PPARγ x SGLT2

Recruitment in NATiV3 clinical trial continues in both cohorts with over 80% of the targeted number of patients enrolled in the main cohort and 100% in the exploratory cohort of NATiV3. Analysis of the baseline characteristics of all patients randomized in the main cohort of NATiV3 show a patient profile similar to patients randomized in the NATIVE Phase IIb clinical trial. A blinded analysis of all randomized patients suggests weight gain plateaus and stabilizes between week 24 and 36. First visit of the last patient of NATiV3 is anticipated to occur during the second half of 2024, and topline results are expected at the beginning of the second half of 2026. Patent portfolio strengthened with new patent secured protecting the compound until 2043. The Company is currently working on multiple fronts to secure financing to fund the continuity of its activities. July 5, 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 patients with metabolic dysfunction-associated steatohepatitis (“MASH”), also known as non-alcoholic steatohepatitis (“NASH”), and other diseases with significant unmet medical needs, today provided an update on its clinical program evaluating lanifibranor for the treatment of MASH/NASH and its financial position. Frederic Cren, Chairman, Chief Executive Ofiicer, and cofounder of Inventiva stated: "We have made good progress with the recruitment in our Phase III clinical trial and continue to see a strong engagement of clinical trial sites in NATiV3. We are encouraged by the patient characteristics we are seeing in the main cohort of NATiV3 compared to those of our Phase IIb trial and above all by the plateau effect we see in the weight gain curve which confirms the differentiated profile of our panPPAR compound versus single PPAR gamma compounds such as pioglitazone. The data obtained from our various clinical studies demonstrate that lanifibranor could fully address the broad spectrum of the disease and recent presented data at the EASL Liver Congress from other compounds in development further bolster our belief in the potential of oral lanifibranor for use alone or in combination therapy. We are continuing to evaluate financing options to extend our current cash runway and continue our activities as we are determined to bring lanifibranor to market as a treatment option for patients with MASH.” The recruitment in NATiV3 is advancing with screening ongoing at 347 sites across 19 countries. As of July 5, 2024, 1,027 patients have been randomized of which 784 patients in the main cohort of NATiV3, representing 82% of the targeted number. The geographical distribution of the main cohort confirms that North America and Western Europe are the key contributors to patient recruitment (67% and 21% respectively) while China has only contributed marginally (2% of patients). The targeted number of 200 patients to be recruited in the exploratory cohort has been met with 243 patients randomized to date. The recruitment in the exploratory will continue until recruitment is complete in the main cohort. The Company estimates that, given the number of patients currently in screening who are eligible for enrolment in the main cohort, the Company must recruit an additional 165 patients. Due to a delay of approximately 3 to 5 months in recruitment, the Company is currently now targeting: the last patient first visit for the second half of 2024 and the publication of the topline results in the beginning of the second half of 2026. The baseline characteristics of the patients enrolled so far in the main cohort are in line with the expectations of the Company and are consistent with those from the NATIVE Phase IIb clinical trial of lanifibranor in patients with MASH/NASH (“NATIVE”). In addition, 13% of patients enrolled in the main cohort were receiving a stable dose of GLP1 receptor agonist and 9% a stable dose of SGLT2 inhibitors at baseline and should provide the Company with insights on the potential of the benefits of a combination of these class of products with lanifibranor. Importantly, a blinded review which included 780 patients enrolled in the main cohort of NATiV3 (placebo and treatment arms pooled) showed a similar weight gain as the one observed during the NATIVE Phase IIb trial which seems to plateau and stabilize after 24 to 36 weeks of treatment, and this even in the subgroup of patients who have gained more than 5% weight. If confirmed, this encouraging result highlights the particular profile of lanifibranor versus single PPAR gamma in particular pioglitazone, where such a plateau effect has not been observed1. We continue to work to reinforce lanifibranor patent portfolio. As of today, lanifibranor patent portfolio is made up of 20 patent families comprising both patents and patent applications fully owned by Inventiva. These patent families are respectively directed to lanifibranor product, method of treatment, combination therapy, process, formulation and diagnostic methods. With our patent family directed to crystalline forms of lanifibranor (patent applications pending), the company expects to potentially extend protection on lanifibranor product until at least 2043. Considering the Company’s cost structure and forecasted expenditures, and without taking into account additional cash preservation measures that the Company may implement in the short term, the Company estimates that its cash, cash equivalents and deposits will allow the Company to fund its operations as planned through the second half of July 20242. The Company estimates that, as of May 31, 2024, the Company’s cash and cash equivalents were (non-audited) €9.6 million, short-term deposits were €0.1 million3, and long-term deposits were €10.0 million4, compared with €26.9 million, €0.01 million and €9 million, respectively, as of December 31, 2023. In order to finance its activities and advance its development objectives for its research and development programs, the Company will need to raise additional funds. To date, the Company has explored a variety of transactions, including the issuance of debt, equity and other instruments, which thus far have not been successful. However, the Company is working to complete a royalty-based financing that would extend its cash runway through the summer of 2024, which it anticipates announcing in the near-term. Even if the royalty-based financing is successful (of which there can be no assurance), the Company will need to raise additional funds, and it is continuing to actively evaluate potential financing (including debt, equity and equity-linked or other instruments) and strategic options. Lanifibranor, Inventiva’s lead product candidate, is an orally-available small molecule that acts to induce antifibrotic, anti-inflammatory and beneficial vascular and metabolic changes in the body by activating all three peroxisome proliferator-activated receptor (“PPAR”) isoforms, which are well-characterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that is designed to target all three PPAR isoforms in a moderately potent manner, with a well-balanced activation of PPARα and PPARδ, and a partial activation of PPARγ. While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only pan-PPAR agonist in clinical development for the treatment of MASH/NASH. Inventiva believes that lanifibranor’s moderate and balanced pan-PPAR binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and pre-clinical studies to date. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor for the treatment of MASH/NASH. NATiV3 is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the long-term efficacy and safety of lanifibranor (800mg/daily and 1200mg/daily) in adult patients with biopsy-proven non-cirrhotic MASH/NASH and F2/F3 stage of liver fibrosis. The trial takes place in 24 countries and in more than 400 clinical sites and recruits approximately 900 patients to be treated over a 72-week period. The effect of lanifibranor will be assessed on several histological endpoints, including MASH/NASH resolution and improvement of fibrosis of at least one stage. An exploratory cohort is anticipated to enroll approximately 200 patients with MASH/NASH and fibrosis screen-failed on histology for the main NATiV3 clinical trial. Inventiva anticipates that this exploratory cohort may allow the generation of additional data using non-invasive tests and contribute to the regulatory safety database requirement to support the planned submission for potential accelerated approval to the Food and Drug Administration (FDA) and potential conditional approval to the European Medicines Agency (EMA) of lanifibranor for the treatment of MASH/NASH. Topline results of NATiV3 are expected for the second half 2026. For more information about NATiV3, visit clinicaltrials.gov. 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/NASH and other diseases with significant unmet medical need. The Company benefits from a strong expertise and experience in the domain 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/NASH, 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 1 Sanyal A et al. NEJM, 362 ; 18, 2010 2 This estimate is based on the Company’s current business plan and excludes any 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. 3 Short-term deposits are classified as "other current assets" in the consolidated statement of financial position under IFRS and are considered by the Company to be liquid and readily available. 4 The two-year long-term deposit can be accessed before expiry of the term with 31 days' notice and is considered liquid by the Company. The content above comes from the network. if any infringement, please contact us to modify.

近日，Inventiva公司宣布，小分子泛PPAR激动剂lanifibranor联用SGLT2抑制剂恩格列净（empagliflozin）治疗代谢功能障碍相关性脂肪性肝炎（MASH）/非酒精性脂肪性肝炎（NASH）和控制不佳的2型糖尿病（T2D）患者的2期概念验证试验LEGEND取得了良好的中期分析结果，达到了主要疗效终点。 此次公布结果的LEGEND试验是一项多中心、随机、安慰剂对照的2期概念验证试验，治疗周期为24周。非肝硬化MASH/NASH的诊断基于既往组织学评估或非侵入性方法（包括影像学检查）的组合。按照方案的计划，63名随机患者中有一半完成24周的治疗期或过早停止治疗后进行中期分析。 中期分析结果显示，与安慰剂组相比，lanifibranor治疗组和lanifibranor联用恩格列净治疗组的糖化血红蛋白水平（HbA1c）水平显著下降，达到了主要疗效终点。 此外，几种肝损伤指标、葡萄糖和脂质代谢指标以及肝脂肪变性指标也具有统计学意义的改善。 在为期24周的研究中，接受lanifibranor联合恩格列净治疗的患者体重保持稳定，可能解决了在一些接受lanifibranor治疗的患者中观察到的体重增加和代谢方面的问题。此外，lanifibranor单药和lanifibranor联用恩格列净可显著降低患者腹部内脏脂肪（VAT）与皮下脂肪（SAT）的比率，这反映了促炎症内脏脂肪向代谢健康脂肪组织的转变。 安全性方面，患者接受lanifibranor 800 mg每天一次单药或联用恩格列净治疗24周的耐受性良好，无安全问题报告。 Lanifibranor是一种口服小分子泛PPAR激动剂，它对PPARα和PPARδ产生均衡的激活，并且能够部分激活PPARγ，诱导体内抗纤维化、抗炎症反应，和有益的血管和代谢变化。Inventiva认为lanifibranor适度且平衡的泛PPAR结合特征有助于实现在临床试验和临床前研究中观察到的良好耐受性特征。2020年10月，lanifibranor获得了美国FDA授予的突破性疗法认定，用于治疗NASH/MASH。 参考资料：[1] Inventiva announces positive results from the Phase II, LEGEND, Proof-of-Concept study combining lanifibranor with empagliflozin in patients with MASH/NASH and T2D. Retrieved March 19, 2024, from https://www.globenewswire.com/news-release/2024/03/18/2848135/0/en/Inventiva-announces-positive-results-from-the-Phase-II-LEGEND-Proof-of-Concept-study-combining-lanifibranor-with-empagliflozin-in-patients-with-MASH-NASH-and-T2D.html 内容来源于网络，如有侵权，请联系删除。

LEGEND achieved its primary efficacy endpoint by significantly lowering HbA1c level in both the lanifibranor arm and in the lanifibranor with empagliflozin arm compared to placebo. Statistical significance was also achieved on several markers of liver injury, markers of glucose and lipid metabolism, as well as hepatic steatosis. Patients treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24 weeks study, addressing the moderate, metabolically healthy, weight gain that has been observed in some patients treated with lanifibranor. Treatment with lanifibranor alone and in combination with empagliflozin decreased the ratio of visceral abdominal fat to subcutaneous fat, reflecting a shift from pro-inflammatory visceral fat towards metabolically healthy adipose tissue. The treatment with lanifibranor 800mg/once daily alone or in combination with empagliflozin for 24 weeks was well tolerated, with no safety concerns reported. Inventiva will host an investor webcast Tuesday, March 19th at 8am ET (details below). March 18, 2024 – Inventiva (Euronext Paris and Nasdaq: IVA), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), and other diseases with significant unmet medical needs, today announces positive results of its interim analysis of the Phase II, Proof-of-Concept clinical trial, LEGEND, evaluating lanifibranor in combination with empagliflozin in patients with MASH/NASH and poorly controlled Type 2 Diabetes (T2D). The LEGEND trial has been designed as a multi-center, randomized, 24-week treatment, placebo-controlled Phase II Proof-of-Concept trial to assess the safety and efficacy of lanifibranor in combination with the SGLT2 inhibitor empagliflozin for the treatment of patients with non-cirrhotic MASH/NASH and T2D. The trial is double-blind for the placebo arm and lanifibranor (800mg daily) arm, and open-label for the combination of lanifibranor (800mg daily) and empagliflozin (10 mg daily) arm. The diagnosis of non-cirrhotic MASH/NASH was based on historic histology evaluation or a combination of non-invasive methods including diagnostic methods including imaging. As planned per protocol, the interim analysis was done once half of the 63 planned randomized patients with MASH completed the 24-week treatment period or prematurely discontinued from treatment. The study achieved the primary efficacy endpoint with an absolute reduction in Hemoglobin A1c (HbA1c) of 1.14% and 1.59% in patients with MASH and T2D treated with lanifibranor (800mg daily) or in combination with empagliflozin (10mg daily) at week 24 compared to an increase of 0.26% observed in the placebo arm. The study also demonstrated a statistically significant reduction in hepatic steatosis measured by MRI-PDFF1, in patients treated with lanifibranor alone and in combination with empagliflozin, -47% and -38% respectively, compared to placebo (0%). 83% and 67% of patients treated with lanifibranor alone or in combination with empagliflozin respectively, showed a reduction greater or equal to 30% of their hepatic fat, compared to 0% in the placebo arm. In addition, the study demonstrated a statistically significant effect on several secondary and exploratory endpoints, including liver enzymes (alanine aminotransferase (“ALT”) and aspartate aminotransferase (“AST”)), insulin resistance (HOMA-IR), HDL, and adiponectin (see tables below). Markers of liver inflammation and fibrosis (corrected T1 relaxation time (cT1) assessed by LiverMultiScan®) were assessed for the first time with lanifibranor and showed a significant effect with lanifibranor alone and in combination with empagliflozin. The study also demonstrated that patients treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24 weeks study, addressing the moderate, metabolically healthy, weight gain that can be observed in some patients treated with lanifibranor alone. Furthermore, these results demonstrated a significant relative reduction in the VAT/SAT ratio (visceral and subcutaneous adipose tissue) in patients treated with lanifibranor alone or in combination with empagliflozin, -5% and -17% respectively, compared to an increase of 11% in patients under placebo. This result reflects a shift from pro-inflammatory visceral fat towards metabolically healthy adipose tissue. The treatment with lanifibranor 800mg/daily alone and in combination with empagliflozin 10mg/daily for 24 weeks appears to be well tolerated, with no safety concerns reported. Dr. Michael Cooreman, M.D., Chief Medical Officer of Inventiva: “The results of the LEGEND study announced today further illustrate the potential of lanifibranor to address the broad spectrum of the disease biology of MASH and T2D. These data complement the already published dataset of lanifibranor demonstrating fibrosis improvement and MASH resolution but also its role as a potent insulin sensitizer. With roughly 50% of the U.S. population estimated to have either prediabetes or diabetes, and the well-established correlation between MASH and T2D, lanifibranor has a unique mechanism of action to potentially address the medical need of patients with both MASH and T2D. We wish to thank the patients who participated in the study and the investigators of LEGEND.” Dr. Onno Holleboom, MD PhD, endocrinologist and associate professor at Amsterdam UMC, co-principal investigator of the LEGEND Phase II clinical trial: “It is a big step seeing these positive results of LEGEND demonstrating the impact of lanifibranor on steatosis, inflammation and fibrosis while stabilizing weight with empagliflozin in patients with poorly controlled T2D and MASH. The study was designed as a proof of concept and these results are significant and strengthen confidence in the potential of lanifibranor to address the specific metabolic unbalance in patients with T2D while also addressing steatosis and fibrosis, a hepatic consequence of insulin resistance.” Prof. Michelle Lai, M.D., Ph.D., Beth Israel Deaconess Medical Center and co-principal investigator of the LEGEND Phase II clinical trial, said: “These LEGEND results provide valuable insights on the complementary mechanisms of action of an SGLT2 inhibitor and the panPPAR agonist, lanifibranor. MASH is a multifaceted disease that we believe will benefit from combination therapies in order to properly address the full cardiometabolic spectrum of the disease. These results of LEGEND suggest that lanifibranor in combination with empagliflozin could be an ideal combination for patients we care for in our clinic who suffer from T2D and MASH.” Given that the primary endpoint of LEGEND was met, and statistically significant results were achieved on several key additional markers, the Company has decided to stop the recruitment as defined per protocol. More details on these results are expected to be presented in upcoming scientific conferences and submitted for publication. Conference call Inventiva will host a conference call and webcast with slide presentation on Tuesday, March 19, 2024 at 8:00 am ET (New York time) 1:00 pm CET (Paris time). Introduced by Frederic Cren, Chairman, CEO and cofounder of Inventiva, this event will be as follow: Presentation of LEGEND Results - Michael Cooreman, M.D., CMO of Inventiva Metabolic and hepatic benefits of lanifibranor - Stephen Harrison, M.D., Pinnacle Clinical Research and principal investigator of the exploratory cohort of NATiV3, Phase III clinical trial Vascular benefits of lanifibranor - Sven Francque, M.D., University Hospital Antwerp, co-principal investigator of NATiV3, Phase III clinical trial Opportunity for lanifibranor - Frederic Cren, CEO and cofounder of Inventiva The conference call and the slides of the presentation will be webcast live at: https://edge.media-server.com/mmc/p/hyuvxf9a and will also be available on Inventiva’s website: Investor Presentations - Inventiva Pharma. In order to receive the conference access information necessary to participate to the conference call, it is required to register in advance using the following link: https://register.vevent.com/register/BI334d62953abb41cea27de99dc5da974c . Participants will need to use the conference access information provided in the e-mail received at the point of registering (dial-in number and access code). Lanifibranor, Inventiva’s lead product candidate, is an orally-available small molecule that acts to induce anti-fibrotic, anti-inflammatory and beneficial vascular and metabolic changes in the body by activating all three peroxisome proliferator activated receptor (PPAR) isoforms, which are well characterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that is designed to target all three PPAR isoforms in a moderately potent manner, with a ‑wellbalanced‑ activation of PPARα and PPARδ, and a partial activation of PPARγ. While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only panPPAR‑ agonist in clinical development for the treatment of MASH/NASH. Inventiva believes that lanifibranor’s moderate and balanced panPPAR‑ binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and preclinical studies to date. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor‑ for the treatment of MASH/NASH. 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/NASH, and other diseases with significant unmet medical need. The Company benefits from a strong expertise and experience in the domain 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/NASH, a common and progressive chronic liver disease for which there are currently no approved therapies. 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 The content above comes from the network. if any infringement, please contact us to modify.