- 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 webcastTuesday, March 19 th at8am ET (details below).
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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.
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.
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.
Summary HbA1C improvement at Week 24 | |||
Full Analysis Seta (N=30) | |||
Placebo (n=9) | Lani 800mg (n=11) | Lani 800mg +Empa 10mg (n=10) | |
HbA1c (%), LS Mean Absolute Change from Baseline to Week 24 | 0.26 | -1.14* | -1.59** |
Completersb (N=24) | |||
Placebo (n=5) | Lani 800mg (n=11) | Lani 800mg +Empa 10mg (n=8) | |
Responders with HbA1C level < 6.5% at Week 24 (%) | 0 | 55 | 63 |
Responders with HbA1c absolute decrease ≥1% from baseline, at Week 24 (%) | 0 | 64 | 88 |
a Two patients were not considered in the Full Analysis Set because we do not have post-treatment HbA1c values available *p<0.01, **p<0.001, versus placebo (Mixed Model Repeated Measure [MMRM]) b Eight patients were not considered in the Completers set because of premature discontinuation before Week 24 or missing data due to prior intercurrent events (Rescue medication or significant diet modification affecting the primary endpoint). LS= |
Summary of improvement in non-invasive measures of hepatic steatosis, inflammation and fibrosis markers, and liver injury, at Week 24 | |||
Full Analysis Set | |||
Mean Change from Baseline to Week 24 | Placebo | Lani 800mg | Lani 800mg +Empa 10mg |
MRI-PDFF (%)a | 0 (n=5) | -47* (n=12) | -38* (n=9) |
cT1 (ms)b | 15 (n=4) | -82 (n=12) | -85 (n=9) |
ALT (%)a | 2.5 (n=9) | -36.4** (n=12) | -51.3*** (n=10) |
AST (%)a | 17.1 (n=9) | -24.7** (n=12) | -34.6*** (n=10) |
a LS Mean relative change from baseline to week 24, from an Analysis of Covariance model (ANCOVA) or Mixed Model Repeated Measure (MMRM) b LS Mean absolute change from baseline to week 24, from an ANCOVA. *p≤0.05, **p<0.01, ***p<0.001, versus placebo (ANCOVA or MMRM) ALT: Alanine Aminotransferase, AST: Aspartate Aminotransferase, cT1: Corrected T1, LS= |
Summary of improvement in Cardiometabolic Markers and Weight, at Week 24 | |||
Full Analysis Set | |||
Mean Change from Baseline to Week 24 | Placebo | Lani 800mg | Lani 800mg +Empa 10mg |
HDL-C (mmol/L)a | -0.01 (n=9) | 0.17 (n=12) | 0.22* (n=10) |
Insulin (pmol/L)a | -58.3 (n=9) | -93.9 (n=11) | -155.1* (n=10) |
HOMA-IR (%)b | -7 (n=9) | -51* (n=11) | -69** (n=10) |
Adiponectinc | 1.1 (n=9) | 2.8* (n=11) | 3.0* (n=10) |
Body weightd (%) | -0.8 (n=5) | 3.6 (n=12) | -0.4 (n=8) |
VAT/SAT (%)b | 11 (n=4) | -5 (n=8) | -17** (n=7) |
a LS Mean absolute change from baseline to week 24 b LS Mean relative change from baseline to week 24 c LS Mean fold change from baseline to week 24 d Relative change from baseline to week 24 *p<0.05, **p<0.01, ***p<0.001, versus placebo (Mixed Model Repeated Measure [MMRM] or Analysis of Covariance (ANCOVA)). HDL-C: High density lipoprotein cholesterol, HOMA: Homeostasic model assessment, LS= |
Conference call
Introduced by
- Presentation of LEGEND Results -
Michael Cooreman , M.D., CMO ofInventiva - 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 ofInventiva
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).
About lanifibranor
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.
About
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.
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.
Contacts
EVP, Strategy and Corporate Affairs media@inventivapharma.com +1 202 499 8937 | Aude Lepreux / Media relations inventiva@brunswickgroup.com +33 1 53 96 83 83 | Westwicke, an Investor relations patti.bank@westwicke.com +1 415 513-1284 |
Important Notice
This press release contains “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 pre-clinical programs and clinical trials, including design, duration, timing, recruitment costs, screening and enrollment for those trials, including the ongoing NATiV3 Phase III clinical trial with lanifibranor in MASH/NASH and the LEGEND Phase II, Proof-of-Concept combination trial with lanifibranor and empagliflozin in patients with MASH/NASH and T2D, 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, the potential therapeutic benefits including reduction in HbA1c, reduction in hepatic steatosis, the effect on liver enzymes (ALT and AST), insulin resistance (HOMA-IR), HDL, adiponectin, liver inflammation and fibrosis, and reduction in the VAT/SAT ratio, of lanifibranor alone and in combination with empagliflozin in patients with MASH/NASH and T2D, of Inventiva’s product candidates, including lanifibranor alone and in combination with empagliflozin, the effect of lanifibranor alone and in combination with empagliflozin on the weight of the patients receiving treatment, the tolerability and safety profile of lanifibranor observed during trials, 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, the estimated market size and patient population, potential regulatory submissions, approvals and commercialization, Inventiva’s pipeline and preclinical and clinical development plans, the potential development of and regulatory pathway for odiparcil, and future activities, expectations, plans, growth and prospects of
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1 MRI-PDFF: Magnetic resonance imaging-derived proton density fat fraction
Attachment
Inventiva - PR - Results LEGEND - EN - 03 18 2024
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