* Improvements were observed for insulin resistance (insulin levels, HOMA-IR),
lipid metabolism (triglycerides, HDL-cholesterol, apolipoproteins), control
of glycemia (HbA1c, fasting glucose (FG) levels), systemic inflammation (hs-

    CRP, ferritin), hepatic steatosis and diastolic blood pressure.
  * Among the patients who had prediabetes at study entry and were treated with
    lanifibranor, the majority had fasting glucose levels within the normal
    range at the end of treatment. No patient treated with lanifibranor with
    normal glucose levels at study entry progressed to prediabetes during
    treatment, unlike in the placebo arm.
  * Adiponectin levels were increased by lanifibranor while they remained low
    and unchanged under placebo. Adiponectin increase was correlated with
    improvement of cardiometabolic health.

* A greater proportion of patients with MASH/NASH and high cardiovascular risk

    treated with either dose of lanifibranor saw their cardiovascular risk
    improved to intermediate or low risk compared to patients in the placebo
    arm.
  * Improvements in cardiometabolic health markers were similar regardless of
    the patients' diabetes and obesity status and regardless of weight change
    during treatment with lanifibranor.

Daix (France), Long Island City (New York, United States), May 13, 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 announced the publication (https://www.nature.com/articles/s41467-024-47919-9) in the peer-reviewed scientific journal Nature Communications of additional results from its NATIVE Phase IIb clinical trial demonstrating the improvement of markers of cardiometabolic health in patients with MASH/NASH treated with lanifibranor.
In the NATIVE Phase IIb clinical trial which demonstrated improvement on liver histology following a 24-week period with lanifibranor 800mg and 1200mg daily, including NASH resolution and fibrosis improvement, a broad panel of markers of cardiometabolic health were also measured. Following lanifibranor treatment, the
trial demonstrated significant improvement in patients with MASH/NASH with and without Type 2 Diabetes and with or without obesity of markers of insulin resistance (fasting insulin level, HOMA-IR), glycemic control (fasting glucose, HbA1c), lipid metabolism (triglycerides, HDL-C, APO-B, APO-B/APO-A1), adiponectin, systemic inflammation (hs-CRP, ferritin), diastolic blood pressure and hepatic steatosis (histological grading and ultrasound-based (Fibroscan CAP(TM))) (see table below).
Importantly, lanifibranor treatment also led to lower fasting glucose to normal levels in 71% of patients with MASH/NASH and prediabetes treated with the 1200mg dose and 67% of patients treated with the 800mg dose versus 11% of patients on placebo. In addition, no patients treated with either dose of lanifibranor with MASH/NASH and normoglycemia at baseline progressed to prediabetes at week 24, versus 26% of patients in the placebo arm.
Furthermore, 38% and 44% of patients with MASH/NASH and high cardiovascular risk
(based on markers of lipids and inflammation) treated with 1200mg and 800mg of lanifibranor, respectively, improved to intermediate or low cardiovascular risk at week 24, and 44% and 35% of patients at intermediate risk improved to low risk when treated with 1200mg and 800mg of lanifibranor, respectively. However, in the placebo arm, only 26% of patients at high cardiovascular risk improved to
intermediate risk and 13% improved from intermediate to low cardiovascular risk.
The weight gain observed in a portion of the patient population treated with lanifibranor was shown to be associated with improvement of all markers of cardiometabolic health, similarly to patients treated with lanifibranor who maintained a stable weight throughout the study. This finding is in contrast to the weight gain observed in patients on placebo, which was associated with a worsening of cardiometabolic markers. These results highlight the critical difference between the weight gain that can be observed with lanifibranor which can be defined as metabolically healthy and is associated with an improvement in
insulin resistance, and the weight gain observed in patients under placebo which
is metabolically unhealthy and is influenced by lifestyle.
In addition, the increase in adiponectin levels following treatment with 1200mg
and 800mg of lanifibranor occurred in 95% and 86% of patients, respectively, versus only in 10% of patients in the placebo arm. The increase in adiponectin level at week 24 was correlated with improvement of markers of insulin resistance, glycemic control, lipid metabolism and steatosis, as well as hs- CRP, aminotransferases and improvement in liver histological endpoints for disease activity and fibrosis.
Michael Cooreman, M.D., Chief Medical Officer at Inventiva, commented: "Patients
with MASH/NASH generally present with poor metabolic health resulting to a large
extent from insulin resistance, affecting their glucose and lipid metabolism, causing systemic inflammation and significantly increasing their risk for cardiovascular events. It is key for these patients to target the hepatic manifestations of the disease and also improve their cardiometabolic health. We believe these results from the NATIVE trial demonstrates the potential of lanifibranor to address the broad disease biology of MASH/NASH from insulin resistance to fibrosis. We use this opportunity to express our appreciation and thanks to all patients, investigators and their staff for having made this relevant clinical study possible."
Prof. Manal Abdelmalek, M.D., M.P.H., Mayo Clinic and co-principal investigator
of the NATIVE Phase IIb clinical trial, added: "This cardiometabolic dataset
from the NATIVE Phase IIb clinical trial exemplifies the need for a
comprehensive and multidisciplinary management of patients with MASH/NASH and
increases our confidence in the potential for lanifibranor as a treatment option
for patients with MASH/NASH, who typically have a cardiometabolic profile
associated with cardiovascular disease."
Prof. Sven Francque, M.D., Ph.D., Antwerp University Hospital and co-principal
investigator of the Phase IIb NATIVE clinical trial, said: "This analysis of
results from the NATIVE trial on the cardiometabolic health markers adds to the
body of evidence for lanifibranor's potential. Furthermore, these new data shed
more light on the importance of managing the full-spectrum of MASH/NASH
disease."
Prof. Arun Sanyal, Director of the Stratvitz-Sanyal Institute for Liver Disease
and Metabolic Health and Interim Chair of the Division of Gastroenterology,
Hepatology and Nutrition, Virginia commonwealth University, commented: "This
publication highlights the need to treat MASH/NASH more holistically, taking
into account the competing threats to life from mainly cardiometabolic and
hepatic risks. It is exciting to note that lanifibranor, which is now in
advanced Phase III clinical development for the treatment of NASH also
significantly improved the cardiometabolic risk profile and insulin sensitivity
as central component of the disease process. These compelling data further
support the promise of lanifibranor for this patient population."

   Summary of lanifibranor treatment versus placebo on cardiometabolic health
                      markers at Week 24 (n=247 patients)

+-------------------------------+----------------------------------------------+
| |Adjusted mean difference versus placebo at EOT| | | (SE) | +-------------------------------+----------------+-----------------------------+
| | Lani 800mg | Lani 1200mg | +-------------------------------+----------------+-----------------------------+
|Insulin Resistance | +-------------------------------+----------------+-----------------------------+
|Fasting insulin levels (pmol/L)| -83 (16) *** | -79 (17) *** | +-------------------------------+----------------+-----------------------------+
|HOMA?IR(+) | -4.0 (0.9) *** | -4.1 (0.9) *** | +-------------------------------+----------------+-----------------------------+
|Glycemic control | +-------------------------------+----------------+-----------------------------+
|Fasting glucose (mmol/L) |-1.02 (0.16) ***| -0.84 (0.16) *** | +-------------------------------+----------------+-----------------------------+
|HbA1c (%) |-0.45 (0.07) ***| -0.49 (0.07) *** | +-------------------------------+----------------+-----------------------------+
|Lipid metabolism and apolipoprotein levels | +-------------------------------+----------------+-----------------------------+
|Tryglycerides (mmol/L) |-0.55 (0.13) ***| -0.50 (0.12) *** | +-------------------------------+----------------+-----------------------------+
|HDL-C (mmol/L) |0.16 (0.03) *** | 0.10 (0.03) ** | +-------------------------------+----------------+-----------------------------+
|APO-B (mg/dL) | -9.7 (2.9) *** | -9.8 (2.9) *** | +-------------------------------+----------------+-----------------------------+
|APO-B/APO-A1 |-0.08 (0.03) ** | -0.06 (0.02) * | +-------------------------------+----------------+-----------------------------+
|APO-C3 (ug/mL) | -18 (6) *** | -20 (6) *** | +-------------------------------+----------------+-----------------------------+
|Systemic inflammation | +-------------------------------+----------------+-----------------------------+
|hs-CRP (mg/L) | -2.2 (0.7) *** | -1.5 (0.7) * | +-------------------------------+----------------+-----------------------------+
|Ferritin (µg/L) | -84 (21) *** | -72 (21) *** | +-------------------------------+----------------+-----------------------------+
|Liver tests | +-------------------------------+----------------+-----------------------------+
|ALT (U/L) | -25 (5) *** | -23 (5) *** | +-------------------------------+----------------+-----------------------------+
|AST (U/L) | -15 (5) *** | -12 (5) ** | +-------------------------------+----------------+-----------------------------+
|GGT (U/L) | -48 (8) *** | -32 (8) *** | +-------------------------------+----------------+-----------------------------+
|Blood pressure | +-------------------------------+----------------+-----------------------------+
|Diastolic blood pressure (mmHg)| -3.9 (1.5) * | -2.5 (1.5) | +-------------------------------+----------------+-----------------------------+
|Steatosis | +-------------------------------+----------------+-----------------------------+
|CAP(TM) (dB/m) | -16 (9) * | -23 (9) * |
+-------------------------------+----------------+-----------------------------+
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