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Interest continues to grow in developing new strategies to reduce systemic inflammation as a means of improving outcomes in heart failure patients DENVER, Feb. 27, 2024 (GLOBE NEWSWIRE) -- SeaStar Medical Holding Corporation (Nasdaq: ICU), a medical device company developing proprietary solutions to reduce the consequences of hyperinflammation on vital organs, announces publication of a manuscript discussing the role of chronic dysregulated systemic inflammation in heart failure and the potential application of the adult Selective Cytopheretic Device, part of the Quelimmune™ product family, in enabling previously ineligible patients with severe disease to receive a left ventricular assist device (LVAD) or heart transplant in the peer-reviewed European Journal of Heart Failure February 2024, Pitt, B., Iyer, S.P.N. and Humes, H.D. (2024), Eur J Heart Fail. https://doi-org.libproxy1.nus.edu.sg/10.1002/ejhf.3177. The manuscript, titled “New Opportunity for Targeting Systemic Inflammation in Patients with Heart Failure through Leukocyte Immunomodulation” cites increasing evidence of the role of chronic systemic inflammation in patients with heart failure and discusses the Adult SCD’s potential to improve hypertensive heart failure and mortality following hospitalization for acute or worsening heart failure. The manuscript reviews the positive effect of the Adult SCD in a previously announced first-in-human case report of a 71-year-old patient with cardiorenal syndrome who was deemed ineligible for cardiac transplantation or a LVAD due to worsening renal function and right ventricular dysfunction. Following treatment with the Adult SCD, this patient was effectively bridged to LVAD three days after discontinuing treatment and was subsequently discharged without further complications. This study was the basis for Adult SCD receiving a Breakthrough Device Designation in cardiorenal syndrome from the U.S. Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER) in September 2023. “Systemic inflammation is one component in the multi-factorial pathophysiology of heart failure, and the use of anti-inflammatory strategies in patients with acute or worsening heart failure is not novel ,” said lead manuscript author and heart failure expert Bertram Pitt, MD, FACC, Division of Internal Medicine (Emeritus), University of Michigan School of Medicine. “Prior attempts targeting singular proinflammatory factors as well as systemic immunosuppression with glucocorticoids in patients with acute heart failure have yielded unclear results, raising the need to identify new strategies. An alternative strategy may be to target cellular sources of proinflammatory molecules such as activated leucocytes.” “Our novel extracorporeal device has shown significant promise in targeting active neutrophils and monocytes to quell systematic inflammation, leading to improved outcomes in hyperinflammatory acute conditions including acute kidney injury, acute respiratory distress syndrome and cardiorenal syndrome,” said manuscript co-author Sai Prasad N. Iyer, Ph.D., SeaStar Medical’s Vice President, Medical Affairs and Clinical Development. “While our manuscript discusses a positive outcome in one patient following treatment for six hours daily over six consecutive days, the results suggest that more study with Adult SCD is warranted for patients with heart failure and hyperinflammation.” On February 22, 2024 SeaStar Medical announced the Humanitarian Device Exemption (HDE) FDA Approval Order for the Pediatric SCD (SCD-PED now known as Quelimmune) for use in children weighing 10 kilograms or more with acute kidney injury due to sepsis or a septic condition requiring kidney replacement therapy (KRT). About Hyperinflammation Hyperinflammation is the overproduction or overactivity of inflammatory cells that can lead to damage of vital organs. It occurs when the body overproduces inflammatory effector cells and other molecules that can be toxic, damaging to vital organs and result in multi-organ failure and even death. This is known as the cytokine storm. About the Selective Cytopheretic Device (SCD)The SCD is a patented cell-directed extracorporeal device that employs immunomodulating technology to selectively target proinflammatory neutrophils and monocytes during CKRT and reduces the hyperinflammatory milieu including the cytokine storm that causes inflammation, organ failure and possible death in critically ill patients. Unlike pathogen removal and other blood-purification tools, the device is integrated with CKRT hemofiltration systems to selectively target and transition proinflammatory monocytes to a reparative state and promote activated neutrophils to be less inflammatory. The SCD selectively targets the most highly activated proinflammatory neutrophils and monocytes. These cells are then returned back into the body through the blood, and the body is signaled to lower its inflammatory environment and focus on repair. This unique immunomodulation approach may promote long-term organ recovery and eliminate the need for future KRT, including dialysis. About SeaStar MedicalSeaStar Medical is a medical technology company that is redefining how extracorporeal therapies may reduce the consequences of excessive inflammation on vital organs. SeaStar Medical’s novel technologies rely on science and innovation to provide life-saving solutions to critically ill patients. The Company is developing and commercializing cell-directed extracorporeal therapies that target the effector cells that drive systemic inflammation, causing direct tissue damage and secreting a range of pro-inflammatory cytokines that initiate and propagate imbalanced immune responses. For more information visit www.seastarmedical.com or visit us on LinkedIn or X. Forward-Looking StatementsThis press release contains certain forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1955. These forward-looking statements include, without limitation, the SCD’s ability to treat hyperinflammation and the expected results of clinical trials and studies. Words such as “believe,” “project,” “expect,” “anticipate,” “estimate,” “intend,” “strategy,” “future,” “opportunity,” “plan,” “may,” “should,” “will,” “would,” “will be,” “will continue,” “will likely result,” and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are predictions, projections and other statements about future events that are based on current expectations and assumptions and, as a result, are subject to significant risks and uncertainties that could cause the actual results to differ materially from the expected results. Most of these factors are outside SeaStar Medical’s control and are difficult to predict. Factors that may cause actual future events to differ materially from the expected results include, but are not limited to: (i) the risk that SeaStar Medical may not be able to obtain regulatory approval of its SCD product candidates; (ii) the risk that SeaStar Medical may not be able to raise sufficient capital to fund its operations, including clinical trials; (iii) the risk that SeaStar Medical and its current and future collaborators are unable to successfully develop and commercialize its products or services, or experience significant delays in doing so, including failure to achieve approval of its products by applicable federal and state regulators, (iv) the risk that SeaStar Medical may never achieve or sustain profitability; (v) the risk that SeaStar Medical may not be able to access funding under existing agreements, including the equity line of credit and forward purchase agreements; (vi) the risk that third-parties suppliers and manufacturers are not able to fully and timely meet their obligations, (vii) the risk of product liability or regulatory lawsuits or proceedings relating to SeaStar Medical’s products and services, (viii) the risk that SeaStar Medical is unable to secure or protect its intellectual property, and (ix) other risks and uncertainties indicated from time to time in SeaStar Medical’s Annual Report on Form 10-K, including those under the “Risk Factors” section therein and in SeaStar Medical’s other filings with the SEC. The foregoing list of factors is not exhaustive. Forward-looking statements speak only as of the date they are made. Readers are cautioned not to put undue reliance on forward-looking statements, and SeaStar Medical assume no obligation and do not intend to update or revise these forward-looking statements, whether as a result of new information, future events, or otherwise. Contact: LHA Investor Relations Jody Cain (310) 691-7100 Jcain@lhai.com # # #

Topline data from vafidemstat's PORTICO Phase IIb trial in Borderline Personality Disorder (BPD) reported with promising results in secondary endpoints of overall severity and control of agitation/aggressionCompany planning to request an End-of-Phase II meeting with the FDA to discuss plans for a registrational Phase III trial in BPDContinues to enroll patients in Phase IIb EVOLUTION trial with vafidemstat in schizophreniaContinues to recruit patients in FRIDA trial with iadademstat in combination with gilteritinib in relapsed/refractory FLT3-mutant AML patientsResearch and development (R&D) expenses of $3.9 and $16.6 million for the quarter and twelve months ended December 31, 2023, respectively MADRID, Spain and BOSTON, Feb. 26, 2024 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with a strong unmet medical need, today reported financial results for the fourth quarter ended December 31, 2023 and provided a corporate update on recent developments. Dr Carlos Buesa, Oryzon’s Chief Executive Officer, said: “Oryzon continued with a strong path in its clinical programs in the fourth quarter. In CNS, we recently presented topline results for our Phase IIb PORTICO trial evaluating vafidemstat as a treatment for Borderline Personality Disorder (BPD). Although the primary endpoints were not met, two important secondary endpoints evaluating improvement in overall BPD disease severity and in agitation/aggression reached nominal statistical significance, and the results across all the primary and secondary efficacy endpoints favored vafidemstat over placebo. This is the first time, to the best of our knowledge, that a large, randomized Phase II trial in BPD had two secondary endpoints that met statistical significance reflecting clinically meaningful improvements in overall BPD severity and in agitation/aggression. In a disease with currently no approved drugs, and no established regulatory endpoints yet, PORTICO’s results across these two important endpoints are paving the way, in our opinion, to define a registrational Phase III trial, based for the first time on a well-controlled study that has enrolled a truly representative real-world BPD population. Once the full analysis is completed, the company will request an End-of-Phase II meeting with the FDA to discuss the design of a Phase III. Our Phase IIb trial with vafidemstat in schizophrenia, EVOLUTION, has also continued to enroll patients. We continue working for a future submission of an IND to initiate HOPE in 2024, the first randomized Phase I/II personalized medicine trial with an LSD1 inhibitor, in Kabuki Syndrome patients.” Dr Buesa continued: “In oncology, we also continued to make progress this quarter in both iadademstat’s ongoing clinical trials. In the FRIDA trial in combination with gilteritinib in relapsed/refractory FLT3-mutant AML patients, the second cohort is fully enrolled and ongoing, and the company’s assessment on the initial preliminary data looks very promising when compared to gilteritinib alone in historical data. We expect to communicate some preliminary data at the EHA Conference next June in Madrid. The collaborative trial with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in neuroendocrine tumors is also actively recruiting patients. In addition, we are expanding iadademstat’s clinical development through additional clinical trials under our CRADA with the NCI and through investigator-initiated studies in SCLC in combination with ICIs and in first line AML in combination with venetoclax and azacitidine.” Dr Buesa added: “While we have experienced a clear advance in our clinical pipeline, on the financial side, the company has continued its budgetary discipline. This, and the combination of non-dilutive funds (private and public grants and loans from commercial Spanish banks) with the withdrawal of €10 million from our €45 million Convertible Bond program allows us to extend the runway until 2025 and to focus now on the next conversations with the FDA and EMA and our clinical execution.” Fourth Quarter and Recent Highlights Vafidemstat in large multifactorial CNS indications: Topline results from PORTICO, a multicenter, double-blind, randomized, placebo-controlled Phase IIb conducted in the U.S. and EU to evaluate the efficacy and safety of vafidemstat in BPD patients, were reported on January 5, 2024. The primary endpoints, improvement in Borderline Personality Disorder Checklist (BPDCL) and in agitation/aggression by the Clinical Global Impression – Severity Agitation/Aggression (CGI-S A/A), did not reach statistical significance. However, nominal statistical significance was achieved on the secondary endpoint Borderline Evaluation of Severity (BEST), an overall measure of BPD disease severity, at weeks 8-12 (p = 0.042), with a relative reduction observed in the vafidemstat-treated group over the placebo group of 28.9%. Nominal statistical significance was also achieved on the secondary endpoint State-Trait Anger Expression Inventory 2 (STAXI-2) Trait Anger, a measure of agitation and aggression, at weeks 8-12 (p = 0.026), with a relative reduction observed in the vafidemstat-treated group over the placebo group of 46.7%. Results across all primary and secondary efficacy endpoints consistently favored vafidemstat over placebo. Global Statistical Test (GST p-values) confirmed a consistent trend across efficacy endpoints. Vafidemstat was safe and well-tolerated. Adverse events (AEs) were generally consistent with the safety profile of vafidemstat seen to date, with no new safety findings. Based on the efficacy and safety results, Oryzon intends to request an end-of-Phase II meeting with the FDA to discuss plans for a registrational Phase III study for the treatment of BPD. The company is currently completing the full data analysis and plans to provide a full data presentation at a psychiatric conference later this year, as well as in a peer-reviewed journal publication.The EVOLUTION Phase IIb clinical trial with vafidemstat in patients with schizophrenia continues to enroll patients. This Phase IIb study aims to evaluate the efficacy of vafidemstat on negative symptoms and cognitive impairment in patients with schizophrenia. This project is partially financed with public funds from the Spanish Ministry of Science and Innovation and is being carried out in various Spanish hospitals. Vafidemstat in monogenic CNS indications: We continue the preparations of a new precision medicine trial in Kabuki Syndrome (KS). The company is in a dialogue with the regulatory agencies to refine the final design of this trial and expects to submit an IND for HOPE to the U.S. Food and Drug Administration (FDA) in 2024. Iadademstat in oncology: FRIDA, an open-label, multicenter Phase Ib clinical trial of iadademstat in combination with gilteritinib in patients with relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) harboring a FMS-like tyrosine kinase mutation (FLT3mut+), continues to enroll patients. The first cohort has been completed (six patients), and the combination was safe and showed strong antileukemic activity. The second cohort (six patients) is fully enrolled and ongoing. The primary objectives of the trial are to evaluate the safety and tolerability of iadademstat in combination with gilteritinib in patients with FLT3mut+ R/R AML and to establish the Recommended Phase 2 Dose (RP2D) for this combination. Secondary objectives include the evaluation of the treatment efficacy, measured as the rate of complete remission and complete remission with partial hematological recovery (CR/CRh), the Duration of Responses (DoR), and the assessment of Measurable Residual Disease (MRD). The study is being conducted in the U.S. and will accrue up to approximately 45 patients. If successful, Oryzon and the FDA have agreed to hold a meeting to discuss the best plan to further develop this combination in this much-in-need AML population.The Company is further expanding the clinical development of iadademstat in AML through an Investigator-initiated study (IIS). This trial will be a Phase Ib dose-finding study to evaluate iadademstat in combination with venetoclax and azacitidine in first-line AML patients, led by Oregon Health & Science University (OHSU). The trial received FDA IND approval in 4Q2023 and is expected to begin enrolling patients in 1Q2024.The collaborative Phase II basket trial of iadademstat in combination with paclitaxel in platinum R/R small cell lung cancer (SCLC) and extrapulmonary high-grade neuroendocrine tumors (NET trial) continues to enroll patients. This trial is being conducted in the U.S. under a collaborative clinical research agreement with the FCCC, under which the FCCC will be conducting different collaborative combination clinical trials with iadademstat, with Oryzon providing funding, the drug, and technical expertise.A new clinical trial of iadademstat in combination with an immune checkpoint inhibitor (ICI) in first-line metastatic SCLC, which will be conducted under the Cooperative Research and Development Agreement (CRADA) signed with the National Cancer Institute (NCI) in the United States, is under preparation. This trial will be led by the Memorial Sloan Kettering Cancer Center (MSKCC), which plans to file the IND with the FDA in 1Q2024.The STELLAR trial, a randomized, multicenter Phase Ib/II study of iadademstat plus a checkpoint inhibitor in first-line extensive-stage SCLC, will be informed and refined from the findings of the CRADA-MSKCC trial in the same space and with the same design that is expected to start in 1Q2024, as mentioned above. The company believes that STELLAR could potentially support an application for accelerated approval. Earlier stage programs: ORY-4001, Oryzon’s highly selective histone deacetylase 6 (HDAC6) inhibitor nominated as a clinical candidate for the treatment of certain neurological diseases such as Charcot-Marie-Tooth disease (CMT), Amyotrophic Lateral Sclerosis (ALS) and others, is progressing through IND enabling studies to prepare it for clinical studies. The Company recently announced that is has received a 0.5 million USD grant from the ALS Association in the U.S. to support the regulatory preclinical development of ORY-4001 for ALS. ORY-4001 has been previously shown to reverse disease progression symptoms in a CMT mice model which reliably recapitulates many of the symptoms of this condition in humans, improving myelination and restoring axon integrity in the sciatic nerve, and improving compound muscle action potential and nerve conduction. These results are fruit of a collaboration entered in 2022 between Oryzon and the CMT Research Foundation (CMTRF), a U.S.-based patient-led, non-profit organization focused on delivering treatments and cures for CMT.Oryzon has received two new grants to further explore the role of epigenetic targets in the treatment of neuronal pathologies. These are two collaborative projects with public research centers, focused on the discovery and validation of novel biomarkers and epigenetic targets for the treatment of neuronal pathologies. The projects have a global budget of 2.3 million euros, of which Oryzon will receive up to 1.4 million euros. Financial Update: Fourth Quarter 2023 Financial Results Research and development (R&D) expenses were $3.9 and $16.6 million for the quarter and twelve months ended December 31, 2023, respectively, compared to $5.0 and $18.1 million for the quarter and twelve months ended December 31, 2022. General and administrative expenses were $1.2 and $4.2 million for the quarter and twelve months ended December 31, 2023, respectively, compared to $1.2 and $4.8 million for the quarter and twelve months ended December 31, 2022. Net losses were $1.4 and $5.0 million for the quarter and twelve months ended December 31, 2023, respectively, compared to $1.6 and $5.9 million for the quarter and twelve months ended December 31, 2022. The result is as expected, given the biotechnology business model where companies in the development phase typically have a long-term maturation period for products, and do not have recurrent income. Negative net result was $3.7 million (–$0.064 per share) for the twelve months ended December 31, 2023, compared to a negative net result of $4.5 million (–$0.085 per share) for the twelve months ended December 31, 2022 Cash, cash equivalents and marketable securities totaled $13.5 million as of December 31, 2023. ORYZON GENOMICS, S.A.BALANCE SHEET DATA (AUDITED)1(Amounts in thousands US $) December 31st, 2023 December 31st, 2022 Cash and cash equivalents13,544 22,737Marketable securities0 0Total Assets118,125 110,606 Deferred revenue12 0Total Stockholders' equity90,361 77,405 ORYZON GENOMICS, S.A. STATEMENTS OF OPERATIONS (AUDITED)1 (US $, amounts in thousands except per share data) Three Months Ended December 31st Twelve Months Ended December 31st 20232022 20232022 Collaboration Revenue 00 00 Operating expenses: Research and Development 3,8675,033 16,63118,050 General and administrative 1,1871,249 4,2474,822 Total operating expenses 5,0546,282 20,87822,872 Loss from Operations -5,054-6,282 -20,878-22,872 Other income, net 3,6194,693 15,85117,016 Net Loss -1,435-1,589 -5,027-5,856 Net Financial & Tax -468-863 1,3221,342 Net Result -1,903-2,452 -3,705-4,514 Loss per share allocable to common stockholders: Basic -0.03-0.05 -0.06-0.08 Weighted average Shares outstanding Basic 58,451,07054,284,176 57,616,23653,336,257 1 Spanish GAAP * Exchange Euro/Dollar (1.1050 for 2023 and 1.0666 in 2022) About OryzonFounded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS and iadademstat in oncology, in several Phase II clinical trials. The company has other pipeline assets directed against other epigenetic targets like HDAC-6, where ORY-4001 has been nominated as clinical candidate for the treatment of certain neurological disorders such as CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com About Iadademstat Iadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (see Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12.doi: 10.1016 / j.ccell.2018.02.002.). A FiM Phase I/IIa clinical trial with iadademstat in R/R AML patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi (see Salamero et al, J Clin Oncol, 2020, 38(36): 4260-4273. doi: 10.1200/JCO.19.03250). Iadademstat has shown encouraging safety and efficacy data in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation). Iadademstat is currently being evaluated in combination with gilteritinib in the ongoing Phase Ib FRIDA trial in patients with relapsed/refractory AML with FLT3 mutations. Beyond hematological cancers, the inhibition of LSD1 has been proposed as a valid therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors (NET), medulloblastoma and others. In a Phase IIa trial in combination with platinum/etoposide in second line ED-SCLC patients (CLEPSIDRA trial), preliminary activity and safety results have been reported (see Navarro et al., ESMO 2018 poster). Iadademstat is being evaluated in a collaborative Phase II basket study with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and the company is preparing a new trial in combination with immune checkpoint inhibitors (ICI) in SCLC. Oryzon has entered into a Cooperative Research and Development Agreement (CRADA) with the U.S. National Cancer Institute (NCI) to collaborate on potential further clinical development of iadademstat in different types of solid and hematological cancers; a first trial in combination with ICI in SCLC is under preparation. In total iadademstat has been dosed so far to more than 130 cancer patients in four clinical trials. Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. About Vafidemstat Vafidemstat (ORY-2001) is an oral, CNS-optimized LSD1 inhibitor. The molecule acts on several levels: it reduces cognitive impairment, including memory loss and neuroinflammation, and at the same time has neuroprotective effects. In animal studies vafidemstat not only restores memory but reduces the exacerbated aggressiveness of SAMP8 mice, a model for accelerated aging and Alzheimer’s disease (AD), to normal levels and also reduces social avoidance and enhances sociability in murine models. In addition, vafidemstat exhibits fast, strong, and durable efficacy in several preclinical models of multiple sclerosis (MS). Oryzon has performed two Phase IIa clinical trials in aggressiveness in patients with different psychiatric disorders (REIMAGINE) and in aggressive/agitated patients with moderate or severe AD (REIMAGINE-AD), with positive clinical results reported in both. Additional finalized Phase IIa clinical trials with vafidemstat include the ETHERAL trial in patients with Mild to Moderate AD, where a significant reduction of the inflammatory biomarker YKL40 has been observed after 6 and 12 months of treatment, and the pilot, small-scale SATEEN trial in Relapse-Remitting and Secondary Progressive MS, where anti-inflammatory activity has also been observed. Vafidemstat has also been tested in a Phase II in severe Covid-19 patients (ESCAPE) assessing the capability of the drug to prevent ARDS, one of the most severe complications of the viral infection, where it showed significant anti-inflammatory effects in severe Covid-19 patients. Vafidemstat is being investigated in neuropsychiatric disorders in two double-blind, randomized, placebo-controlled Phase IIb trials: one in schizophrenia, named EVOLUTION (recruitment ongoing), and another one in Borderline Personality disorder (BPD), named PORTICO, recently finalized, with topline data and in the process of completing the full data analysis. Based on PORTICO’s topline results, the company is planning to request an End-of-Phase II meeting with the FDA to discuss options for a registrational Phase III trial in BPD. The company is also deploying a CNS precision medicine approach with vafidemstat in genetically-defined patient subpopulations of certain CNS disorders and is preparing a clinical trial in Kabuki Syndrome patients. The company is also exploring the clinical development of vafidemstat in other neurodevelopmental syndromes. FORWARD-LOOKING STATEMENTS This communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates” and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisión Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forward‐looking statements, whether as a result of new information, future events or otherwise. This press release is not an offer of securities for sale in the United States or any other jurisdiction. Oryzon’s securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of Oryzon’s securities to be made in the United States will be made by means of a prospectus that may be obtained from Oryzon or the selling security holder, as applicable, that will contain detailed information about Oryzon and management, as well as financial statements. IR, USIR & Media, EuropeSpainOryzonAshley R. RobinsonSandya von der WeidPatricia Cobo/Mario CorderaEmili TorrellLifeSci Advisors, LLCLifeSci Advisors, LLCAtreviaChief Business Officer+1 617 430 7577+41 78 680 05 38+34 91 564 07 25+34 673 33 97 65+34 93 515 1313arr@lifesciadvisors.comsvonderweid@lifesciadvisors.compcobo@atrevia.commcordera@atrevia.cometorrell@oryzon.com

Application based on results from the TRIDENT-1 and CARE trials, in which Augtyro demonstrated clinically meaningful response rates If approved, Augtyro will provide a new, next-generation option for patients with NTRK-positive locally advanced or metastatic solid tumors who have high unmet medical needs The U.S. Food and Drug Administration assigned a target action date of June 15, 2024 PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has accepted the supplemental New Drug Application (sNDA) for Augtyro™ (repotrectinib) for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity. The filing acceptance is based on results from the registrational Phase 1/2 TRIDENT-1 trial (adult patients with NTRK-positive solid tumors) and CARE study (pediatric patients with NTRK-positive solid tumors). The FDA granted the application Priority Review status and assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 15, 2024. “While great advancements have been made over the last decade, patients with NTRK-positive locally advanced or metastatic solid tumors still experience significant unmet needs. New and effective treatment options that may improve durability of response and address resistance to existing tyrosine kinase inhibitors are critical to helping patients with these aggressive tumors,” said Joseph Fiore, vice president, global program lead, Augtyro, Bristol Myers Squibb. “We look forward to working closely with the FDA on the review of our application for Augtyro for this tumor-agnostic indication and potentially offering patients with NTRK-positive disease a new, durable treatment option.” The filing was based on the results from the TRIDENT-1 and CARE trials. In the TRIDENT-1 study, Augtyro demonstrated clinically meaningful response rates in patients with NTRK-positive locally advanced or metastatic solid tumors. Durability of response was robust, including among patients whose tumors harbor common resistance mutations, and intracranial responses were observed. Augtyro showed a safety pro was well tolerated and generally manageable. The study remains ongoing to assess long-term outcomes and additional endpoints. Results from TRIDENT-1 were supported by data from the CARE study, which evaluates Augtyro in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene alterations. Additionally, in November 2023 the U.S. Food and Drug Administration approved Augtyro for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer NSCLC. Bristol Myers Squibb thanks the patients and investigators involved with the TRIDENT-1 and CARE clinical trials. Turning Point Therapeutics is a wholly owned subsidiary of the Bristol-Myers Squibb Company. As of August 2022, Bristol Myers Squibb acquired the company, including its asset repotrectinib. About TRIDENT-1 TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of Augtyro in patients with advanced solid tumors, including non-small cell lung cancer (NSCLC). Phase 1/2 includes patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK fusions. Additional analyses of the trial are still being conducted; asymptomatic central nervous system (CNS) metastases are allowed. The trial excludes patients with symptomatic brain metastases, among other exclusion criteria. Phase 1 of the trial included the dose escalation that determined the recommended Phase 2 dose. Phase 2 of the trial has a primary endpoint of overall response rate (ORR). Key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by Blinded Independent Central Review (BICR), progression-free survival (PFS), and intracranial response in six distinct expansion cohorts, including tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive locally advanced or metastatic solid tumors. About CARE CARE is a Phase 1/2 open-label, safety, tolerability, pharmacokinetics and anti-tumor activity clinical trial evaluating Augtyro in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene alterations. Phase 1 of the study aims to evaluate the safety and tolerability at different dose levels. Phase 1 of the trial has primary endpoints of dose limiting toxicities (DLTs) and pediatric recommended Phase 2 dose (RP2D). Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DOR) and intracranial ORR (IC-ORR). Phase 2 of the study will seek to demonstrate the efficacy and anti-tumor activity of Augtyro in pediatric and young adult patients. The primary endpoint of Phase 2 is ORR and secondary endpoints include CBR, TTR, DOR, IC-ORR, progression-free survival (PFS), central nervous system PFS (CNS-PFS) and overall survival (OS). About NTRK-Positive Solid Tumors Neurotrophic tropomyosin kinase receptors (NTRK) are a family of receptors involved in neural development. NTRK gene fusions can play a role in the development of cancer. They are rare in patients with solid tumors with less than 1% of patients testing positive, though may be more frequent in patients with secretory breast cancer, infantile fibrosarcoma, thyroid cancer, gastrointestinal stromal tumors, spitzoid tumors and infantile fibrosarcoma, among other cancers. Per international treatment guidelines, targeted agents are part of the treatment armamentarium for patients with a tumor harboring this gene alteration. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Augtyro Augtyro (TPX-0005, BMS-986472) is a next-generation tyrosine kinase inhibitor (TKI) targeting ROS1-positive or NTRK-positive locally advanced or metastatic solid tumors, including non-small cell lung cancer (NSCLC), where there remain significant unmet medical needs for patients. Augtyro was designed to improve durability of response and with favorable properties for human brain penetration to enhance intracranial activity. It is being studied in a registrational Phase 1/2 trial in adults (TRIDENT-1) and a Phase 1/2 trial in pediatric patients (CARE). Augtyro has demonstrated clinically meaningful results and was granted three Breakthrough Therapy Designations (BTDs) by the FDA for the treatment of patients with: ROS1-positive metastatic NSCLC who have not been treated with a ROS1 TKI; ROS1-positive metastatic NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; and advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with one or two prior tropomyosin receptor kinase (TRK) TKIs (with or without prior chemotherapy) and have no satisfactory alternative treatments. Augtyro was also previously granted four fast-track designations in patients with: ROS1-positive advanced NSCLC who have been treated with disease progression following one prior line of platinum-based chemotherapy and one prior line of a ROS1 TKI; ROS1-positive advanced NSCLC who have not been treated with a ROS1 TKI; ROS1-positive advanced NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; and advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK TKIs and have no satisfactory alternative treatments. Augtyro was also granted an Orphan Drug designation by the U.S. Food and Drug Administration (FDA). INDICATION AUGTYROTM (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). Warnings & Precautions IMPORTANT SAFETY INFORMATION Central Nervous System Adverse Reactions Among the 351 patients who received AUGTYRO in the TRIDENT-1 study, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 75% with Grade 3 or 4 events occurring in 4%. Dizziness, including vertigo, occurred in 64% and Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 6 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 12% required dose reduction of AUGTYRO due to dizziness. Ataxia, including gait disturbance and balance disorder, occurred in 29% of the 351 patients; Grade 3 ataxia occurred in 0.3%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 6% of patients, 8% required dose reduction and one patient (0.3%) permanently discontinued AUGTYRO due to ataxia. Cognitive disorder, including memory impairment and disturbance in attention, occurred in 23% of the 351 patients. Cognitive disorders included memory impairment (13%), disturbance in attention (11%), and confusional state (2%); Grade 3 cognitive disorders occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 1.7% required dose reduction and 0.6% permanently discontinued AUGTYRO due to cognitive adverse reactions. Mood disorders occurred in 6% of the 351 patients. Mood disorders occurring in >1% of patients included anxiety (2.8%), irritability (1.1%), and depression (1.4%); Grade 4 mood disorders (mania) occurred in 0.3% of patients. Dose interruption was required in 0.3% of patients and 0.3% required a dose reduction due to mood disorders. Sleep disorders including insomnia and hypersomnia occurred in 15% of the 351 patients. Sleep disorders observed in >1% of patients were somnolence (8%), insomnia (6%) and hypersomnia (1.1%). Dose interruption was required in 0.9% of patients, and 0.3% required a dose reduction due to sleep disorders. The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases. Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Interstitial Lung Disease (ILD)/Pneumonitis Among the 351 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred in 2.9%; Grade 3 ILD/pneumonitis occurred in 1.1%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.6% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed. Hepatotoxicity Among the 351 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 35%, increased aspartate aminotransferase (AST) occurred in 40%, including Grade 3 or 4 increased ALT in 2% and increased AST in 2.6%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.4% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.6%. Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity. Myalgia with Creatine Phosphokinase (CPK) Elevation Among the 351 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.6%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement. Hyperuricemia Among the 351 patients treated with AUGTYRO, 18 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.9% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication. Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Skeletal Fractures Among 351 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.6%), feet (0.6%), spine (0.3%), acetabulum (0.3%), sternum (0.3%), and ankles (0.3%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients. Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures. Embryo-Fetal Toxicity Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose. Adverse Reactions Among 351 patients who received AUGTYRO for ROS1-positive NSCLC and other solid tumors in the TRIDENT-1 trial, the most common (>20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%). In a subset of 264 patients who received AUGTYRO for ROS1-positive NSCLC, the most common (≥20%) adverse reactions were dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%). Drug Interactions Effects of Other Drugs on AUGTYRO Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO. P-gp Inhibitors Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Strong and Moderate CYP3A Inducers Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO. Effects of AUGTYRO on other Drugs Certain CYP3A4 Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling. Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates. Contraceptives Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives. Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females to use an effective nonhormonal contraceptive. Please see U.S. Full Prescribing Information for AUGTYRO About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that Augtyro (repotrectinib) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such treatment for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. It should be noted that acceptance of the application does not change the standards for FDA approval. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023 as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news