Ganciclovir

- LIVTENCITY Is the First and Only Inhibitor of CMV-specific UL97 Protein Kinase Approved in China for the Treatment of Adults With Post-transplant CMV Infection/Disease Refractory* to Conventional Anti-CMV Treatment - Approval Based on Phase 3 TAK-620-303 SOLSTICE Study Demonstrating Maribavir Was Superior to Conventional Therapies at Week 8, for Primary Endpoint1 - CMV Is One of the Most Common and Serious Post-transplant Infections and Can Lead to Other Serious Infections, Loss of Transplanted Organ and Failure of Graft2,3 OSAKA, Japan & CAMBRIDGE, Massachusetts--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that LIVTENCITY® (maribavir) has been approved by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with post-hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet. LIVTENCITY is the first and only inhibitor of CMV-specific UL97 protein kinase in China for this indication. LIVTENCITY was granted Breakthrough Therapy Designation by China Center for Drug Evaluation (CDE) in 2021. “The approval of LIVTENCITY by the NMPA of China recognizes the critical need for post-transplant care and that CMV infection, when not successfully treated, can pose serious challenges to transplant recipients that can lead to complications such as increased organ rejection and hospitalization rates,” said Ramona Sequeira, president, Global Portfolio Division, Takeda. “This approval will help redefine the CMV treatment landscape for transplant patients in China and is a positive step forward toward addressing an unmet need for this community.” The NMPA approval is based on the results of the Phase 3 SOLSTICE trial, which evaluated the safety and efficacy of maribavir versus conventional antiviral therapies – ganciclovir, valganciclovir, cidofovir or foscarnet – for the treatment of patients with CMV infection/disease refractory* to prior therapies. In the SOLSTICE trial, LIVTENCITY was superior to conventional therapies at Week 8 for the primary endpoint of confirmed CMV viremia clearancea in post-transplant adults with refractory* CMV infection.1 The NMPA approval marks the 12th approval of LIVTENCITY around the world for post-transplant CMV refractory* to prior therapies, including four other major markets beyond China: the United States, Canada, Australia and the European Union.4-7 Out of the estimated 200,000 adult transplants per year globally, CMV is one of the most common infections experienced by transplant patients with an estimated incidence rate of 16%-56% in SOT and 30%-80% in HSCT recipients.8,9 About LIVTENCITY LIVTENCITY (maribavir), an orally bioavailable anti-CMV compound, is the first and only antiviral agent that targets and inhibits the UL97 protein kinase and thus its natural substrates.1 It is approved by the National Medical Products Administration (NMPA) of China for the treatment of adults with post-HSCT or SOT cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet. Product Name LIVTENCITY 200 mg film coated tablets. Generic Name Maribavir Posology and Administration LIVTENCITY should be initiated by a physician experienced in the management of patients who have undergone solid organ transplant or hematopoietic stem cell transplant. Posology: The recommended dose of LIVTENCITY is 400 mg (two 200 mg tablets) twice daily resulting in a daily dose of 800 mg for 8 weeks. Treatment duration may need to be individualized based on the clinical characteristics of each patient. Pediatric population: The safety and efficacy of LIVTENCITY in patients below 18 years of age have not been established. No data are available. Method of administration: Oral use. LIVTENCITY is intended for oral use only and can be taken with or without food. The film coated tablet can be taken as a whole tablet, a crushed tablet, or a crushed tablet through a nasogastric or orogastric tube. About Takeda’s SOLSTICE Trial The TAK-620-303 (SOLSTICE) trial (NCT02931539, EudraCT 2015-004725-13) was a global, multicenter, randomized, open-label, active-controlled superiority trial to assess the efficacy and safety of treatment with either maribavir or conventional antiviral therapy in 352 hematopoietic stem cell transplant and solid organ transplant recipients with CMV infection refractory* to one or a combination of the conventional antiviral therapies: ganciclovir, valganciclovir, foscarnet, or cidofovir. Adult patients underwent a 2-week screening period, followed by randomization 2:1 to maribavir (n=235) (400 mg, twice daily) or conventional antiviral therapies (n=117) (as dosed by the investigator) for up to 8 weeks. After completion of the treatment period, subjects entered a 12-week follow-up phase.1 The trial’s primary efficacy endpoint was confirmed CMV viremia clearance a at the end of Week 8. The key secondary endpoint was confirmed CMV viremia clearance and CMV infection symptom control† at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.1 About CMV CMV is a beta herpesvirus that commonly infects humans; serologic evidence of prior infection can be found in 40-100% of various adult populations.10 CMV typically resides latent and asymptomatic in the body but may reactivate during periods of immunosuppression. Serious disease may occur in individuals with compromised immune systems, which includes patients who receive immunosuppressants associated with various types of transplants including HSCT or SOT.8 Out of the estimated 200,000 adult transplants per year globally, CMV is one of the most common viral infections experienced by transplant recipients, with an estimated incidence rate between 16-56% in SOT recipients and 30-80% in HSCT recipients.8,9 In transplant recipients, reactivation of CMV can lead to serious consequences including graft loss and, in extreme cases, can be fatal.1,2 Existing therapies to treat post-transplant CMV infections may demonstrate serious side effects that require dose adjustments or may fail to adequately suppress viral replication.11 Additionally, existing therapies may require or prolong hospitalization due to administration.11,12 About Takeda Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit . LIVTENCITY Safety Information Contraindications Hypersensitivity to the active substance or to any of the excipients and co-administration with ganciclovir or valganciclovir. Special warnings and precautions for use Virologic failure can occur during and after treatment with LIVTENCITY. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. CMV DNA levels should be monitored, and resistance mutations should be investigated in patients who do not respond to treatment. Treatment should be discontinued if maribavir resistance mutations are detected. LIVTENCITY is not expected to be effective in treating CMV CNS infections (e.g. meningo encephalitis). LIVTENCITY has the potential to increase the concentrations of immunosuppressants that are cytochrome P450 (CYP)3A/P-gp substrates with narrow therapeutic margins (including tacrolimus, cyclosporine, sirolimus and everolimus). The plasma levels of these immunosuppressants must be frequently monitored throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY, and doses should be adjusted, as needed. The concomitant use of LIVTENCITY and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to: possible clinically significant adverse reactions from greater exposure of concomitant medicinal products. reduced therapeutic effect of LIVTENCITY. Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’. Pregnancy & Breast-feeding: LIVTENCITY is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast feeding should be discontinued during treatment with LIVTENCITY. Interactions If dose adjustments of concomitant medicinal products are made due to treatment with maribavir, doses should be readjusted after treatment with maribavir is completed. Effect of other medicinal products on maribavir: Co-administration of maribavir with strong cytochrome P450 3A (CYP3A) inducers rifampicin, rifabutin or St. John’s wort is not recommended. If co-administration of maribavir with other strong or moderate CYP3A inducers (e.g., carbamazepine, efavirenz, phenobarbital and phenytoin) cannot be avoided, the maribavir dose should be increased to 1 200 mg twice daily. No dose adjustment is needed when maribavir is co-administrated with CYP3A inhibitors. Effect of maribavir on other medicinal products: Co-administration of maribavir with valganciclovir and ganciclovir is contraindicated. Concomitant administration of maribavir and medicinal products that are sensitive substrates of CYP1A2 with a narrow therapeutic window (e.g., tizanidine and theophylline) should be avoided due to the risk for lack of efficacy of CYP1A2 substrates. When the immunosuppressants tacrolimus, cyclosporine, everolimus or sirolimus are co-administered with maribavir, immunosuppressant levels should be frequently monitored throughout treatment with maribavir, especially following initiation and after discontinuation of maribavir and dose adjusted, when needed. Caution should be exercised when maribavir and sensitive P-gp substrates (e.g., digoxin, dabigatran) are co administered. Serum digoxin concentrations should be monitored, and dose of digoxin may need to be reduced, as needed. Co-administration of maribavir with sensitive BCRP substrates such as rosuvastatin, is expected to increase their exposure and lead to undesirable effects. Adverse Reactions Very common (≥1/10) Taste disturbance, Diarrhea, Nausea, Vomiting, Fatigue Common (≥1/100 to <1/10) Headache, Abdominal pain upper, Decreased appetite, Immunosuppressant drug level increased, Weight decreased The most commonly reported serious adverse reactions were diarrhea (2%) and nausea, weight decreased, fatigue, immunosuppressant drug concentration level increased, and vomiting (all occurring at >1%). Please consult the LIVTENCITY (maribavir) approved label before prescribing, particularly in relation to dosing and treatment monitoring. For the European Union, please consult the Summary of Products Characteristics (SmPC). For China, please consult the LIVTENCITY China Package Leaflet. For full U.S. Prescribing Information, including the approved indication and important safety information, please visit: Important Notice For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws. The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies. Forward-Looking Statements This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: or at . Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results. Medical information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. * Including a subgroup with genotypic resistance to conventional therapies. a Defined as confirmed CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <137 IU/mL) in two consecutive samples separated by at least five days. † CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline. References Avery R, Alain S, Alexander BD, et al. SOLSTICE Trial Investigators. Maribavir for refractory cytomegalovirus infections with or without resistance post-transplant: results from a phase 3 randomized clinical trial. Clin Infect Dis. 2022;75(4):690–701. doi:10.1093/cid/ciab988 Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infection & Chemotherapy. 2013;45(3):260 Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10(4):233-238. doi:10.1016/j.hemonc.2017.05.001 Takeda. Health Canada approves Takeda’s LIVTENCITYTM (maribavir) the first and only treatment for adults with post-transplant cytomegalovirus (CMV) infection. Published September 20, 2022. Accessed December 12, 2023. Takeda. Takeda’s LIVTENCITY (maribavir) approved by U.S. FDA as the first and only treatment for people ages 12 and older with post-transplant cytomegalovirus (CMV), refractory (with or without genotypic resistance) to conventional antiviral therapies. Published November 23, 2021. Accessed December 12, 2023. Therapeutic Goods Administration (TGA). LIVTENCITY maribavir 200 mg film coated tablet bottle (380132) [Australian product information]. Therapeutic Goods Administration (TGA). Published October 8, 2022. Takeda. European Commission (EC) approves LIVTENCITY (maribavir) for the treatment of adults with post-transplant cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies. Published November 11, 2022. Accessed December 12, 2023. Azevedo LS, Pierrotti LC, Abdala E, et al. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paolo). 2015;70(7):515-523. doi:10.6061/clinics/2015(07)09 Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther. 2018;(7):1-16. doi:10.1007/s40121-017-0180-z de la Hoz RE, Stephanie G, Sherlock C. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol. 2002;25(Suppl 1):S1-S12. doi:10.1016/s1386-6532(02)00091-4 Chemaly RF, Chou S, Einsele H, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019;68(8):1420-1426. doi:10.1093/cid/ciy696 Martín-Gandul C, Pérez-Romero P, González-Roncero FM, et al. Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. J Infect. 2014;69(5):500-6. doi:10.1016/j.jinf.2014.07.001

Strong R&D progress & attractive commercial deals, including additional Tranexamic Acid RTU out-licensing dealsPotential U.S. market approval for Maxigesic® IV in H2 2023Promising new product candidates driving innovation and on track for a planned acceleration towards a portfolio of 30 assets before 2025Revenues of €3 million, net loss decreased to €10.8 million with increased R&D expenses€43 million in cash & cash equivalents, no financial debtWebcast at 1PM GMT / 2PM CET/ 9AM EST (register here) Liège, Belgium - REGULATED INFORMATION – 15 March 2023 – 7PM CET – Hyloris Pharmaceuticals SA (Euronext Brussels: HYL), a specialty biopharma company committed to addressing unmet medical needs through reinventing existing medications, today announces its financial and operational results for the year ending on 31 December 2022, as well as its business outlook for 2023 and beyond. Stijn Van Rompay, chief executive officer of Hyloris, commented: “Our strategy is as successful as it is unique, and 2022 and early 2023 has proven this once again. In an exceptionally difficult year for both the financial markets and the healthcare sector, we successfully raised €15 million and announced HY-083, a product candidate targeting idiopathic rhinitis. This was followed in early 2023 by the in-licensing of a product candidate targeting hypophosphatemia. Other pipeline assets progressed at a rapid pace and are well underway to providing real solutions to unmet medical needs in the upcoming years.” “Several clinical trials will be conducted over the course of 2023 and our team is paving the way to a market authorization for Maxigesic® IV in the U.S. before year-end,” Van Rompay continued. “Our headcount grew from 21 at the end of 2021 to 39 today, nearly doubling in size and adding tremendous amounts of expertise throughout our business. Thanks to proactive cost and cash management and sufficient cash to support the current portfolio, Hyloris is geared for an acceleration of its strategy with an increased focus on repurposed products bringing more value to underserved patient populations and Hyloris shareholders. We reviewed around 200 opportunities in 2022 and aim to grow the portfolio to 30 product candidates and marketed products before 2025. I am excited about the opportunities we are currently evaluating and eager to disclose new deals to our shareholders in the near future.” New product candidates added to the pipeline HY-083 was announced in November 2022. This novel, proprietary formulation will be administered intranasally to treat idiopathic rhinitis. Idiopathic rhinitis is a medical disorder characterized by a nasal symptoms that resemble nasal allergies and hay fever (allergic rhinitis) but are not related to a known cause like allergens or infectious triggers. Idiopathic rhinitis features an overexpression of TRPV1-receptors in the nasal mucosa giving rise to nasal obstruction (a stuffy nose), rhinorrhea (a runny nose) and sneezing, chronically affecting quality of life in patients. Our product candidate aims to activate and depolarize these receptors in the nose. An estimated 7% of the world population is affected by idiopathic rhinitis, representing an estimated 19 million people in the U.S. alone. 13% of them have moderate to severe idiopathic rhinitis, leading them to actively seek out specialist care. Hyloris seeks to offer a new, unique, safe and approved targeted therapy treatment option. HY-088 was announced in January 2023, the Company in-licensed the technology to develop development of an oral liquid targeting hypophosphatemia, a mineral deficiency in the blood. In severe forms, this condition can be life threatening. The condition can result in muscle and bone weakness, respiratory or heart failure, seizures or coma amongst others. There is a wide range of underlying conditions leading to hypophosphatemia which could be hereditary (such as X-linked hypophosphatemia, hypophosphatemic rickets, osteomalacia, Cushing syndrome) or acquired (anorexia nervosa, recovery phase of diabetes-related ketoacidosis, alcohol withdrawal, respiratory alkalosis, long term use of diuretic and phosphate binders). Chronic hypophosphatemia can become life threatening, making direct treatment of the hypophosphatemia desirable in cases where treating the underlying condition does not solve the mineral deficiency. It is estimated hypophosphatemia affects around 5% of hospitalized patients, and a subpopulation needs direct treatment during and/or after their hospital stay. Treatment protocols for patients deficient in phosphate are well-established and have proven useful in other situations of bone mineral imbalance. Oral administration is the preferred way of treating hypophosphatemia, although in most countries no approved drugs exist. Currently, physicians mostly rely on compounded drugs which have, by definition, not been submitted for regulatory scrutiny regarding safety, efficacy, and quality. Further commercial roll-out Maxigesic® IV, a unique combination of paracetamol and ibuprofen used for post-operative non-opioid pain management, is currently licensed to partners covering over 100 countries across the globe. During 2022 and early 2023: A Complete Response Letter from the United States Food and Drug Administration (FDA) was received, stating that it was unable to complete its review, requesting additional information relating to potential leachable and extractable compounds expected to be present in the drug product based on the drug product packaging. Importantly, the agency did not report any issues related to the data generated during the clinical development program.Hyloris and its partners believe to be able to address the recommendations made and resubmit Maxigesic® IV before the summer of 2023 with a potential New Drug Application (NDA) approval by the end of 2023. The non-opioid analgesic space and the market for post-operative pain is growing rapidly and is forecasted to reach $1.7 billion in 2028 in the U.S., up from $745 million in 2019.1Submissions were made in 15 countries in Asia, Africa and Latin America, including large pharmaceutical markets such as Canada and Mexico.Marketing authorizations have been granted in several countries including Italy, Norway, Indonesia, The Netherlands, Finland, Singapore and Hong Kong.Launches occurred in 7 countries including Denmark, Sweden, Finland, Norway and The Netherlands. Imminent launches are expected in several additional countries, bringing the total number of countries where Maxigesic® IV will be available up to more than 20.4 U.S. patents were granted to Hyloris, ranging in expiry between 2035 and 2039. Sotalol IV is a novel, intravenous, patented, IV formulation of Sotalol for the treatment of atrial fibrillation and life-threatening ventricular arrhythmias developed for the U.S. market. In 2022 further commercial efforts were made to accelerate commercial roll-out, inclusion in hospital drug formularies and clinical education of hospital staff. Other commercial highlights Tranexamic Acid RTU Out-licensing agreements were signed in early 2023, covering an important European country and a major Southeast Asian country, with a combined population of over 60 million people. Earlier agreements have been signed in 2021 for Australia, New-Zealand and Canada. In doing so, the Company confirms its strategy to out-license near the end of the product development and to prioritize downstream revenue of the product candidates over upfront milestone payments. Regulatory submission in the partnered territories is expected within 2023, and additional out-licensing agreements are expected, going forward. Thomas Jacobsen, chief business development officer of Hyloris, commented: “Thanks to recent out-licensing deals, the previously untapped global potential of tranexamic acid RTU was brought further into view. We now believe the future sales volume for tranexamic acid RTU outside of the United States could outpace the future sales volume within the U.S.” Tranexamic acid RTU is an antifibrinolytic drug. By inhibiting the fibrinolysis, tranexamic acid promotes the formation of blood clots HY-038 In December 2022, the Company out-licensed HY-038, a generic and non-core asset for an out-licensing fee of €1 million. In doing so, Hyloris highlighted its increased focus on repurposed product candidates which offer a bigger difference in patient outcomes, as well as a higher expected return on investment. Cardiovascular portfolio in Q4 of 2022, Hyloris and its development partner API renegotiated specific commercial agreements. As a consequence, no further royalties are payable on Sotalol IV to API, except if the in-market net product sales exceed USD 100 million. As part of renegotiation of commercial terms, the Company made prepayments of expected future royalties amounting to $0.7 million. R&D update In 2022, R&D activities have progressed on all fronts, bringing our range of 14 product candidates and 3 high-barrier generic products closer to market in different ways, following in the footsteps of 2 products which are already marketed today. Some development timelines were impacted by the Covid19-pandemic and the required transfer of manufacturing activities to alternative third-party manufacturers. Multiple discussions are being held with regulatory agencies and partners to confirm and validate development plans. A new and improved R&D lab is under construction at Légiapark in Liège (Belgium), where our head office moved after the summer of 2022. This will allow the Company to perform drug formulation and analytical activities in-house for its growing pipeline, further streamlining processes and more effectively deploying internal resources. Cardiovascular portfolio In its entirety, the cardiovascular portfolio covers a broad range of indications in the biggest therapeutic segment globally. With products advancing through or towards the clinical study phase, Hyloris expects to make impactful differences in patients’ lives. Main highlights for 2022 and expected milestones for 2023 include: Aspirin IV: The clinical phase of the study assessing the pharmacokinetics has been completed in 2022. Preliminary data has shown faster onset and good tolerability of Aspirin IV with more analytical work required. An additional clinical study is under preparation.A strategic review led to a change in the contract manufacturing organisation (CMO) for the manufacture of registration batches for the New Drug Application (NDA).Aspirin IV is an intravenous (IV) formulation of acetylsalicylic acid (ASA). Aspirin is not available in the U.S. as an IV product. Milrinone: Hyloris has contracted a CDMO for development and manufacturing. A successful Type C meeting with the FDA was concluded, confirming development plans for a novel, extended-release formulation offering convenient oral dosing for a selected population of end-stage heart failure (HF) patients. HY-074: The FDA has confirmed the development of the proposed formulation can be pursued. Hyloris is preparing for the manufacturing of validation and registration batches. Non-clinical work is expected to finish before H2 of 2023. HY-074 is an intravenous formulation of current standard of care treatment for acute coronary syndrome (ACS) to offer faster onset of action (and thereby potentially reducing the risk of death), more convenient administration (more notably in patients who are nauseated or unconscious), and dosage control. It is currently available in oral form, which should allow for an optimal switching strategy from the oral form to an IV. Dofetilide IV: Both formulation development and non-clinical studies have been successfully completed. A new CMO was contracted to ensure reliable development and supply, hereby incurring a delay as a consequence of the transfer. Other Value-Added Programs Our added-value programs are progressing well. Several discussions are ongoing with regulatory agencies to confirm and validate development plans. Main highlights for 2022 and expected milestones for 2023 include: Tranexamic Acid Oral Mouth Rinse (previously HY-004): Positive Phase 1-results showed that HY-004 was found to be well-tolerated under varied conditions with no serious adverse events following tooth extraction. Hyloris also plans to investigate its use for broader related indications in patients undergoing oral surgical procedures with or without bleeding disorders that would benefit from a locally acting antifibrinolytic agent. Recruitment for a Phase 3 study will have started before H2 of 2023. Miconazole/Domiphen Bromide: Recruitment for the phase 2 clinical trial is completed and last patient last visit (LPLV) will have occurred by Q2 2023. The results of this Phase 2 study will guide the Company for the preparation and design of the next clinical trial. Hyloris is co-funding the development of Miconazole/Domiphen Bromide, a topical synergistic combination treatment for Recurrent Vulvovaginal Candidiasis (rVVC), a chronic and debilitating vaginal infection commonly caused by the yeast Candida albicans. This condition affects nearly 10% of women during their lifetime. MCZ/DB has a strong scientific and business rationale. AlenuraTM: Multiple clinical trials are expected to start throughout 2023, including a four-arm Phase 2, prospective, randomized, double-blind, placebo-controlled, multi-center, single-dose, pharmacodynamic study comparing AlenuraTM to its 2 individual components (alkalinized lidocaine and heparin) as well as placebo. AlenuraTM, is a first-line drug treatment for acute pain in interstitial cystitis/bladder pain syndrome (IC/BPS), a condition affecting at least 6 million people in the U.S. AlenuraTM is a patented, innovative, clinical-stage bladder instillation product candidate that combines lidocaine in a new alkalinized form with heparin. Thanks to the novel dual mode-of-action, AlenuraTM has the unique potential to i) immediately relieve pain, and ii) augment the mucous inner layer of the bladder wall. Plecoid Agents: The definition of the preferred formulation has progressed significantly in anticipation of clinical trials. These chelating agents could improve the effectiveness of existing chemotherapy in patients with acute myeloid leukemia (AML) and small cell lung cancer (SCLC). Previous studies suggested that elevated levels of toxic metals are associated with inferior survival in patients with AML (160.000 patients globally). Atomoxetine oral liquid: An innovative taste masking strategy was deployed, targeting a preferred taste for young patients, following FDA feedback. Atomoxetine is used primarily for the treatment of patients with attention deficit hyperactivity disorder (ADHD). This product candidate allows for improved dosing (as patient specific dosing is also in part based on body weight) and convenience. Other oral liquid products in this therapeutic segment have captured significant market share in competition with oral solids, underlining the need for a (novel) oral liquid formulation of Atomoxetine. HY-029: A successful pilot study demonstrating bioequivalence was completed in 2022. A pivotal study can be expected to start in H2 of 2023. Industrial batch manufacturing has been conducted to demonstrate pharmaceutical quality of the medicinal product and robustness of the manufacturing process. HY-029 is a liquid formulation of an existing antiviral drug that is currently only available in oral solid form. Management & Board changes Both the C-level executives and all board members remained in their respective positions, providing continuity in the company's leadership. Business Outlook With 16 reformulated and repurposed molecules, and 3 high-barrier generics, several clinical trials are expected to start and/or finish within 2023. The Company aims to accelerate growth of the product pipeline, with the end goal of reaching 30 product candidates before 2025. Assuming continued strategic out-licensing, commercial success for Maxigesic® IV and Sotalol IV, additional non-dilutive funding and milestone payments, the Company believes it is sufficiently capitalized to execute the full development of the current pipeline assets (14 product candidates, 3 generics and 2 commercial products). Webcast details The Company will host a webcast conducted in English to present its 2022 annual results and 2023 Business Outlook, followed by a live Q&A session. The webcast will start on March 16th 2023 at 2PM CET / 1PM GMT / 9AM EST. To join the webcast, please register at Hyloris.com/webcast FINANCIAL HIGHLIGHTS 2022 Year ended 31 December (in € thousand) 2022 2021 Variance Revenues 2.951 3.096 -4,7% Cost of sales (94) (107) Research and development expenses (10,151) (5,056) 100,8% General and administration expenses (3,517) (2,900) 21,3% Shares’ issuance related expenses - - Earnings/losses from Associates and joint ventures (130) (191) -31,9% Other operating result 303 (5,381) Operating result (10,638) (10,541) 0,9% Net financial result (127) (741) -82,9% Income Taxes (4) (297) -98,7% Result for the period (10,770) (11,579) -7,0% Net operating cash flow (13,154) (11,250) 16,9% Cash and cash equivalents 43,457 50,012 -13,1% Financial Review 2022 Income statementIn 2022, total revenues remained stable around €3 million, driven by increased royalties received for Maxigesic® IV and Sotalol IV, the out-licensing agreement of €1 million for HY-038 with QliniQ, IP and regulatory services rendered to development partners.In 2021, most revenue was comprised of one-time milestone payment (€1.8 million) related to Maxigesic® IV. Research and development expenses increased to €10.15 million in 2022 versus €5.06 million in 2021, in line with several product candidates maturing from early to late-stage development, as well as the expansion of the number of product candidates and increased headcount of the research and development team. Total general and administrative expenses amounted to €3.52 million versus €2.90 million last year and is mainly explained by additional communication and legal/HR costs. The company remains focus on strong cost and cash management. As a result, Hyloris closed 2022 with an operating loss of €10.64 million. This was mainly driven by increased R&D expenses for supporting the development of the portfolio. The net financial loss in 2022 was €0.13 million. Financial income amounted to €0.47 million, comprising mostly a net currency gain of €0.40 million and interest received on deposits of €0.07 million, versus €0.03 million last year. Financial expenses amounted to €0.59 million versus €0.77 million in 2021 and comprised mostly the impact of the interest rates renegotiation of the shareholder loans, bank interest expenses, currency losses and bank fees. In 2022, Hyloris successfully renegotiated the terms of the shareholder loans, resulting in lower interest rates. As a result, net losses in 2022 decreased to €10.77 million versus €11.58 million in 2021. Statement of financial position The Company’s non-current assets mainly consist of (1) investments in joint ventures of € 3.9 million at year-end 2022, (2) intangible assets of €3.6 million at year-end 2022 including capitalized development, purchased assets and in-licensing costs, versus €2.94 million in 2021, (3) the conversion of the loan to Pleco into shares of €1.0 million, (4) a prepayment of future royalties to API of $0.7 million and (5) a tax credit. Hyloris does not capitalize research and development expenses until the filing for a marketing authorization for the applicable product candidate. Research and development expenditures incurred during the period were accounted for as operating expenses. When an intangible asset is acquired and capitalized, the amortization begins when the asset is available for commercialization. The Company’s current assets mainly consist of €43.46 million in cash and cash equivalents on total assets of €61.86 million, and trade and other receivables of €5.13 million which mainly consist of services rendered to partners, milestones from AFT related to Maxigesic and out-licensing revenue (€1.0 million) from Qliniq. In 2022, Hyloris raised an amount of €15 million in gross proceeds via an accelerated bookbuild, offering 967,742 new shares, the capital and share premium increased with respectively €6 thousand and €2.83 million through the exercise of 1,200,000 outstanding transactions warrants leading to company’s equity amounted to €55.04 million. By year-end all shareholder loans were repaid, making the Company free of any financial debt on 31 December 2022. The same shareholders expressed their conditional willingness to support the Company with a renewed shareholder loan in the future if needed. Cash flow statementNet cash outflow from operating activities was €13.15 million in 2022, compared to €11.25 million in 2021. As part of renegotiation of commercial terms, the Company made prepayments of expected future royalties amounting to $0.7 million to API. Net cash outflow from investing activities was €1.24 million in 2022, compared to €3.08 million in 2021, and mainly related to investments in joint ventures, capital expenditure and capitalization of development expenses. The financing activities amounted to a net cash inflow of €7.84 million in 2022 compared to a net cash outflow of €0.06 million in 2021 mainly driven by the net proceeds from the private placement via an accelerated bookbuild for net proceeds of €14.34 million, proceeds from the execution of transaction warrants for €2.83 million and the reimbursement of the shareholder loans for €9.28 million including accumulated interest. Consequently, the cash and cash equivalents amounted to €43.46 million end of 2022 versus €50.01 million at the end of 2021. CONSOLIDATED STATEMENT OF FINANCIAL POSITION FOR THE YEAR ENDED DECEMBER 31 ASSETS (in thousands of euros) 31-Dec-22 31-Dec-21 Non-current assets 11,063 9,485 Intangible assets 3,607 2,944 Property, plant and equipment 176 122 Right-of-use assets 885 173 Equity accounted investments 3,948 4,079 Other investment, including derivatives 1.000 453 Trade and other receivables 1.447 1.714 Current assets 50,801 53,959 Trade and other receivables 5,127 2,321 Other investment, including derivatives 469 528 Prepayments 1,748 1,098 Cash and cash equivalents 43,457 50,012 TOTAL ASSETS 61,863 63,444 EQUITY AND LIABILITIES(in thousands of euros) 31-Dec-22 31-Dec-21 Equity 55.045 48.056 Share capital 140 129 Share premium 121,513 103,693 Retained earnings (53,476) (43,226) Result of the period (10,770) (11,579) Share based payment 1.621 2.391 Cost of Capital (4,460) (3,827) Other reserves 476 476 Non-current liabilities 1.047 409 Borrowings 747 109 Other financial liabilities 300 300 Current liabilities 5,772 14,978 Borrowings 138 65 Other financial liabilities 3,212 11,815 Trade and other liabilities 2,422 2,749 Current tax liabilities - 349 TOTAL EQUITY AND LIABILITIES 61,863 63,444 CONSOLIDATED STATEMENT OF PROFIT OR LOSS AND OTHER COMPREHENSIVE INCOME FOR THE YEAR ENDED DECEMBER 31 in € thousands 2022 2021 Revenue 2,951 3,096 Cost of sales (94) (107) Gross profit 2,857 2,988 Research and development expenses (10,151) (5,056) Selling, general and administrative expenses (3,517) (29) Share of result of equity-accounted investees, net of tax (130) (191) Other operating income 315 389 Other operating expenses (12) (5.770) Operating profit/(loss) (EBIT) (10,638) (10,541) Financial income 466 32 Financial expenses (594) (773) Profit/(loss) before taxes (10,766) (11,282) Income taxes (4) (297) PROFIT/(LOSS) FOR THE PERIOD (10,770) (11,579) CONSOLIDATED STATEMENT OF CHANGES IN EQUITY FOR THE YEAR ENDED DECEMBER 31 (in thousands of euros) Attributable to equity holders of the Company Total Equity Share capital Share premium Other reserves Retained earnings Share-based payment reserve Cost of Capital Other reserves Balance at December 31, 2021 129 103,693 2,391 (3,827) 476 (54,805) 48,056 Private Placement Via an Accelerated Bookbuild Offering 5 14,995 (634) 14,366 Equity Transaction via Transaction Warrants 6 2,826 (1,329) 1,329 2,832 Share-based payments 560 560 Total comprehensive income (10,770) (10,770) Balance at December 31, 2022 140 121,513 1,622 (4,460) 476 (64,246) 55,045 CONSOLIDATED STATEMENT OF CASH FLOWS FOR THE YEAR ENDED DECEMBER 31 in € thousands 2022 2021 CASH FLOW FROM OPERATING ACTIVITIES Net result (10,770) (11,579) Adjustments to reconcile net loss to net cash provided by operating activities: Depreciation, amortisation and impairments 196 137 Share-based payment expense 560 576 Derivatives financial instruments 52 - R&D Tax Credit (315) - Interest expenses on shareholders loans 164 - Loss on drecognition of shareholders loans 486 198 Equity transaction costs 29 - Losses from Associates and joint ventures 130 191 Losses on disposal of PPE 16 Other non-cash adjustments 16 (1) Changes in working capital: Trade and other receivables (2,230) (2,068) Other investment, including derivatives (27) (1,627) Prepayments (650) 856 Trade and Other liabilities (468) Other current and non-current liabilities - 2.063 Cash generated from operations (12,812) (11,253) Interest paid 7 3 Income Taxes paid (349) Net cash generated from operating activities (13,154) (11,250) CASH FLOW FROM INVESTING ACTIVITIES Purchases of property, plant and equipment (101) (107) Purchases of Intangible assets (638) (954) Proceeds from disposal of intangible assets - 219 Acquisition of Other Investments (500) (21) Investments in associates and joint ventures - (1,270) Repayment received from other financial assets - 216 Payment of other financial assets - (1,157) Discontinued operations Net cash provided by/(used in) investing activities (1,239) (3,075) CASH FLOW FROM FINANCING ACTIVITIES Reimbursements of borrowings and other financial liabilities (7,376) Reimbursements of lease liabilities (79) (62) Proceeds from other non-current liabilities 0 - Proceeds from Private Placement via ABB 14,337 - Proceeds from Execution Transactions Warrants 2,832 - Interests paid (1,877) - Net cash provided by/(used in) financing activities 7,838 (62) NET INCREASE (DECREASE) IN CASH AND CASH EQUIVALENTS (6,555) (14,387) CASH AND CASH EQUIVALENTS at beginning of year 50,012 64,399 CASH AND CASH EQUIVALENTS at end of year, calculated 43,457 50,012 Audit ReportThe statutory auditor, KPMG Bedrijfsrevisoren - Réviseurs d’Entreprises, represented by Olivier Declercq, has confirmed that the audit procedures, which have been substantially completed, have not revealed any material misstatement in the accounting information included in the Company’s annual announcement. About Hyloris Pharmaceuticals SA Hyloris is a specialty biopharma company focused on innovating, reinventing, and optimising existing medications to address important healthcare needs and deliver relevant improvements for patients, healthcare professionals and payors. Hyloris has built a broad, patented portfolio of 16 reformulated and repurposed value-added medicines that have the potential to offer significant advantages over available alternatives. Outside of its core strategic focus, the Company also has 3 high barrier generic products in development and registration phase. Two products are currently in initial phases of commercialisation with partners: Sotalol IV for the treatment of atrial fibrillation, and Maxigesic® IV, a non-opioid post-operative pain treatment. The Company’s development strategy primarily focuses on the FDA’s 505(b)2 regulatory pathway, which is specifically designed for pharmaceuticals for which safety and efficacy of the molecule have already been established. This pathway can reduce the clinical burden required to bring a product to market, and significantly shorten the development timelines and reduce costs and risks. Hyloris is based in Liège, Belgium. For more information, visit https://hyloris.com/ and follow us on LinkedIn. For more information, contact Hyloris Pharmaceuticals:Stijn Van Rompay, CEOstijn.vanrompay@hyloris.com+32 (0)4 346 02 07Jean-Luc Vandebroek, CFOjean-luc.vandebroek@hyloris.com+32 (0)478 27 68 42Sven Watthy, Investor Relations & Communications managerSven.watthy@hyloris.com+32 (0)499 71 15 29 Disclaimer and forward-looking statements Hyloris means “high yield, lower risk”, which relates to the 505(b)(2) regulatory pathway for product approval on which the Company focuses, but in no way relates or applies to an investment in the Shares. Certain statements in this press release are “forward-looking statements.” These forward-looking statements can be identified using forward-looking terminology, including the words "believes", "estimates," "anticipates", "expects", "intends", "may", "will", "plans", "continue", "ongoing", "potential", "predict", "project", "target", "seek" or "should", and include statements the Company makes concerning the intended results of its strategy. These statements relate to future events or the Company’s future financial performance and involve known and unknown risks, uncertainties, and other factors, many of which are beyond the Company’s control, that may cause the actual results, levels of activity, performance or achievements of the Company or its industry to be materially different from those expressed or implied by any forward-looking statements. The Company undertakes no obligation to publicly update or revise forward-looking statements, except as may be required by law. 1 DelveInsight Market Research Report (2020) Attachment PR Annual Results FY22 FINAL