Ipsen Presents New Late-Breaking Data for IQIRVO® in Primary Biliary Cholangitis

Ipsen's IQIRVO Shows Clinically Meaningful Fatigue Improvement in PBC

Ipsen announced new late-breaking results for IQIRVO (elafibranor) in primary biliary cholangitis (PBC) from the pivotal ELATIVE® Phase III trial and two real-world studies, presented at the EASL congress. The data reinforce IQIRVO as a second-line PBC treatment, demonstrating rapid and robust alkaline phosphatase (ALP) reduction, significant fatigue improvement in patients with moderate-to-severe fatigue, and pruritus relief. A post hoc analysis of ELATIVE showed 67% of IQIRVO patients achieved clinically meaningful fatigue improvement versus 31% on placebo at Week 52 (p=0.020). A U.S. real-world analysis reported 59% of patients with ALP 1-1.67 x ULN achieved ALP normalization at 6 months. Interim Phase IV ELFINITY® study findings also showed rapid ALP reductions and improvements in fatigue and pruritus.

• A post hoc analysis of the pivotal ELATIVE Phase III study revealed that patients with moderate-to-severe fatigue at baseline experienced significantly greater reductions in fatigue with IQIRVO compared to placebo over 52 weeks. A clinically meaningful improvement in fatigue was achieved by 67% of patients on IQIRVO versus 31% on placebo (p=0.020) at Week 52, with benefits observed as early as Week 4 across multiple dimensions of physical and mental fatigue, including extreme exhaustion and difficulty thinking clearly.
• A U.S. real-world analysis, utilizing the Health Verity database, demonstrated IQIRVO's effectiveness in reducing alkaline phosphatase (ALP) levels in PBC patients with ALP elevated between 1-1.67 times the upper limit of normal. This study showed that 72% of second-line treatment-naïve patients achieved a ≥15% ALP reduction, with mean ALP declining from 174 U/L to 131 U/L, and 59% achieving ALP normalization at 6 months, highlighting a key treatment goal for improved long-term prognosis.
• Interim month 3 findings from the global Phase IV ELFINITY® study, conducted in routine clinical practice, further supported IQIRVO's rapid and sustained ALP reductions, with biochemical response achieved in 55% of patients. Over half of patients with moderate-to-severe fatigue at baseline experienced clinically meaningful improvements by month 3, alongside clinically important improvements in pruritus. The study also confirmed a favorable tolerability profile, consistent with prior studies, with no serious or severe treatment-emergent adverse events reported.

The Persistent Challenges and Unmet Needs in PBC Treatment

Current treatment approaches for Primary Biliary Cholangitis face several significant obstacles that impact patient outcomes and clinical management. Despite advances in therapeutic options, substantial gaps remain in treatment efficacy, physician knowledge, and clinical practice implementation.

• Limited first-line treatment efficacy: Up to 40% of patients show inadequate response to ursodeoxycholic acid (UDCA), which remains the standard first-line treatment, with studies demonstrating no beneficial effect on symptoms or liver histology after 2 years of treatment despite improvements in serum liver tests.

• Second-line therapy challenges: Obeticholic acid (OCA), initially approved as second-line therapy, recently lost its marketing authorization in the EU due to unfavorable risk-benefit balance, while newer agents like seladelpar and elafibranor show variable response rates depending on baseline alkaline phosphatase levels.

• Significant physician knowledge gaps: Overall mean awareness score for PBC among physicians was only 62.6%, with critical knowledge deficits regarding second-line therapies (only 6.8% awareness of steroid use) and substantial disparities between specialists and primary care providers.

• Treatment personalization limitations: Challenges persist in developing personalized treatment approaches, identifying robust endpoints beyond alkaline phosphatase normalization, and improving quality of life outcomes for patients with varying disease severity.

• Access and implementation barriers: Broader access to effective new therapies remains limited, while targeted medical education for primary care physicians is essential to ensure timely referral and optimize patient outcomes across different healthcare settings.

IQIRVO's Impact on ALP, Fatigue, and Pruritus in PBC

UDCA remains the first-line therapy for PBC, though approximately 25-40% of patients demonstrate inadequate response and require second-line treatments. Recent phase 3 trials have established the efficacy of newer therapeutic options, with FDA-approved second-line therapies showing significant biochemical improvements and potential symptom relief.

• UDCA monotherapy achieves biochemical response in 60-75% of patients, with treated patients showing reduced mortality (adjusted hazard ratio 0.57; 95% CI, 0.52-0.64) and gaining an average of 2.24 years in life expectancy compared to standard care

• Obeticholic acid demonstrates biochemical response rates of 47.2% at 12 months, increasing to 68.6% at 36 months, though 45% of patients discontinue treatment over 48 months due to adverse effects, with 12-month non-responders showing heightened clinical event risk (hazard ratio 4.50)

• Elafibranor achieved 51% biochemical response versus 4% placebo in the phase 3 ELATIVE trial (difference 47 percentage points; P<0.001), with 15% of patients achieving ALP normalization compared to none in placebo group

• Triple therapy combinations (UDCA + OCA + fibrates) show significantly superior response rates compared to dual therapy, with higher rates of ALP normalization, deep response, and biochemical remission (all p<0.001)

• PPAR agonists combined with UDCA demonstrate significantly greater ALP reduction compared to UDCA alone (MD -131.15, 95% CI -155.95 to -106.36) in meta-analysis of 17 studies involving 1,219 patients

• Post-transplant outcomes remain excellent for PBC patients, with current five- and ten-year survival rates of 88% and 78% respectively, while the need for liver transplantation has decreased with improved medical management

Elafibranor's Dual PPAR Agonism and the PBC Treatment Landscape

Several PPAR agonists are being investigated for similar indications as elafibranor, primarily targeting NAFLD/MASLD through metabolic pathway modulation. The clinical development programs show varied intervention models ranging from phase 2 studies to comprehensive meta-analyses across multiple patient populations.

Key Efficacy Findings: Lanifibranor demonstrated significant IHTG reduction (-44% vs -12% placebo, p<0.01), with 65% of patients achieving ≥30% IHTG reduction compared to 22% on placebo. Meta-analysis data showed improvements in lipid profiles (HDL-C +9.87%, triglycerides -26.90%) though fibrosis improvement was not statistically significant (OR 1.26, p=0.08). All PPAR agonist classes demonstrated efficacy for NAFLD treatment (P<0.05) with good safety profiles, though gastrointestinal adverse events were commonly reported.

IQIRVO's Comprehensive Data Reshapes Second-Line PBC Management

The recent presentation of new data for IQIRVO (elafibranor) at EASL marks a significant moment for the management of primary biliary cholangitis (PBC), a chronic autoimmune liver disease that often leaves patients with debilitating symptoms despite first-line treatment. Elafibranor, a dual peroxisome proliferator-activated receptor (PPAR) α/δ agonist, has recently secured accelerated FDA approval and a positive opinion in the EU, positioning it as a critical second-line option for patients who do not adequately respond to or tolerate ursodeoxycholic acid (UDCA).

The comprehensive data package reinforces IQIRVO's robust efficacy, particularly its ability to achieve rapid and significant reductions in alkaline phosphatase (ALP) levels, a key biochemical marker of cholestasis. Real-world evidence further supports this, showing a notable rate of ALP normalization. Beyond biochemical improvements, the new findings highlight a clinically meaningful improvement in fatigue for patients experiencing moderate-to-severe symptoms, a crucial differentiator given that fatigue is a pervasive and often undertreated aspect of PBC that severely impacts quality of life. Additionally, the data indicate relief from pruritus, another burdensome symptom.

However, the evolving landscape also presents considerations. While elafibranor offers a favorable safety profile compared to some alternatives, common gastrointestinal adverse events like abdominal pain and diarrhea were observed. Furthermore, as a relatively new entrant, long-term data on histological outcomes and transplant-free survival are still accumulating, which will be vital for broader clinical confidence and guideline integration. The market is also becoming increasingly competitive with other PPAR agonists, such as seladelpar, demonstrating similar efficacy profiles, potentially leading to a more fragmented treatment paradigm.

Ultimately, these advancements underscore a shift towards more personalized treatment strategies in PBC. Clinicians now have additional well-tolerated options that not only address biochemical markers but also offer tangible improvements in patient-reported symptoms like fatigue and pruritus. This move beyond solely biochemical endpoints to a more holistic approach, considering individual patient needs and symptom burden, is poised to redefine optimal care for those living with PBC.