CYBB

-- Prioritizing Set of High Value Programs in Core Areas of Focus; Modularity of Prime Editing Platform Expected to Allow Prime Medicine to Generate Follow-on Candidates Rapidly and Efficiently -- -- Initial Clinical Data from Phase 1/2 Trial in CGD Expected in 2025 While Advancing Wilson’s Disease Program Toward Expected IND Application and/or CTA in 1H 2026 -- -- Today Announced Strategic Research Collaboration and License Agreement with Bristol Myers Squibb to Develop and Commercialize Multiple Prime Edited Ex Vivo T-cell Therapies -- -- Together with $110 Million Upfront Consideration Received Under Agreement with Bristol Myers Squibb, Anticipated Cost Savings are Expected to Extend Cash Runway into the First Half of 2026 -- CAMBRIDGE, Mass., Sept. 30, 2024 (GLOBE NEWSWIRE) -- Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today announced that it is focusing its pipeline on a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path, and each expected to provide the foundation for expansion into additional opportunities. “We founded Prime Medicine with a singular vision: to apply our groundbreaking Prime Editing platform to address the genetic causes of debilitating diseases and provide patients with long-lasting cures,” said Keith Gottesdiener, M.D., President and Chief Executive Officer of Prime Medicine. “Over the past four years, we have started to translate this vision into reality, advancing PM359 into the clinic and generating preclinical data that show we can reproducibly and durably correct disease causative mutations in multiple cell types and successfully deliver Prime Editors across target tissues. In addition, we are encouraged by recent commentary from the U.S. Food and Drug Administration, which is increasingly supportive of modular approaches to developing genetic therapies, for which we believe Prime Editing is uniquely suited. We believe that Prime Medicine has the potential to change the treatment paradigm for a wide range of diseases, which collectively impact millions of people.” Dr. Gottesdiener continued, “In order to maximize Prime Editing’s reach, we believe now is the time to strategically focus our efforts on a set of high value programs. Importantly, each prioritized program is intended to serve as a beachhead, allowing us to advance our technological leadership across a number of target tissues and cell types, while providing insights into research and development, regulatory strategy, CMC and delivery that will potentially allow us to progress our follow-on programs more rapidly and efficiently. In parallel, we plan to continue to leverage strategic business development, such as the collaboration with Bristol Myers Squibb that we announced this morning, to further extend Prime Editing’s reach. We expect to share first-in-human clinical data from our Phase 1/2 trial in CGD in 2025 and new preclinical data for our Wilson’s Disease program in the fourth quarter of 2024, as we work to bring this paradigm-shifting technology to patients.” Prime Medicine’s Focused Pipeline Hematology, Immunology & Oncology Prime Medicine will focus on the development of two programs for the treatment of chronic granulomatous disease (CGD), which together have the potential to address the vast majority of people living with CGD: PM359, an ex vivo autologous hematopoietic stem cell (HSC) product for the treatment of p47phox CGD. Approximately one quarter of patients with CGD present with a mutation in p47phox. In April 2024, the U.S. Food and Drug Administration (FDA) cleared Prime Medicine’s investigational new drug (IND) application for PM359, less than one month after the IND filing. The Company has initiated a Phase 1/2 clinical trial to assess the safety, biological activity and preliminary efficacy of PM359 in adult and pediatric patients and continues to expect initial clinical data from the study in 2025. Once proof-of-concept is established, Prime Medicine expects to advance PM359 rapidly into a pivotal study. PM359 has received rare pediatric drug designation and orphan drug designation from the FDA. Ex vivo HSC product for the treatment of X-linked CGD. Prime Medicine today announced its first follow-on program in hematology and immunology. Building on its efforts in p47phox CGD, Prime Medicine is advancing a program for X-linked CGD, which utilizes its Prime Assisted Site-Specific Integrate Gene Editing (PASSIGE™) technology, and is expected to address over 90 percent of known mutations in the CYBB gene with a single approach. Mutations in the CYBB gene occur in approximately two thirds of patients with CGD. Prime Medicine intends to leverage modular elements from across the PM359 program, including the IND filing, chemistry, manufacturing and controls (CMC) work and clinical trial, with the aim to accelerate advancement of its X-CGD program. BMS Collaboration: Ex vivo T-Cell Therapies. As announced this morning, Prime Medicine entered into a strategic research collaboration and license agreement with Bristol Myers Squibb, a global leader in cell therapy for hematology, immunology, and oncology, to develop and commercialize multiple Prime Edited ex vivo T-cell therapies. Under the terms of the agreement, Prime Medicine will design optimized Prime Editor and PASSIGE reagents for a select number of targets in immunological diseases and cancer; Bristol Myers Squibb will be responsible for development, manufacturing and commercialization of the next generation cell therapies, with support from Prime Medicine in gene editing strategy and reagent development. Under the terms of the agreement, Prime Medicine will receive a $55 million upfront payment and a $55 million equity investment from Bristol Myers Squibb. Prime Medicine is also eligible to receive more than $3.5 billion in milestones, including up to $1.4 billion in development milestones and more than $2.1 billion in commercialization milestones, along with royalties on net sales. Liver Lipid nanoparticle (LNP) Prime Editor for the treatment of Wilson’s Disease. Prime Medicine is focused on advancing its Wilson’s Disease program, which targets prevalent mutations in the ATP7B gene. Prime Medicine expects to present new preclinical data and initiate IND-enabling activities for this program in the fourth quarter of 2024, and intends to file an IND and/or clinical trial application (CTA) in the first half of 2026. The program will use Prime Medicine’s universal LNP, a multi-component and modular delivery system that the Company expects will be used across all liver disease programs, allowing more rapid and cost-efficient expansion into follow-on rare and non-rare liver indications. Lung LNP / adeno-associated virus (AAV) Prime Editors for the treatment of Cystic Fibrosis (CF). With funding from the Cystic Fibrosis Foundation, Prime Medicine is continuing to advance two strategies to potentially cure CF: hotspot editing and PASSIGE. Using hotspot editing, the Company aims to address multiple mutations at mutational hotspots with a small number of Prime Editors; using PASSIGE, the Company aims to address nearly all people with CF with a single superexon insertion strategy. Through the Cystic Fibrosis Foundation, Prime Medicine has access to infrastructural support and foundational guidance, including established assays, animal models reagents and patient samples, which may accelerate advancement of the Company’s Prime Editors for CF. Additional ProgramsIn order to pursue its prioritized high value programs as rapidly as possible, the Company is identifying partnership opportunities to advance its other programs, including those for neurological diseases, cell therapy, ocular diseases and hearing loss. Prime Medicine expects that business development will continue to play a critical role in accelerating and funding its pipeline, allowing the Company to maximize the potential and reach of Prime Editing, including in areas outside its core focus. Prime Medicine may also choose to advance these programs through internal efforts in the future. Updated Financial GuidanceAs a result of this strategic pipeline prioritization, Prime Medicine will streamline its operating expenses and capital expenditures. Together with the $110 million upfront consideration received from Bristol Myers Squibb under the strategic research collaboration and license agreement announced this morning, Prime Medicine expects its cash runway to fund operations into the first half of 2026. About Prime MedicinePrime Medicine is a leading biotechnology company dedicated to creating and delivering the next generation of gene editing therapies to patients. The Company is deploying its proprietary Prime Editing platform, a versatile, precise and efficient gene editing technology, to develop a new class of differentiated one-time curative genetic therapies. Designed to make only the right edit at the right position within a gene while minimizing unwanted DNA modifications, Prime Editors have the potential to repair almost all types of genetic mutations and work in many different tissues, organs and cell types. Taken together, Prime Editing’s versatile gene editing capabilities could unlock opportunities across thousands of potential indications. Prime Medicine is currently progressing a diversified portfolio of investigational therapeutic programs organized around our core areas of focus: hematology, immunology and oncology, liver and lung. Across each core area, Prime Medicine is focused initially on a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path, and each expected to provide the foundation for expansion into additional opportunities. Over time, the Company intends to maximize Prime Editing’s broad and versatile therapeutic potential, as well as the modularity of the Prime Editing platform, to rapidly and efficiently expand beyond the diseases in its current pipeline, potentially including additional genetic diseases, immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases, which collectively impact millions of people. For more information, please visit www.primemedicine.com. © 2024 Prime Medicine, Inc. All rights reserved. PRIME MEDICINE, the Prime Medicine logos, and PASSIGE are trademarks of Prime Medicine, Inc. All other trademarks referred to herein are the property of their respective owners. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Prime Medicine’s beliefs and expectations regarding: the potential of PM359 to correct the causative mutation of CGD; the anticipated maturation into a clinical-stage company by bringing PM359 into clinical development in 2024 with initial clinical data from the ongoing Phase 1/2 clinical trial of PM359 expected in 2025; the initiation, timing, progress, and results of its research and development programs, preclinical studies and future clinical trials, and the release of data related thereto; the collaboration with Bristol Myers Squibb and the intended and potential benefits thereof, including the receipt of potential milestone and royalty payments from commercial product sales, if any; certain activities and next steps to support the Company’s maturation into a clinical-stage company, including opening an IND and/or CTA application, clinical data expectations, establishing proof-of-concept, advancing programs into lead optimization, advancing preclinical studies and initiating IND-enabling activities, and establishing AAV delivery platform and route of administration for neuromuscular programs; the potential for Prime Editors to more precisely and effectively achieve genetic modification; the potential for Prime Editors to repair genetic mutations and offer curative genetic therapies for a wide spectrum of diseases; the potential of Prime Editors to reproducibly correct disease-causing genetic mutations across different tissues, organs and cell types, and the capacity of its Prime Editing and PASSIGE technology to edit CAR-T cells for the treatment of certain cancers and immune diseases; its ability to demonstrate superior off-target profiles for Prime Editing programs; exploring business development opportunities that could accelerate existing work and the benefits thereof; the modularity of the Prime Editing platform and the benefits thereof; its expectations regarding the breadth of Prime Editing technology and the implementation of its strategic plans for its business, programs, and technology; the potential of Prime Editing to unlock opportunities across thousands of potential indications; and its expected cash runway.. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: the development and optimization of new technologies; the scope of protection Prime Medicine is able to establish and maintain for intellectual property rights covering its Prime Editing technology; Prime Medicine’s ability to identify and enter into future license agreements and collaborations; the effect of unfavorable macroeconomic conditions or market volatility resulting from general economic, industry and market conditions, including rising interest rates, inflation, and adverse developments affecting the financial services industry; and Prime Medicine’s expectations regarding the anticipated timeline of its cash runway and future financial performance. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Prime Medicine’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Prime Medicine’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Prime Medicine explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor ContactHannah DeresiewiczPrecision AQ212-362-1200hannah.deresiewicz@precisionaq.com Media ContactDan Budwick, 1ABdan@1ABmedia.com

Preclinical proof-of-concept data show the therapeutic potential of OTL-104 for NOD2 Crohn’s disease, a severe and treatment-refractory form of the disease In vivo data demonstrate the development of CAR-Treg cells from genetically engineered HSCs as a potential one-time treatment for autoimmune disorders Company to host conference call and webcast Tuesday, May 23 at 8:00 a.m. EDT BOSTON and LONDON, May 18, 2023 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today presented new data from the company’s hematopoietic stem cell (HSC) gene therapy research pipeline targeting larger indications at the ongoing 26th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Los Angeles. Presentations include preclinical proof-of-concept data from OTL-104, the company’s investigational HSC gene therapy for the treatment of nucleotide-binding oligomerization domain containing protein 2 (NOD2) Crohn’s disease, as well as in vivo preclinical data demonstrating the development of functional CAR-Treg cells from genetically engineered HSCs. Both programs were designed and developed in Orchard’s own research laboratories utilizing the company’s proprietary HSC gene therapy platform. “These data continue to demonstrate the power of our HSC gene therapy platform and its applicability beyond our rare neurometabolic franchise into diseases with larger patient populations,” said Fulvio Mavilio, Ph.D., chief scientific officer of Orchard Therapeutics. “Due to their unique ability to self-renew and differentiate into multiple cell types that migrate to tissues and organs often inaccessible to other therapeutic modalities, HSC-based gene therapies have immense therapeutic and collaborative potential. We look forward to advancing IND-enabling activities for our research program in NOD2 Crohn’s disease and further developing the HSC-derived CAR-Treg cell technology.” OTL-104 (NOD2 Crohn’s Disease) Preclinical Data Summary Using established in vitro and in vivo models of NOD2 deficiency, including NOD2 knockout mice and HSC-derived macrophages from Crohn’s patients with biallelic NOD2 mutations, Orchard researchers evaluated the safety and efficacy of HSC gene therapy in restoring NOD2-dependent immune responses. The chimeric promoter used in OTL-104 was originally developed and clinically tested in patients with X-linked chronic granulomatous disease (X-CGD), where enhanced expression of gp91-Phox in myeloid and monocyte lineages was demonstrated. In a poster session tomorrow, the first preclinical proof-of-concept data will highlight the therapeutic potential of this approach, including: OTL-104, a lentiviral vector expressing NOD2 under the control of a myeloid-directed chimeric promoter, fully restores NOD2-dependent immune responses in macrophages derived from HSCs obtained from Crohn’s patients carrying biallelic NOD2 mutations to within the range of healthy donor cells. Transplantation of OTL-104 in NOD2 knockout mice reconstitutes NOD2 expression in intestinal tissue resident cells and broadly restores NOD2-dependent innate immune cell functions. Taken together, these results confirm the negative impact of NOD2 deficiency in primary immune activation and support the therapeutic potential of HSC gene therapy to provide long-term correction of NOD2 Crohn’s disease. Work to evaluate OTL-104’s ability to correct an induced NOD2 knockout mouse model of ileitis is currently ongoing. The company expects to commence IND- and CTA-enabling studies in the second half of 2023, with a potential filing now anticipated in the first half of 2025. HSC CAR-Treg cell Technology Preclinical Data Summary Yesterday’s poster session demonstrates the feasibility of utilizing HSC gene therapy to provide stable and targeted immunotherapy, through the ability of HSCs to differentiate into T regulatory (Treg) cells engineered to express chimeric antigen-specific receptors (CAR). This approach combines the proven durability of HSC gene therapy with the specific suppressive activity of CAR-Treg cells, providing an alternative to current treatments which fail to effectively control chronic autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and Type 1 diabetes. Data from transplanted mice show that the preferential expression of CAR in HSC-derived regulatory T cells in vivo does not significantly alter the development, phenotype or function of these suppressive immune cells. Also, the functionality of the CAR receptor is demonstrated when HSC-derived CAR-Tregs can be activated ex vivo by exposure to a CAR-specific ligand, producing the immunosuppressive cytokine IL-10. The company will continue to advance its preclinical research activities aimed at further demonstrating the feasibility and applicability of its HSC CAR-Treg cell technology. Conference Call and Webcast A live webcast to recap the data will be available under "News & Events" in the Investors & Media section of the company's website at on Tuesday May 23, 2023, at 8:00 a.m. EDT. A replay of the webcast will be archived on the Orchard website following the presentation. About OTL-104 and NOD2 Crohn’s Disease Crohn’s disease is a form of Inflammatory Bowel Disease (IBD), a condition affecting the gastrointestinal tract. Mutations in a number of genes are known to confer susceptibility to the risk of Crohn’s, and among these the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene is the most common genetic factor. NOD2 deficiency results in an impaired detection and clearance of bacteria penetrating the gut during gastrointestinal infection. This leads to a form of Crohn’s disease more severe and refractory to existing therapies, with manifestations including chronic abdominal pain, diarrhea, weight loss, fatigue, malnutrition and for some patients, more severe intestinal damage requiring surgical resection. Epidemiological studies suggest NOD2 genetic variants causing functional defects are associated with 7 to 10% of all cases of Crohn’s, with up to 200,000 patients in the U.S. and Europe with two NOD2 mutated alleles. There is currently no cure for Crohn's disease, and long-term, effective treatment options are limited. Current clinical management for Crohn’s disease includes use of immune-suppressive medications, biological agents such as anti-TNF, steroids and surgical resection. OTL-104 is an investigational HSC gene therapy in development for the potential treatment of patients with NOD2 Crohn’s disease. As the pathogenesis of NOD2 Crohn’s disease is associated with the function of cells of the hematopoietic system, OTL-104 may therefore be used to restore NOD2 function to immune cells such as tissue resident macrophages within the gastrointestinal tract. OTL-104 is designed to introduce the NOD2 gene into cells of the hematopoietic system by lentiviral transduction of a patient’s own HSCs, and the gene-modified cells can then be infused back into the patient. About Orchard’s Proprietary HSC T-reg Cell Technology HSC gene therapy is well-suited to address severe autoimmune disorders due to the ability of HSCs to differentiate into regulatory T-cells (Tregs) which are a specialized subset of T-cells that can suppress inflammation and be harnessed as a cell therapy with an approach similar to that used to create chimeric antigen receptor T-cells (CAR-Ts). Orchard’s approach aims to combine the demonstrated durability of HSC gene therapy in genetic diseases with the specific suppressive potential of Tregs. Orchard has established a proprietary position covering the concept, therapeutic application and specifics of HSC-antigen-specific Treg therapy. About Orchard Therapeutics At Orchard Therapeutics, our vision is to end the devastation caused by genetic and other severe diseases. We aim to do this by discovering, developing and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, a patient’s own blood stem cells are genetically modified outside of the body and then reinserted, with the goal of correcting the underlying cause of disease in a single treatment. In 2018, the company acquired GSK’s rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Today, Orchard is advancing a pipeline spanning preclinical, clinical and commercial stage HSC gene therapies designed to address serious diseases where the burden is immense for patients, families and society and current treatment options are limited or do not exist. Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit , and follow us on Twitter and LinkedIn. Availability of Other Information About Orchard Investors and others should note that Orchard communicates with its investors and the public using the company website ( ), the investor relations website (ir.orchard-tx.com), and on social media (Twitter and LinkedIn), including but not limited to investor presentations and investor fact sheets, U.S. Securities and Exchange Commission filings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchard’s investor relations website and may include additional social media channels. The contents of Orchard’s website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933. Forward-looking Statements This press release contains forward-looking statements, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchard’s business and product development strategy and goals, including the therapeutic potential of the programs mentioned in this press release, Orchard’s expectations with respect to regulatory submissions for its product candidates, and Orchard’s expectations regarding its ongoing preclinical and clinical trials, including the timing of enrollment for clinical trials and release of additional preclinical and clinical data, and the likelihood that data from clinical trials will be positive and support further clinical development and regulatory approval of Orchard's product candidates. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchard’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials will not continue or be repeated in Orchard’s ongoing or planned clinical trials, will be insufficient to support regulatory submissions or support or maintain marketing approval in the US or European Union, or that long-term adverse safety findings may be discovered; and the risk that any one or more of Orchard’s product candidates will not be approved, successfully developed or commercialized. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchard’s most recent annual or quarterly report filed with the U.S. Securities and Exchange Commission (SEC), as well as subsequent filings and reports filed with the SEC. The forward-looking statements contained in this press release reflect Orchard’s views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law. Contacts Investors Renee Leck Senior Director, Investor Relations +1 862-242-0764 Renee.Leck@orchard-tx.com Media Benjamin Navon Director, Corporate Communications +1 857-248-9454 Benjamin.Navon@orchard-tx.com

TOTUM•854 protects human cells of the vascular wall, particularly against inflammation and oxidative stress, which is key to preventing worsening of high blood pressure. TOTUM•854 also reduces angiotensin I-converting enzyme (ACE1) activity, one of the main modes of action known to reduce blood pressure. The bioavailability study also confirms the presence of 10 metabolites of interest in human serum after oral administration of 3.7 g of TOTUM•854, the daily clinical dose used in the Phase II/III INSIGHT clinical study. In line with the preclinical data, these very strong results confirm the potential of TOTUM•854 against mild to moderate high blood pressure in humans and provide strong prospects for late clinical development. With a view to marketing TOTUM•854, Valbiotis is targeting the signature of international partnerships and will market directly on the French market; the market for mild to moderate high blood pressure currently includes 123 million adults in the United States and Europe1. LA ROCHELLE, France--(BUSINESS WIRE)-- Regulatory News: Valbiotis (FR0013254851 – ALVAL, PEA / SME eligible) (Paris:ALVAL), a commercially oriented Research and Development company, with a commercial purpose, committed to scientific innovation for preventing and combating metabolic and cardiovascular diseases, announces positive results in the bioavailability and mode of action clinical study conducted on TOTUM•854 against high blood pressure, the number one cardiovascular risk factor worldwide. The mode of action results demonstrate a protective effect of TOTUM•854 on vascular wall cells and a reduction in angiotensin I-converting enzyme (ACE1) activity in humans. These robust data confirm the potential of TOTUM•854 to reduce blood pressure at the earliest stages of arterial hypertension, which affect 123 million people in the US and Europe1. They hold great promise for the late-stage clinical development of TOTUM•854. Pascal SIRVENT, Director of Discovery and Preclinical and Translational Research, member of the Executive Committee, comments: "These innovative bioavailability and mode of action studies once again demonstrate their scientific value for the development of our plant-based active substances. In line with our preclinical work, we can now confirm that TOTUM•854 preserves the integrity of the cells of the blood vessel wall, more specifically of its endothelium. Damage to the vascular wall is a major mechanism in the progression of high blood pressure. Moreover, we also discovered that this active substance acts on the angiotensin pathway, a well-known target of anti-hypertensive strategies. This first-in-human evidence confirms the relevance of TOTUM•854's positioning in the early stages of the disease and bodes well for the ongoing Phase II/III clinical efficacy studies in high blood pressure." TOTUM•854, a patented active substance based on a combination of plant extracts, is developed to reduce blood pressure in people with mild to moderate hypertension, a risk factor for cardiovascular disease. Mild to moderate arterial hypertension now affects 123 million adults in the United States and the 5 major European countries1. No non-drug product has strong clinical evidence or a specific health claim. TOTUM•854 is currently in the final phase of clinical development before being marketed. Valbiotis aims to sign one or more international commercial partnerships while it will market this active substance in France itself, in accordance with the strategy announced on October 7, 2022 (press release of October 7, 2022). TOTUM•854 will be marketed in two stages. The first step will be based on the recommendation by healthcare professionals, thanks to the Phase II/III results. In a second step, obtaining a proprietary health claim will strengthen the medical positioning of TOTUM•854, especially with patients/consumers. Enrollment in the first Phase II/III clinical trial (INSIGHT study) is expected to be completed by half-year 2023. Results of the bioavailability and mode of action clinical study on TOTUM•854 The TOTUM•854 bioavailability and mode of action clinical study, conducted in 10 healthy volunteers, first confirmed the presence of 10 metabolites of interest2, mainly polyphenolic compounds, in volunteers' serum3. These analyses were performed after taking 3.7 g of TOTUM•854 orally, the daily clinical dose also used in the Phase II/III INSIGHT clinical study. Ex vivo mode of action analyses then demonstrated a triple protective effect of these metabolites on human blood vessel wall cells (endothelial cells): increased resistance and viability of these cells to stress induced by excess lipids; strong protection against inflammatory processes, with a significant decrease in the production of pro-inflammatory agents such as interleukin 1-ß (IL1-ß) and in the expression of MCP-1 and VCAM-2 markers; protection against oxidative stress with a decrease in the concentration of free radicals and a reduced expression of the Nox2 enzyme. Mode of action tests also revealed a reduction in angiotensin I-converting enzyme (ACE1) activity, an enzyme well known in the pathophysiology of high blood pressure. This protective effect on the vascular wall in humans confirms the data already obtained in preclinical studies and presented at the annual meetings of the American Heart Association (AHA), the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) in 2022. Above all, it confirms the preventive positioning of TOTUM•854 in the early stages of high blood pressure. In the initial phases of the disease, when blood pressure rises, the vascular wall undergoes damage involving inflammation and oxidative stress. Ultimately, these changes lead to the narrowing of blood vessels: hypertension worsens, becomes chronic and requires long-term pharmacological treatment. Protection of the vascular wall is therefore a major challenge in the management of early high blood pressure, in order to prevent the progression of the condition. The innovative protocol of the TOTUM•854 bioavailability and mode of action clinical study The study was conducted on 10 healthy volunteers in an open-label setting and followed a protocol combining metabolomics and mode of action. Prof. Gisèle PICKERING, coordinator of the Clinical Investigation Center at Clermont-Ferrand University Hospital, was the principal investigator4. Metabolomic analysis consists of characterizing the metabolites of an active substance in serum, i.e., the molecules derived from this active substance after their intestinal absorption and their passage into the blood. After a single oral intake of 3.7 g of TOTUM•854, the daily clinical dose also used in the INSIGHT Phase II/III clinical study, analysis of the volunteers' serum confirmed the presence of 10 metabolites of interest, polyphenolic compounds mostly known to exert biological activity on metabolism. Kinetic measurements confirmed good bioavailability of these metabolites in serum within three hours after oral administration of TOTUM•854. In a second step, serum from volunteers was collected after oral intake of 3.7 g TOTUM•854. This serum rich in active metabolites was used to conduct in vitro mode of action tests on human umbilical vein endothelial cells (HUVECs), exposed to massive lipid intake, or lipotoxic stress, generating inflammation and oxidative stress. About Valbiotis Valbiotis is a commercially oriented Research & Development company, committed to scientific innovation for preventing and combating metabolic and cardiovascular diseases in response to unmet medical needs. Valbiotis has adopted an innovative approach, aiming to revolutionize healthcare by developing a new class of health nutrition products designed to reduce the risk of major metabolic diseases, relying on a multi-target strategy enabled by the use of plant-based terrestrial and marine resources. Internationally, its products are intended to be the subject of licensing or distribution agreements with global and regional health and nutrition players. In France, Valbiotis will be responsible for marketing its own products. Created at the beginning of 2014 in La Rochelle, the Company has forged numerous partnerships with leading academic centers. The Company has established three sites in France – Périgny, La Rochelle (17) and Riom (63) – and a subsidiary in Quebec City (Canada). Valbiotis is a member of the "BPI Excellence" network and has been recognized as an "Innovative Company" by the BPI label. Valbiotis has also been awarded "Young Innovative Company" status and has received major financial support from the European Union for its research programs via the European Regional Development Fund (ERDF). Valbiotis is a PEA-SME eligible company. For more information about Valbiotis, please visit: Name: Valbiotis ISIN code: FR0013254851 Ticker symbol: ALVAL EnterNext© PEA-PME 150 This press release contains forward-looking statements about Valbiotis’ objectives. Valbiotis considers that these projections are based on rational hypotheses and the information available to Valbiotis at the present time. However, in no way does this constitute a guarantee of future performance, and these projections may be affected by changes in economic conditions and financial markets, as well as certain risks and uncertainties, including those described in the Valbiotis Universal Registration Document filed to the French Financial Markets Regulator (AMF) on May 19, 2022, and completed by an amendment on November 8, 2022. This document is available on the Company’s website ( ). This press release and the information it contains do not constitute an offer to sell or subscribe, or a solicitation to purchase or subscribe to Valbiotis’ shares or financial securities in any country. 1Elevated LDL, pre-HTA and NAFL preliminary market estimation, AEC Partners, 2020. 2Molecules from TOTUM•854, after they have been absorbed from the intestine and passed into the bloodstream. 3The fraction of blood remaining after all blood cells (red blood cells, leukocytes, platelets) and fibrinogen (a protein involved in coagulation) have been removed. 4ID-RCB: 2021-A02695-36