Lanifibranor

Inventiva secures €21.4 million leading to completion of the first tranche of the financing for c. €116 million, part of the multi-tranche equity financing of up to €348 million announced on October 14, 2024. Proceeds from the completed first tranche to be primarily used to advance Inventiva’s Phase III, NATiV3 clinical trial evaluating lanifibranor in patients with MASH. Appointment of Mark Pruzanski as new Chairman of the Board of Directors and Srinivas Akkaraju as new member of the Board of Directors. Daix (France), New York City (New York, United States), December 16, 2024 – Inventiva (Euronext Paris and Nasdaq: IVA) (“Inventiva” or the “Company”), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of metabolic dysfunction-associated steatohepatitis (“MASH”) and other diseases with significant unmet medical needs, today announced that, following the general meeting of the shareholders held on December 11, 2024 (the “General Meeting”), the Board of Directors decided to use the delegations granted by the General Meeting to issue the second phase of Tranche 1 (the “T1 bis Transaction”) for a gross amount of €21.4 million (net amount of €20.1 million) of the multi-tranche equity financing of up to €348 million announced on October 14, 2024 (the “Multi-Tranche Financing”). Frédéric Cren, Chief Executive Officer of Inventiva, stated: "We are pleased to announce that we secured €21.4 million successfully completing the first tranche of the financing announced in October. The multi-tranche equity raise of up to €348 million has been instrumental to keep Inventiva on track with recruitment for our pivotal Phase III clinical trial of our asset lanifibranor. We believe that lanifibranor holds significant potential to address unmet medical needs, and we are encouraged by the intensification of trial activities, with a completion of our recruitment expected in the first half of 2025. I am also delighted to welcome Mark and Srinivas to our Board of Directors. Their expertise and strategic insights will be invaluable as we advance our clinical program and prepare for a potential NDA filing for lanifibranor." On October 14, 20241 the Company announced the Multi-Tranche Financing and the completion of a capital increase of an aggregate of €94.1 million through the issuance of 34,600,507 new ordinary shares of the Company, par value €0.01 per share (the “T1 New Shares”) at a price of €1.35 per T1 New Share, and the issuance of 35,399,481 prefunded warrants to purchase up to 35,399,481 ordinary shares at an exercise price of €0.01 per new ordinary share (the “T1 BSAs”) at a subscription price of €1.34 per T1 BSA, subject to the satisfaction of customary closing conditions. Settlement and delivery of the T1 New Shares and the T1 BSAs, took place on October 17, 2024. Following issuance of the T1 New Shares and T1 BSAs, and the subsequent adoption by shareholders of the appropriate resolutions by the General Meeting, the Board of Directors decided on December 13, 2024 to use the delegations granted by the General Meeting to proceed with the T1 bis Transaction, consisting of 7,872,064 new ordinary shares (the “T1 bis Shares”) at a subscription price of €1.35 per T1 bis Share and 8,053,847 pre-funded warrants to purchase up to 8,053,847 ordinary shares at an exercise price of €0.01 per new ordinary share (the “T1 bis BSAs”) at a subscription price of €1.34 per T1 bis BSA, for aggregate gross proceeds of €21,419,441.38. Reasons for the issuance and use of the proceeds of the T1 bis Transaction The Company intends to use the net proceeds of €20.1 million from the T1 bis Transaction, together with available cash, as follows: approximately 85% for the clinical program evaluating lanifibranor for the treatment of MASH (“NATiV3”) and, in the event of positive NATiV3 results, for the submission of a new drug application, and the remainder, approximately 15%, for general corporate purposes. The Company has undertaken not to use these proceeds for the early redemption of its financial debt prior to its scheduled maturity or for the repurchase of securities issued as part of the T1 bis Transaction, subject to the implementation of its liquidity contract with Kepler Cheuvreux. Working capital statement As of the date of this press release, the Company believes that its net working capital would not be sufficient to meet its obligations over the next 12 months. As of September 30, 2024, 2024, the Company had cash and cash equivalents of €13.9 million, compared with cash and cash equivalents of €26.9 million and €9.0 million of long-term deposit2 at December 31, 2023. Taking into account its current cost structure and expected expenses and taking into account the (i) the receipt of €94.1 million in gross proceeds from the issuance of the T1 New Shares and the T1 BSAs, (ii) the anticipated receipt of €21.4 million in gross proceeds from the T1 bis Transaction, and (iii) the first milestone of $10 million (gross proceeds) received under the amendment to the licensing agreement with Chia Tai Tianqing Pharmaceutical (Guangzhou) CO., LTD. (“CTTQ”), the Company estimates that its cash, cash equivalents and deposits would enable it to finance its operations until the middle of the third quarter of 20253. Accordingly, the Company will not have sufficient net working capital to meet its current obligations over the next 12 months from the date of this press release. Based on its current business plan, the Company estimates that to cover its obligations until mid-December 2025 its additional cash requirements amount to between €120 million and €130 million. Subject to satisfaction of the applicable conditions precedent, if the second tranche of the Multi-Tranche Financing is completed for anticipated gross proceeds of €116 million, the Company could extend its financial visibility beyond 12 months. To the extent the applicable conditions precedent for the issuance of the second tranche of the Multi-Tranche Financing are not satisfied and/or the T3 Triggering Event (as defined in the press release published on October 14, 2024) does not occur and, therefore, the Company does not receive any of the contemplated gross proceeds from the issuance of the ABSAs or exercise of the T3 BSAs (each as defined in the press release published on October 14, 2024), the Company will need to raise additional funds to support its business and its research and development programs as currently contemplated through: other potential public offerings or private placements of equity or debt instruments; or potential strategic options such as business development partnerships and/or licensing agreements. Main characteristics of the T1 bis Transaction Pursuant to the 5th to 32nd resolutions of the General Meeting and in accordance with Articles L. 225-138 and seq. of the French Commercial Code (Code de commerce), the Board of Directors held on December 13, 2024 has decided to issue, without shareholders’ preferential subscription rights, the T1 bis Shares to the investors named in resolutions 6 to 22 of the General Meeting and the T1 bis BSAs to the investors named in resolutions 24 to 32 of the General Meeting. Conditions precedent to the issuance and subscription of the T1 bis Shares and T1 bis BSAs The issuance by the Company of the T1 bis Shares and T1 bis BSAs was subject to the approval of the General Meeting no later than December 16, 2024 and the absence of a “material adverse change” (defined as any event, breach or circumstance, individually or in the aggregate, that has had or could reasonably be expected to have a material adverse effect on the clinical development stages of lanifibranor, or on the manufacture of the new drug in preparation for commercial launch, or with respect to the company's ability to successfully complete the NATiV3 trial and obtain the necessary Food and Drug Administration approvals) between October 17, 2024 and the settlement and delivery of the T1 bis Shares and T1 bis BSAs. Subscription price of the T1 bis Shares and the T1 bis BSAs On December 11, 2024, the General Meeting set the subscription price (i) of each T1 bis Share to €1.35 (i.e., €0.01 nominal value and €1.34 premium) (the “T1 bis Subscription Price”) and (ii) of each T1 bis BSAs to €1.34, which corresponds to the T1 bis Subscription Price (i.e., €1.35) reduced by the nominal value of an ordinary share (€0.01). Allocation of the T1 bis Transaction The number of T1 bis Shares and T1 bis BSAs were subscribed by each investor pro rata to the number of T1 New Shares and T1 BSAs subscribed for by such investor. Form of the T1 bis Shares and the T1 bis BSAs The T1 bis Shares shall be registered in pure registered form (au nominatif pur) under French law until the earlier of (x) the date of settlement-delivery of T2 New Shares (as defined in the press release published on October 14, 2024) or (y) May 20, 2025. Thereafter, the T1 bis Shares will be held at the option of the holder either in registered form (au nominatif) or in bearer form (au porteur). The T1 bis BSAs will be securities giving access to the capital within the meaning of Article L. 228-91 of the French Commercial Code. They will be issued in dematerialized form and held in pure registered form (au nominatif pur) until the expiration of the lock-up (described below) in the securities account opened in the name of the investor in the books of the Company's account keeper. No physical document evidencing ownership of the T1 bis BSAs will be issued. The T1 bis BSAs will not be listed but will be admitted to Euroclear. The shares issued upon the exercise of T1 bis BSAs (the “T1 bis Warrant Shares”) will be held in pure registered form (au nominatif pur) until expiration of the lock-up and thereafter at the option of the holder, in registered form (au nominatif) or in bearer form (au porteur). As soon as they are issued, the T1 bis Shares and T1 bis Warrant Shares will be automatically assimilated to the Company's ordinary shares and will be admitted to trading on the regulated market of Euronext Paris under ISIN number FR0013233012. Lock-up on T1 bis Shares, T1 bis BSAs and T1 bis Warrant Shares Investors participating in the T1 bis Transaction have agreed to a lock-up on the T1 bis Shares, the T1 bis BSAs and the T1 bis Warrant Shares until the earlier of (x) the issuance date of the ABSAs or (y) May 20, 2025, subject to certain exceptions (including transfers to an affiliate to the investor, to another investor, or, subject to the agreement of the Company in its sole discretion, to any third party who makes the same lock-up commitment on the T1 bis Shares and on the T1 bis BSAs and T1 bis Warrant Shares). Representation of T1 bis BSAs The T1 bis BSAs holders will each be grouped automatically for the defense of their common interests in a masse. The masses will act, in part, through a representative and, in part, through collective decisions of the relevant holders. T1 bis Transaction participants BVF Partners LP (“BVF”), which holds approximately 9.8% of the share capital and approximately 8.6% of the voting rights of the Company as of the date hereof and not taking into account the T1 bis Transaction, subscribed to 1,872,668 T1 bis BSAs for an amount of approximately €2.5 million. Assuming the issuance of the T1 bis Shares and the T1 bis BSAs, BVF will hold approximately 9.0% of the share capital of the Company, on a non-diluted basis immediately following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs. New Enterprise Associates (“NEA”), which holds approximately 9% of the share capital and approximately 7.8% of the voting rights of the Company as of the date hereof and not taking into account the T1 bis Transaction, subscribed to 514,846 T1 bis Shares for an amount of approximately €700,000 and to 2,917,464 T1 bis BSAs for an amount of approximately €3.9 million. Assuming the issuance of the T1 bis Shares and the T1 bis BSAs, NEA will hold approximately 8.8% of the share capital of the Company, on a non-diluted basis immediately following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs. Sofinnova Crossover I SLP (“Sofinnova”), which holds approximately 7.4% of the share capital and approximately 7.5% of the voting rights of the Company as of the date hereof and not taking into account the T1 bis Transaction, subscribed to 311,654 T1 bis Shares for an amount of approximately €420,000. Assuming the issuance of the T1 bis Shares and the T1 bis BSAs, Sofinnova will hold approximately 7.1% of the share capital of the Company, on a non-diluted basis immediately following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs. Yiheng Capital Management, L.P., (“Yiheng”), which holds approximately 6.3% of the share capital and approximately 5.5% of the voting rights of the Company as of the date hereof and not taking into account the T1 bis Transaction, subscribed to 370,689 T1 bis Shares for an amount of approximately €500,000. Assuming the issuance of the T1 bis Shares and the T1 bis BSAs, Yiheng will hold approximately 6.2% of the share capital of the Company, on a non-diluted basis immediately following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs. Invus Public Equities, (“Invus”), which holds approximately 8.7% of the share capital and approximately 7.6% of the voting rights of the Company as of the date hereof and not taking into account the T1 bis Transaction, subscribed to 1,372,924 T1 bis Shares for an amount of approximately €1.8 million. Assuming the issuance of the T1 bis Shares and the T1 bis BSAs, Yiheng will hold approximately 9.5% of the share capital of the Company, on a non-diluted basis immediately following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs. Andera Partners, (“Andera”), which holds approximately 5.8% of the share capital and approximately 5.0% of the voting rights of the Company as of the date hereof and not taking into account the T1 bis Transaction, subscribed to 1,139,527 T1 bis Shares for an amount of approximately €1.5 million. Assuming the issuance of the T1 bis Shares and the T1 BSAs, Andera will hold approximately 6.5% of the share capital of the Company, on a non-diluted basis immediately following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs. Perceptive Advisors, (“Perceptive”), which holds approximately 5.2% of the share capital and approximately 4.5% of the voting rights of the Company as of the date hereof and not taking into account the T1 bis Transaction, subscribed to 1,029,693 T1 bis Shares for an amount of approximately €1.3 million and to 343,321 T1 bis BSAs for an amount of approximately €460,000. Assuming the issuance of the T1 bis Shares and the T1 bis BSAs, Perceptive will hold approximately 5.8% of the share capital of the Company, on a non-diluted basis immediately following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs. Governance As previously announced, Mark Pruzanski and Srinivas Akkaraju have been appointed as directors by the shareholders, replacing Pierre Broqua and Sofia BVBA, represented by Chris Buyse, during the General Meeting for a term expiring at the end of the annual general meeting to be held in 2027 to approve the financial statements for the year ending December 31, 2026. The General Meeting also approved (i) a remuneration policy for the Chairperson of the Board of Directors and for the Chief Executive Officer applicable in respect of the current year from the date of separation of the functions of the Chairperson of the Board of Directors and the Chief Executive Officer, (ii) an amendment to the remuneration policy of the Deputy Chief Executive Officer and (ii) an amendment to the remuneration policy of the directors. On December 13, 2024, the Board of Directors acknowledged the separation of the roles of the Chairperson of the Board of Directors and the Chief Executive Officer as well as the appointment of Mark Pruzanski as Chairperson of the Board of Directors and Frédéric Cren as Chief Executive Officer. Up to four new members of the Board of Directors may be appointed or co-opted, during the next general meeting and at the latest, during the general meeting of shareholders convened to approve the financial statements for the year ending December 31, 2025, (other than Frédéric Cren, Mark Pruzanski and Srinivas Akkaraju), one of which upon the proposal of BVF, and three of which upon the proposal of each of the three largest subscribers. Exemption of a French Listing Prospectus The Company, for the purpose of listing the T1 bis Shares and the T1 bis Warrant Shares issuable upon exercise of the T1 bis BSAs on the regulated market of Euronext Paris, is exempt from the requirement to file with the Autorité des marchés financiers a French-language listing prospectus, as these securities are fungible with securities already admitted to trading on the same regulated market, and represent, over a twelve-month period, less than 30% of the number of securities already admitted to trading on the same regulated market in accordance with Article 1(5)(a) of Regulation (EU) 2017/1129 of the European Parliament and of the Council of 14 June 2017, as amended by Regulation (EU) 2024/2809 of 23 October 2024. Impact of the T1 bis Transaction on the share capital Following the settlement and delivery of the T1 bis Shares and the T1 bis BSAs, the Company’s share capital will be €949,497.59, divided into 94,949,759 shares. For illustration purposes, the impact of the issuance of the T1 bis Shares and the T1 bis Warrant Shares (assuming full exercise) on the ownership of a shareholder holding 1% of the Company’s share capital prior to the T1 bis Transaction and not subscribing to it, is as follows (calculation made on the basis of the Company's share capital as of October 30, 2024): Percentage of capital Non-diluted basis Diluted basis(1) Before issuance of the T1 bis Shares and T1 bis BSAs 1% 0.65% After issuance of the T1 bis Shares and the T1 bis BSAs 0.92 % 0.62 % After issuance of the T1 bis Shares and Warrant Shares upon exercise of the T1 bis BSAs 0.85 % 0.58 % (1) Calculations are based on the assumption that all share subscription warrants (BSA) and warrants for the subscription of business creators’ shares (BSPCE) will be exercised and that all allocated free shares (actions gratuites) will vest. Impact of the T1 bis Transaction on shareholders' equity For illustration purposes, the impact of the issuance of the T1 bis Shares and the T1 bis Warrant Shares (assuming full exercise) on the Company's equity per share (calculation made on the basis of the Company's equity at October 30, 2024) is as follows: Equity per share in euros Non-diluted basis Diluted basis(1) Before issuance of the T1 bis Shares and T1 bis BSAs € - 0.21 € -0.14 After issuance of the T1 bis Shares and the T1 bis BSAs € - 0.08 € - 0.06 After issuance of the T1 bis Shares and Warrant Shares upon exercise of the T1 bis BSAs € 0.03 € 0.02 (1) Calculations are based on the assumption that all share subscription warrants (BSA) and warrants for the subscription of business creators' shares (BSPCE) will be exercised and that all allocated free shares (actions gratuites) will vest. Evolution of the shareholding structure in connection with the T1 bis Transaction The shareholding structure of the Company prior to the T1 bis Transaction is set forth below: Shareholding prior to the T1 bis Transaction On a non-diluted basis Shareholders Number of Shares % of share capital Number of voting rights % of voting rights Frédéric Cren 5,612,224 6.45% 11,224,448 11.23% Pierre Broqua 3,882,500 4.56% 7,765,000 7.77% Sub-total – Concert 9,494,724 10.91% 18,989,448 19.0% BVF Partners L.P. 8,545,499 9.81% 8,545,499 8.55% New Enterprise Associates (NEA) 7,835,884 9.00% 7,835,884 7.84% Invus 7,606,810 8.74% 7,606,810 7.61% Sofinnova 6,440,093 7.40% 7,480,654 7.49% Yiheng 5,474,986 6.29% 5,474,986 5.48% Qatar Holding LLC 5,157,233 5.92% 5,157,233 5.16% Andera Partners 5,008,620 5.75% 5,008,620 5.01% Perceptive 4,525,862 5.20% 4,525,862 4.53% Employees 1,338,127 1.54% 2,282,563 2.28% ISLS Consulting 111,000 0.13% 222,000 0.22% Treasury shares 106,115 0.12% - 0.00% Directors (non-executive) 10,000 0.01% 10,000 0.01% Free floats 25,422,742 29.20% 26,799,821 26.81% Total 87,077,695 100.00% 99,939,380 100.00% The issuance of T1 bis Shares and the T1 bis BSAs will have the following impact on the allocation of the share capital and the voting rights of the Company: Shareholding following the issuance of the T1 bis Shares and the T1 bis BSAs On a non-diluted basis Shareholders Number of Shares % of share capital Number of voting rights % of voting rights Frédéric Cren (Family) 5,612,224 5.91% 11,224,448 10.41% Pierre Broqua 3,882,500 4.09% 7,765,000 7.20% Sub-total – Concert 9,494,724 10.00% 18,989,448 17.61% Invus 8,979,734 9.46% 8,979,734 8.33% BVF Partners L.P. 8,545,499 9.00% 8,545,499 7.93% New Enterprise Associates (NEA) 8,350,730 8.79% 8,350,730 7.75% Sofinnova 6,751,746 7.11% 7,792,307 7.23% Andera Partners 6,148,147 6.48% 6,148,147 5.70% Yiheng 5,845,675 6.16% 5,848,675 5.42% Perceptive 5,555,555 5.85% 5,555,555 5.15% Qatar Holding LLC 5,157,233 5.43% 5,157,233 4.78% Eventide 5,059,258 5.33% 5,059,258 4.69% Employees 1,338,127 1.41% 2,282,563 2.12% ISLS Consulting 111,000 0.12% 222,000 0.21% Treasury shares 106,115 0.11% 0 0.00% Directors (non-executive) 10,000 0.01% 10,000 0.01% Free float 23,496,216 24.75% 24,873,295 23.07% Total 94,949,759 100.00% 107,811,444 100.00% About Inventiva Inventiva is a clinical-stage biopharmaceutical company focused on the research and development of oral small molecule therapies for the treatment of patients with MASH and other diseases with significant unmet medical need. The Company benefits from a strong expertise and experience in the field of compounds targeting nuclear receptors, transcription factors and epigenetic modulation. Inventiva is currently advancing one clinical candidate, has a pipeline of two preclinical programs and continues to explore other development opportunities to add to its pipeline. Inventiva’s lead product candidate, lanifibranor, is currently in a pivotal Phase III clinical trial, NATiV3, for the treatment of adult patients with MASH, a common and progressive chronic liver disease. Inventiva’s pipeline also includes odiparcil, a drug candidate for the treatment of adult MPS VI patients. As part of Inventiva’s decision to focus clinical efforts on the development of lanifibranor, it suspended its clinical efforts relating to odiparcil and is reviewing available options with respect to its potential further development. Inventiva is also in the process of selecting a candidate for its Hippo signaling pathway program. The Company has a scientific team of approximately 90 people with deep expertise in the fields of biology, medicinal and computational chemistry, pharmacokinetics and pharmacology, and clinical development. It owns an extensive library of approximately 240,000 pharmacologically relevant molecules, approximately 60% of which are proprietary, as well as a wholly owned research and development facility. Inventiva is a public company listed on compartment B of the regulated market of Euronext Paris (ticker: IVA, ISIN: FR0013233012) and on the Nasdaq Global Market in the United States (ticker: IVA). www.inventivapharma.com Contacts Inventiva Pascaline ClercEVP of Global External Affairsmedia@inventivapharma.com +1 202 499 8937 Brunswick GroupTristan Roquet Montegon /Aude Lepreux /Julia CailleteauMedia relationsinventiva@brunswickgroup.com +33 1 53 96 83 83 Westwicke, an ICR CompanyPatricia L. BankInvestor relationspatti.bank@westwicke.com +1 415 513-1284 Important NoticeThis press release contains certain “forward-looking statements” within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this press release are forward-looking statements. These statements include, but are not limited to, forecasts and estimates with respect to Inventiva’s cash resources, the anticipated proceeds from the T1 bis Transaction and Inventiva’s expected use of such proceeds, satisfaction of the closing conditions and timing of closing, settlement and delivery of the T1 bis Transaction, Inventiva’s cash position following the closing of the T1 bis Transaction, the satisfaction in part or full of the T2 Conditions Precedent, the occurrence of the T3 Triggering Event, the anticipated proceeds from Tranche 2 of the Multi-Tranche Financing and the exercise by the investors of the warrants and pre-funded warrants issued or to be issued in connection with the Multi-Tranche Financing, Inventiva’s expectations with respect to ownership in its share capital by certain investors, forecasts and estimates with respect to Inventiva’s pre-clinical programs and clinical trials, including design, protocol, duration, timing, recruitment, costs, screening and enrollment for those trials, including the ongoing NATiV3 Phase III clinical trial of lanifibranor in MASH, and the results and timing thereof and regulatory matters with respect thereto, clinical trial data releases and publications, the information, insights and impacts that may be gathered from clinical trials, potential regulatory submissions, approvals and commercialization, Inventiva’s pipeline and preclinical and clinical development plans, the clinical development of and regulatory plans and pathway for lanifibranor, and future activities, expectations, plans, growth and prospects of Inventiva. Certain of these statements, forecasts and estimates can be recognized by the use of words such as, without limitation, “believes”, “anticipates”, “expects”, “intends”, “plans”, “seeks”, “estimates”, “may”, “will”, “would”, “could”, “might”, “should”, “designed”, “hopefully”, “target”, “potential”, “opportunity”, “possible”, “aim”, and “continue” and similar expressions. Such statements are not historical facts but rather are statements of future expectations and other forward-looking statements that are based on management's beliefs. These statements reflect such views and assumptions prevailing as of the date of the statements and involve known and unknown risks and uncertainties that could cause future results, performance, or future events to differ materially from those expressed or implied in such statements. Actual events are difficult to predict and may depend upon factors that are beyond Inventiva's control. There can be no guarantees with respect to pipeline product candidates that the clinical trial results will be available on their anticipated timeline, that future clinical trials will be initiated as anticipated, that product candidates will receive the necessary regulatory approvals, or that any of the anticipated milestones by Inventiva or its partners will be reached on their expected timeline, or at all. Future results may turn out to be materially different from the anticipated future results, performance or achievements expressed or implied by such statements, forecasts and estimates due to a number of factors, including that interim data or data from any interim analysis of ongoing clinical trials may not be predictive of future trial results, the recommendation of the DMC may not be indicative of a potential marketing approval, Inventiva cannot provide assurance on the impacts of the Suspected Unexpected Serious Adverse Reaction on enrollment or the ultimate impact on the results or timing of the NATiV3 trial or regulatory matters with respect thereto, that Inventiva is a clinical-stage company with no approved products and no historical product revenues, Inventiva has incurred significant losses since inception, Inventiva has a limited operating history and has never generated any revenue from product sales, Inventiva will require additional capital to finance its operations, in the absence of which, Inventiva may be required to significantly curtail, delay or discontinue one or more of its research or development programs or be unable to expand its operations or otherwise capitalize on its business opportunities and may be unable to continue as a going concern, Inventiva’s ability to obtain financing, to enter into potential transactions and Inventiva’s ability to satisfy in part or full the closing conditions for the T1 bis Transaction and T2 Conditions Precedent, and whether and to what extent the prefunded warrants issued in connection with the Multi-Tranche Financing may be exercised and by which holders, Inventiva's future success is dependent on the successful clinical development, regulatory approval and subsequent commercialization of current and any future product candidates, preclinical studies or earlier clinical trials are not necessarily predictive of future results and the results of Inventiva's and its partners’ clinical trials may not support Inventiva's and its partners’ product candidate claims, Inventiva's expectations with respect to its clinical trials may prove to be wrong and regulatory authorities may require holds and/or amendments to Inventiva’s clinical trials, Inventiva’s expectations with respect to the clinical development plan for lanifibranor for the treatment of MASH may not be realized and may not support the approval of a New Drug Application, Inventiva and its partners may encounter substantial delays beyond expectations in their clinical trials or fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities, the ability of Inventiva and its partners to recruit and retain patients in clinical studies, enrollment and retention of patients in clinical trials is an expensive and time-consuming process and could be made more difficult or rendered impossible by multiple factors outside Inventiva's and its partners’ control, Inventiva's product candidates may cause adverse drug reactions or have other properties that could delay or prevent their regulatory approval, or limit their commercial potential, Inventiva faces substantial competition and Inventiva’s and its partners' business, and preclinical studies and clinical development programs and timelines, its financial condition and results of operations could be materially and adversely affected by geopolitical events, such as the conflict between Russia and Ukraine and related sanctions, impacts and potential impacts on the initiation, enrollment and completion of Inventiva’s and its partners’ clinical trials on anticipated timelines and the conflict in the Middle East and the related risk of a larger conflict, health epidemics, and macroeconomic conditions, including global inflation, fluctuations in interest rates, uncertain financial markets and disruptions in banking systems. Given these risks and uncertainties, no representations are made as to the accuracy or fairness of such forward-looking statements, forecasts, and estimates. Furthermore, forward-looking statements, forecasts and estimates only speak as of the date of this press release. Readers are cautioned not to place undue reliance on any of these forward-looking statements. Please refer to the Universal Registration Document for the year ended December 31, 2023 filed with the Autorité des Marchés Financiers on April 3, 2024 as amended on October 14, 2024 and the Annual Report on Form 20-F for the year ended December 31, 2023 filed with the Securities and Exchange Commission (the “SEC”) on April 3, 2024 and the Half-Year Report for the six months ended June 30, 2024 on Form 6-K filed with the SEC on October 15, 2024 for other risks and uncertainties affecting Inventiva, including those described under the caption “Risk Factors”, and in future filings with the SEC. Other risks and uncertainties of which Inventiva is not currently aware may also affect its forward-looking statements and may cause actual results and the timing of events to differ materially from those anticipated. All information in this press release is as of the date of the release. Except as required by law, Inventiva has no intention and is under no obligation to update or review the forward-looking statements referred to above. Consequently, Inventiva accepts no liability for any consequences arising from the use of any of the above statements. DisclaimersThis press release does not constitute an offer to sell or the solicitation of an offer to buy securities in any jurisdiction, and shall not constitute an offer, solicitation or sale in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of that jurisdiction.The distribution of this document may, in certain jurisdictions, be restricted by local legislations. Persons into whose possession this document comes are required to inform themselves about and to observe any such potential local restrictions. France The T1 bis Shares and the T1 bis BSAs (the “Securities”) have not been and will not be offered or sold to the public in France (except for public offerings defined in Article L.411-2 1° of the French Monetary and Financial Code).The Securities may only be offered or sold in France pursuant to Article L. 411-1 of the French Monetary and Financial Code to “qualified investors” (as such term is defined in Article 2(e) of Prospectus Regulation) acting for their own account, and in accordance with Articles L. 411-1, L. 411-2 and D. 411-2 to D.411-4 of the French Monetary and Financial Code.This announcement is not an advertisement and not a prospectus within the meaning of the Prospectus Regulation. European Economic AreaIn relation to each Member State of the European Economic Area (each, a ‘‘Member State’’) no offer to the public of Securities may be made in that Member State other than: to any legal entity which is a ‘‘qualified investor’’ as defined in the Prospectus Regulation;to fewer than 150 natural or legal persons (other than a qualified investor as defined in the Prospectus Regulation), subject to obtaining the prior consent of the representatives of the Placement Agents for any such offer; orin any other circumstances falling within Article 1(4) of the Prospectus Regulation, provided that no such offer of Securities shall require us or any Placement Agent to publish a prospectus pursuant to Article 3 of the Prospectus Regulation or supplement a prospectus pursuant to Article 23 of the Prospectus Regulation and each person who initially acquires any shares or to whom any offer is made will be deemed to have represented, acknowledged and agreed to and with each of the Placement Agents and the Company that it is a ‘‘qualified investor’’ as defined in the Prospectus Regulation. For the purposes of this provision, the expression an ‘‘offer to the public’’ in relation to any Securities in any Member State means the communication in any form and by any means of sufficient information on the terms of the offer and any Securities to be offered so as to enable an investor to decide to purchase any ordinary shares. United Kingdom This document is only being distributed to, and is only directed at, persons in the United Kingdom that (i) are “investment professionals” falling within Article 19(5) of the Financial Services and Markets Act 2000 (Financial Promotion) Order 2005 (as amended, the “Order”), (ii) are persons falling within Article 49(2)(a) to (d) (“high net worth companies, unincorporated associations, etc.”) of the Order, or (iii) are persons to whom an invitation or inducement to engage in investment activity (within the meaning of Article 21 of the Financial Services and Markets Act 2000) in connection with the issuance or sale of any securities may otherwise lawfully be communicated or caused to be communicated (all such persons together being referred to as “Relevant Persons”). This document is directed only at Relevant Persons and must not be acted on or relied on by persons who are not Relevant Persons. Any investment or investment activity to which this document relates is available only to Relevant Persons and will be engaged in only with Relevant Persons. United States of America This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities in the United States of America, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.None of the securities issued or to be issued in connection with the Multi-Tranche Financing have been registered under the Securities Act of 1933, as amended, and such securities may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements. 1 Press release of October 14, 20242 The long-term deposit had a two year-term, were accessible prior to the expiration of the term with a notice period of 31 days and were considered as liquid by the Company3 This estimate is based on the Company’s current business plan and excludes any proceeds from subsequent tranches of the Multi-Tranche Financing, potential milestones payable to or by the Company and any additional expenditures related to the potential continued development of the odiparcil program or resulting from the potential in licensing or acquisition of additional product candidates or technologies, or any associated development the Company may pursue. The Company may have based this estimate on assumptions that are incorrect, and the Company may end up using its resources sooner than anticipated. Attachment Inventiva - PR - Financing T1bis - EN - 12 16 2024

“ 点击蓝字 关注我们 王多伟 中国药科大学特聘副研究员，硕士生导师，药理学博士，曾于 2018 年赴美国医学院Albert Einstein College of Medical 从事博士后研究工作。目前已在国际重要学术期刊 PNAS、Gut、Cell Rep、Hepatology、Cancer Lett 等发表 SCI 论文 10 余篇。主持国家自然科学基金面上项目及青年项目各 1 项。主要研究方向为肝癌治疗靶标的发现和确证，抗体及新抗原疫苗等肝癌治疗产品的研发。 肝纤维化发生机制及相关治疗药物研究进展PPS  郭飞宇，王多伟 * （中国药科大学多靶标天然药物全国重点实验室，江苏 南京 211198） [摘要] 肝损伤引起的肝细胞死亡会导致肌成纤维细胞激活，进而分泌大量细胞外基质，造成肝纤维化。肝纤维化是慢性肝病向肝硬化发展过程中的关键步骤，但目前临床上公认有效的肝纤维化治疗药物较少。因此，深入了解肝纤维化的发生机制并寻找其新的治疗靶点十分重要。对肝纤维化发生机制以及临床治疗药物研究进展进行综述，以期为肝纤维化的预防和治疗提供参考。 1 引言 肝脏疾病每年导致全球近 200 万人死亡，对人类健康造成严重威胁 [1]。肝纤维化是病毒性肝炎、酒精性肝病、代谢功能障碍相关的脂肪性肝炎（metabolic dysfunction-associated steatohepatitis，MASH）、胆汁淤积性肝病等晚期慢性肝病的共同病理特征 [2]。肝损伤引起肝细胞大量死亡后，细胞外基质蛋白和纤维结缔组织会在肝脏中过度沉积，造成纤维化 [3-4]。随后，肝纤维化产生的过量纤维进一步改变肝脏结构，形成瘢痕和再生结节，从而导致肝功能异常和肝脏血流阻力增加 [5]。目前，临床有效的肝纤维化治疗药物较少，且局限于控制病因的药物和中药。因此，深入了解肝纤维化发生发展机制，寻找新的肝纤维化治疗靶点，对于解决肝纤维化治疗难题至关重要。本文对肝纤维化发生机制及临床治疗药物研究进展进行综述，旨在为肝纤维化的预防和治疗提供参考。 2 肝纤维化的发生机制 肝纤维化发生机制涉及多种复杂因素，主要包括肝细胞损伤、炎症反应、肝星状细胞（hepatic stellate cell，HSC）激活和细胞外基质沉积。其中肝损伤是肝纤维化发生的基础，当肝脏受到酒精、药物、病毒或代谢异常等刺激时，肝细胞遭受损伤，主要表现为细胞膜流动性降低和通透性增加以及线粒体受损。随后肝损伤引起白细胞介素（interleukin，IL）-1β 等炎症因子释放，诱导 HSC 活化。激活的HSC 转化为肌成纤维细胞，迁移至损伤部位，加速增殖并分泌细胞外基质，导致纤维化的形成 [5]。以下将从慢性肝炎病毒感染、酒精性肝损伤、代谢功能障碍相关肝损伤和胆汁淤积性肝损伤 4 个方面介绍肝纤维化的发生机制。 2.1 慢性肝炎病毒感染 慢性肝炎病毒感染是影响全球数亿人的重要健康问题，其中慢性乙型肝炎患者数量超过 2.57 亿，慢性丙型肝炎患者数量超过 1.5 亿 [6]。慢性肝炎病毒感染可以进一步发展为肝纤维化，其机制主要涉及炎症反应和 HSC 的激活。  肝炎病毒感染可损伤肝细胞并直接引起炎症反应。乙型肝炎病毒（hepatitis B virus，HBV）感染肝细胞后，病毒的 X 蛋白通过髓样分化初级应答蛋白88（myeloid differentiation primary response protein 88，MyD88）途径促进 IL-6 的分泌，加剧肝脏炎症 [7]。而丙型肝炎病毒（hepatitis C virus，HCV）的核心蛋白和 NS3 蛋白通过 Toll 样受体 2（Toll like receptor 2，TLR2），激活 IL-1 受体相关激酶（IL-1 receptor-associated kinase，IRAK）和激活蛋白-1（activator protein-1，AP-1），引起炎症反应 [8]。同时，肝细胞被 HCV 感染后还可以分泌 C-C 基序趋化因子配体（C-C motif chemokine ligand，CCL）2 和 CCL21 等趋化因子，招募淋巴细胞，加剧肝脏炎症 [9]。慢性肝炎病毒除了通过感染并损伤肝细胞来引起炎症反应，还可以通过 HSC 加剧肝脏炎症，研究表明，在乙型肝炎肝纤维化晚期患者中，HSC通过前列腺素 E2（prostaglandin E2，PGE2）/前列腺素 E 受体 2（prostaglandin E receptor 2，EP2）途径以及 PEG2/EP4 途径增加肝组织中辅助性 T 细胞17（T helper cell 17，Th17）的数量 [10]，而 Th17 通过分泌IL-6、IL-17和IL-23等炎症因子，引发炎症[11]。此外，HSC 与 HCV 感染的肝细胞共培养时，HSC可通过分泌 IL-1α 上调肝细胞中 CCAAT/增强子结合蛋白 β（CCAAT/enhancer binding protein β，C/EBP β）的表达，促进肝细胞分泌 IL-6 等炎症因子，加剧肝脏炎症 [12]。以上研究表明，HBV 和 HCV 不仅可以直接损伤肝细胞、造成炎症，还可以通过HSC 间接作用于肝细胞，进而加剧肝脏炎症，最终促进肝纤维化进程 [13-15]。 HSC 的活化是肝纤维化形成的关键因素，激活的 HSC 转化为肌成纤维细胞 [16]，分泌细胞外基质，导致肝纤维化的形成。HBV 和 HCV 感染通过激活HSC 促进肝纤维化进程。HBV 的 X 蛋白通过 c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）和细胞外信号调节激酶（extracellular signal-regulated kinase，ERK）信号通路，促进肝细胞分泌结缔组织生长因子（connective tissue growth factor，CTGF）等促纤维化因子，激活 HSC[17]，同时 HBV 感染的肝细胞还会通过分泌含有 miRNA-222 的外泌体激活 HSC[18]。感染 HCV 的肝细胞通过分泌转化生长因子-β（transforming growth factor-β，TGF-β）和血小板衍生生长因子（platelet-derived growth factor，PDGF），诱导 HSC 活化，同时通过抑制自然杀伤细胞分泌 γ 干扰素（interferon-γ，IFN-γ）， 抑制HSC 的凋亡 [19]，从而促进肝纤维化进程。慢性肝炎病毒感染引起肝纤维化的过程复杂，其机制涉及多条信号通路的激活，相关信号通路及其激活机制与作用如表 1 所示。 2.2 酒精性肝损伤   全球每年约有 300 万人因有害使用酒精死亡，占总死亡人数的 5.3%。酒精可通过其代谢物乙醛、氧化应激反应、线粒体功能障碍、脂肪积聚和肠道微生物紊乱造成肝损伤，导致肝脏炎症并进一步发展为肝纤维化 [25]。  乙醇在肝脏中代谢产生乙醛，乙醛与肝细胞的蛋白质、核酸和脂质形成加合物，进而引起内质网应激反应与未折叠蛋白反应（unfolded protein response，UPR），造成肝细胞损伤 [26]。此外，长期饮酒会诱导细胞色素 P450 2E1（cytochrome P450 2E1，CYP2E1）表达增加，其产生 ROS，从而引起氧化应激反应，造成肝细胞损伤 [9]。乙醇摄入还会导致线粒体功能障碍，主要表现为线粒体去极化和线粒体自噬 [27]，线粒体功能障碍造成的能量代谢异常可促进 ROS 产生，引起氧化应激并损伤肝细胞。乙醇还可以通过激活固醇调节元件结合蛋白（sterol regulatory element binding protein，SREBP）1 或SREBP2，促进脂肪酸和胆固醇的合成，导致肝细胞积聚脂滴、小叶中心气球样病变和Mallory小体形成，引起肝损伤 [9]。有研究表明，乙醇及其代谢产物会导致微生物合成饱和长链脂肪酸减少，介导肠道微生物群紊乱，造成肝损伤 [28]。研究发现，粪肠球菌在酒精性肝炎患者粪便中显著增加，其分泌的溶细胞素会造成肝细胞损伤，且溶细胞素阳性的粪肠球菌数量与肝病的严重程度及患者死亡率呈显著正相关 [29]，以上研究表明肠道微生物失调在酒精性肝损伤中也扮演了重要角色。  肝细胞损伤后会释放损伤相关的分子模式（damage associated molecular pattern，DAMP），并通过 TLR4 造成肝脏炎症 [30]。另外，长期饮酒会引起肠道通透性增加和细菌过度繁殖，促进脂多糖（lipopolysaccharide，LPS）从肠道入血 [31]。LPS 作为一种内毒素，在肝脏中激活巨噬细胞的 TLR4，并通过 MyD88 依赖途径和 MyD88 非依赖途径，引起炎症反应 [32]。其中 MyD88 依赖途径通过激活巨噬细胞的 NF-κB 信号通路，诱导巨噬细胞分泌肿瘤坏死因子 -α（tumor necrosis factor-α，TNF-α）等炎症因子，导致炎症反应 [33]。在 MyD88 非依赖途径中，能诱导产生 β 干扰素的含 TIR 结构域的衔 接 蛋 白（TIR domain-containing adaptor inducing interferon-β，TRIF）和 TRIF 相关接头分子（TRIFrelatedadaptor molecule，TRAM） 形成复合物，导致 κB 抑制因子激酶（inhibitor of κB kinase，IKK）的募集，诱导干扰素调节因子 3（interferon regulatory factor 3，IRF3）的磷酸化，从而诱导巨噬细胞分泌 IFN-β 等炎症因子 [34]，导致炎症反应。而 TNF-α 等炎症因子可以招募中性粒细胞和骨髓来源巨噬细胞（bone marrow-derived macrophage，BMDM），并促使其释放 ROS 和炎症因子，进一步加剧肝脏炎症。另外，这些炎症因子还会激活肌成纤维细胞，促进其分泌细胞外基质和 TGF-β 等促纤维化因子，促进肝纤维化进程 [35-36]（见图 1）。 2.3 代谢功能障碍相关肝损伤  代谢功能障碍相关的脂肪性肝病（metabolic dysfunction-associated steatotic liver disease，MASLD）是常见的慢性肝脏疾病，全球患病率约为25%[37]，其主要病理特征为脂肪积累。肝细胞的脂肪积累可进一步导致肝细胞线粒体功能障碍、内质网应激和氧化应激，引起肝细胞损伤 [38]。MASLD中脂肪积累由脂肪酸转运蛋白（fatty acid transport protein，FATP）表达增加、过氧化物酶体增殖物激活受体 γ（peroxisome proliferator activated receptor γ，PPARγ）激活和蛋氨酸胆碱缺乏（methioninecholine-deficient，MCD）饮食引起。FATP主要负责促进脂肪酸的吸收，其在 MASLD 发展过程中表达增加。研究发现，敲除 FATP 可显著减轻高脂小鼠肝脏中脂肪积累，提示 FATP 在 MASLD 中发挥重要作用 [39]。PPARγ 是关键的脂肪生成调节因子，在MASLD 中被脂肪酸、二十烷酸和氧化磷脂激活 [40]，促进脂肪生成并导致脂肪积累。蛋氨酸和胆碱对磷脂和极低密度脂蛋白（very low density lipoprotein，VLDL）的合成十分重要，使用 MCD 饲料喂养动物，可以限制动物摄入蛋氨酸和胆碱，导致其肝细胞无法有效合成磷脂和分泌 VLDL，从而引起脂肪积累和肝脏损伤 [41]，表明蛋氨酸和胆碱是维持正常肝脏功能和脂肪代谢的重要营养素，MCD 通过抑制磷脂合成和 VLDL 分泌，引起脂肪积累。 MASH 由 MASLD 进展而来，全球患病率约为 3% ~ 5% [42]。与 MASLD 单纯的脂肪积累不同，MASH 的病理特征还包括炎症和纤维化，这与其过程中的炎症反应和 HSC 激活密切相关。 研究表明，MASH 通过内质网应激增加Caspase-2 表达，后者通过激活 SREBP，引起肝细胞中胆固醇与甘油三酯的过量积累，从而增加脂毒性，加剧肝脏炎症 [43]。研究表明，白细胞分化抗原36（cluster of differentiation 36，CD36） 在 MASH患者肝细胞质膜上表达增加。CD36 是一种脂肪酸转移酶，其棕榈酰化可以调节自身分布与功能，抑制 CD36 棕榈酰化不仅可以改善脂肪酸代谢紊乱，还能减轻炎症反应，为 MASH 提供了新的治疗策略 [44]。临床上，MASH 患者常出现肠道通透性增加，这导致 LPS 可以通过门静脉进入肝脏，LPS 的入侵进一步激活 Kupffer 细胞，促使其产生 IL-1β、TNF-β、IL-6 等促炎因子，并招募单核细胞，最终加剧肝脏炎症 [45]。 MASH 中的炎症状态诱导免疫细胞释放PDGF、TGF-β、TNF-α、IL-1 等细胞因子，并通过诱导 HSC 的活化与增殖促进肝纤维化进程。研究显示，用脂肪酸处理的 HepG2 细胞，在缺氧诱导因子 -1α（hypoxia inducible factor-1α，HIF-1α）的稳定剂氯化钴的化学诱导下发生缺氧后，可以分泌细胞外囊泡（extracellular vesicle，EV），激活 LX-2细胞，这表明 MASH 中局部的缺氧环境可能通过促进肝细胞分泌 EV 激活 HSC，从而促进肝纤维化进程 [46]。同时，研究发现 MASH 患者中骨形态发生蛋白 8B（bone morphogenetic protein 8B，BMP8B）表达增 加，BMP8B 属于 TGF-β 超家族，其可通过SMAD2/3 和 SMAD1/5/9 途径激活 HSC，造成肝纤维化。鉴于健康肝脏中 BMP8B 表达较低，抑制 BMP8B 可能成为 MASH 的潜在治疗方法 [47]。此外，高脂高糖饮食引起的肠道菌群失调通过促进病原体相关分子模式（pathogen-associated molecular pattern，PAMP）释放，激活 TLR 信号通路，诱导HSC 活化，促进肝纤维化进程 [48]。 2.4 胆汁淤积性肝损伤 胆汁淤积性肝病是由胆汁淤积、胆管进行性破坏和持续肝内炎症引起的一类慢性肝病，可进一步发展为肝纤维化和胆汁性肝硬化 [49]。此类疾病包括原发性胆汁性肝硬化（primary biliary cirrhosis，PBC）和原发性硬化性胆管炎（primary sclerosing cholangitis，PSC），其主要病理特征为胆汁分泌异常和胆管阻塞 [50]。在不同地区，PBC 的患病率为 1.91/100 000 ~ 40.2/100 000，而 PSC 的患病率为 0 ~ 31.7/100 000[51]。胆汁淤积性肝损伤引起肝纤维化的机制主要涉及胆汁酸淤积和胆管反应。  胆汁酸淤积是肝纤维化发展过程中的关键起始因素，由胆管阻塞或胆汁分泌异常引起，可以诱导线粒体产生氧化应激，从而引起线粒体受损和细胞死亡。胆汁酸转运蛋白在维持胆汁酸稳态方面起重要作用，可以避免肝脏中的胆汁酸淤积 [9]，但在胆汁淤积性肝损伤中，维生素 D 受体（vitamin D receptor，VDR）可通过抑制胆盐输出泵（bile salt export pump，BSEP）的表达，引起胆汁酸淤积，加剧肝脏炎症 [52]。  胆汁酸淤积还会引起胆管反应，并促进肌成纤维细胞的活化和增殖 [53]，胆管反应以胆管细胞增殖、基质变化和炎症细胞浸润为主要病理特征。胆汁淤积引起的炎症反应会促进骨髓来源的IBA1+CD16lowCD163low 巨噬细胞浸润至肝脏非实质区，激活胆管反应 [54]。胆管反应可以促进胆管上皮细胞分泌 TGF-β、CTGF、血小板衍生生长因子B 亚基（platelet-derived growth factor-BB，PDGFBB）和内皮素-1（endothelin-1，ET-1），形成复杂的细胞因子网络，诱导 HSC 转化为肌成纤维细胞，并促进肌成纤维细胞增殖 [55]。此外，研究表明，胆汁来源的 NF-κB 诱导激酶（NF-κB-inducing kinase，NIK）在胆管反应中起调节作用，通过 IL1β、IL-4、IL-6、诱导型一氧化氮合酶（induciblenitric oxide synthase，iNOS）、TNF-α、CCL2 和TGF-β 等细胞因子激活巨噬细胞与 HSC，发挥促炎促纤维化作用 [56]。 3 肝纤维化治疗药物相关研究 当前，肝纤维化的治疗药物主要通过对致病因素（如病毒、乙醇、代谢功能障碍）的根除，以及对肝纤维化病灶的治疗和对疾病发展过程的遏制与逆转，保护肝脏结构与功能。以下根据肝纤维化药物的作用靶点，从抗病毒、抗酒精性肝损伤、代谢调节及抗纤维化 4 个方面对已经批准上市和处于临床研究阶段的肝纤维化治疗药物进行总结。肝纤维化因其病因复杂以及治疗难度大，目前临床上有效的治疗药物较少，仅有一种药物 [ 瑞司美替罗（resmetirom）] 上市，而 selonsertib、emricasan、irbesartan、cenicriviroc 等临床候选药物已被陆续宣告其临床研究的失败 [49]，因此，肝纤维化治疗药物的研发仍是重点及难点。 3.1 抗病毒药物 对于由病毒性肝炎引起的肝纤维化，抗病毒治疗是首选方法。有效的抗病毒治疗可以减少病毒复制，从而减轻肝脏的炎症和纤维化。目前，抗 HBV药物聚乙二醇干扰素 α-2a[57] 和抗 HCV 药物利巴韦林 [58] 已获批上市。此外，Cai 等 [59] 报道了抗肝纤维化新药羟尼酮（hydronidone）用于治疗乙型肝炎肝纤维化患者的Ⅱ期临床研究结果。该研究采用随机、双盲、对照试验方案，将恩替卡韦（entecavir）作为基础治疗药物，3 种不同剂量的羟尼酮作为联合治疗药物。结果显示，使用中剂量（270 mg · d-1）的羟尼酮进行联合治疗取得了 56.1% 的肝纤维化逆转率，因此，羟尼酮针对乙型肝炎纤维化的治疗极具前景。目前该药的临床研究已推进至Ⅲ期。 3.2 抗酒精性肝损伤药物 过量饮酒是肝病发生的主要原因之一 [60]，酗酒会导致一系列肝损伤，其被统称为酒精相关肝病。近年来，酒精性肝损伤发展至肝纤维化的发病率呈上升趋势。 目前，已有治疗酒精性肝病的药物上市，包括美他多辛（metadoxine）、还原型谷胱甘肽钠（reduced glutathione sodium）和硫普罗宁（tiopronin）。研究表明，美他多辛可以通过激活乙醛脱氢酶，促进乙醇和乙醛的代谢，从而减少乙醇和乙醛毒性作用时间，治疗酒精性肝损伤 [61]。其也可以发挥抗氧化作用，进而预防由乙醇和乙醛引起的谷胱甘肽耗竭，维持胞内的氧化还原平衡，并降低 TNF-α 水平，从而治疗酒精性肝损伤 [62]。硫普罗宁可通过促进乙醇代谢，抑制甘油三酯在肝脏中的积聚，维持肝细胞谷胱甘肽浓度以及抑制过氧化物的产生，从而治疗酒精性肝损伤 [63]。  坎地沙坦（candesartan）作为一种抗肾素药物，可以阻断血管紧张素Ⅱ 1 型受体（angiotensin II type 1 receptor，AT1-R）。有研究选取了 85 例经肝活检确诊的酒精性肝损伤相关的中度肝纤维化患者并随机分组，进行坎地沙坦和熊去氧胆酸联合治疗或单独给予熊去氧胆酸治疗。采用 Laennec 组织病理学分级系统进行评估，坎地沙坦组在肝纤维化的组织学改善方面显著优于对照组（33.3% vs 11.6%，P = 0.020）；此 外，采 用 NAS 评分系统进行分析，结果显示坎地沙坦组的纤维化评分从治疗前的（3.4±1.4）降至（3.1±1.5）（P = 0.005），而 对照组无显著变化 [64]。上述结果表明坎地沙坦对酒精性肝纤维化患者具有治疗作用。  瑞沙托维（resatorvid）作为 TLR4 的抑制剂，可以与 TLR4 胞内区域结合，从而抑制 LPS 引起的炎症反应与肝细胞损伤，并减少 TNF-α 和 IL-6 等炎症因子产生，进而减少肝细胞死亡 [65]。此外，瑞沙托维还可以抑制成纤维细胞的分化与胶原合成 [66]，提示该药对肝纤维化有潜在的治疗效果。已有研究表明，瑞沙托维可抑制小鼠的肝纤维化进程 [67]。目前，该候选药物正处于治疗酒精性肝病的Ⅱ期临床研究阶段。  3.3 代谢调节剂 MASLD 和 MASH 是由代谢性疾病引起的进行性慢性肝脏疾病，可导致肝脏炎症和纤维化，最终演变为肝硬化和肝细胞癌。甲状腺激素在调节肝脏脂代谢中起关键作用，β 型甲状腺激素抵抗（resistance to thyroid hormone β，RTHβ）综合征患者由于 THR 基因突变，导致肝脏对甲状腺激素的敏感性降低。研究表明 RTHβ 患者循环中的游离脂肪酸浓度升高，肝脏中出现脂肪变性，该研究结果提示甲状腺激素对肝脏脂质代谢具有重要作用，并为针对甲状腺激素受体-β（thyroid hormone receptor-β，THR-β） 的选择性激动剂的开发提供了依据 [68]。研究表明，甲状腺功能减退症可能是 MASH 发病的驱动因素 [69]。生理条件下，甲状腺释放的四碘甲状腺原氨酸（T4）被碘甲状腺原氨酸脱碘酶 1（deiodinase，DIO1）脱碘为肝脏中代谢活跃的游离三碘甲状腺原氨酸（T3）。游离 T3 可以和 THR-β 结合，并促进其与类视黄醇 X 受体（retinoid X receptor，RXR）形成异二聚体，从而改变肉碱棕榈酰转移酶1（carnitine palmitoyltransferase 1，CPT1）的转录。而 CPT1 可通过调节线粒体脂肪酸氧化以及抑制固醇调节元件结合转录因子 1（sterol regulatory element binding transcription factor 1，Srebf1）活性，减少脂肪生成。而在 MASH 和晚期纤维化患者中，肝内甲状腺激素信号传导受损，这会抑制 DIO1 将游离 T4 转化为游离 T3，并促进 DIO3 将游离 T4 转化为无活性反向T3（rT3），从而导致脂毒性物质的进一步积累 [69-70]。瑞司美替罗是一种靶向肝脏、小分子口服的 THR-β选择性激动剂，其摄取过程由肝脏特异性的有机阴离子转运多肽1B1（organic anion transporting polypeptide 1B1，OATP1B1）介导，可以模拟甲状腺激素对 THR-β 的激动作用，降低肝脏脂质含量，缓解肝脏炎症和纤维化 [69-70]。 3.4 抗纤维化药物 抗纤维化药物针对肝纤维化的病灶及发展过程进行遏制与逆转，从而保护肝脏结构与功能，该类药物包括奥贝胆酸（obeticholic acid）和氟非尼酮（fluorofenidone）。  氟非尼酮是一种小分子吡啶类药物，具有广谱抗纤维化和抗炎作用。其可作用于活化的 HSC，靶向 TGF-β1 介导的细胞信号通路，减轻肝纤维化。同时，氟非尼酮对肝纤维化大鼠有显著的治疗作用，能明显减轻其肝损伤及纤维化程度，减轻肝小叶的结构破坏及汇管区纤维组织的异常增生 [71]。 Intercept Pharmaceuticals 公司已提交将奥贝胆酸用于治疗肝纤维化的上市申请。奥贝胆酸是鹅去氧胆酸（chenodiol，CDCA）的类似物，具有胆汁酸样特性，因此可以通过肠肝循环在肝脏和胃中激活法尼醇X 受体（farnesoid X receptor，FXR），从而治疗肝脂肪变性、炎症和纤维化并提高胰岛素敏感性 [72]。  此外，利福昔明-α 是一种不可吸收的抗生素，目前已成为酒精性肝纤维化的一种潜在治疗药物 [73]。其主要通过减少酒精性肝损伤中肠道菌群的促纤维化作用，抑制 LPS 对 TLR4 的激活，进而减少 HSC和内皮细胞产生纤连蛋白 [74]，由此治疗酒精性肝损伤相关的肝纤维化。目前已开展该药治疗酒精性肝损伤相关的肝纤维化的Ⅱ期临床试验 [75]。 3.5 小结 随着对肝纤维化发生发展机制认识的不断加深，针对该疾病领域的药物研发也呈现出蓬勃发展的态势。表 2 总结了当前处于Ⅱ、Ⅲ期临床阶段及已上市的常见肝纤维化治疗药物的相关信息，包括其药物类型、作用机制、适应证和研发阶段（见表2）。 4 结语与展望 肝纤维化是慢性肝病进程中的关键步骤，其导致肝脏结构和功能异常，严重影响患者的生存率和生活质量。肝损伤是肝纤维化发展的基础，本文从慢性肝炎病毒感染、酒精性肝损伤、代谢功能障碍相关肝损伤和胆汁淤积性肝损伤 4 个角度系统地介绍了肝纤维化的发生机制。在肝纤维化治疗方面，目前临床有效药物较少，大部分处于研究阶段。本文根据肝纤维化药物的作用靶点，从抗病毒药物、抗酒精性肝损伤药物、代谢调节剂及抗纤维化药物4 个方面总结了目前已上市以及处于临床研究阶段的肝纤维化治疗药物。  肝纤维化常出现在外界因素刺激引起的肝细胞损伤之后，因此预防和治疗肝纤维化的首要策略是祛除引起肝脏慢性损伤的病因，例如治疗慢性肝炎病毒感染、酒精性肝损伤和非酒精性肝损伤。HSC的活化和增殖是肝纤维化过程中的重要环节，因此可以通过靶向 HSC 活化，研发抗纤维化药物。另外，已有大量实验及临床研究表明，肝纤维化具有可逆性，因此该疾病的治疗或可通过调节肝纤维化的逆转来实现。 参考文献： [1]  Asrani S K, Devarbhavi H, Eaton J, et al. 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A study to test safety and efficacy of BI456906 in adults with non-alcoholic steatohepatitis (NASH) and fibrosis (F1-F3)[EB/OL]. [2024-05-20]. https://clinicaltrials.gov/study/ NCT04771273. 美编排版：朱玲欣 感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2024年第11期。 《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。 《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。 《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。 联系《药学进展》↓↓↓ 编辑部官网：pps.cpu.edu.cn； 邮箱：yxjz@163.com； 电话：025-83271227。 欢迎投稿、订阅！ 往期推荐 聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航 我知道你在看哟