Leishmaniasis

Scientists have discovered the specific enzyme that a species of sandfly uses to produce a pheromone attractant, which could lead to the creation of targeted traps to control them and reduce the spread of the potentially fatal disease, Leishmaniasis. Scientists have discovered the specific enzyme that a species of sandfly uses to produce a pheromone attractant, which could lead to the creation of targeted traps to control them and reduce the spread of the potentially fatal disease, Leishmaniasis. The team from the University of Nottingham's School of Chemistry analysed the genome of the Lutzomyia longipalpis, a species of sandfly native to Brazil and South America that can spread a disease called Leishmaniasis. The study identified the enzyme, called a Terpene Synthase that is responsible for making the terpene pheromone sobralene, that the insect uses to attract others for mating, a discovery that could lead to the development of commercial traps for targeting and controlling this type of sandfly. The research has been published today in PNAS. Over 90 sandfly species are known to transmit Leishmania parasites that are spread to humans through being bitten, but Lutzomyia longipalpis is themajor carrier of the disease in South America. The most common symptoms of the disease are skin ulcers and lesions which can leave life-long scars, in more serious cases people can become very unwell with fever, weight loss, enlargement of the spleen and liver, and anaemia. The most serious form of the disease, known as visceral leishmaniasis, is invariably fatal within 2-years if untreated. Most cases of visceral leishmaniasis occur in Brazil, but the disease can be found in large parts of the tropics and subtropics. Terpenes are widely used in nature for chemical communication, but understanding how these structurally diverse natural products are produced by insects is only now beginning to emerge. Males of the sandfly, Lutzomyia longipalpis, use terpene pheromones to lure females and other males to mating sites. Terpene synthases are responsible for the biosynthesis of many chemicals used by plants and microorganisms for defense and communication. This research identifies the first insect terpene synthase (TPS) from the insect Lutzomyia. It offers the potential for sustainable production of this compound through biocatalysis. Professor Neil Oldham from the University of Nottingham's School of Chemistry led the study, he said: "Finding this enzyme has been very difficult and we have been hunting for it for over 2 years., The Lutzomyia genome contains an unusually high number of candidate terpene synthase genes, but thanks to the persistence of Dr Charlie Ducker, a talented researcher on the team, we were able to find the one that makes the pheromone." "The beauty of the pheromone approach is that it is very specific for this insect and so the next stage of the project will be to engineer microorganisms to make the enzyme in a way that would produce the pheromone. If we can then find a way to scale this up for commercial use this would be a way to control the populations of these insects and hopefully reduce the spread of Leishmaniasis."

FDA approved LIKMEZ™ (ATI-1501) for Metronidazole Oral Suspension 500mg/5mL Additional USAFA funding commitment from the U.S. Air Force Academy, intended to advance the ATI-1701 program toward an IND submission to the FDA Engaging regulatory authorities to align on ATI-1801 development plans HALIFAX, Nova Scotia, Feb. 13, 2024 (GLOBE NEWSWIRE) -- Appili Therapeutics Inc. (TSX:APLI; OTCPink: APLIF) (the “Company” or “Appili”), a biopharmaceutical company focused on drug development for infectious diseases and biodefense products, today announced its financial and operational results for the third quarter of its fiscal year 2024, which ended on December 31, 2023. All figures are stated in Canadian dollars unless otherwise stated. In recent months, we've achieved significant milestones by solidifying ATI-1701 government partnerships, engaging regulatory authorities for ATI-1801, and bringing our most advanced innovative asset, LIKMEZ™ (ATI-1501) to market through our partner. Beginning 2024, Appili’s skilled team stands with a clear vision, and committed funding enabling us to execute on our infectious disease program priorities, said Don Cilla, Pharm.D., M.B.A., President and Chief Executive Officer of Appili. “Additionally, the issuance of the patent claims for ATI-1701, shortly after receiving an additional funding commitment from USAFA, strengthens the programs position in biodefense and the new methods are expected to allow Appili to further develop a valuable vaccine that is urgently needed on the market”. Operational Highlights LIKMEZ™ ATI-1501: FDA Approved Product, In September 2023, Appili announced the FDA approval of LIKMEZ™ (ATI-1501), our proprietary taste-masked liquid suspension reformulation of metronidazole, through our U.S. partner, Saptalis Pharmaceuticals LLC. LIKMEZ is the first and only FDA approved ready-made suspension of metronidazole for the treatment of antimicrobial infections that addresses the unmet need in patients with dysphagia to avoid risks associated with drug compounding, and discontinuation related anti-microbial resistance. Saptalis launched LIKMEZ in November 2023 and commercial sales in the United States are ongoing. The FDA approval of LIKMEZ, shortly after securing patent coverage through 2039, is an important milestone that demonstrates Appili’s ability to identify promising opportunities and develop and monetize them for the benefit of both patients and shareholders. Collaborating with Saptalis, Appili earned US$600,000 in milestone payments in fiscal 2024. Appili expects to receive sales-based milestone payments and royalties from Saptalis based on sale of the product. ATI-1701, our Biodefense Vaccine Candidate with Strong Government Support ATI-1701 is a novel, live-attenuated vaccine for the prevention of F. Tularensis, has received awards totaling US$14 million from the U.S. Air Force Academy (“USAFA”). Under the terms of the USAFA Cooperative Agreement, Appili oversees a comprehensive development program for ATI-1701, which includes nonclinical studies, CMC/manufacturing, clinical preparatory, and regulatory activities to support an IND submission in 2025. Appili was granted a pre-IND meeting with the FDA to discuss ATI-1701’s regulatory, CMC, toxicology, and Phase 1 strategies and expects to receive feedback in early 2024. ATI-1801, our Licensed Topical Antiparasitic Product ATI-1801 is a novel topical formulation of paromomycin (15% w/w) under advanced clinical development for the treatment of cutaneous leishmaniasis, a disfiguring infection of the skin that affects hundreds of thousands of people around the world annually. In January 2024, Appili requested a meeting with the FDA to discuss the previously generated Phase 3 data and agree on the necessary registration package to support a New Drug Application submission, which the Company expects will include available nonclinical, manufacturing, and clinical data generated to date. Annual Financial Results The Company prepares its financial statements in accordance with IFRS as issued by the International Accounting Standard Board and Part I of Chartered Professional Accountants of Canada Handbook–Accounting. All figures are stated in Canadian dollars unless otherwise stated. The net loss and comprehensive loss of $0.2 million or $0.00 loss per share for the three months ended December 31, 2023, was $2.4 million lower than the net loss and comprehensive loss of $2.6 million or $0.02 loss per share during the three months ended December 31, 2022. This relates mainly to an increase in milestone revenue of $0.5 million, an increase in government assistance of $2.0 million and a decrease in general and administrative expenses of $0.9 million. These decreases were offset by an increase in research and development expenses of $0.9 million and an increase in financing costs of $0.2 million. As of December 31, 2023, the Company had cash of $0.6 million, compared to $2.5 million on March 31, 2023. As of February 13, 2024, the Company had 121,266,120 issued and outstanding Common Shares, 7,957,000 stock options, and 44,856,874 warrants outstanding. This press release should be read in conjunction with the Company’s unaudited interim condensed financial statements for the third quarter of the 2024 fiscal year and the related MD&A, copies of which are available under the Company’s pro SEDAR+ at . About Appili Therapeutics Appili Therapeutics is a biopharmaceutical company that is purposefully built, portfolio-driven, and people-focused to fulfill its mission of solving life-threatening infectious diseases. By systematically identifying urgent infections with unmet needs, Appili’s goal is to strategically develop a pipeline of novel therapies to prevent deaths and improve lives. The Company is currently advancing a diverse range of anti-infectives, including an FDA approved ready-made suspension of metronidazole for the treatment of antimicrobial infections, a vaccine candidate to eliminate a serious biological weapon threat, and a topical antiparasitic for the treatment of a disfiguring disease. Led by a proven management team, Appili is at the epicenter of the global fight against infection. For more information, visit . Forward looking statements This news release contains “forward-looking statements”, including with respect to the funding commitment from USAFA and expected timing of invoice payment, further anticipated milestones and the timing thereof, the Company’s development plans and timelines with respect to ATI-1501, ATI-1701 and ATI-1801, , the timing of any milestone and/or royalty payments in respect of ATI-1501, and the Company’s expectations with respect to its ability to operate as a going concern and satisfy its ongoing working capital requirements. Wherever possible, words such as “may,” “would,” “could,” “should,” “will,” “anticipate,” “believe,” “plan,” “expect,” “intend,” “estimate,” “potential for” and similar expressions have been used to identify these forward-looking statements. These forward-looking statements reflect the current expectations of the Company’s management for future growth, results of operations, performance and business prospects and opportunities and involve significant known and unknown risks, uncertainties and assumptions, including, without limitation, those listed in the annual information form of the Company dated June 22, 2023, and the other filings made by the Company with the Canadian securities regulatory authorities (which may be viewed at ). Should one or more of these risks or uncertainties materialize or should assumptions underlying the forward-looking statements prove incorrect, actual results, performance or achievements may vary materially from those expressed or implied by the forward-looking statements contained in this news release. These factors should be considered carefully, and prospective investors should not place undue reliance on the forward-looking statements. The Company disclaims any intention or obligation to revise forward-looking statements whether as a result of new information, future developments or otherwise, except as required by law. Media Contact: Jenna McNeil, Communications Manager Appili Therapeutics E: JMcNeil@AppiliTherapeutics.com Investor Relations Contact: Don Cilla, President and CEO Appili Therapeutics E: Info@AppiliTherapeutics.com

EMA gives positive opinion to Fexinidazole Winthrop as first oral treatment of acute form of sleeping sickness (rhodesiense) found in East and Southern Africa Paris, Geneva and Nairobi. December 15, 2023. Sanofi, DNDi and the HAT-r-ACC consortium announce the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive scientific opinion of Fexinidazole Winthrop as first oral treatment of acute form of sleeping sickness (rhodesiense). This positive opinion is for the treatment in adults and children six years of age or older and weighing at least 20 kg, of both first-stage (haemo-lymphatic) and second-stage (meningo-encephalitic) Trypanosoma brucei (T.b.) rhodesiense sleeping sickness, an acute and lethal form of this parasitic disease found in Eastern and Southern Africa. This CHMP opinion follows an application by Sanofi under Article 58 and clinical trials in Malawi and Uganda led by the non-profit medical research organization Drugs for Neglected Diseases initiative (DNDi). The CHMP first adopted in 2018, a positive opinion of Fexinidazole Winthrop as the first all-oral treatment , in adults and children six years of age or older and weighing at least 20 kg, of both first-stage (haemo-lymphatic) and second-stage (meningo-encephalitic) of the more common T.b. gambiense form of sleeping sickness found in West and Central Africa. Sleeping sickness, or human African trypanosomiasis (HAT), is usually fatal without treatment. Both forms of sleeping sickness are transmitted by the bite of infected tsetse flies, which are found in 36 African countries. It causes neuropsychiatric symptoms, including aggressiveness, psychosis, a debilitating disruption of sleep patterns that have given this neglected disease its name, and ultimately, death. Dietmar Berger, MD, PhDHead of Development and Chief Medical Officer, Sanofi“The CHMP’s positive opinion is another step forward in Sanofi’s commitment to help deliver innovative treatments to vulnerable patient communities impacted by sleeping sickness, a deadly neglected tropical disease. By working with WHO and DNDi, we have made tremendous progress in improving treatment outcomes and simplifying treatment delivery. This partnership and our donation of Fexinidazole Winthrop through Foundation S, reflect our mission to provide innovative treatments to patients, no matter where they live.” For the T.b. rhodesiense variant, Fexinidazole Winthrop is indicated as a 10-day, once-daily oral treatment. Data from DNDi’s Phase 2/3 clinical trial were recently presented at the European Congress of Tropical Medicine and International Health and showed that Fexinidazole Winthrop was highly effective in treating the T.b. rhodesiense form of sleeping sickness and is a safe alternative to the existing drugs. In periodic follow-up evaluations that continued for 12 months after treatment, only one patient (2.94%) with the advanced form of the disease had relapsed and required treatment with the arsenic derivative that is the standard of care for patients with the most severe stage of the disease. Dr Westain NyirendaPrincipal Investigator and physician at Rumphi Hospital in Malawi“T.b. rhodesiense sleeping sickness is a terrifying disease that progresses more rapidly than T.b. gambiense, killing quickly if untreated. Until now, due to the lack of innovation for this strain of sleeping sickness, old and toxic treatment options have to be administered in a hospital under strict surveillance. Having a simple and safer oral pill to treat this frightening disease will allow doctors to rapidly save lives. It will also help patients to trust the new treatment.” While humans are the main host of T.b. gambiense, T.b. rhodesiense is a zoonotic disease, meaning that the infection can spread from animals to humans. Cattle and wild animals such as bushbucks and zebras are the most common reservoirs for this disease. Movements of these animals – potentially sparked by droughts or changes in climate – could put new populations at risk of T.b. rhodesiense sleeping sickness. In some cases, tourists visiting game reserves have been infected with T.b. rhodesiense. Dr Olaf Valverde MordtClinical Project Leader for sleeping sickness, DNDi“We are already seeing how an all-oral treatment for T.b. gambiense sleeping sickness has simplified the treatment of this variant in countries like the Democratic Republic of Congo. Although there are comparatively few cases of T.b. rhodesiense, last year Ethiopia recorded its first cases since the 1970s. The drought at the time of the infections brought humans and cattle in closer proximity to tsetse flies’ habitat. Environmental changes could be one of the reasons behind this resurgence.” The CHMP opinion today paves the way for the update of WHO guidelines on treatment for sleeping sickness, and distribution by WHO of Fexinidazole Winthrop in African countries where T.b. rhodesiense is prevalent. Fexinidazole Winthrop will be donated to WHO by Foundation S, Sanofi’s philanthropic organization. Dr Ibrahima Socé FallDirector of Neglected Tropical Diseases, World Health Organization “The impact of climate change extends to the shifting geographical spread of vector-borne diseases such as sleeping sickness, heightening the likelihood of spillover events where diseases transfer from animals to humans. These shifts disproportionately affect the most vulnerable communities, underscoring the urgency of sustained investment in programs addressing NTDs. This includes the development of innovative tools and improved treatment methods. We extend our gratitude to our partners DNDi for their research for the most neglected and Sanofi for their ongoing support and contribution to these vital efforts.” Fexinidazole Winthrop has already been registered in the Democratic Republic of the Congo and Uganda as a treatment for T.b. gambiense and is recommended for use in a further 10 African countries: (Angola, Burkina Faso, Central African Republic, Chad, Congo, Côte d'Ivoire, Equatorial Guinea, Gabon, Guinea, and South Sudan). Dr Michelle HelinskiSenior Project Officer for Neglected Infectious Diseases at the European and Developing Countries Clinical Trials Partnership Association (EDCTP) “We congratulate the HAT-r-ACC consortium on developing a better treatment option for this truly neglected disease and are thrilled with the positive opinion by CHMP.” The DNDi clinical trial for T.b. rhodesiense was conducted by the HAT-r-ACC Consortium, with funding from the European and Developing Countries Clinical Trials Partnership Association (EDCTP2) programme supported by the European Union; Fundação para a Ciência e a Tecnologia from Portugal; Swiss Agency for Development and Cooperation (SDC), from Switzerland; Médecins Sans Frontières International; and UK International Development, United Kingdom; and other private foundations and individuals. About SanofiWe are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve people’s lives. Our team, across some 100 countries, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the center of our ambitions. Sanofi is listed on EURONEXT: SAN and NASDAQ: SNY About DNDiThe Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit medical research organization that discovers, develops, and delivers safe, effective, and affordable treatments for neglected people. DNDi is developing medicines for sleeping sickness, leishmaniasis, Chagas disease, river blindness, mycetoma, dengue, paediatric HIV, advanced HIV disease, cryptococcal meningitis, and hepatitis C. Its research priorities include children’s health, gender equity and gender-responsive R&D, and diseases impacted by climate change. Since its creation in 2003, DNDi has joined with public and private partners across the globe to deliver twelve new treatments, saving millions of lives. dndi.org About HAT-r-ACCThe HAT-r-ACC consortium brings together a broad range of partners with expertise in sleeping sickness and capacity building in remote health settings. This research, training, and community engagement experience is essential to run the clinical trial in remote settings with a very small target population. The consortium partners include the Malawi Ministry of Health (MMoH), the Uganda National Health Research Organisation (UNHRO), the Makerere University in Uganda, Epicentre (MSF) in France, the Lisbon Institute of Hygiene and Tropical medicine (IHMT) in Portugal, the Institut de Recherche pour le Développement (IRD) in France, the WHO, and the Swiss Tropical and Public Health Institute (Swiss TPH). Sanofi Media RelationsSandrine Guendoul | + 33 6 25 09 14 25 | sandrine.guendoul@sanofi.comEvan Berland | +1 215 432 0234 | evan.berland@sanofi.comNicolas Obrist | + 33 6 77 21 27 55 | nicolas.obrist@sanofi.comVictor Rouault | + 33 6 70 93 71 40 | victor.rouault@sanofi.com Sanofi Investor RelationsEva Schaefer-Jansen | + 33 7 86 80 56 39 | eva.schaefer-jansen@sanofi.comArnaud Delépine | + 33 6 73 69 36 93 | arnaud.delepine@sanofi.comCorentine Driancourt | + 33 6 40 56 92 21 | corentine.driancourt@sanofi.comFelix Lauscher | + 1 908 612 7239 | felix.lauscher@sanofi.comTarik Elgoutni| + 1 617 710 3587 | tarik.elgoutni@sanofi.comNathalie Pham | + 33 7 85 93 30 17 | nathalie.pham@sanofi.com DNDi Media ContactFrédéric Ojardias in Geneva | +41 79 431 62 16 | fojardias@dndi.org Sanofi Forward-Looking StatementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. 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The risks and uncertainties also include the uncertainties discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in Sanofi’s annual report on Form 20-F for the year ended December 31, 2022. Other than as required by applicable law, Sanofi does not undertake any obligation to update or revise any forward-looking information or statements. Attachment Press_Release