Elafibranor for Primary Biliary Cholangitis: A Comprehensive Review of the ELATIVE Phase 3 Trial

Table of Contents

• Key Points
• Background: What Is Primary Biliary Cholangitis?
• Current Treatments and Their Limitations
• What Is Elafibranor and How Does It Work?
• How Was the ELATIVE Trial Conducted?
• What Did the Trial Measure?
• Who Participated in the Trial?
• Primary Results: Biochemical Response
• Secondary Results: Alkaline Phosphatase Normalization
• Results for Itch (Pruritus)
• Other Secondary Findings
• Safety and Side Effects
• How the Data Were Analyzed
• What These Results Mean for Patients
• Limitations of the Study
• Recommendations and Next Steps
• Frequently Asked Questions
• Source Information

Key Points

• In a 161-patient trial, 51% on elafibranor achieved a biochemical response at 52 weeks versus 4% on placebo.
• Alkaline phosphatase normalized in 15% on elafibranor versus none on placebo.
• Elafibranor did not significantly reduce itch intensity as measured by the WI-NRS.
• Common side effects were gastrointestinal: abdominal pain, diarrhea, nausea, and vomiting; most were mild or moderate.
• Longer-term data are needed to confirm whether biochemical improvements reduce cirrhosis, transplant, or death.

Background: What Is Primary Biliary Cholangitis?

Primary biliary cholangitis (PBC) is a rare, chronic liver disease that occurs when the body's immune system attacks the small bile ducts inside the liver. The disease destroys the interlobular bile ducts. These are the tiny tubes that carry bile out of the liver. This leads to a buildup of bile in the liver, a condition called cholestasis. Eventually it leads to liver scarring (fibrosis).

The disease occurs predominantly in women aged 40 years and older, and its prevalence is increasing worldwide. If left untreated, primary biliary cholangitis can progress to cirrhosis (permanent scarring of the liver), the need for a liver transplant, and premature death.

Doctors use two key blood tests to track how the disease is progressing: alkaline phosphatase (an enzyme that rises when bile ducts are damaged) and bilirubin (a yellow pigment produced when red blood cells break down). Higher levels of these markers are correlated with a higher risk of poor outcomes. Doctors use these markers as prognostic indicators. This means they help predict how the disease will develop over time.

Current Treatments and Their Limitations

The only approved first-line therapy for patients with primary biliary cholangitis is ursodeoxycholic acid (UDCA), a tertiary hydrophilic bile acid. This medication helps move bile through the liver and reduces its toxic effects.

However, ursodeoxycholic acid does not work well enough for everyone. Up to 40% of patients have an inadequate response to this treatment, and 3 to 5% of patients experience unacceptable adverse events (side effects) that force them to stop taking it.

For patients who cannot tolerate or do not respond adequately to ursodeoxycholic acid, the only approved second-line treatment is obeticholic acid, a selective farnesoid X receptor agonist. But this drug also has limitations. Fewer than 50% of patients achieve a biochemical response. The drug may worsen pruritus (itching). Pruritus is already a common and distressing symptom of primary biliary cholangitis.

Some doctors have used fibrates (a class of drugs normally used to lower cholesterol) as an off-label second-line therapy. These drugs have shown potential for improving biochemical response and decreasing pruritus in patients with primary biliary cholangitis. However, an efficacious and safe long-term treatment remains an unmet need for this patient population.

What Is Elafibranor and How Does It Work?

Elafibranor is an oral medication that acts as a dual peroxisome proliferator-activated receptor (PPAR) alpha and delta agonist. In simpler terms, elafibranor activates two specific receptor proteins in the body — PPAR-alpha and PPAR-delta — which then modulate (adjust) the activity of certain genes.

Through this downstream modulation of nuclear receptor targets, elafibranor decreases the toxic effects of bile acids and reduces inflammation in the liver.

Before this phase 3 trial, a 12-week phase 2 trial involving patients with primary biliary cholangitis showed that treatment with elafibranor significantly reduced biomarkers of disease activity. No safety concerns were identified in that earlier study. The ELATIVE trial was designed to confirm those findings in a larger, more rigorous study.

How Was the ELATIVE Trial Conducted?

The ELATIVE trial was a multinational, phase 3, double-blind, placebo-controlled trial. "Double-blind" means that neither the patients nor their doctors knew which treatment each patient was receiving. "Placebo-controlled" means that one group of patients received an inactive pill (placebo) for comparison.

The trial enrolled patients 18 to 75 years of age. These patients had received a diagnosis of primary biliary cholangitis. They had had an inadequate response to ursodeoxycholic acid or unacceptable side effects with ursodeoxycholic acid. The trial was conducted at 82 sites in 14 countries.

Key inclusion criteria required patients to have an alkaline phosphatase level at least 1.67 times the upper limit of the normal range. That upper limit is 174 U per liter for women and 215 U per liter for men. Patients also needed a total bilirubin level no more than 2 times the upper limit of normal. That upper limit is 41 micromoles per liter.

Patients were excluded if they had autoimmune hepatitis or primary biliary cirrhosis–autoimmune hepatitis overlap, or if they had evidence of clinically significant hepatic decompensation (liver failure).

Trial design: Patients were randomly assigned in a 2:1 ratio to receive either once-daily elafibranor at a dose of 80 mg or placebo. This means that for every 2 patients who received elafibranor, 1 patient received placebo. Randomization was stratified (balanced) according to two factors:

• Whether the patient's alkaline phosphatase level was greater than 3 times the upper limit of normal or their total bilirubin level was above the upper limit of normal (yes or no)
• Whether the patient's score on the Worst Itch Numeric Rating Scale (WI-NRS) was greater than or equal to 4 (yes or no). The WI-NRS is a scale where patients rate their worst itching from 0 (no itch) to 10 (worst itch imaginable)

Patients who were already receiving a stable dose of ursodeoxycholic acid were permitted to continue this treatment throughout the trial.

The double-blind period had two parts. In part one, patients received their assigned treatment (elafibranor or placebo) in a double-blind manner for at least 52 weeks. In part two, patients continued their assigned regimen after week 52 until all patients had completed their week 52 assessment, or for a maximum of 104 weeks, whichever came first.

After the double-blind period ended, patients could enter an open-label extension period and receive elafibranor for up to 5 additional years.

The trial was designed by a steering group of clinical experts and representatives from the sponsors (GENFIT and Ipsen). The investigators gathered the data, and data analyses were performed by the sponsors. The trial followed International Council for Harmonisation Good Clinical Practice guidelines, applicable regulatory requirements, and the principles of the Declaration of Helsinki. All patients provided written informed consent.

What Did the Trial Measure?

The primary end point was a biochemical response at week 52. A patient was considered to have achieved a biochemical response if they met all three of the following criteria:

1. An alkaline phosphatase level less than 1.67 times the upper limit of the normal range
2. A reduction of at least 15% in alkaline phosphatase from baseline (the starting level)
3. Total bilirubin at or below the upper limit of normal

The key secondary end points were:

• Normalization of the alkaline phosphatase level at week 52
• One measure was a change in pruritus (itch) intensity from baseline through week 52 and through week 24. This change was measured on the WI-NRS among patients with moderate-to-severe pruritus. Moderate-to-severe pruritus was defined as a WI-NRS score of 4 or higher at baseline.

Other secondary end points included changes from baseline to week 52 in several measures:

• Patient-reported outcomes related to pruritus, assessed with the primary biliary cirrhosis–40 (PBC-40) questionnaire and the 5-D itch scale
• Levels of alkaline phosphatase, total bilirubin, albumin, gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, IgG, and IgM
• The international normalized ratio (a measure of blood clotting)
• The enhanced liver fibrosis score is calculated from three markers of liver fibrosis. These markers are hyaluronic acid, procollagen type III amino-terminal peptide, and tissue inhibitor of matrix metalloproteinase-1. A score below 7.7 indicates no-to-mild fibrosis.
• Liver stiffness, as measured by transient elastography (FibroScan; scores range from 2 to 75 kPa, with higher values indicating greater liver stiffness)
• Biomarkers of bile acid synthesis (7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19)
• Lipid variables (total cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, and triglycerides)

The PBC-40 questionnaire contains 40 items, each scored from 1 (or 0 for some items related to itch, social function, and symptoms) to 5, with higher scores indicating worse quality of life. The 5-D itch scale measures the degree, duration, direction, disability, and distribution of itching. Direction means improvement or worsening. Disability means effect on daily activities. Total scores range from 5 to 25. Higher scores indicate worse itch-related quality of life.

Who Participated in the Trial?

From September 2020 through June 2022, a total of 161 patients were randomly assigned to receive elafibranor (108 patients) or placebo (53 patients). These patients made up both the intention-to-treat population (all patients who were randomized) and the safety population (all patients who received at least one dose).

The intention-to-treat population of patients with moderate-to-severe pruritus at baseline included 66 patients (44 in the elafibranor group and 22 in the placebo group).

Patient demographics and clinical characteristics at baseline were similar between the two groups. Here is a detailed breakdown:

• Age: The mean age was 57.1 years (standard deviation ±8.7 years). In the elafibranor group, the mean age was 57.5 ± 8.4 years; in the placebo group, it was 56.4 ± 9.3 years.
• Sex: Overall, 96% of patients were women (154 of 161). In the elafibranor group, 94% were women (102 of 108); in the placebo group, 98% were women (52 of 53).
• Race: Overall, 91% of patients were White (147 of 161). In the elafibranor group, 94% were White (101 of 108); in the placebo group, 87% were White (46 of 53).
• Time since diagnosis: The mean time since diagnosis was 8.0 ± 6.2 years. In the elafibranor group, it was 7.9 ± 5.9 years; in the placebo group, it was 8.3 ± 6.8 years.
• Alkaline phosphatase level: The mean baseline level was 321.9 ± 150.9 U per liter. In the elafibranor group, it was 321.3 ± 121.9 U per liter; in the placebo group, it was 323.1 ± 198.6 U per liter. Overall, 39% of patients (63 of 161) had an alkaline phosphatase level greater than 3 times the upper limit of normal.
• Total bilirubin level: The mean baseline level was 9.6 ± 5.1 micromoles per liter. In the elafibranor group, it was 9.7 ± 5.1 micromoles per liter; in the placebo group, it was 9.4 ± 5.0 micromoles per liter.
• Aspartate aminotransferase level: The mean baseline level was 45.7 ± 27.2 U per liter. In the elafibranor group, it was 45.0 ± 24.2 U per liter; in the placebo group, it was 47.2 ± 32.8 U per liter.
• Alanine aminotransferase level: The mean baseline level was 49.6 ± 32.6 U per liter. In the elafibranor group, it was 49.3 ± 29.4 U per liter; in the placebo group, it was 50.3 ± 38.7 U per liter.
• Gamma-glutamyltransferase level: The mean baseline level was 215.5 ± 197.4 U per liter. In the elafibranor group, it was 213.3 ± 186.1 U per liter; in the placebo group, it was 220.0 ± 220.3 U per liter.
• Concurrent ursodeoxycholic acid use: Overall, 95% of patients (153 of 161) were taking ursodeoxycholic acid at baseline. In the elafibranor group, 94% (102 of 108) were taking it; in the placebo group, 96% (51 of 53) were taking it.
• WI-NRS score: The mean baseline score was 3.3 ± 2.8. In the elafibranor group, it was 3.3 ± 2.8; in the placebo group, it was 3.2 ± 2.9. Overall, 41% of patients (66 of 161) had moderate-to-severe pruritus (WI-NRS score of 4 or higher).
• Liver stiffness: The mean baseline liver stiffness was 10.1 ± 8.2 kPa. In the elafibranor group, it was 9.9 ± 7.8 kPa; in the placebo group, it was 10.7 ± 8.9 kPa. Overall, 31% of patients (48 of 154) had liver stiffness greater than 10.0 kPa.
• Bridging fibrosis or cirrhosis: Among patients who underwent a liver biopsy, 43% (20 of 47) had bridging fibrosis or cirrhosis. In the elafibranor group, 39% (12 of 31) had bridging fibrosis or cirrhosis; in the placebo group, 50% (8 of 16) had bridging fibrosis or cirrhosis.
• Liver stiffness greater than 10 kPa or bridging fibrosis (or both) or cirrhosis: Overall, 35% of patients (54 of 154) met this composite criterion. In the elafibranor group, 34% (35 of 104) met this criterion; in the placebo group, 38% (19 of 50) met this criterion.

Primary Results: Biochemical Response

At week 52, a biochemical response (the primary end point) was observed in a significantly greater percentage of patients in the elafibranor group than in the placebo group. The percentage was 51% (55 of 108 patients) for elafibranor versus 4% (2 of 53 patients) for placebo. This represents a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001).

The P value of less than 0.001 means there is less than a 0.1% probability that this result occurred by chance alone. In other words, the finding is highly statistically significant.

A response to elafibranor appeared to occur within 4 weeks after initiation of treatment and was maintained through 52 weeks. The results of supplementary analyses were consistent with these primary results, and subgroup analyses showed similar findings across different patient groups.

Secondary Results: Alkaline Phosphatase Normalization

Normalization of the alkaline phosphatase level at week 52 (a key secondary end point) occurred in 15% of patients in the elafibranor group and in 0% of patients in the placebo group. This represents a difference of 15 percentage points (95% CI, 6 to 23; P=0.002).

The P value of 0.002 means there is a 0.2% probability that this result occurred by chance alone — a statistically significant finding.

The percentage of patients with normalization of the alkaline phosphatase level was consistently higher in the elafibranor group through week 52 than in the placebo group. Subgroup analyses of alkaline phosphatase normalization showed similar findings across different patient groups.

Reductions from baseline in alkaline phosphatase levels were observed in the elafibranor group within 4 weeks after initiation of treatment. These reductions appeared to be sustained at levels lower than those in the placebo group through week 52, with a between-group estimated percentage-point difference of −40.6 ± 5.3 (95% CI, −47.8 to −33.5).

Results for Itch (Pruritus)

Some patients had moderate-to-severe pruritus at baseline: 44 patients in the elafibranor group and 22 in the placebo group. Among these patients, the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups. The change was −1.93 for elafibranor versus −1.15 for placebo. The difference was −0.78 (95% CI, −1.99 to 0.42; P=0.20).

Similarly, from baseline through week 24, the least-squares mean change in the WI-NRS score did not differ significantly between the elafibranor group and the placebo group: −1.60 versus −1.26. The difference was −0.34 (95% CI, −1.49 to 0.80).

The P value of 0.20 for the week 52 analysis means there is a 20% probability that this result occurred by chance alone. This is not statistically significant, meaning the trial did not demonstrate that elafibranor reduced itch intensity more than placebo.

However, among patients with moderate-to-severe pruritus at baseline, the changes from baseline to week 52 appeared to favor elafibranor over placebo for two other itch-related measures:

• The itch domain of the PBC-40 quality-of-life questionnaire (least-squares mean difference, −2.3; 95% CI, −4.0 to −0.7)
• The total score on the 5-D itch scale (least-squares mean difference, −3.0; 95% CI, −5.5 to −0.5)

The changes in other domains of the PBC-40 questionnaire over 52 weeks were similar in the two groups.

Other Secondary Findings

At week 52, levels of 7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19 appeared to be lower in patients who received elafibranor than in those who received placebo. These two substances are biomarkers of bile acid synthesis.

The levels of total cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides were lower in patients who received elafibranor than in those who received placebo within 4 weeks after baseline. Lower levels of triglycerides and VLDL cholesterol with elafibranor than with placebo were sustained through week 52. HDL cholesterol levels remained stable with elafibranor treatment from baseline through week 52.

Changes from baseline to week 52 in other liver-related variables and immunoglobulins (IgG and IgM) were also measured and reported in the trial.

Safety and Side Effects

Similar percentages of patients in the two groups had adverse events. Similar percentages had adverse events considered to be related to the trial regimen. Similar percentages had severe or serious adverse events. Similar percentages had adverse events leading to discontinuation of elafibranor or placebo.

Adverse events that occurred in more than 10% of patients and more frequently in patients receiving elafibranor than in those receiving placebo were predominantly gastrointestinal in nature. These included:

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting

The majority of adverse events were of mild or moderate intensity. Two patients who received elafibranor died during the clinical trial — one from postoperative complications after a surgical operation for an abdominal hernia repair, and one from biliary sepsis and acute kidney injury in a patient with end-stage liver disease — and neither death was considered related to the treatment.

How the Data Were Analyzed

The trial was designed to enroll 150 patients (100 in the elafibranor group and 50 in the placebo group). This sample size would provide a power of at least 90%, at a two-sided alpha level of 0.05. This power would detect a between-group difference of 35 percentage points in the proportion of patients with a biochemical response at week 52.

"Power" refers to the probability that the trial would detect a true difference between treatments if one exists. "Alpha level" refers to the threshold for statistical significance.

The primary analysis was based on data from the double-blind period, with efficacy end points assessed at week 52. Safety analyses included data up to 104 weeks.

The primary end point and key secondary end points were assessed with a prespecified fixed-sequence testing approach at a two-sided alpha of 0.05. This means the researchers tested each hypothesis in a predetermined order, stopping when a nonsignificant result was encountered. Other secondary end points are reported as point estimates and 95% confidence intervals. These were not adjusted for multiple testing. These should not be used in place of hypothesis testing or to infer definitive treatment effects.

Analyses of the primary end point and the key secondary end point of alkaline phosphatase normalization at week 52 were performed in the intention-to-treat population. The analyses used the exact Cochran–Mantel–Haenszel test, stratified according to the randomization factors.

For these two binary end points, a composite strategy of imputation of nonresponse was applied. This applied among patients who had intercurrent events before week 52. Intercurrent events were discontinuation of the trial regimen or use of rescue therapy for primary biliary cholangitis. Some patients did not have intercurrent events and had missing data at week 52. Response data for these patients were imputed with data from the closest nonmissing assessment from the double-blind period. That assessment was before or after the date of the theoretical week 52 visit.

The change from baseline in the WI-NRS score through week 52 and through week 24 in patients with moderate-to-severe pruritus was compared using a mixed model for repeated measures. In this model, a hypothetical strategy was applied. Under this strategy, any outcomes after the occurrence of intercurrent events were considered to be missing data. Intercurrent events were discontinuation of the trial regimen or the use of rescue therapy for pruritus. These outcomes were handled within the model under the assumption that the patient continued the trial regimen. Missing data not related to the occurrence of an intercurrent event were similarly handled under a missing-at-random assumption.

What These Results Mean for Patients

The ELATIVE trial demonstrated that elafibranor, at a dose of 80 mg once daily, produced significantly greater improvements in relevant biochemical indicators of cholestasis (bile flow problems) than placebo. This was in patients with primary biliary cholangitis who had an inadequate response to ursodeoxycholic acid or unacceptable side effects with ursodeoxycholic acid.

Specifically, more than half of patients taking elafibranor (51%) achieved a biochemical response at week 52, compared with only 4% of patients taking placebo. This is a clinically meaningful difference. Elevated alkaline phosphatase and bilirubin levels are used as prognostic indicators of disease progression. This means they help predict the risk of cirrhosis, need for liver transplantation, and premature death.

Additionally, 15% of patients taking elafibranor achieved normalization of their alkaline phosphatase levels, compared with none in the placebo group. Normalization of alkaline phosphatase is considered an important treatment goal in primary biliary cholangitis.

However, the trial did not demonstrate that elafibranor significantly reduced itch intensity as measured by the WI-NRS, the primary measure of pruritus. This is an important finding, as pruritus is a common and distressing symptom of primary biliary cholangitis that significantly affects quality of life.

It is worth noting that some other itch-related measures appeared to favor elafibranor over placebo. These measures were the PBC-40 itch domain and the 5-D itch scale. These were secondary end points and were not adjusted for multiple testing. Therefore, these measures should be interpreted with caution.

The safety profile of elafibranor was generally manageable. The most common side effects were gastrointestinal in nature (abdominal pain, diarrhea, nausea, and vomiting), and the majority were mild or moderate in intensity. Similar percentages of patients in both groups experienced serious adverse events or discontinued treatment due to adverse events.

Limitations of the Study

The ELATIVE trial has several limitations that patients and clinicians should consider:

• Duration: The primary analysis was conducted at 52 weeks. While this is a standard timeframe for assessing biochemical response in primary biliary cholangitis, longer-term data are needed. Longer-term data are needed to determine whether the biochemical improvements translate into reduced risk of cirrhosis, liver transplantation, and death.
• Itch results: The trial did not meet its key secondary end point for reducing itch intensity as measured by the WI-NRS. This means that elafibranor's effect on pruritus remains uncertain.
• Sample size: The trial enrolled 161 patients, which is relatively small, though appropriate for a rare disease. Subgroup analyses may have limited statistical power.
• Population: The trial population was predominantly female (96%) and White (91%), which reflects the demographics of primary biliary cholangitis but may limit generalizability to other populations.
• Secondary end points: Other secondary end points were not adjusted for multiple testing and should not be used to infer definitive treatment effects.
• Open-label extension: Patients could enter an open-label extension period after the double-blind period, which may introduce bias in longer-term analyses.

Recommendations and Next Steps

Based on the results of the ELATIVE trial, elafibranor represents a promising new treatment option. Elafibranor is for patients with primary biliary cholangitis who have an inadequate response to or unacceptable side effects with ursodeoxycholic acid.

Patients who are considering elafibranor should discuss the following with their healthcare provider:

1. Eligibility: Elafibranor was studied in patients 18 to 75 years of age with an alkaline phosphatase level at least 1.67 times the upper limit of normal and a total bilirubin level no more than 2 times the upper limit of normal.
2. Expected benefits: Approximately half of patients taking elafibranor achieved a biochemical response at 52 weeks, and 15% achieved normalization of alkaline phosphatase levels.
3. Itch: The trial did not demonstrate a significant reduction in itch intensity as measured by the WI-NRS. Patients whose primary concern is pruritus should discuss this with their provider.
4. Side effects: The most common side effects were gastrointestinal (abdominal pain, diarrhea, nausea, and vomiting). Most were mild or moderate.
5. Monitoring: Patients taking elafibranor should have regular blood tests to monitor liver function and other parameters.
6. Long-term data: Longer-term studies are needed to confirm whether the biochemical improvements seen with elafibranor translate into reduced risk of cirrhosis, liver transplantation, and death.

The trial was funded by GENFIT and Ipsen. The ELATIVE trial is registered on ClinicalTrials.gov with the number NCT04526665.

Frequently Asked Questions

What is primary biliary cholangitis (PBC)?

PBC is a rare, chronic liver disease where the immune system attacks the small bile ducts inside the liver. This leads to bile buildup (cholestasis) and eventually liver scarring. It occurs mostly in women aged 40 and older. Without treatment, it can progress to cirrhosis, need for liver transplant, and premature death.

What is elafibranor and how does it work?

Elafibranor is an oral medication that activates two receptor proteins, PPAR-alpha and PPAR-delta. This adjusts the activity of certain genes, which decreases the toxic effects of bile acids and reduces liver inflammation. It is being studied for patients with primary biliary cholangitis who do not respond adequately to or cannot tolerate ursodeoxycholic acid.

Who was eligible for the ELATIVE trial of elafibranor?

The trial enrolled patients aged 18 to 75 with primary biliary cholangitis who had an inadequate response to or unacceptable side effects from ursodeoxycholic acid. They needed an alkaline phosphatase level at least 1.67 times the upper limit of normal and a total bilirubin level no more than 2 times the upper limit of normal. Patients with certain other liver conditions were excluded.

Did elafibranor reduce itching (pruritus)?

The trial did not show that elafibranor significantly reduced itch intensity as measured by the Worst Itch Numeric Rating Scale (WI-NRS) in patients with moderate-to-severe itching. However, two other itch-related measures—the PBC-40 itch domain and the 5-D itch scale—appeared to favor elafibranor, but these were secondary and not adjusted for multiple testing.

What are the side effects of elafibranor?

The most common side effects were gastrointestinal: abdominal pain, diarrhea, nausea, and vomiting. These occurred more often with elafibranor than placebo. Most were mild or moderate. Similar percentages of patients in both groups had serious adverse events or stopped treatment due to side effects. Two patients who received elafibranor died during the clinical trial — one from postoperative complications after a surgical operation for an abdominal hernia repair, and one from biliary sepsis and acute kidney injury in a patient with end-stage liver disease — and neither death was considered related to the treatment.

What does a biochemical response mean for patients?

A biochemical response means meeting three criteria: alkaline phosphatase below 1.67 times the upper limit of normal, at least a 15% drop in alkaline phosphatase from baseline, and total bilirubin at or below the upper limit of normal. These markers help predict risk of cirrhosis, liver transplant, and premature death. However, longer-term data are needed to confirm that these improvements translate into reduced risk of those outcomes.

I have primary biliary cholangitis and my doctor says I don't respond well enough to ursodeoxycholic acid — when should I get a second opinion about starting elafibranor?

A second opinion is reasonable when your alkaline phosphatase remains at least 1.67 times the upper limit of normal and your bilirubin stays no more than 2 times the upper limit of normal despite ursodeoxycholic acid treatment, since that is the group studied. In the ELATIVE trial, 51% of patients taking elafibranor achieved a biochemical response at 52 weeks versus 4% taking placebo, and 15% normalized alkaline phosphatase. Itch intensity did not improve significantly, and gastrointestinal side effects were more common. An independent review can help weigh these trade-offs. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis NEJM 2023

Authors: K.V. Kowdley, C.L. Bowlus, C. Levy, U.S. Akarca, M.R. Alvares-da-Silva, P. Andreone, M. Arrese, C. Corpechot, S.M. Francque, M.A. Heneghan, P. Invernizzi, D. Jones, F.C. Kruger, E. Lawitz, M.J. Mayo, M.L. Shiffman, M.G. Swain, J.M. Valera, V. Vargas, J.M. Vierling, A. Villamil, C. Addy, J. Dietrich, J.-M. Germain, S. Mazain, D. Rafailovic, B. Taddé, B. Miller, J. Shu, C.O. Zein, and J.M. Schattenberg, for the ELATIVE Study Investigators' Group

Publication: The New England Journal of Medicine, 2024;390:795-805

DOI: 10.1056/NEJMoa2306185

Published online: November 13, 2023

Funding: GENFIT and Ipsen

ClinicalTrials.gov number: NCT04526665

This patient-friendly article is based on peer-reviewed research.