Effective Date

Date of Origin   

01-01-2025           

Iqirvo®

(elafibranor)

Tablet

Treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.

This indication is approved under accelerated approval based on reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Limitations of Use: Use of Iqirvo is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

8

Livdelzi®

(seladelpar)

Capsule

Treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Limitations of Use: Use of Livdelzi is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy)

Ocaliva®

(obeticholic acid)

Tablet

For the treatment of adult patients with primary biliary cholangitis (PBC)

• without cirrhosis or
• with compensated cirrhosis who do not have evidence of portal hypertension,

either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA

1

Primary Biliary Cholangitis

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune chronic progressive cholestatic liver disease that predominantly affects women. PBC is characterized by a T-lymphocyte-mediated attack on small intralobular bile ducts eventually leading to their gradual destruction and disappearance, ultimately leading to cirrhosis and liver failure. Patients with PBC may be asymptomatic, or they may present with symptoms such as fatigue, pruritus, jaundice, cholestatic liver enzymes, and signs and symptoms of cirrhosis. Common laboratory test abnormalities in patients with PBC include elevated alkaline phosphatase (ALP), antimitochondrial antibodies (AMA), antinuclear antibodies (ANA), and hyperlipidemia.(2-5)

AMA is found in 95% of PBC patients. In approximately 5% to 10% of the patients, AMA is absent or present only in low titer (≤1/80), when immunofluorescent techniques are used. The presence or absence of AMA, rather than the magnitude of antibody level, is most important in diagnosis. In some patients, antinuclear antibodies, particularly anti‐glycoprotein 210 (anti‐gp210) and/or anti‐sp100, are present and may correlate with prognosis; in some other AMA‐negative patients, antibodies against the major M2 components (PDC‐E2 and 2‐oxoglutaric acid dehydrogenase complex), are present using enzyme‐linked immunosorbent assay or Western blotting techniques. In addition, nearly all AMA‐negative PBC patients have PBC‐specific antinuclear antibodies, including sp100 and gp210, which are present in over 30% of PBC patients negative for AMA by indirect immunofluorescence.(2)

According to the American Association for the Study of Liver Diseases (AASLD) 2018 Practice Guidance on Primary Biliary Cholangitis, the diagnosis of PBC is generally based on the presence of at least two of the following criteria:(2)

1. Biochemical evidence of cholestasis based on alkaline phosphatase (ALP) elevation
2. Presence of AMA, or other PBC‐specific autoantibodies, including sp100 or gp210, if AMA is negative.
3. Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts

Management of PBC includes treatment of symptoms and complications that result from chronic cholestasis and suppression of the underlying pathogenic process (destruction of small intralobular hepatic bile ducts). Ursodeoxycholic acid (ursodiol, UDCA) is first-line therapy for PBC. UDCA improves biochemical indices and delays histologic progression, ultimately enhancing survival. UDCA has minimal side effects and is generally well tolerated.(2,3)

Biochemical response should be assessed after 1 year of treatment with UDCA using one of many published criteria:(2,5)

In patients with an inadequate response to UDCA, obeticholic acid can be used in combination with UDCA or it can be used as monotherapy in patients who are unable to tolerate UDCA. When one of these binary definitions for response to UDCA is used, up to 40% of PBC patients will have an inadequate response to treatment. In addition, scoring systems based on continuous variables have been specifically developed to assess prognosis after initiation of therapy with UDCA. These scores identify patients who are at increased risk for progression to death or liver transplantation and who may benefit from adjuvant therapy. Transient elastography can also be used to risk‐stratify patients with PBC: in one study, those with a liver stiffness greater than 9.6 kPa were 5 times more likely to progress with clinical decompensation, death, or transplant.(2) Fibrates can be considered as an off-label alternative for patients with PBC and an inadequate response to UDCA, but are discouraged in patients with decompensated liver disease.(7) 

Treatment response is monitored using liver biochemical tests. The bilirubin level is the best predictor of survival and is the most important component in all mathematical models of prognosis in PBC. Serum ALP less than twice the upper limit of normal with treatment is a reliable predictor of treatment response. Transient elastography is emerging as a technique to assess prognosis and treatment response as well. Improvement is typically observed within a few weeks, and 90% of the improvement usually occurs by 6-9 months; about 20% of patients achieve normalization of liver biochemistries after two years.(2,3)

Efficacy

Ocaliva (obeticholic acid) is a farnesoid X receptor (FXR) agonist. FXR is a nuclear receptor expressed in the liver and intestine. FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol as well as by increased transport of bile acids out of hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.(1)

Obeticholic acid was approved based on a randomized, double-blind, placebo controlled, 12-month trial in patients with PBC (POISE – NCT01473524). Inclusion criteria included an intolerance to UDCA or a suboptimal biochemical response to UDCA after 12 months of UDCA. Suboptimal biochemical response (treatment failure) was defined as ALP 1.67 times the upper limit of normal (ULN) or greater, and/or total bilirubin greater than the ULN but less than 2 times ULN.(1,6) Of note, the suboptimal biochemical response, defined for the study inclusion, was based on a modification of the Toronto criteria.(5,6) Primary endpoints for responders were defined as 3 criteria: ALP less than 1.67 times the ULN, total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%.(1)

Iqirvo (elafibranor) and its main active metabolite GFT1007 are peroxisome proliferator-activated receptor (PPAR) agonists, both of which activate PPAR-alpha, PPAR-gamma, and PPAR-delta in vitro. However, the mechanism by which elafibranor exerts its therapeutic effects in patients with PBC is not well understood. Pharmacological activity that is potentially relevant to therapeutic effects includes inhibition of bile acid synthesis through activation of PPAR-alpha and PPAR-delta. The signaling pathway for PPAR-delta was reported to include Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol.(8)

The efficacy of Iqirvo was evaluated in a 12 month, randomized, double-blind, placebo-controlled study (NCT04526665) in patients with PBC with an inadequate response or intolerance to UDCA and when applicable continued UDCA. Most patients (95%) received study treatment (Iqirvo or placebo) in combination with UDCA or as monotherapy if unable to tolerate UDCA.  Patients were included in the study if their ALP was greater than or equal to 1.67-times the ULN and total bilirubin (TB) was less than or equal to 2-times the ULN. Patients were excluded if they had other liver disease or in case of decompensated cirrhosis. The primary endpoint was at Week 52, where biochemical response was defined as achieving ALP less than 1.67-times ULN (defined as 129 U/L for males and 104 U/L for females), TB less than or equal to ULN (1.20 mg/dL), and ALP decrease greater than or equal to 15% from baseline. ALP normalization (i.e., ALP less than or equal to ULN) at Week 52 was a key secondary endpoint. A reduction in mean alkaline phosphatase (ALP) from baseline was observed as early as 4 weeks after treatment compared to the placebo group and lower ALP was generally maintained through week 52. Overall, Iqirvo demonstrated greater improvement in biochemical response and ALP normalization at Week 52 compared to placebo and 96% of patients had a baseline TB concentration less than or equal to ULN.(8)

Safety

Ocaliva has the following boxed warning:(1)

Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with Ocaliva treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis. Ocaliva is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension. Permanently discontinue Ocaliva in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions while on treatment.

Ocaliva is contraindicated in patients with the following:(1)

• decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event
• compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia)
• complete biliary obstruction

Iqirvo and Livdelzi do not have any contraindications. However, use of these agents are not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).(8,9)

1

Ocaliva prescribing information. Intercept Pharmaceuticals, Inc. May 2022.

2

Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 69(1):p 394-419, January 2019. | DOI: 10.1002/hep.30145.

3

Laschtowitz A, de Veer RC, Van der Meer AJ, Schramm C. Diagnosis and treatment of primary biliary cholangitis. United European Gastroenterol J. 2020 Jul;8(6):667-674. doi: 10.1177/2050640620919585. Epub 2020 Apr 16. PMID: 32299307; PMCID: PMC7437077.

4

Tanaka A. Current understanding of primary biliary cholangitis. Clin Mol Hepatol. 2021 Jan;27(1):1-21. doi: 10.3350/cmh.2020.0028. Epub 2020 Dec 3. PMID: 33264835; PMCID: PMC7820210.

5

European Association for the Study of the Liver (EASL) 2017 Clinical Practice Guidelines: The Diagnosis and Management of Patients with Primary Biliary Cholangitis.

6

Corpechot C, Poupon R, Chazouilleres O. New Treatments/Targets for Primary Biliary Cholangitis. J Hepatol Reports. 2019;1(3):203-213.

7

Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2021 Practice Guidance Update from the American Association for the Study of Liver Diseases (AASLD).

8

Iqirvo prescribing information. Ipsen Biopharmaceuticals, Inc. June 2024.

9

Livedelzi prescribing information. Gilead Sciences, Inc. August 2024.

Iqirvo

elafibranor tab

80 MG

M ; N ; O ; Y

N

Ocaliva

obeticholic acid tab

10 MG ; 5 MG

M ; N ; O ; Y

N

Livdelzi

seladelpar lysine cap

10 MG

M ; N ; O ; Y

N

Iqirvo

elafibranor tab

80 MG

30

Tablets

30

DAYS

Livdelzi

seladelpar lysine cap

10 MG

30

Capsules

30

DAYS

Ocaliva

Obeticholic Acid Tab 10 MG

10 MG

30

Tablets

30

DAYS

Ocaliva

Obeticholic Acid Tab 5 MG

5 MG

30

Tablets

30

DAYS

Iqirvo

elafibranor tab

80 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Livdelzi

seladelpar lysine cap

10 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Ocaliva

obeticholic acid tab

10 MG ; 5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Iqirvo

elafibranor tab

80 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Livdelzi

seladelpar lysine cap

10 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Ocaliva

Obeticholic Acid Tab 10 MG

10 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Ocaliva

Obeticholic Acid Tab 5 MG

5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PA

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The patient has a diagnosis of primary biliary cholangitis (PBC) AND ALL of the following:
      1. Diagnosis has been confirmed by at least TWO of the following:
         1. There is biochemical evidence of cholestasis with an alkaline phosphatase (ALP) elevation
         2. ONE of the following:
            1. Positive presence of antimitochondrial antibody (AMA) OR
            2. Positive presence of other PBC-specific autoantibodies (e.g., sp100, gp210) if AMA is negative 
         3. Histologic evidence of nonsuppurative destruction cholangitis and destruction of interlobular bile ducts AND
      2. The prescriber has measured the patient’s baseline alkaline phosphatase (ALP) level and total bilirubin level (prior to therapy with the requested agent) AND
      3. ONE of the following:
         1. BOTH of the following:
            1. The patient has tried and had an inadequate response after at least 1 year of therapy with ursodeoxycholic acid (UDCA) (inadequate response defined as ALP greater than the upper limit of normal [ULN], and/or total bilirubin greater than ULN but less than 2x ULN, after 1 year of treatment with UDCA) AND
            2. The patient will continue treatment with ursodeoxycholic acid (UDCA) in combination with the requested agent OR
         2. The patient has an intolerance or hypersensitivity to therapy with ursodeoxycholic acid (UDCA) OR
         3. The patient has an FDA labeled contraindication to ursodeoxycholic acid (UDCA) OR
   2. The patient has another FDA labeled indication for the requested agent AND
2. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., gastroenterologist, hepatologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. ONE of the following:
   1. The patient has a diagnosis of primary biliary cholangitis (PBC) AND ALL of the following:
      1. ONE of the following:
         1. The requested agent will be used in combination with ursodeoxycholic acid (UDCA) OR
         2. The patient has an intolerance, hypersensitivity, or an FDA labeled contraindication to therapy with ursodeoxycholic acid (UDCA) OR
      2. The patient has had an alkaline phosphatase (ALP) decrease of greater than or equal to 15% from baseline (prior to therapy with the requested agent) AND ALP is less than the upper limit of normal (ULN) AND
      3. The patient’s total bilirubin is less than or equal to the upper limit of normal (ULN) OR
   2. The patient has another FDA labeled indication for the requested agent AND
3. The patient has had clinical benefit with the requested agent AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., gastroenterologist, hepatologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication

Length of Approval: up to 12 months