GLI1

This article will continue to review the antitumor targets of the GPCR family and the therapeutic drugs that have been marketed. 05 SMOThe Smoothened (SMO) receptor is a key signal transduction receptor in the Hedgehog signaling pathway and belongs to the GPCR family, featuring the classical seven-transmembrane domain structure. The SMO receptor plays a vital role in the activation of the Hedgehog signaling pathway. The discovery of the Hedgehog signaling pathway dates back to 1980 when Christiane Nüsslein-Volhard and Eric Wieschaus, during their research on the embryonic development of fruit flies, identified gene mutations affecting the segmental development of the Drosophila larvae through genetic screening. These genes were later named Hedgehog genes because their mutant flies' embryos had a spiky appearance reminiscent of hedgehogs. The Hedgehog signaling pathway is highly conserved evolutionarily, playing significant roles not only in fruit flies but also in vertebrates, including in processes such as cell differentiation, cell proliferation, cellular senescence, tumorigenesis, malignant transformation, and tumor resistance. With further research, scientists have identified that the Hedgehog pathway involves a series of proteins, particularly core components that include two membrane proteins, Patched and Smoothened (SMO), along with three transcription factors (Gli1/2/3). The activity of the Hedgehog signaling pathway is regulated by multiple mechanisms, and abnormal pathway activity is associated with various diseases, including birth defects and tumors. In the absence of a Hedgehog ligand, the SMO receptor is inhibited by the Patched (PTCH) receptor, which acts as a tumor suppressor protein that restricts SMO activity and prevents signal transduction. When Hedgehog ligands such as Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), or Desert Hedgehog (Dhh) bind to the PTCH receptor, this inhibition is released, leading to the accumulation and activation of SMO within the cell. Activation of SMO further triggers downstream signaling pathways, particularly the activation of the GLI (Glioma-associated oncogene) family of transcription factors. These transcription factors exist in a repressive form when the signaling pathway is inactive, and upon SMO activation, they are dephosphorylated and converted into an active form, which then enters the nucleus to activate the expression of Hedgesten target genes. Vismodegib (brand name Erivedge™), an oral SMO receptor antagonist, was developed by Genentech and approved by the FDA in January 2012 in the United States. It is primarily used for the treatment of locally advanced or metastatic basal cell carcinoma, especially in patients who are not suitable for surgery or radiation therapy. In 2009, Genentech first disclosed the early drug discovery data of the SMO receptor antagonist candidate drug GDC-0449. Researchers used mouse embryonic fibroblasts harboring a luciferase reporter gene plasmid and performed high-throughput screening downstream of Gli binding sites. When the Hedgehog signaling pathway in these cells was stimulated, the activity of luciferase could be measured optically. Hedgehog pathway antagonists reduce the strength of this signal, leading researchers to obtain lead compounds. Subsequent SAR (Structure-Activity Relationship) studies yielded the candidate drug GDC-0449. At a low dose of 12.5 mg/kg, GDC-0449 was able to completely regress tumors in an orthotopic xenograft mouse model of medulloblastoma that entirely depended on the Hedgehog signaling pathway. Between 2009 and 2012, the Genentech team published two clinical research papers consecutively in the New England Journal of Medicine, reporting the efficacy and safety of Vismodegib in treating advanced basal cell carcinoma. The results showed that among 33 patients with metastatic basal cell carcinoma, the independently assessed response rate was 30%. Among 63 patients with locally advanced basal cell carcinoma, the independently assessed response rate was 43%, with 13 patients (21%) achieving a complete response. The median duration of response for both groups was 7.6 months. In terms of safety, over 30% of patients experienced adverse reactions such as muscle spasms, hair loss, taste disturbances, weight loss, and fatigue. It was reported that 25% of patients experienced severe adverse reactions; 7 patients died due to adverse reactions. Sonidegib (NVP-LDE225), developed by the Novartis team, is a SMO receptor antagonist also used for the treatment of locally advanced, recurrent basal cell carcinoma post-surgery and radiation, or in cases unsuitable for surgery and radiation. Sonidegib works by inhibiting a mechanism known as SMO activation, thereby blocking the Hh signaling pathway and exhibiting antitumor activity across various animal models. In a transgenic mouse pancreatic tumor model, tumors in mice treated with Sonidegib were reduced by 95% compared to untreated mice. In 2014 and 2015, the Novartis team published clinical research papers detailing trial data for Sonidegib used in patients with advanced or metastatic basal cell carcinoma. In the primary efficacy analysis cohort, 20 out of 55 patients (36%) receiving 200 mg of Sonidegib achieved an objective response, and 39 out of 116 patients (34%) receiving 800 mg of Sonidegib achieved an objective response. Among the 200 mg Sonidegib group, 18 of 42 patients (43%) with locally advanced basal cell carcinoma achieved an objective response via central review, and 2 out of 13 patients (15%) with metastatic disease also achieved an objective response. In the 800 mg Sonidegib group, 35 out of 93 locally advanced patients (38%) obtained an objective response through central review, and 4 out of 23 metastatic disease patients (17%) also achieved an objective response. Compared to the 800 mg group, the 200 mg group experienced fewer adverse events leading to dose reduction or treatment discontinuation. The most common grade 3-4 adverse events were elevated creatine kinase and increased lipase levels. In the 200 mg group of 79 patients, 11 (14%) experienced severe adverse events; in the 800 mg group of 150 patients, 45 (30%) experienced severe adverse events. Overall, the benefit-risk ratio of 200 mg Sonidegib provides a new treatment option for patients with advanced basal cell carcinoma. In June 2015, the U.S. FDA approved Sonidegib for the treatment of adult basal cell carcinoma. In 2021, Sonidegib was approved for market in Mainland China, becoming the first SMO receptor antagonist approved in China. Following the market entries of Genentech's Vismodegib and Novartis's Sonidegib Phosphate, Pfizer's SMO antagonist drug, Glasdegib Maleate, was approved in 2018 for the treatment of patients with acute myeloid leukemia. The representative molecular formula for SMO antagonists is as follows: 06 TSHRThe Thyroid-Stimulating Hormone Receptor (TSHR) is a gene that encodes a GPCR controlling the metabolism of thyroid cells. This protein acts as a receptor for thyroid-stimulating hormone (TSH) and thyroxine. In addition to the thyroid, TSHR expression has also been confirmed in various tissues including the brain, bone marrow, peripheral blood, and bones. Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the production of thyroid hormones by the thyroid gland. TSH is primarily synthesized in the thyrotroph cells of the anterior and nodular portions of the pituitary gland. Additionally, hematopoietic cells in the bone marrow, particularly monocyte/macrophage precursors, have also been shown to be a source of TSH. TSH binds to TSHR in the thyroid, stimulating the production and release of thyroid hormones. TSH is a non-covalently linked heterodimeric glycoprotein composed of alpha and beta subunits. The alpha subunit is common with other glycoprotein hormones, such as luteinizing hormone and follicle-stimulating hormone, while the beta subunit is unique to each hormone. TSH signaling can stimulate the secretion of vascular endothelial growth factor (VEGF), leading to angiogenesis and accelerating genomic instability in thyroid cancer. The tumorigenic role of TSH in thyroid cancer has been established. Many patients with differentiated thyroid cancer undergo radioactive iodine ablation postoperatively to remove residual normal thyroid tissue. Several non-randomized studies suggest that radioactive iodine ablation can reduce mortality and recurrence rates. Thyrotropin alfa is a recombinant form of thyroid-stimulating hormone, developed by Genzyme, and was initially approved by the U.S. FDA in 1998 as a diagnostic tool for managing patients undergoing recurrence monitoring of well-differentiated thyroid cancer. This product helps to enhance the sensitivity of tests while allowing patients to avoid potential debilitating symptoms associated with thyroid hormone withdrawal. In 2008, the FDA approved a new supplementary indication for Thyrotropin Alfa for use in conjunction with radioactive iodine to ablate or destroy residual thyroid tissue in patients who have undergone thyroidectomy for cancer. A study published in the New England Journal of Medicine in 2012 demonstrated that low-dose radioactive iodine combined with thyrotropin alfa is as effective as high-dose radioactive iodine, with a lower incidence of adverse events. In the diagnosis and treatment of thyroid cancer, the use of Thyrotropin alfa enhances the uptake of radioactive iodine by these cells, thereby improving the effectiveness of radioactive iodine treatment or enhancing the clarity of imaging during radioactive iodine scans, helping physicians to more accurately assess the status of the disease. Outside of thyroid cancer, the incidence of prostate cancer, lung cancer, and colorectal cancer has been linked to low levels of TSH. For example, various mutations such as missense mutations, nonsense mutations, silent mutations, frameshift deletions, and in-frame deletions have been observed in cancers like colorectal cancer, skin cancer, and thyroid cancer. 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WARRINGTON, Pa., April 08, 2024 (GLOBE NEWSWIRE) -- Windtree Therapeutics, Inc. (“Windtree” or the “Company”) (NasdaqCM: WINT), today announced that on April 2, 2024 the Company entered into an asset purchase agreement with Varian Biopharmaceuticals, Inc. (“Varian”) to acquire certain of its assets, including a proprietary atypical protein kinase C iota inhibitor (aPKCi). The Company also completed a $1.5 million convertible note bridge financing. The acquired Varian asset platform is a novel, potential high-potency, specific, aPKCi with possible broad use in oncology as well as certain rare malignant diseases. The asset platform includes two formulations: VAR-101 (topical) and VAR-102 (oral). In consideration of the purchase of the Varian assets, on April 2, 2024, the Company issued to certain of Varian’s creditor investors a total of 5,500 shares of Series B Convertible Preferred Stock, par value $0.001 per share (the “Preferred Shares”), that have an initial conversion price of $0.3603, which is subject to adjustment to no lower than $0.0721. Dividends on the Preferred Shares shall accrue at 10.0% per annum, subject to limited exceptions. With successful development, the Company would pay up to $2.3 million in milestone payments upon the achievement of certain regulatory and clinical development milestones relating to the acquired assets with the Company having the option to pay such milestone payments either in cash or the Company’s common stock. Protein kinase inhibitors are a class of anti-cancer therapeutics that have made a significant impact on the treatment of cancers. Among the kinase targets for further development are the Protein Kinase C (“PKC”) family, which are key components of many signaling pathways that drive the formation of cancer. aPKCi is a promising atypical PKC iota isozyme with defined oncogenic role in multiple signaling pathways, and in the initiation and development of multiple tumor types. GLI-1 is a transcription factor at the terminal end of the Hedgehog (Hh) signaling pathway, and many other important pathways, including RAS-RAF, TGFb, and P14K-AKT-mTOR. In many tumor types, high levels of GLI-1 expression is a negative prognostic marker. Pre-clinical data of the acquired platform showed dose dependent modulation of basal cell carcinoma cell viability and GLI-1 pathway modulation in vitro, as well as dose dependent anti-tumor activity in xenograft mouse models of non-small cell lung cancer and pancreatic ductal carcinoma. The protein kinase inhibitor adds to Windtree’s product candidate portfolio of novel pre-clinical and late-stage clinical product candidates and development programs, including SERCA2a activators and programs in out-licensed partnership. “Completion of the Varian asset acquisition and the bridge financing represents a potentially transformative next step for Windtree. Adding an innovative protein kinase inhibitor that has what we believe is an exciting pre-clinical data package with two formulations in development to our existing portfolio of product candidates creates an additional opportunity for value creation as we advance and look to partner our late and early-stage SERCA2a activator platform, including istaroxime,” said Craig Fraser, Chief Executive Officer of Windtree. “We see potential application in both rare and more prevalent tumor types, both in monotherapy and in combination with other agents. We believe there will be options for targeted disease selection and differentiation due to the potential for high specificity and topical formulation to treat various skin cancers. In the weeks to come, I look forward to providing updates on the use of this newly acquired capital and plans for our portfolio and programs, including licensing activity for istaroxime and our SERCA2a activators as well as our company strategy to have a stronger balance sheet and opportunities to further leverage our experience to grow the business.” In addition to the asset purchase, on April 2, 2024, the Company entered into a securities purchase agreement with certain investors whereby the Company agreed to sell to such investors $1.5 million in senior convertible notes (the “Notes”) for aggregate gross proceeds of $1.5 million (the “Notes Offering”). The Notes have an initial conversion price of $0.3603, which is subject to adjustment upon the occurrence of specified events to no lower than $0.0721 (subject to any stock split, stock dividend, stock combination, recapitalization or other similar transaction). The Company may, at its option, redeem the Notes subject to certain conditions and terms in the securities purchase agreement. The Notes may convert in a subsequent financing or will accrue interest at a rate of 10% per annum and mature on January 2, 2025, unless previously converted or redeemed. The Company intends to use the net proceeds from the Notes Offering for general corporate purposes. The Company agreed to seek stockholder approval for the issuance of all of the Company’s common stock issuable upon conversion of the Notes and the Preferred Shares in accordance with the rules and regulations of the Nasdaq Stock Market. Additional details are available by reading the Company’s Current Report on Form 8-K relating to the Varian asset acquisition and senior convertible note bridge financing, which was filed with the Securities and Exchange Commission on April 8, 2024. About Istaroxime Istaroxime is a first-in-class dual-mechanism therapy designed to improve both systolic and diastolic cardiac function. Istaroxime is a positive inotropic agent that increases myocardial contractility through inhibition of Na+/K+- ATPase with a complimentary mechanism that facilitates myocardial relaxation through activation of the SERCA2a calcium pump on the sarcoplasmic reticulum enhancing calcium reuptake from the cytoplasm. Data from multiple Phase 2 studies in patients with early cardiogenic shock or acute decompensated heart failure demonstrate that istaroxime infused intravenously significantly improves cardiac function and blood pressure without increasing heart rate or the incidence of cardiac rhythm disturbances. About Pure SERCA2a Activators These compounds activate SERCA2a and Windtree Therapeutics' research and development program is evaluating these preclinical product candidates, including oral and intravenous SERCA2a activator heart failure compounds. About Windtree Therapeutics, Inc. Windtree Therapeutics, Inc. is a biotechnology company focused on advancing early and late-stage innovative therapies for critical conditions and diseases. Windtree’s portfolio of product candidates includes istaroxime, a Phase II candidate with SERCA2a activating properties for acute heart failure and associated cardiogenic shock, pre-clinical SERCA2a activators for heart failure and VAR-101 and VAR-102, pre-clinical precision aPKCi inhibitors that are being developed for potential in rare and broad oncology applications. Windtree also has a licensing business model with partnership out-licenses currently in place. Forward Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The Company may, in some cases, use terms such as "predicts," "believes," "potential," "proposed," "continue," "estimates," "anticipates," "expects," "plans," "intends," "may," "could," "might," "will," "should" or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are based on information available to the Company as of the date of this press release and are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the Company’s current expectations. Examples of such risks and uncertainties include: the Company’s ability to secure significant additional capital as and when needed; the Company’s ability to obtain approval for the issuance of all of the Company’s common stock issuable upon conversion of the Notes and the Preferred Shares; risks and uncertainties associated with the success and advancement of the clinical development programs for istaroxime and the Company’s other product candidates, including pre-clinical candidates such as VAR-101 and VAR-102; the Company’s ability to access the debt or equity markets; the Company’s ability to manage costs and execute on its operational and budget plans; the results, cost and timing of the Company’s clinical development programs, including any delays to such clinical trials relating to enrollment or site initiation; risks related to technology transfers to contract manufacturers and manufacturing development activities; delays encountered by the Company, contract manufacturers or suppliers in manufacturing drug products, drug substances, and other materials on a timely basis and in sufficient amounts; risks relating to rigorous regulatory requirements, including that: (i) the U.S. Food and Drug Administration or other regulatory authorities may not agree with the Company on matters raised during regulatory reviews, may require significant additional activities, or may not accept or may withhold or delay consideration of applications, or may not approve or may limit approval of the Company’s product candidates, and (ii) changes in the national or international political and regulatory environment may make it more difficult to gain regulatory approvals and risks related to the Company’s efforts to maintain and protect the patents and licenses related to its product candidates; risks that the Company may never realize the value of its intangible assets and have to incur future impairment charges; risks related to the size and growth potential of the markets for the Company’s product candidates, and the Company’s ability to service those markets; the Company’s ability to develop sales and marketing capabilities, whether alone or with potential future collaborators; the rate and degree of market acceptance of the Company’s product candidates, if approved; the economic and social consequences of the COVID-19 pandemic and the impacts of political unrest, including as a result of geopolitical tension, including the conflict between Russia and Ukraine, the People’s Republic of China and the Republic of China (Taiwan), and the evolving events in Israel and Gaza, and any sanctions, export controls or other restrictive actions that may be imposed by the United States and/or other countries which could have an adverse impact on the Company’s operations, including through disruption in supply chain or access to potential international clinical trial sites, and through disruption, instability and volatility in the global markets, which could have an adverse impact on the Company’s ability to access the capital markets. These and other risks are described in the Company’s periodic reports, including its Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and Current Reports on Form 8-K, filed with or furnished to the Securities and Exchange Commission and available at www.sec.gov. Any forward-looking statements that the Company makes in this press release speak only as of the date of this press release. The Company assumes no obligation to update forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. Contact Information:Eric Curtisecurtis@windtreetx.com

18 May 2023 BiodexaPharmaceuticalsEnters into Non-binding Letter of Intentfor Proposed Acquisition of Varian Biopharmaceuticals Biodexa Pharmaceuticals PLC (NASDAQ: BDRX) (“Biodexa” or the “Company”), a clinical stage biopharmaceutical company developing a pipeline of products aimed at primary and metastatic cancers of the brain is pleased to announce that it has signed non-binding letter of intent to potentially acquire Varian Biopharmaceuticals, Inc. (“VarianBio”), a private US precision oncology company developing novel therapeutics for the treatment of cancer. Background to the proposed acquisition In recent communications, the Company has referenced a shift in strategy from a drug delivery company to a therapeutics company. Currently, the Company’s only clinical asset is MTX110 which is being developed for three intractable rare and orphan brain cancers. The Company’s intention is to add to, and diversify, its development pipeline with a continued focus on rare and orphan products and/or oncology therapeutics and VarianBio represents the first of such opportunity. Information on VarianBio VarianBio is developing a high-potency, specific atypical protein kinase C iota (“aPKCi”) inhibitor with best-in-class potential as a treatment for various oncology indications with an initial focus on basal cell carcinoma (BCC) and molecularly targeted solid tumors. VarianBio’s rationally designed aPKCi small molecule inhibitor candidate that has been optimized for potency, selectivity and tolerability. aPKCi has been implicated as an oncogene in a number of human cancers, including BCC, cutaneous T-cell lymphoma (CTCL), non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), colorectal cancer, and pancreatic cancer, among others. aPKCi has also been demonstrated to have a role in allowing the immune system to recognize tumors, recruit immune cells into the area, and ramp up the anti-tumor response to kill cancer cells in the lab by shrinking their tumors. The active pharmaceutical ingredient in VAR-101/102, a novel aPKCi inhibitor, has demonstrated dose dependent anti-tumor activity in murine and human BCC cell lines, as well as other cancer models. VAR-101 will be developed in a topical formulation for BCC which has the potential to offer optimal clinical utility as a surgical neoadjuvant or adjuvant therapy. Following completion of IND-enabling skin toxicology studies, VAR-101 is targeting to start a Phase I proof-of-concept study in the first quarter of 2024. VAR-102, an oral formulation of the active aPKCi inhibitor, lends itself to broader applications in multiple tumor types. The Company believes that VAR-101 and VAR-102, if approved, could represent significant medical and commercial opportunities. Terms of the proposed acquisition Under the non-binding letter of intent, VarianBio will merge into an acquisition subsidiary of the Company and it is proposed that VarianBio equity and debt holders (together,“VarianBio Securityholders”) will receive 10MM of the Company’s American Depositary Shares (“ADSs”), at close as initial consideration. On a pro forma basis, prior to the planned financing discussed below, VarianBio Securityholders will own approximately 34% of the post-acquisition Company. VarianBio Securityholders will receive up to a further 6MM ADSs, issuable in two phases: 3MM upon the commencement of the first pivotal registration study of a VarianBio product and an additional 3MM upon the first FDA approval of a VarianBio product. In addition, pursuant to the non-binding heads of terms, the Company plans to raise not less than US$7.0MM, net of expenses, which will be used to fund VAR-101 through its Phase I proof-of-concept study that VAR-101 is targeting to commence in the first quarter of 2024. The acquisition agreement is also expected to contain other customary conditions, including shareholder approval, and appropriate representations and warranties by the parties. For more information, please contact: Biodexa Pharmaceuticals PLC Stephen Stamp, CEO and CFO Tel: +44 29 20480 180 Varian Biopharmaceuticals, Inc. Jeffrey Davis, CEO Tel: +1 239-302-1644 Edison Group (Investor Relations) Alyssa Factor Tel: +1 (860) 573 9637 Email: afactor@edisongroup.com About Biodexa Pharmaceuticals PLC Biodexa Pharmaceuticals PLC (listed on NASDAQ: BDRX) is a clinical stage biopharmaceutical company developing a pipeline of products aimed at primary and metastatic cancers of the brain. The Company’s lead candidate, MTX110, is being studied in aggressive rare/orphan brain cancer indications including recurrent glioblastoma and diffuse midline glioma. MTX110 is a liquid formulation of the histone deacetylase (HDAC) inhibitor, panobinostat. This proprietary formulation enables delivery of the product via convection-enhanced delivery (CED) at potentially chemotherapeutic doses directly to the site of the tumour, by-passing the blood-brain barrier and avoiding systemic toxicity. Biodexa is supported by three proprietary drug delivery technologies focused on improving the bio-delivery and bio-distribution of medicines. Biodexa’s headquarters and R&D facility is in Cardiff, UK. For more information visit About Varian Biopharmaceuticals, Inc. Varian Biopharmaceuticals, Inc. (“VarianBio”) is private precision oncology company developing novel therapeutics for the treatment of cancer. Precision oncology, whereby physicians use DNA testing to look for genetic mutations of the unique tumors, holds the promise of more targeted treatment recommendations with therapies designed to fight specific tumor types. A recently published global Precision Oncology Market analysis by Reports and Data found the global precision oncology market size amounted to US$49.9 billion in 2019 and is expected to grow at a CAGR of 99% over the next eight years to reach US$99.7 billion in 2027. VarianBio is developing a best-in-class high-potency, specific atypical protein kinase C iota (“aPKCi”) inhibitor for the treatment of various tumor types in multiple formulations. Recent scientific publications have characterized aPKCi as an oncogene whose activity may play a fundamental role in the regulation of cancer-associated transcription factors including GLI-1 and K-RAS. VarianBio’s lead drug candidate, VAR-101, is being developed in a topical formulation for the treatment of basal cell carcinoma. VAR-102, an oral formulation, is being developed for the treatment of a wide variety of solid tumors where studies have shown potent aPKCi inhibition would be impactful, including non-small cell lung cancer (NSCLC), pancreatic cancer and colorectal cancer. For more information on Varian Biopharmaceuticals, Inc., visit Forward-Looking Statements Certain statements in this announcement may constitute "forward-looking statements" within the meaning of legislation in the United Kingdom and/or United States. Such statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and are based on management's belief or interpretation. All statements contained in this announcement that do not relate to matters of historical fact should be considered forward-looking statements. Reference should be made to those documents that Biodexa shall time to time or announcements that may be made by Biodexa in accordance with the rules and regulations promulgated by the US Securities and Exchange Commission, which contains and identifies other important factors that could cause actual results to differ materially from those contained in any projections or forward-looking statements. These forward-looking statements speak only as of the date of this announcement. All subsequent written and oral forward-looking statements by or concerning Biodexa or VarianBio are expressly qualified in their entirety by the cautionary statements above. Except as may be required under relevant laws in the United States, Biodexa does not undertake any obligation to publicly update or revise any forward-looking statements because of new information, future events or otherwise arising. No Offer or Solicitation This announcement or any part of it is for information purposes only and is not intended to and it does not constitute an offer to sell or issue or the solicitation of an offer to subscribe for or buy or an invitation to subscribe for or purchase any securities or the solicitation of any vote or approval in respect of such actions in any jurisdiction, nor shall there be any sale, issuance or transfer of securities in any jurisdiction in contravention of applicable law. Important Notices This announcement does not constitute a recommendation concerning any investor’s investment decision with respect to the Company’s securities. Any indication in this announcement of the price at which ordinary shares or ADSs have been bought or sold in the past cannot be relied upon as a guide to future performance. The price of shares and any income expected from them may go down as well as up and investors may not get back the full amount invested upon disposal of the shares. Past performance is no guide to future performance. This announcement does not identify or suggest, or purport to identify or suggest, the risks (direct or indirect) that may be associated with an investment in the Company’s securities. The contents of this announcement are not to be construed as legal, business, financial or tax advice. Each investor or prospective investor should consult their or its own legal adviser, business adviser, financial adviser or tax adviser for legal, financial, business or tax advice. Persons (including, without limitation, nominees and trustees) who have a contractual or other legal obligation to forward a copy of this announcement should seek appropriate advice before taking any action. Neither the content of the Company’s website (or any other website) nor the content of any website accessible from hyperlinks on the Company’s website (or any other website) is incorporated into or forms part of this announcement.