statements
This press release includes statements that constitute “forward-looking statements.” These statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may include statements that Viatris has entered into definitive agreements with Biocon for the sale of Viatris’ equity stake in Biocon Biologics; under the definitive agreements, Biocon will acquire all of Viatris’ convertible preferred equity in Biocon Biologics for total consideration of $815 million, consisting of $400 million in cash and $415 million in newly issued equity shares of Biocon; this agreement is another important step in Viatris’ evolution; monetizing the value of our equity stake in Biocon Biologics and regaining access to the biosimilars market globally provides significant additional optionality as we continue to build a portfolio of generics, established brands and innovative brands that can contribute to our future growth; under the terms of the agreements, Viatris will sell its equity stake in Biocon Biologics to Biocon for $400 million in cash and $415 million in equity shares of Biocon Limited, which will be listed and traded on the National Stock Exchange of India; the shares are subject to a six-month lock up period; transaction value will be subject to related taxes; the terms of the definitive agreements accelerate the expiration of biosimilars non-compete restrictions previously placed on Viatris in 2022 in connection with Viatris’ sale of its biosimilars portfolio and related commercial and other capabilities to Biocon Biologics; these restrictions will expire immediately at the time of close for all ex-U.S. markets and in November 2026 for U.S. markets; the transaction is expected to close in Q1 2026, subject to satisfaction of closing conditions. Because forward-looking statements inherently involve risks and uncertainties, actual future results may differ materially from those expressed or implied by such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to: actions and decisions of healthcare and pharmaceutical regulators; our ability to comply with applicable laws and regulations; changes in healthcare and pharmaceutical laws and regulations in the U.S. and abroad; any regulatory, legal or other impediments to Viatris’ ability to bring new products to market; products in development and/or that receive regulatory approval may not achieve expected levels of market acceptance, efficacy or safety; longer review, response and approval times as a result of evolving regulatory priorities and reductions in personnel at health agencies; Viatris’ or its partners’ ability to develop, manufacture, and commercialize products; the scope, timing and outcome of any ongoing legal proceedings, and the impact of any such proceedings on Viatris; Viatris’ failure to achieve expected or targeted future financial and operating performance and results; goodwill or impairment charges or other losses; any changes in or difficulties with the Company’s manufacturing facilities; risks associated with international operations; changes in third-party relationships; the effect of any changes in Viatris’ or its partners’ customer and supplier relationships and customer purchasing patterns; the impacts of competition; changes in the economic and financial conditions of Viatris or its partners; uncertainties regarding future demand, pricing and reimbursement for the Company’s products; uncertainties and matters beyond the control of management, including but not limited to general political and economic conditions, potential adverse impacts from future tariffs and trade restrictions, inflation rates and global exchange rates; and the other risks described in Viatris’ filings with the Securities and Exchange Commission (“SEC”). Viatris routinely uses its website as a means of disclosing material information to the public in a broad, non-exclusionary manner for purposes of the SEC’s Regulation Fair Disclosure (Reg FD). Viatris undertakes no obligation to update these statements for revisions or changes after the date of this press release other than as required by law.

SOURCE Viatris Inc.