Inventiva (NASDAQ:IVA) CEO Andrew Obenshain said the company is preparing for a second-half phase 3 readout for lanifibranor in metabolic dysfunction-associated steatohepatitis (MASH), describing the trial as fully enrolled and in the process of data cleaning ahead of database lock and top-line results.
MASH landscape and Inventiva’s recent changes
Obenshain said the MASH field has “evolved tremendously” in recent years after a history of clinical failures, citing two approvals, multiple acquisitions, and what he described as validation of commercial potential. He pointed to Madrigal’s work as evidence the fibrosis stage 2 and stage 3 (F2/F3) segment could represent a “billion-dollar market.”
“People and money are what actually makes a biotech hum,” he said, adding that the company now has the team and capital needed to execute the phase 3 program and prepare for potential regulatory filing.
Lanifibranor positioning and market segmentation
Lanifibranor is a pan-PPAR agonist being studied for F2 and F3 patients. Obenshain argued the drug could fit as an oral therapy added on top of GLP-1 drugs, which he expects to be a common “backbone” treatment in MASH.
On market sizing, he said there are more than 15 million patients with MASH in the U.S., and that diagnosis rates are rising with new product launches and increasing awareness. He said the current addressable F2/F3 population is approximately 375,000 patients. He described a segmentation framework based on fibrosis stage (F2 vs. F3) and diabetes status (around 40% non-diabetic and 60% diabetic), forming “a nice two-by-two grid” with roughly equal patient counts in each segment.
Obenshain suggested lanifibranor may be particularly attractive for F3 patients due to the clinical focus on preventing progression to cirrhosis (F4) and because, in his words, physicians may choose the “biggest hammer” against fibrosis in that setting. He compared lanifibranor’s phase 2b fibrosis effect size (18% after six months versus placebo) with resmetirom’s (which he said showed a 12% effect size after 12 months). He also said lanifibranor has shown an ability to reduce HbA1c, which he believes may make it more compelling for patients with diabetes.
He added that resmetirom and lanifibranor could be closer substitutes in F2 non-diabetic patients, where tolerability considerations such as weight gain may influence patient and physician preferences.
NATiV3 trial design, enrollment, and dropouts
Obenshain said the phase 3 NATiV3 trial is randomized 1:1:1 across placebo, 800 mg daily, and 1,200 mg daily dosing arms, with 1,009 patients in the main registrational cohort. Patients are treated for 18 months, with liver biopsies at baseline and at the end of treatment, along with noninvasive tests (NITs) during the study.
He also described an additional blinded exploratory cohort for patients who screen-failed the biopsy criteria for the registrational population—those found to have F1 or F4 instead of F2 or F3. Inventiva has enrolled about 400 patients in that group, he said, with the majority being F1 and roughly 100 being F4. He said data from F1 and F4 patients could help inform a future outcomes trial, with F4 positioned as a likely next development direction.
On retention, Obenshain said the trial was powered conservatively with an assumption that dropout rates could be as high as 30% given the longer 18-month duration versus earlier studies. He said the company previously disclosed it was below the 30% threshold required for a financing tranche, without providing a specific figure, and that the trial remains “well within the power” assumptions.
Endpoints, population differences, and background therapies
Obenshain said Inventiva’s phase 2b study had a different primary endpoint (SAF score), but it also measured fibrosis and steatosis outcomes that are central to phase 3. He said NATiV3’s primary endpoint is a dual requirement: improvement in fibrosis stage and improvement in steatosis (fatty liver), which he described as a more difficult hurdle and potentially less vulnerable to placebo effects. He stated the dual endpoint effect size in phase 2b was 24%, while fibrosis alone was 18%, and said phase 3 powering was done more conservatively than those phase 2b results.
He highlighted several differences between phase 2 and phase 3 populations:
- Fibrosis stages: Phase 2 included F1 patients, while phase 3 excludes them; Obenshain said removing F1 patients made effect sizes “the same to slightly better.”
- Diabetes prevalence: Phase 3 includes more patients with diabetes, which he attributed to U.S.-based enrollment; he said efficacy in patients with diabetes was “the same to slightly better.”
- GLP-1 use: GLP-1 drugs were not available during phase 2; in phase 3, about 14% of patients entered on a stable GLP-1 dose, which he said should be balanced across arms.
He added that patients were allowed to add GLP-1s or SGLT2s during the study, but not at higher “MASH dose” levels; rather, the permitted doses were intended for diabetes control. He said a “mid-single digit” percentage of patients added GLP-1 therapy during the study.
Safety, weight gain, and combination considerations
Addressing historical concerns around PPAR drugs, Obenshain said lanifibranor is a novel chemical entity and not based on the thiazolidinedione (TZD) backbone. He described it as rationally designed using lessons from prior PPAR programs, including seeking more modest PPAR-gamma binding (which he compared to pioglitazone rather than rosiglitazone) while also engaging PPAR-alpha and PPAR-delta.
On weight gain, he said about 50% of patients experienced no weight gain, 20% had under 5% weight gain, and 30% had 5% or more. He said the weight gain tends to rise and plateau after about six months, and described early volume expansion followed by changes in fat distribution and muscle effects as contributing factors. He also said Inventiva conducted a study combining lanifibranor with an SGLT2 inhibitor, which he said mitigated weight gain completely.
He characterized weight gain as more of a tolerability than a safety issue, noting that while about 30% of phase 2 patients gained weight, it was reported as an adverse event in only “low double digits” as a percentage, suggesting many physicians did not view it as an adverse event.
Looking ahead, Obenshain said GLP-1 combinations make sense and suggested an all-oral regimen pairing an oral GLP-1 with lanifibranor could be attractive. He noted that resmetirom has been used alongside GLP-1s, citing a figure he said was about 50% based on public comments.
On strategic interest, he said some pharma executives have been “burned by PPAR” historically, but that he believes phase 3 data should address those concerns if positive.
On funding, Obenshain said Inventiva is “structuring ourselves to be able to launch this ourselves.” He said the company has cash runway to Q3 2027, assuming positive data and receipt of a third financing tranche of EUR 118 million, and that the additional runway would provide flexibility to determine next steps, including potential fundraising to support NDA approval and commercialization.
About Inventiva (NASDAQ:IVA)
Inventiva (NASDAQ: IVA) is a clinical‐stage biopharmaceutical company focused on the discovery, development and commercialization of small molecule therapies for the treatment of metabolic, inflammatory, and fibrotic diseases. The company’s core expertise lies in the modulation of nuclear receptors and signaling pathways that regulate fibrosis, inflammation and metabolic dysfunction. Inventiva’s scientific platform integrates medicinal chemistry, in vitro and in vivo pharmacology, and translational sciences to advance a diversified pipeline of therapeutic candidates.
The company’s lead asset, lanifibranor (IVA337), is a pan-PPAR agonist in Phase III development for nonalcoholic steatohepatitis (NASH) and has demonstrated anti-inflammatory and anti-fibrotic effects in preclinical and clinical studies.
