Drugs, Health Technologies, Health Systems

Reimbursement Recommendation

Seladelpar (Lyvdelzi)

Indication: For the treatment of primary biliary cholangitis, in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA alone, or as monotherapy in adults unable to tolerate UDCA

Sponsor: Gilead Sciences Canada, Inc.

Final Recommendation: Reimburse with conditions

Summary

What Is the Reimbursement Recommendation for Lyvdelzi?

Canada’s Drug Agency (CDA-AMC) recommends that Lyvdelzi be reimbursed by public drug plans for the treatment of primary biliary cholangitis (PBC), in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA alone, or as monotherapy in adults unable to tolerate UDCA if certain conditions are met.

Why Did CDA-AMC Recommend Reimbursement?

The Canadian Drug Expert Committee (CDEC) determined that Lyvdelzi demonstrates acceptable clinical value versus Iqirvo and Ocaliva in patients with PBC. Lyvdelzi, elafibranor (Iqirvo), and obeticholic acid (Ocaliva) are used in combination with UDCA in adults whose PBC has an inadequate response to UDCA alone or as monotherapy in adults with UDCA intolerance. This determination alone was sufficient for CDEC to recommend that Lyvdelzi be reimbursed. Given that Lyvdelzi is expected to be an alternative to Iqirvo or Ocaliva, acceptable clinical value refers to at least comparable value versus Iqirvo or Ocaliva.

Evidence from 1 clinical trial demonstrated that treatment with Lyvdelzi (in combination with UDCA in patients whose PBC has an inadequate response to UDCA or as monotherapy in those with UDCA intolerance) resulted in improved response to treatment (alkaline phosphatase [ALP] < 1.67 × upper limit of normal [ULN], normal total bilirubin level, and a decrease in ALP ≥ 15% from baseline) and improved pruritus after 1 year of treatment when compared with placebo. Although evidence from 1 indirect treatment comparison for Lyvdelzi versus Iqirvo or Ocaliva was associated with methodological limitations and showed imprecise results, CDEC felt the results did not demonstrate significant differences in outcomes comparing the treatments and found it reasonable to consider them similar in efficacy and safety.

Lyvdelzi meets some important patient needs by offering an additional treatment option that could improve treatment response and normalize ALP levels.

Which Patients Are Eligible for Coverage?

Lyvdelzi should only be covered to treat adult patients who have a diagnosis of PBC that has either not responded adequately to UDCA treatment after treatment for at least a year (with a stable dose maintained for a minimum of 3 months), or who have intolerance to UDCA treatment, and who have a total bilirubin level of no higher than 2 times the ULN. In addition, patients should have no history or current evidence of other liver diseases. Initial coverage for Lyvdelzi should not exceed 12 months.

What Are the Conditions for Reimbursement?

Lyvdelzi should only be reimbursed if prescribed by or in consultation with a specialist, such as a gastroenterologist, a hepatologist, or another physician with expertise in managing PBC. Lyvdelzi should be negotiated so that the drug program cost of Lyvdelzi does not exceed the drug program cost of treatment with the least costly relevant comparator for the same indication. For renewal after the initial authorization, Lyvdelzi should follow the same renewal criteria as Iqirvo and Ocaliva, in accordance with the reimbursement criteria of each public drug plan for treating PBC. For ongoing renewals, physicians must confirm that the patient’s initial response to Lyvdelzi achieved during the first 12 months has been maintained. Renewal of coverage should be assessed on an annual basis.

Review Background

Highlights of Input From Interested Parties

The patient group Canadian PBC Society noted the following regarding impact of the disease, unmet needs, and important outcomes:

The clinician group Canadian Network for Autoimmune Liver Disease and the clinical experts consulted by CDA-AMC noted the following regarding unmet needs arising from the disease and the place in therapy for the drug under review:

The participating public drug programs raised potential implementation issues related to considerations for initiation, discontinuation, and prescribing of therapy; generalizability of trial populations to broader populations; and care provision issues.

Recommendation

With a vote of 13 in favour to 0 against, the Canadian Drug Expert Committee (CDEC) recommends that seladelpar be reimbursed for the treatment of PBC in combination with UDCA in adults whose PBC has an inadequate response to UDCA alone or as monotherapy in adults with UDCA intolerance only if the conditions listed in Table 1 are met.

Table 1: Reimbursement Conditions and Reasons

Reimbursement condition

Reason

Implementation guidance

Initiation

1. Treatment with seladelpar should be reimbursed when initiated in adults who have all the following:

1.1. A PBC diagnosis as demonstrated by at least 2 of 3 diagnostic factors:

1.1.1. ALP ≥ 1.67 × ULN for ≥ 6 months

1.1.2. positive AMA titre or presence of PBC-specific ANAs

1.1.3. liver biopsy consistent with PBC.

1.2. PBC has an inadequate response to UDCA after a prior UDCA trial of ≥ 12 months, and a stable dose for ≥ 3 months, or an intolerance to UDCA treatment. An inadequate response is defined as ALP ≥ 1.67 × ULN.

1.3. Total bilirubin level of ≤ 2 × ULN.

Evidence from the RESPONSE trial demonstrated that treatment with seladelpar resulted in a clinical benefit in patients with these characteristics. The majority of patients (approximately 94%) included in the RESPONSE trial were receiving UDCA at baseline. Therefore, there is limited evidence about the safety and efficacy of seladelpar for patients with UDCA intolerance.

CDEC noted that lack of response to UDCA should be assessed after at least 12 months of treatment. The clinical experts consulted by CDA-AMC noted that 6 months is an appropriate duration for a therapeutic trial of UDCA in patients with PBC. CDEC acknowledged clinical expert input but noted that the duration for a trial of UDCA outlined in condition 1.2 aligns with the characteristics of the trial population. The recommended dosage of UDCA for first-line use is 13 mg/kg to 15 mg/kg per day, according to the European Association for the Study of the Liver 2017 guidelines.

There is no universal definition of UDCA intolerance, as per the clinical expert input. CDEC agreed with the clinical experts that the determination of intolerance to UDCA can be based on clinical judgment. In the RESPONSE trial, patients with intolerance to UDCA treatment must not have received UDCA for at least 3 months before screening.

Seladelpar could be initiated similarly to elafibranor and obeticholic acid as per the reimbursement criteria for each public drug plan.

2. Patients must not have a history or presence of other concomitant liver diseases.

In the RESPONSE trial, patients with clinically important hepatic decompensation were excluded. There is also no evidence to support a benefit of seladelpar treatment in patients with a history or presence of other concomitant liver diseases because this patient population was not included in the RESPONSE trial.

3. The maximum duration of initial authorization is 12 months.

The RESPONSE trial assessed the primary and secondary end points at week 52.

Renewal

4. For renewal after initial authorization, seladelpar should be renewed in a similar manner to elafibranor and obeticholic acid as per the reimbursement criteria for each public drug plan for the treatment of PBC.

There is no evidence that seladelpar should be held to a different standard than elafibranor and obeticholic acid when considering renewal.

The clinical experts noted to CDEC that in a scenario in which a patients’ ALP level did not drop below 1.67 × ULN but there was still a 15% to 20% reduction from baseline, clinicians would consider these patients to have significantly benefited from seladelpar and would continue this treatment, even though meeting both criteria (ALP < 1.67 × ULN and a decrease in ALP ≥ 15%) is preferable. The clinical experts suggested that treatment should be continued if the reduction in ALP level from baseline was at least 15%; if the reduction in ALP level from baseline is not greater than 15% to 20%, patients should switch to another treatment.

5. For subsequent renewal, the physician must provide proof that the initial response achieved after the first 12 months of therapy with seladelpar has been maintained. Subsequent renewals should be assessed annually.

Annual assessments will help ensure the treatment is used for those benefiting from the therapy and would reduce the risk of unnecessary treatment.

Prescribing

6. Seladelpar must be prescribed by, or in consultation with, a specialist such as a gastroenterologist, a hepatologist, or another clinician with expertise in managing PBC.

This is meant to ensure that seladelpar is prescribed to patients for whom it is appropriate and that AEs are managed in an optimized and timely manner.

Seladelpar could be prescribed similarly to elafibranor and obeticholic acid as per the reimbursement criteria for each public drug plan.

Pricing

7. The drug program cost of seladelpar should be negotiated so that it does not exceed the drug program cost of treatment with the least costly relevant comparator for the same indication.a

Based on the committee’s assessment of the evidence, seladelpar is expected to have comparable clinical value as elafibranor and OCA. Therefore, the drug program cost of seladelpar should be no more than elafibranor or OCA.

Feasibility of adoption

8. The economic feasibility of adoption of seladelpar must be addressed.

At the submitted price, the incremental budget impact of seladelpar is expected to be greater than $40 million in years 1, 2, and 3.

AE = adverse event; ALP = alkaline phosphatase; AMA = antimitochondrial antibody; ANA = antinuclear antibody; CDA-AMC = Canada’s Drug Agency; CDEC = Canadian Drug Expert Committee; PBC = primary biliary cholangitis; UDCA = ursodeoxycholic acid; ULN = upper limit of normal.

aCDEC noted that relevant comparators are treatments reimbursed as second-line therapies for PBC (e.g., obeticholic acid).

Rationale for the Recommendation

Clinical Value

Based on the totality of the clinical evidence, CDEC concluded that seladelpar demonstrates acceptable clinical value compared with appropriate comparators (elafibranor, obeticholic acid [OCA]) in adults with PBC in combination with UDCA in patients whose PBC has an inadequate response to UDCA alone or as monotherapy in patients with UDCA intolerance. Given that seladelpar is expected to be an alternative to elafibranor or OCA, acceptable clinical value refers to at least comparable value versus elafibranor or OCA.

Evidence from 1 double-blind, phase III, randomized controlled trial (RESPONSE; N = 193) demonstrated that treatment with seladelpar resulted in added benefit in biochemical response, ALP normalization, and improved pruritus compared with placebo in adults with PBC whose PBC has an inadequate response to intolerance to UDCA. CDEC considered the between-group difference in the proportion of patients with biochemical response and ALP normalization at 12 months and the change from baseline in the pruritus numerical rating score (NRS) (in patients with a baseline score > 4, indicating moderate to severe pruritus) at 6 and 12 months to be clinically important. However, for the HRQoL outcome, there appears to be little to no difference between groups at 12 months. The effect of seladelpar on clinical outcomes, such as progression to end-stage liver disease or transplant-free survival, is unknown. There are no notable safety concerns with seladelpar when compared to placebo. The committee considered that the harms associated with seladelpar appeared consistent with the known safety profile of this drug class.

No head-to-head comparisons between seladelpar and relevant comparators were submitted for review. Although the sponsor-submitted indirect evidence (1 network meta-analysis [NMA] and 1 anchored matched-adjusted indirect comparison [MAIC]) informing the comparison of seladelpar versus OCA and elafibranor was associated with methodological limitations and imprecisions, CDEC felt the results did not demonstrate significant differences in outcomes between the treatments and found it reasonable to consider them comparable in efficacy and safety.

Further information on the committee’s discussion regarding clinical value is provided in the Summary of Deliberation section.

Developing the Recommendation

The determination of acceptable clinical value was sufficient for CDEC to recommend reimbursement of seladelpar. As part of the deliberation on whether to recommend reimbursement, the committee also considered unmet clinical need, unmet nonclinical need, and health inequity. Information on this discussion is provided in the Unmet Clinical Need and the Distinct Social and Ethical Considerations domains in the Summary of Deliberation section.

Because CDEC recommended that seladelpar be reimbursed, the committee also deliberated on whether reimbursement conditions should be added to address important economic considerations, health system impacts, social and ethical considerations, or to ensure clinical value is realized. The resulting reimbursement conditions, with accompanying reasons and implementation guidance, are stated in Table 1.

Summary of Deliberation

CDEC considered all domains of value of the deliberative framework before developing its recommendation: clinical value, unmet clinical need, distinct social and ethical considerations, economic considerations, and impacts on health systems. For further information on the domains of value, refer to Expert Committee Deliberation at Canada’s Drug Agency.

The committee considered the following key discussion points, organized by the 5 domains of value.

Clinical Value

Unmet Clinical Need

Distinct Social and Ethical Considerations

Economic Considerations

Impacts on Health Systems

Sources of Information Used by the Committee

To make its recommendation, the committee and subcommittee considered the following information (links to the full documents for the review can be found on the project webpage):

CDEC Information

Members of the Committee

Dr. Peter Jamieson (Chair), Dr. Kerry Mansell (Vice-Chair), Sally Bean, Daryl Bell, Dan Dunsky, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Dr. Dennis Ko, Dr. Christine Leong, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Carla Velastegui, Dr. Edward Xie, and Dr. Peter Zed.

Meeting date: November 26, 2025

Regrets: Three expert committee members did not attend.

Conflicts of interest: None